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Chapter 10 - Respiratory System


Morton Lippmann

The respiratory system extends from the breathing zone just outside of the nose and mouth through the conductive airways in the head and thorax to the alveoli, where respiratory gas exchange takes place between the alveoli and the capillary blood flowing around them. Its prime function is to deliver oxygen (O2) to the gas-exchange region of the lung, where it can diffuse to and through the walls of the alveoli to oxygenate the blood passing through the alveolar capillaries as needed over a wide range of work or activity levels. In addition, the system must also: (1) remove an equal volume of carbon dioxide entering the lungs from the alveolar capillaries; (2) maintain body temperature and water vapour saturation within the lung airways (in order to maintain the viability and functional capacities of the surface fluids and cells); (3) maintain sterility (to prevent infections and their adverse consequences); and (4) eliminate excess surface fluids and debris, such as inhaled particles and senescent phagocytic and epithelial cells. It must accomplish all of these demanding tasks continuously over a lifetime, and do so with high efficiency in terms of performance and energy utilization. The system can be abused and overwhelmed by severe insults such as high concentrations of cigarette smoke and industrial dust, or by low concentrations of specific pathogens which attack or destroy its defence mechanisms, or cause them to malfunction. Its ability to overcome or compensate for such insults as competently as it usually does is a testament to its elegant combination of structure and function.

Mass Transfer

The complex structure and numerous functions of the human respiratory tract have been summarized concisely by a Task Group of the International Commission on Radiological Protection (ICRP 1994), as shown in figure 10.1 . The conductive airways, also known as the respiratory dead space, occupy about 0.2 litres. They condition the inhaled air and distribute it, by convective (bulk) flow, to the approximately 65,000 respiratory acini leading off the terminal bronchioles. As tidal volumes increase, convective flow dominates gas exchange deeper into the respiratory bronchioles. In any case, within the respiratory acinus, the distance from the convective tidal front to alveolar surfaces is short enough so that efficient CO2-O2 exchange takes place by molecular diffusion. By contrast, airborne particles, with diffusion coefficients smaller by orders of magnitude than those for gases, tend to remain suspended in the tidal air, and can be exhaled without deposition.

Figure 10.1 Morphometry, cytology, histology, function and structure of the respiratory tract  and regions used in the 1994 ICRP dosimetry model

A significant fraction of the inhaled particles do deposit within the respiratory tract. The mechanisms accounting for particle deposition in the lung airways during the inspiratory phase of a tidal breath are summarized in figure 10.2 . Particles larger than about 2 µm in aerodynamic diameter (diameter of a unit density sphere having the same terminal settling (Stokes) velocity) can have significant momentum and deposit by impaction at the relatively high velocities present in the larger airways. Particles larger than about 1 µm can deposit by sedimentation in the smaller conductive airways, where flow velocities are very low. Finally, particles with diameters between 0.1 and 1 µm, which have a very low probability of depositing during a single tidal breath, can be retained within the approximately 15% of the inspired tidal air that is exchanged with residual lung air during each tidal cycle. This volumetric exchange occurs because of the variable time-constants for airflow in the different segments of the lungs. Due to the much longer residence times of the residual air in the lungs, the low intrinsic particle displacements of 0.1 to 1 µm particles within such trapped volumes of inhaled tidal air become sufficient to cause their deposition by sedimentation and/or diffusion over the course of successive breaths.

Figure 10.2 Mechanisms for particle deposition in lung airways

The essentially particle-free residual lung air that accounts for about 15% of the expiratory tidal flow tends to act like a clean-air sheath around the axial core of distally moving tidal air, such that particle deposition in the respiratory acinus is concentrated on interior surfaces such as airway bifurcations, while interbranch airway walls have little deposition.

The number of particles deposited and their distribution along the respiratory tract surfaces are, along with the toxic properties of the material deposited, the critical determinants of pathogenic potential. The deposited particles can damage the epithelial and/or the mobile phagocytic cells at or near the deposition site, or can stimulate the secretion of fluids and cell-derived mediators that have secondary effects on the system. Soluble materials deposited as, on, or within particles can diffuse into and through surface fluids and cells and be rapidly transported by the bloodstream throughout the body.

Aqueous solubility of bulk materials is a poor guide to particle solubility in the respiratory tract. Solubility is generally greatly enhanced by the very large surface-to-volume ratio of particles small enough to enter the lungs. Furthermore, the ionic and lipid contents of surface fluids within the airways are complex and highly variable, and can lead to either enhanced solubility or to rapid precipitation of aqueous solutes. Furthermore, the clearance pathways and residence times for particles on airway surfaces are very different in the different functional parts of the respiratory tract.

The revised ICRP Task Group's clearance model identifies the principal clearance pathways within the respiratory tract that are important in determining the retention of various radioactive materials, and thus the radiation doses received by respiratory tissues and other organs after translocation. The ICRP deposition model is used to estimate the amount of inhaled material that enters each clearance pathway. These discrete pathways are represented by the compartment model shown in figure 10.3 .

Figure 10.3 Compartment model to represent time-dependent particle transport from each region  in 1994 ICRP model

Particle transport rate constants shown beside the arrows are reference values in d1. Compartment numbers (shown in the lower right-hand corner of each compartment box) are  used to define clearance pathways. Thus, the particle transport rate from bb1 to BB1 is  denoted m4,7 and has the value 2 d1.

They correspond to the anatomic compartments illustrated in figure 10.1, and are summarized in table 10.1 , along with those of other groups providing guidance on the dosimetry of inhaled particles.

Table 10.1 Respiratory trract regions as defined in particle deposition models.

Anatomic structures included

ACGIH Region

ISO and CEN Regions

1966 ICRP Task Group Region

1994 ICRP Task Group Region

Nose, nasopharynx 

Mouth, oropharynx, laryngopharynx

Head airways (HAR)

Extrathoracic (E)

Nasopharynx (NP)

Anterior nasal passages (ET1)

All other extrathoracic (ET2)

Trachea, bronchi

Tracheobronchial (TBR)

Tracheobronchial (B)

Tracheobronchial (TB)

Trachea and large bronchi (BB)

Bronchioles (to terminal bronchioles)


Bronchioles (bb)

Respiratory bronchioles, alveolar ducts,  alveolar sacs, alveoli

Gas exchange (GER)

Alveolar (A)

Pulmonary (P)

Alveolar-interstitial (AI)

Extrathoracic airways

As shown in figure 10.1 , the extrathoracic airways were partitioned by ICRP (1994) into two distinct clearance and dosimetric regions: the anterior nasal passages (ET1) and all other extrathoracic airways (ET2)-that is, the posterior nasal passages, the naso- and oropharynx, and the larynx. Particles deposited on the surface of the skin lining the anterior nasal passages (ET1) are assumed to be subject only to removal by extrinsic means (nose blowing, wiping and so on). The bulk of material deposited in the naso-oropharynx or larynx  (ET2) is subject to fast clearance in the layer of fluid that covers these airways. The new model recognizes that diffusional deposition of ultrafine particles in the extrathoracic airways can be substantial, while the earlier models did not.

Thoracic airways

Radioactive material deposited in the thorax is generally divided between the tracheobronchial (TB) region, where deposited particles are subject to relatively fast mucociliary clearance, and the alveolar-interstitial (AI) region, where the particle clearance is much slower.

For dosimetry purposes, the ICRP (1994) divided deposition of inhaled material in the TB region between the trachea and bronchi (BB), and the more distal, small airways, the bronchioles (bb). However, the subsequent efficiency with which cilia in either type of airways are able to clear deposited particles is controversial. In order to be certain that doses to bronchial and bronchiolar epithelia would not be underestimated, the Task Group assumed that as much as half the number of particles deposited in these airways is subject to relatively "slow" mucociliary clearance. The likelihood that a particle is cleared relatively slowly by the mucociliary system appears to depend on its physical size.

Material deposited in the AI region is subdivided among three compartments (AI1, AI2 and AI3) that are each cleared more slowly than TB deposition, with the subregions cleared at different characteristic rates.

Figure 10.4  depicts the predictions of the ICRP (1994) model in terms of the fractional deposition in each region as a function of the size of the inhaled particles. It reflects the minimal lung deposition between 0.1 and 1 µm, where deposition is determined largely by the exchange, in the deep lung, between tidal and residual lung air. Deposition increases below 0.1 µm as diffusion becomes more efficient with decreasing particle size. Deposition increases with increasing particle size above 1 µm as sedimentation and impaction become increasingly effective.

Figure 10.4 Fractional deposition in each region of respiratory tract for reference light worker  (normal nose breather) in 1994 ICRP model

Deposition is expressed as a fraction of activity present in volume of ambient air that is inspired,  and activity is assumed to be log-normally distributed as function of particle size (for particles of  density 2.25 g/cm3 and shape factor 1.5). The activity median particle diameter (AMAD) applies  to larger particles, while the activity median thermal diameter (AMTD) applies to smaller particles  where deposition is by diffusion

Less complex models for size-selective deposition have been adopted by occupational health and community air pollution professionals and agencies, and these have been used to develop inhalation exposure limits within specific particle size ranges. Distinctions are made between:

1.     those particles that are not aspirated into the nose or mouth and therefore represent no inhalation hazard

2.     the inhalable (also known as inspirable) particulate mass (IPM)-those that are inhaled and are hazardous when deposited anywhere within the respiratory tract

3.     the thoracic particulate mass (TPM)-those that penetrate the larynx and are hazardous when deposited anywhere within the thorax and

4.     the respirable particulate mass (RPM)-those particles that penetrate through the terminal bronchioles and are hazardous when deposited within the gas-exchange region of the lungs.

In the early 1990s there has been an international harmonization of the quantitative definitions of IPM, TPM and RPM. The size-selective inlet specifications for air samplers meeting the criteria of the American Conference of Governmental Industrial Hygienists (ACGIH 1993), the International Organization for Standardization (ISO 1991) and the European Standardization Committee (CEN 1991) are enumerated in table 10.2 . They differ from the deposition fractions of ICRP (1994), especially for larger particles, because they take the conservative position that protection should be provided for those engaged in oral inhalation, and thereby bypass the more efficient filtration efficiency of the nasal passages.

Table 10.2 Inhalable,thoracic and respirable dust criteria of ACGIH, ISO and CEN, and PM10 criteria of US EPA. 





Particle aero- dynamic diameter (mm)

Inhalable  Particulate  Mass  (IPM) (%)

Particle aero- dynamic diameter (µm)

Thoracic  Particulate  Mass (TPM) (%)

Particle aero- dynamic diameter (µm)

Respirable  Particulate  Mass (RPM) (%)

Particle aero- dynamic diameter (µm)

Thoracic  Particulate  Mass (TPM) (%)

































































































The US Environmental Protection Agency (EPA 1987) standard for ambient air particle concentration is known as PM10, that is, particulate matter less than 10 µm in aerodynamic diameter. It has a sampler inlet criterion that is similar (functionally equivalent) to TPM but, as shown in table 10.2 , somewhat different numerical specifications.

Air Pollutants

Pollutants can be dispersed in air at normal ambient temperatures and pressures in gaseous, liquid and solid forms. The latter two represent suspensions of particles in air and were given the generic term aerosols by Gibbs (1924) on the basis of analogy to the term hydrosol, used to describe dispersed systems in water. Gases and vapours, which are present as discrete molecules, form true solutions in air. Particles consisting of moderate to high vapour pressure materials tend to evaporate rapidly, because those small enough to remain suspended in air for more than a few minutes (i.e., those smaller than about 10 µm) have large surface-to-volume ratios. Some materials with relatively low vapour pressures can have appreciable fractions in both vapour and aerosol forms simultaneously.

Gases and vapours

Once dispersed in air, contaminant gases and vapours generally form mixtures so dilute that their physical properties (such as density, viscosity, enthalpy and so on) are indistinguishable from those of clean air. Such mixtures may be considered to follow ideal gas law relationships. There is no practical difference between a gas and a vapour except that the latter is generally considered to be the gaseous phase of a substance that can exist as a solid or liquid at room temperature. While dispersed in air, all molecules of a given compound are essentially equivalent in their size and probabilities of capture by ambient surfaces, respiratory tract surfaces and contaminant collectors or samplers.


Aerosols, being dispersions of solid or liquid particles in air, have the very significant additional variable of particle size. Size affects particle motion and, hence, the probabilities of physical phenomena such as coagulation, dispersion, sedimentation, impaction onto surfaces, interfacial phenomena and light-scattering properties. It is not possible to characterize a given particle by a single size parameter. For example, a particle's aerodynamic properties depend on density and shape as well as linear dimensions, and the effective size for light scattering is dependent on refractive index and shape.

In some special cases, all of the particles are essentially the same in size. Such aerosols are considered to be monodisperse. Examples are natural pollens and some laboratory-generated aerosols. More typically, aerosols are composed of particles of many different sizes and hence are called heterodisperse or polydisperse. Different aerosols have different degrees of size dispersion. It is, therefore, necessary to specify at least two parameters in characterizing aerosol size: a measure of central tendency, such as a mean or median, and a measure of dispersion, such as an arithmetic or geometric standard deviation.

Particles generated by a single source or process generally have diameters following a log-normal distribution; that is, the logarithms of their individual diameters have a Gaussian distribution. In this case, the measure of dispersion is the geometric standard deviation, which is the ratio of the 84.1 percentile size to the 50 percentile size. When more than one source of particles is significant, the resulting mixed aerosol will usually not follow a single log-normal distribution, and it may be necessary to describe it by the sum of several distributions.

Particle characteristics

There are many properties of particles other than their linear size that can greatly influence their airborne behaviour and their effects on the environment and health. These include:

Surface. For spherical particles, the surface varies as the square of the diameter. However, for an aerosol of given mass concentration, the total aerosol surface increases with decreasing particle size. For non-spherical or aggregate particles, and for particles with internal cracks or pores, the ratio of surface to volume can be much greater than for spheres.

Volume. Particle volume varies as the cube of the diameter; therefore, the few largest particles in an aerosol tend to dominate its volume (or mass) concentration.

Shape. A particle's shape affects its aerodynamic drag as well as its surface area and therefore its motion and deposition probabilities.

Density. A particle's velocity in response to gravitational or inertial forces increases as the square root of its density.

Aerodynamic diameter. The diameter of a unit-density sphere having the same terminal settling velocity as the particle under consideration is equal to its aerodynamic diameter. Terminal settling velocity is the equilibrium velocity of a particle that is falling under the influence of gravity and fluid resistance. Aerodynamic diameter is determined by the actual particle size, the particle density and an aerodynamic shape factor.

Types of aerosols

Aerosols are generally classified in terms of their processes of formation. Although the following classification is neither precise nor comprehensive, it is commonly used and accepted in the industrial hygiene and air pollution fields.

Dust. An aerosol formed by mechanical subdivision of bulk material into airborne fines having the same chemical composition. Dust particles are generally solid and irregular in shape and have diameters greater than 1 µm.

Fume. An aerosol of solid particles formed by condensation of vapours formed by combustion or sublimation at elevated temperatures. The primary particles are generally very small (less than 0.1 µm) and have spherical or characteristic crystalline shapes. They may be chemically identical to the parent material, or may be composed of an oxidation product such as metal oxide. Since they may be formed in high number concentrations, they often rapidly coagulate, forming aggregate clusters of low overall density.

Smoke. An aerosol formed by condensation of combustion products, generally of organic materials. The particles are generally liquid droplets with diameters less than 0.5 µm.

Mist. A droplet aerosol formed by mechanical shearing of a bulk liquid, for example, by atomization, nebulization, bubbling or spraying. The droplet size can cover a very large range, usually from about 2 µm to greater than 50 µm.

Fog. An aqueous aerosol formed by condensation of water vapour on atmospheric nuclei at high relative humidities. The droplet sizes are generally greater than 1 µm.

Smog. A popular term for a pollution aerosol derived from a combination of smoke and fog. It is now commonly used for any atmospheric pollution mixture.

Haze. A submicrometer-sized aerosol of hygroscopic particles that take up water vapour at relatively low relative humidities.

Aitken or condensation nuclei (CN). Very small atmospheric particles (mostly smaller than 0.1 µm) formed by combustion processes and by chemical conversion from gaseous precursors.

Accumulation mode. A term given to the particles in the ambient atmosphere ranging from 0.1 to about 1.0 µm in diameter. These particles generally are spherical (having liquid surfaces), and form by coagulation and condensation of smaller particles that derive from gaseous precursors. Being too large for rapid coagulation and too small for effective sedimentation, they tend to accumulate in the ambient air.

Coarse particle mode. Ambient air particles larger than about 2.5 µm in aerodynamic diameter and generally formed by mechanical processes and surface dust resuspension.

Biological Responses of the Respiratory System to Air Pollutants

Responses to air pollutants range from nuisance to tissue necrosis and death, from generalized systemic effects to highly specific attacks on single tissues. Host and environmental factors serve to modify the effects of inhaled chemicals, and the ultimate response is the result of their interaction. The main host factors are:

1.     age-for example, older people, especially those with chronically reduced cardiovascular and respiratory function, who may not be able to cope with additional pulmonary stresses

2.     state of health-for example, concurrent disease or dysfunction

3.     nutritional status

4.     immunological status

5.     sex and other genetic factors-for example, enzyme-related differences in biotransformation mechanisms, such as deficient metabolic pathways, and inability to synthesize certain detoxification enzymes

6.     psychological state-for example, stress, anxiety and

7.     cultural factors-for example, cigarette smoking, which may affect normal defences, or may potentiate the effect of other chemicals.

The environmental factors include the concentration, stability and physicochemical properties of the agent in the exposure environment and the duration, frequency and route of exposure. Acute and chronic exposures to a chemical may result in different pathological manifestations.

Any organ can respond in only a limited number of ways, and there are numerous diagnostic labels for the resultant diseases. The following sections discuss the broad types of responses of the respiratory system which may occur following exposure to environmental pollutants.

Irritant response

Irritants produce a pattern of generalized, non-specific tissue inflammation, and destruction may result at the area of contaminant contact. Some irritants produce no systemic effect because the irritant response is much greater than any systemic effect, while some also have significant systemic effects following absorption-for example, hydrogen sulphide absorbed via the lungs.

At high concentrations, irritants may cause a burning sensation in the nose and throat (and usually also in the eyes), pain in the chest and coughing producing inflammation of the mucosa (tracheitis, bronchitis). Examples of irritants are gases such as chlorine, fluorine, sulphur dioxide, phosgene and oxides of nitrogen; mists of acids or alkali; fumes of cadmium; dusts of zinc chloride and vanadium pentoxide. High concentrations of chemical irritants may also penetrate deep into the lungs and cause lung oedema (the alveoli are filled with liquid) or inflammation (chemical pneumonitis).

Highly elevated concentrations of dusts which have no chemical irritative properties can also mechanically irritate bronchi and, after entering the gastrointestinal tract, may also contribute to stomach and colon cancer.

Exposure to irritants may result in death if critical organs are severely damaged. On the other hand, the damage may be reversible, or it may result in permanent loss of some degree of function, such as impaired gas-exchange capacity.

Fibrotic response

A number of dusts lead to the development of a group of chronic lung disorders termed pneumoconioses. This general term encompasses many fibrotic conditions of the lung, that is, diseases characterized by scar formation in the interstitial connective tissue. Pneumoconioses are due to the inhalation and subsequent selective retention of certain dusts in the alveoli, from which they are subject to interstitial sequestration.

Pneumoconioses are characterized by specific fibrotic lesions, which differ in type and pattern according to the dust involved. For example, silicosis, due to the deposition of crystalline-free silica, is characterized by a nodular type of fibrosis, while a diffuse fibrosis is found in asbestosis, due to asbestos-fibre exposure. Certain dusts, such as iron oxide, produce only altered radiology (siderosis) with no functional impairment, while the effects of others range from a minimal disability to death.

Allergic response

Allergic responses involve the phenomenon known as sensitization. Initial exposure to an allergen results in the induction of antibody formation; subsequent exposure of the now "sensitized" individual results in an immune response-that is, an antibody-antigen reaction (the antigen is the allergen in combination with an endogenous protein). This immune reaction may occur immediately following exposure to the allergen, or it may be a delayed response.

The primary respiratory allergic reactions are bronchial asthma, reactions in the upper respiratory tract which involve the release of histamine or histamine-like mediators following immune reactions in the mucosa, and a type of pneumonitis (lung inflammation) known as extrinsic allergic alveolitis. In addition to these local reactions, a systemic allergic reaction (anaphylactic shock) may follow exposure to some chemical allergens.

Infectious response

Infectious agents can cause tuberculosis, anthrax, ornithosis, brucellosis, histoplasmosis, Legionnaires' disease and so on.

Carcinogenic response

Cancer is a general term for a group of related diseases characterized by the uncontrolled growth of tissues. Its development is due to a complex process of interacting multiple factors in the host and the environment.

One of the great difficulties in attempting to relate exposure to a specific agent to cancer development in humans is the long latent period, typically from 15 to 40 years, between onset of exposure and disease manifestation.

Examples of air pollutants that can produce cancer of the lungs are arsenic and its compounds, chromates, silica, particles containing polycyclic aromatic hydrocarbons and certain nickel-bearing dusts. Asbestos fibres can cause bronchial cancer and mesothelioma of the pleura and peritoneum. Deposited radioactive particles may expose lung tissue to high local doses of ionizing radiation and be the cause of cancer.

Systemic response

Many environmental chemicals produce a generalized systemic disease due to their effects upon a number of target sites. Lungs are not only the target for many harmful agents but the site of entry of toxic substances which pass through the lungs into the bloodstream without any damage to the lungs. However, when distributed by the blood circulation to various organs, they can damage them or cause general poisoning and have systemic effects. This role of the lungs in occupational pathology is not the subject of this article. However, the effect of finely dispersed particulates (fumes) of several metal oxides which are often associated with an acute systemic syndrome known as metal fume fever should be mentioned.


Ulf Ulfvarson and Monica Dahlqvist

Lung function may be measured in a number of ways. However, the aim of the measurements has to be clear before the examination, in order to interpret the results correctly. In this article we will discuss lung function examination with special regard to the occupational field. It is important to remember the limitations in different lung function measurements. Acute temporary lung function effects may not be discernible in case of exposure to fibrogenic dust like quartz and asbestos, but chronic effects on lung function after long-term (>20 years) exposure may be. This is due to the fact that chronic effects occur years after the dust is inhaled and deposited in the lungs. On the other hand, acute temporary effects of organic and inorganic dust, as well as mould, welding fumes and motor exhaust, are well suited to study. This is due to the fact that the irritative effect of these dusts will occur after a few hours of exposure. Acute or chronic lung function effects also may be discernible in cases of exposure to concentrations of irritating gases (nitrogen dioxide, aldehydes, acids and acid chlorides) in the vicinity of well documented exposure limit values, especially if the effect is potentiated by particulate air contamination.

Lung function measurements have to be safe for the examined subjects, and the lung function equipment has to be safe for the examiner. A summary of the specific requirements for different kinds of lung function equipment are available (e.g., Quanjer et al. 1993). Of course, the equipment must be calibrated according to independent standards. This may be difficult to achieve, especially when computerized equipment is being used. The result of the lung function test is dependent on both the subject and the examiner. To provide satisfactory results from the examination, technicians have to be well trained, and able to instruct the subject carefully and also encourage the subject to carry out the test properly. The examiner should also have knowledge about the airways and lungs in order to interpret the results from the recordings correctly.

It is recommended that the methods used have a fairly high reproducibility both between and within subjects. Reproducibility may be measured as the coefficient of variation, that is, the standard deviation multiplied by 100 divided by the mean value. Values below 10% in repeated measurements on the same subject are deemed acceptable.

In order to determine if the measured values are pathological or not, they must be compared with prediction equations. Usually the prediction equations for spirometric variables are based on age and height, stratified for sex. Men have on the average higher lung function values than women, of the same age and height. Lung function decreases with age and increases with height. A tall subject will therefore have higher lung volume than a short subject of the same age. The outcome from prediction equations may differ considerably between different reference populations. The variation in age and height in the reference population will also influence the predicted values. This means, for example, that a prediction equation must not be used if age and/or height for the examined subject are outside the ranges for the population that is the basis for the prediction equation.

Smoking will also diminish lung function, and the effect may be potentiated in subjects who are occupationally exposed to irritating agents. Lung function used to be considered as not being pathological if the obtained values are within 80% of the predicted value, derived from a prediction equation.


Lung function measurements are carried out to judge the condition of the lungs. Measurements may either concern single or multiple measured lung volumes, or the dynamic properties in the airways and lungs. The latter is usually determined through effort-dependent manoeuvres. The conditions in the lungs may also be examined with regard to their physiological function, that is, diffusion capacity, airway resistance and compliance (see below).

Measurements concerning ventilatory capacity are obtained by spirometry. The breathing manoeuvre is usually performed as a maximal inspiration followed by a maximal expiration, vital capacity (VC, measured in litres). At least three technically satisfactory recordings (i.e., full inspiration and expiration effort and no observed leaks) should be done, and the highest value reported. The volume may be directly measured by a water-sealed or a low-resistive bell, or indirectly measured by pneumotachography (i.e., integration of a flow signal over time). It is important here to note that all measured lung volumes should be expressed in BTPS, that is, body temperature and ambient pressure saturated with water vapour.

Forced expired vital capacity (FVC, in litres) is defined as a VC measurement performed with a maximally forced expiratory effort. Due to the simplicity of the test and the relatively inexpensive equipment, the forced expirogram has become a useful test in the monitoring of lung function. However, this has resulted in many poor recordings, of which the practical value is debatable. In order to carry out satisfactory recordings, the updated guideline for the collection and use of the forced expirogram, published by the American Thoracic Society in 1987, may be useful.

Instantaneous flows may be measured on flow-volume or flow-time curves, while time average flows or times are derived from the spirogram. Associated variables which can be calculated from the forced expirogram are forced expired volume in one second (FEV1, in litres per second), in percentage of FVC (FEV1%), peak flow (PEF, l/s), maximal flows at 50% and 75% of forced vital capacity (MEF50 and MEF25, respectively). An illustration of the derivation of FEV1 from the forced expirogram is outlined in figure 10.5 .

Figure 10.5 Forced expiratory spirogram showing the derivation of FEV1 and FVC  according to the extrapolation principle

In healthy subjects, maximal flow rates at large lung volumes (i.e., at the beginning of expiration) reflect mainly the flow characteristics of the large airways while those at small lung volumes (i.e., the end of expiration) are usually held to reflect the characteristics of the small airways, figure 10.6 . In the latter the flow is laminar, while in the large airways it may be turbulent.

Figure 10.6 Flow-volume curve showing the derivation of peak expiratory flow (PEF), maximal flows  at 50% and 75% of forced vital capacity (MEF50 and MEF25, respectively).

PEF may also be measured by a small portable device such as the one developed by Wright in 1959. An advantage with this equipment is that the subject may carry out serial measurements-for example, at the workplace. To get useful recordings, however, it is necessary to instruct the subjects well. Moreover, one should keep in mind that measurements of PEF with, for example, a Wright meter and those measured by conventional spirometry should not be compared due to the different blow techniques.

The spirometric variables VC, FVC and FEV1 show a reasonable variation between individuals where age, height and sex usually explain 60 to 70% of the variation. Restrictive lung function disorders will result in lower values for VC, FVC and FEV1. Measurements of flows during expiration show a great individual variation, since the measured flows are both effort and time dependent. This means, for example, that a subject will have extremely high flow in case of diminished lung volume. On the other hand, the flow may be extremely low in case of very high lung volume. However, the flow is usually decreased in case of a chronic obstructive disease (e.g., asthma, chronic bronchitis).

The proportion of residual volume (RV), that is, the volume of air which still is in the lungs after a maximal expiration, can be determined by gas dilution or by body plethysmography. The gas dilution technique requires less complicated equipment and is therefore more convenient to use in studies carried out at the workplace. In figure 10.7 , the principle for the gas dilution technique has been outlined. The technique is based on dilution of an indicator gas in a rebreathing circuit. The indicator gas must be sparingly soluble in biological tissues so that it is not taken up by the tissues and blood in the lung. Hydrogen was initially used, but because of its ability to form explosive mixtures with air it was replaced by helium, which is easily detected by means of the thermal conductivity principle.

Figure 10.7 A principal outline of the equipment for determination of total lung capacity (TLC)  according to the helium dilution technique

The subject and the apparatus form a closed system, and the initial concentration of the gas is thus reduced when it is diluted into the gas volume in the lungs. After equilibration, the concentration of indicator gas is the same in the lungs as in the apparatus, and functional residual capacity (FRC) can be calculated by means of a simple dilution equation. The volume of the spirometer (including the addition of the gas mixture into the spirometer) is denoted by  VS, VL is the volume of the lung, Fi is the initial gas concentration and Ff is the final concentration.

     FRC = VL = [(VS·Fi) / Ff] -VS

Two to three VC manoeuvres are carried out to provide a reliable base for the calculation of TLC (in litres). The subdivisions of the different lung volumes are outlined in figure 10.8.

Figure 10.8 Spirogram labelled to show the subdivisions of the total capacity

Due to change in the elastic properties of the airways, RV and FRC increase with age. In chronic obstructive diseases, increased values of RV and FRC are usually observed, while VC is decreased. However, in subjects with badly ventilated lung areas-for example, subjects with emphysema-the gas dilution technique may underestimate RV, FRC and also TLC. This is due to the fact that the indicator gas will not communicate with closed-off airways, and therefore the decrease in the indicator gas concentration will give erroneously small values.

Measures of airway closure and gas distribution in the lungs can be obtained in one and the same manoeuvre by the single breath wash-out technique, figure 10.9. The equipment consists of a spirometer connected to a bag-in-box system and a recorder of continuous measurements of nitrogen concentration. The manoeuvre is carried out by means of a maximal enspiration of pure oxygen from the bag. In the beginning of the expiration, the nitrogen concentration increased as a result of emptying the subject's deadspace, containing pure oxygen. The expiration continues with the air from the airways and alveoli. Finally, air from the alveoli, containing 20 to 40% nitrogen, is expired. When the expiration from the basal parts of the lungs increases, the nitrogen concentration will rise abruptly in case of airway closure in dependent lung regions, figure 10.9 . This volume above RV, at which airways close during an expiration, is usually expressed as closing volume (CV) in percentage of VC (CV%). Distribution of the inspired air in the lungs is expressed as the slope of the alveolar plateau  (%N2 or phase III, %N2/l). It is obtained by taking the difference in nitrogen concentration between the point when 30% of the air is exhaled and the point for airway closure, and dividing this by the corresponding volume.

Figure 10.9 A principal outline of the recording of airway closure  and the slope of the alveolar plateau (%N2).

Ageing as well as chronic obstructive disorders will result in increased values for both CV% and phase III. However, not even healthy subjects have a uniform gas distribution in the lungs, resulting in slightly elevated values for phase III, that is, 1 to 2% N2/l. The variables CV% and phase III are considered to reflect the conditions in the peripheral small airways with an internal diameter about 2 mm. Normally, the peripheral airways contribute to a small part (10 to 20%) of the total airway resistance. Quite extensive changes which are not detectable by conventional lung function tests like dynamic spirometry, may occur, for example, as a result of an exposure to irritating substances in the air in the peripheral airways. This suggests that airway obstruction begins in the small airways. Results from studies also have shown alterations in CV% and phase III before any changes from the dynamic and static spirometry have occurred. These early changes may go into remission when exposure to hazardous agents has ceased.

The transfer factor of the lung (mmol/min; kPa) is an expression of the diffusion capacity of oxygen transport into the pulmonary capillaries. The transfer factor can be determined using single or multiple breath techniques; the single breath technique is considered to be most suitable in studies at the workplace. Carbon monoxide (CO) is used since the back pressure of CO is very low in the peripheral blood, in contrast to that of oxygen. The uptake of CO is assumed to follow an exponential model, and this assumption can be used to determine the transfer factor for the lung.

Determination of TLCO (transfer factor measured with CO) is carried out by means of a breathing manoeuvre including a maximal expiration, followed by a maximal inspiration of a gas mixture containing carbon monoxide, helium, oxygen and nitrogen. After a breath-holding period, a maximal exhalation is done, reflecting the content in the alveolar air, figure 10.10 .

Figure 10.10 A principal outline of the recording of transfer factor

Helium is used for the determination of the alveolar volume (VA). Assuming that the dilution of CO is the same as for helium, the initial concentration of CO, before the diffusion has started, can be calculated. TLCO is calculated according to the equation outlined below, where k depends on the dimensions of the component terms, t is the effective time for breath-holding and log is base 10 logarithm. Inspired volume is denoted Vi and the fractions F of CO and helium are denoted by i and a for inspired and alveolar, respectively.

     TLCO = k Vi (Fa,He/Fi,He) log (Fi,CO Fa,He/Fa,CO Fi,He) (t)-1 

The size of TLCO will depend on a variety of conditions-for example, the amount of available haemoglobin, the volume of ventilated alveoli and perfused lung capillaries and their relation to each other. Values for TLCO decrease with age and increase with physical activity and increased lung volumes. Decreased TLCO will be found in both restrictive and obstructive lung disorders.

Compliance (l/kPa) is a function, inter alia, of the elastic property of the lungs. The lungs have an intrinsic tendency to collaborate-that is, to collapse. The power to keep the lungs stretched will depend on the elastic lung tissue, the surface tension in the alveoli, and the bronchial musculature. On the other hand, the chest wall tends to expand at lung volumes 1 to 2 litres above the FRC level. At higher lung volumes, power has to be applied to further expand the chest wall. At the FRC level, the corresponding tendency in the lungs is balanced by the tendency to expand. The FRC level is therefore denoted by the resting level of the lung.

The compliance of the lung is defined as the change in volume divided by the change in transpulmonary pressure, that is, the difference between the pressures in the mouth (atmospheric) and in the lung, as the result of a breathing manoeuvre. Measurements of the pressure in the lung are not easily carried out and are therefore replaced by measurements of the pressure in the oesophagus. The pressure in the oesophagus is almost the same as the pressure in the lung, and it is measured with a thin polyethylene catheter with a balloon covering the distal 10 cm. During inspiratory and expiratory manoeuvres, the changes in volume and pressure are recorded by means of a spirometer and pressure transducer, respectively. When the measurements are performed during tidal breathing, dynamic compliance can be measured. Static compliance is obtained when a slow VC manoeuvre is carried out. In the latter case, the measurements are carried out in a body plethysmograph, and the expiration is intermittently interrupted by means of a shutter. However, measurements of compliance are cumbersome to perform when examining exposure effects on lung function at the worksite, and this technique is considered to be more appropriate in the laboratory.

A decreased compliance (increased elasticity) is observed in fibrosis. To cause a change in volume, large changes in pressure are required. On the other hand, a high compliance is observed, for example, in emphysema as the result of loss of elastic tissue and therefore also elasticity in the lung.

The resistance in the airways essentially depends on the radius and length of the airways but also on air viscosity. The airway resistance (RL in (kPa/l) /s), can be determined by use of a spirometer, pressure transducer and a pneumotachograph (to measure the flow). The measurements may also be carried out using a body plethysmograph to record the changes in flow and pressure during panting manoeuvres. By administration of a drug intended to cause broncho-constriction, sensitive subjects, as a result of their hyperreactive airways, may be identified. Subjects with asthma usually have increased values for RL.

Acute and Chronic Effects of Occupational Exposure on Pulmonary Function

Lung function measurement may be used to disclose an occupational exposure effect on the lungs. Pre-employment examination of lung function should not be used to exclude job-seeking subjects. This is because the lung function of healthy subjects varies within wide limits and it is difficult to draw a borderline below which it can safely be stated that the lung is pathological. Another reason is that the work environment should be good enough to allow even subjects with slight lung function impairment to work safely.

Chronic effects on the lungs in occupationally exposed subjects may be detected in a number of ways. The techniques are designed to determine historical effects, however, and are less suitable to serve as guidelines to prevent lung function impairment. A common study design is to compare the actual values in exposed subjects with the lung function values obtained in a reference population without occupational exposure. The reference subjects may be recruited from the same (or nearby) workplaces or from the same city.

Multivariate analysis has been used in some studies to assess differences between exposed subjects and matched unexposed referents. Lung function values in exposed subjects may also be standardized by means of a reference equation based on lung function values in the unexposed subjects.

Another approach is to study the difference between the lung function values in exposed and unexposed workers after adjustment for age and height with the use of external reference values, calculated by means of a prediction equation based on healthy subjects. The reference population may also be matched to the exposed subjects according to ethnic group, sex, age, height and smoking habits in order to further control for those influencing factors.

The problem is, however, to decide if a decrease is large enough to be classified as pathological, when external reference values are being used. Although the instruments in the studies have to be portable and simple, attention must be paid both to the sensitivity of the chosen method for detecting small anomalies in airways and lungs and the possibility of combining different methods. There are indications that subjects with respiratory symptoms, such as exertion dyspnoea, are at a higher risk of having an accelerated decline in lung function. This means that the presence of respiratory symptoms is important and so should not be neglected.

The subject may also be followed-up by spirometry, for example, once a year, for a number of years, in order to give a warning against the development of illness. There are limitations, however, since this will be very time-consuming and the lung function may have deteriorated permanently when the decrease can be observed. This approach therefore must not be an excuse for delay in carrying out measures in order to decrease harmful concentrations of air pollutants.

Finally, chronic effects on lung function may also be studied by examining the individual changes in lung function in exposed and unexposed subjects over a number of years. One advantage of the longitudinal study design is that the intersubject variability is eliminated; however, the design is considered to be time-consuming and expensive.

Susceptible subjects may also be identified by comparing their lung function with and without exposure during working shifts. In order to minimize possible effects of diurnal variations, lung function is measured at the same time of day on one unexposed and one exposed occasion. The unexposed condition can be obtained, for example, by occasionally moving the worker to an uncontaminated area or by use of a suitable respirator during a whole shift, or in some cases by performing lung function measurements in the afternoon of a worker's day off.

One special concern is that repeated, temporary effects can result in chronic effects. An acute temporary lung function decrease may not only be a biological exposure indicator but also a predictor of a chronic lung function decrement. Exposure to air pollutants may result in discernible acute effects on lung function, although the mean values of the measured air pollutants are below the hygienic limit values. The question thus arises, whether these effects really are harmful in the long run. This question is hard to answer directly, especially since the air pollution in workplaces often has a complex composition and the exposure cannot be described in terms of mean concentrations of single compounds. The effect of an occupational exposure is also partly due to the sensitivity of the individual. This means that some subjects will react sooner or to a larger extent than others. The underlying pathophysiological ground for an acute, temporary decrease in lung function is not fully understood. The adverse reaction upon exposure to an irritating air contaminant is, however, an objective measurement, in contrast to subjective experiences like symptoms of different origin.

The advantage of detecting early changes in airways and lungs caused by hazardous air pollutants is obvious-the prevailing exposure may be reduced in order to prevent more severe illnesses. Therefore, an important aim in this respect is to use the measurements of acute temporary effects on lung function as a sensitive early warning system that can be used when studying groups of healthy working people.

Monitoring of Irritants

Irritation is one of the most frequent criteria for setting exposure limit values. It is, however, not certain that compliance with an exposure limit based on irritation will protect against irritation. It should be considered that an exposure limit for an air contaminant usually contains at least two parts-a time-weighted average limit (TWAL) and a short-term exposure limit (STEL), or at least rules for exceeding the time-weighted average limit, "excursion limits". In the case of highly irritating substances, such as sulphur dioxide, acrolein and phosgene, it is important to limit the concentration even during very short periods, and it has therefore been common practice to fix occupational exposure limit values in the form of ceiling limits, with a sampling period that is kept as short as the measuring facilities will allow.

Time-weighted average limit values for an eight-hour day combined with rules for excursion above these values are given for most of the substances in the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) list. The TLV list of 1993-94 contains the following statement concerning excursion limits for exceeding limit values:

For the vast majority of substances with a TLV-TWA, there is not enough toxicological data available to warrant a STEL (= short-term exposure limit). Nevertheless, excursions above the TLV-TWA should be controlled even where the eight-hour TWA is within recommended limits.

Exposure measurements of known air contaminants and comparison with well documented exposure limit values should be carried out on a routine basis. There are, however, many situations when the determination of compliance with exposure limit values is not enough. This is the case in the following circumstances (inter alia):

1.     when the limit value is too high to safeguard against irritation

2.     when the irritant is unknown

3.     when the irritant is a complex mixture and there is no suitable indicator known.

As advocated above, the measurement of acute, temporary effects on lung function can be used in these cases as a warning against over-exposure to irritants.

In cases (2) and (3), acute, temporary effects on lung function may be applicable also in testing the efficiency of control measures to decrease exposure to air contamination or in scientific investigations, for example, in attributing biological effects to components of air contaminants. A number of examples follow in which acute, temporary lung function effects have been successfully employed in occupational health investigations.

Studies of Acute, Temporary Lung Function Effects

Work-related, temporary decrease of lung function over a work shift was recorded in cotton workers at the end of 1950. Later, several authors reported work-related, acute, temporary changes of lung function in hemp and textile workers, coal miners, workers exposed to toluene di-isocyanate, fire-fighters, rubber processing workers, moulders and coremakers, welders, ski waxers, workers exposed to organic dust and irritants in water-based paints.

However, there are also several examples where measurements before and after exposure, usually during a shift, have failed to demonstrate any acute effects, despite a high exposure. This is probably due to the effect of normal circadian variation, mainly in lung function variables depending on the size of airway calibre. Thus the temporary decrease in these variables must exceed the normal circadian variation to be recognized. The problem may be circumvented, however, by measuring lung function at the same time of the day at each study occasion. By using the exposed employee as his or her own control, the interindividual variation is further decreased. Welders were studied in this way, and although the mean difference between unexposed and exposed FVC values was less than 3% in 15 examined welders, this difference was significant at the 95% confidence level with a power of more than 99%.

The reversible transient effects on the lungs can be used as an exposure indicator of complicated irritating components. In the study cited above, particles in the work environment were crucial for the irritating effects on the airways and lungs. The particles were removed by a respirator consisting of a filter combined with a welding helmet. The results indicated that the effects on the lungs were caused by the particles in welding fumes, and that the use of a particulate respirator might prevent this effect.

Exposure to diesel exhaust also gives measurable irritative effects on the lungs, shown as an acute, temporary lung function decrease. Mechanical filters mounted on the exhaust pipes of trucks used in loading operations by stevedores relieved subjective disorders and reduced the acute, temporary lung function decrease observed when no filtration was done. The results thus indicate that the presence of particles in the work environment does play a role in the irritative effect on airways and lungs, and that it is possible to assess the effect by measurements of acute changes in lung function.

A multiplicity of exposures and a continually changing work environment may present difficulties in discerning the causal relationship of the different agents existing in a work environment. The exposure scenario in sawmills is an illuminating example. It is not possible (e.g., for economical reasons) to carry out exposure measurements of all possible agents (terpenes, dust, mould, bacteria, endotoxin, mycotoxins, etc.) in this work environment. A feasible method may be to follow the development of lung function longitudinally. In a study of sawmill workers in the wood-trimming department, lung function was examined before and after a working week, and no statistically significant decrease was found. However, a follow-up study carried out a few years later disclosed that those workers who actually had a numerical decrease in lung function during a working week also had an accelerated long-term decline in lung function. This may indicate that vulnerable subjects can be detected by measuring changes in lung function during a working week.


David L.S. Ryon and William N. Rom

The presence of respiratory irritants in the workplace can be unpleasant and distracting, leading to poor morale and decreased productivity. Certain exposures are dangerous, even lethal. In either extreme, the problem of respiratory irritants and inhaled toxic chemicals is common; many workers face a daily threat of exposure. These compounds cause harm by a variety of different mechanisms, and the extent of injury can vary widely, depending on the degree of exposure and on the biochemical properties of the inhalant. However, they all have the characteristic of nonspecificity; that is, above a certain level of exposure virtually all persons experience a threat to their health.

There are other inhaled substances that cause only susceptible individuals to develop respiratory problems; such complaints are most appropriately approached as diseases of allergic and immunological origin. Certain compounds, such as isocyanates, acid anhydrides and epoxy resins, can act not only as non-specific irritants in high concentrations, but can also predispose certain subjects to allergic sensitization. These compounds provoke respiratory symptoms in sensitized individuals at very low concentrations.

Respiratory irritants include substances that cause inflammation of the airways after they are inhaled. Damage may occur in the upper and lower airways. More dangerous is acute inflammation of the pulmonary parenchyma, as in chemical pneumonitis or non-cardiogenic pulmonary oedema. Compounds that can cause parenchymal damage are considered toxic chemicals. Many inhaled toxic chemicals also act as respiratory irritants, warning us of their danger with their noxious odour and symptoms of nose and throat irritation and cough. Most respiratory irritants are also toxic to the lung parenchyma if inhaled in sufficient amount.

Many inhaled substances have systemic toxic effects after being absorbed by inhalation. Inflammatory effects on the lung may be absent, as in the case of lead, carbon monoxide or hydrogen cyanide. Minimal lung inflammation is normally seen in the inhalation fevers (e.g., organic dust toxic syndrome, metal fume fever and polymer fume fever). Severe lung and distal organ damage occurs with significant exposure to toxins such as cadmium and mercury.

The physical properties of inhaled substances predict the site of deposition; irritants will produce symptoms at these sites. Large particles (10 to 20 µm) deposit in the nose and upper airways, smaller particles (5 to 10 µm) deposit in the trachea and bronchi, and particles less than 5 µm in size may reach the alveoli. Particles less than 0.5 µm are so small they behave like gases. Toxic gases deposit according to their solubility. A water-soluble gas will be adsorbed by the moist mucosa of the upper airway; less soluble gases will deposit more randomly throughout the respiratory tract.

Respiratory Irritants

Respiratory irritants cause non-specific inflammation of the lung after being inhaled. These substances, their sources of exposure, physical and other properties, and effects on the victim are outlined in table 10.3 . Irritant gases tend to be more water soluble than gases more toxic to the lung parenchyma. Toxic fumes are more dangerous when they have a high irritant threshold; that is, there is little warning that the fume is being inhaled because there is little irritation.

Table 10.3 Summary of respiratory irritants.


Sources of exposure

Important properties

Injury produced

Dangerous exposure level under 15 min  (PPM)


Plastics, synthetic rubber industry, combustion products

High vapour pressure; high water solubility

Upper airway injury; rarely causes delayed pulmonary oedema


Acetic acid, organic  acids

Chemical industry, electronics, combustion products

Water soluble

Ocular and upper airway injury


Acid anhydrides

Chemicals, paints, and plastics  industries; components of epoxy resins

Water soluble, highly reactive, may cause allergic sensitization

Ocular, upper airway injury, bronchospasm; pulmonary haemorrhage after massive exposure



Plastics, textiles, pharmaceutical manufacturing, combustion products

High vapour pressure, intermediate water solubility, extremely irritating

Diffuse airway and parenchymal injury



Fertilizers, animal feeds, chemicals, and pharmaceuticals manufacturing

Alkaline gas, very high water solubility

Primarily ocular and upper airway burn; massive exposure may cause bronchiectasis


Antimony trichloride, antimony penta-chloride

Alloys, organic catalysts

Poorly soluble, injury likely due to halide ion

Pneumonitis, non-cardiogenic pulmonary oedema



Alloys (with copper), ceramics; electronics, aerospace and nuclear reactor equipment

Irritant metal, also acts as an antigen to promote a long-term granulomatous response

Acute upper airway injury, tracheobronchitis, chemical pneumonitis

25 µg/m3

Boranes (diborane)

Aircraft fuel, fungicide manufacturing

Water soluble gas

Upper airway injury, pneumonitis with massive exposure


Hydrogen bromide

Petroleum refining


Upper airway injury, pneumonitis with massive exposure


Methyl bromide

Refrigeration, produce fumigation

Moderately soluble gas

Upper and lower airway injury, pneumonitis, CNS depression and seizures



Alloys with Zn and Pb, electroplating, batteries, insecticides

Acute and chronic respiratory effects

Tracheobronchitis, pulmonary oedema (often delayed onset over 24-48 hours); chronic low level exposure leads to inflammatory changes and emphysema


Calcium oxide, calcium hydroxide

Lime, photography, tanning, insecticides

Moderately caustic, very high doses required for toxicity

Upper and lower airway inflammation, pneumonitis



Bleaching, formation of chlorinated compounds, household cleaners

Intermediate water solubilty

Upper and lower airway inflammation, pneumonitis and non-cardiogenic pulmonary oedema



Crowd control agent, "tear gas"

Irritant qualities are used to incapacitate; alkylating agent

Ocular and upper airway inflammation, lower airway and parenchymal injury with masssive exposure


o-Chlorobenzomalo- nitrile

Crowd control agent, "tear gas"

Irritant qualities are used to incapacitate

Ocular and upper airway inflammation, lower airway injury with massive exposure


Chloromethyl ethers

Solvents, used in manufacture of other organic compounds


Upper and lower airway irritation, also a respiratory tract carcinogen



Chemical manufacturing, fumigant component

Former First World War gas

Upper and lower airway inflammation


Chromic acid (Cr(IV))

Welding, plating

Water soluble irritant, allergic sensitizer

Nasal inflammation and ulceration, rhinitis, pneumonitis with massive exposure



High temperature alloys, permanent magnets, hard metal tools (with tungsten carbide)

Non-specific irritant, also allergic sensitizer

Acute bronchospasm and/or pneumonitis; chronic exposure can cause lung fibrosis



Manufacture of foam insulation, plywood, textiles, paper, fertilizers, resins; embalming agents; combustion products

Highly water soluble, rapidly metabolized; primarily acts via sensory nerve stimulation; sensitization reported

Ocular and upper airway irritation; bronchospasm in severe exposure; contact dermatitis in sensitized persons


Hydrochloric acid

Metal refining, rubber manufacturing, organic compound manufacture, photographic materials

Highly water soluble

Ocular and upper airway inflammation, lower airway inflammation only with massive exposure


Hydrofluoric acid

Chemical catalyst, pesticides, bleaching, welding, etching

Highly water soluble, powerful and rapid oxidant, lowers serum calcium in massive exposure

Ocular and upper airway inflammation, tracheobronchitis and pneumonitis with massive exposure



Polyurethane production; paints; herbicide and insecticide products; laminating, furniture, enamelling, resin work

Low molecular weight organic compounds, irritants, cause sensitization in susceptible persons

Ocular, upper and lower inflammation; asthma, hypersensitivity pneumonitis in sensitized persons


Lithium hydride

Alloys, ceramics, electronics, chemical catalysts

Low solubility, highly reactive

Pneumonitis, non-cardiogenic pulmonary oedema



Electrolysis, ore and amalgam extraction, electronics manufacture

No respiratory symptoms with low level, chronic exposure

Ocular and respiratory tract inflammation, pneumonitis, CNS, kidney and systemic effects

1.1 mg/m3

Nickel carbonyl

Nickel refining, electroplating, chemical reagents

Potent toxin

Lower respiratory irritation, pneumonitis, delayed systemic toxic effects

8 µg/m3

Nitrogen dioxide

Silos after new grain storage, fertilizer making, arc welding, combustion products

Low water solubility, brown gas at high concentration

Ocular and upper airway inflammation, non-cardiogenic pulmonary oedema, delayed onset bronchiolitis


Nitrogen mustards; sulphur mustards

Military gases

Causes severe injury, vesicant properties

Ocular, upper and lower airway inflammation, pneumonitis

20mg/m3 (N)  1 mg/m3 (S)

Osmium tetroxide

Copper refining, alloy with iridium, catalyst for steroid synthesis and ammonia formation

Metallic osmium is inert, tetraoxide forms when heated in air

Severe ocular and upper airway irritation; transient renal damage

1 mg/m3


Arc welding, copy machines, paper bleaching

Sweet smelling gas, moderate water solubility

Upper and lower airway inflammation; asthmatics more susceptible



Pesticide and other chemical manufacture, arc welding, paint removal

Poorly water soluble, does not irritate airways in low doses

Upper airway inflammation and pneumonitis; delayed pulmonary oedema in low doses


Phosphoric sulphides

Production of insecticides, ignition compounds, matches


Ocular and upper airway inflammation


Phosphoric chlorides

Manufacture of chlorinated organic compounds, dyes, gasoline additives

Form phosphoric acid and hydrochloric acid on contact with mucosal surfaces

Ocular and upper airway inflammation

10 mg/m3

Selenium dioxide

Copper or nickel smelting, heating of selenium alloys

Strong vessicant, forms selenious acid (H2SeO3) on mucosal surfaces

Ocular and upper airway inflammation, pulmonary oedema in massive exposure


Hydrogen selenide

Copper refining, sulphuric acid production

Water soluble; exposure to selenium compounds gives rise to garlic odour breath

Ocular and upper airway inflammation, delayed pulmonary oedema



Manufacture of polystyrene and resins, polymers

Highly irritating

Ocular, upper and lower airway inflammation, neurological impairments


Sulphur dioxide

Petroleum refining, pulp mills, refrigeration plants, manufacturing of sodium sulphite

Highly water soluble gas

Upper airway inflammation, bronchoconstriction, pneumonitis on massive exposure


Titanium tetrachloride

Dyes, pigments, sky writing

Chloride ions form HCl on mucosa

Upper airway injury


Uranium hexafluoride

Metal coat removers, floor sealants, spray paints

Toxicity likely from chloride ions

Upper and lower airway injury, bronchospasm, pneumonitis


Vanadium pentoxide

Cleaning oil tanks, metallurgy


Ocular, upper and lower airway symptoms


Zinc chloride

Smoke grenades, artillery

More severe than zinc oxide exposure

Upper and lower airway irritation, fever, delayed onset pneumonitis


Zirconium tetrachloride

Pigments, catalysts

Chloride ion toxicity

Upper and lower airway irritation, pneumonitis


Adapted from Sheppard 1988; Graham 1994; Rom 1992; Blanc and Schwartz 1994;  Nemery 1990; Skornik 1988.

The nature and extent of the reaction to an irritant depends on the physical properties of the gas or aerosol, the concentration and time of exposure, and on other variables as well, such as temperature, humidity and the presence of pathogens or other gases (Man and Hulbert 1988). Host factors such as age (Cabral-Anderson, Evans and Freeman 1977; Evans, Cabral-Anderson and Freeman 1977), prior exposure (Tyler, Tyler and Last 1988), level of antioxidants (McMillan and Boyd 1982) and presence of infection may play a role in determining the pathological changes seen. This wide range of factors has made it difficult to study the pathogenic effects of respiratory irritants in a systematic way.

The best understood irritants are those which inflict oxidative injury. The majority of inhaled irritants, including the major pollutants, act by oxidation or give rise to compounds that act in this way. Most metal fumes are actually oxides of the heated metal; these oxides cause oxidative injury. Oxidants damage cells primarily by lipid peroxidation, and there may be other mechanisms. On a cellular level, there is initially a fairly specific loss of ciliated cells of the airway epithelium and of Type I alveolar epithelial cells, with subsequent violation of the tight junction interface between epithelial cells (Man and Hulbert 1988; Gordon, Salano and Kleinerman 1986; Stephens et al. 1974). This leads to subepithelial and submucosal damage, with stimulation of smooth muscle and parasympathetic sensory afferent nerve endings causing bronchoconstriction (Holgate, Beasley and Twentyman 1987; Boucher 1981). An inflammatory response follows (Hogg 1981), and the neutrophils and eosinophils release mediators that cause further oxidative injury (Castleman et al. 1980). Type II pneumocytes and cuboidal cells act as stem cells for repair (Keenan, Combs and McDowell 1982; Keenan, Wilson and McDowell 1983).

Other mechanisms of lung injury eventually involve the oxidative pathway of cellular damage, particularly after damage to the protective epithelial cell layer has occurred and an inflammatory response has been elicited. The most commonly described mechanisms are outlined in table 10.4 .

Table 10.4 Mechanisms of lung injury by inhaled substances.

Mechanism of injury

Example compounds

Damage that occurs


Ozone, nitrogen dioxide, sulphur dioxide, chlorine, oxides

Patchy airway epithelial damage, with increased permeability and exposure of nerve fibre endings; loss of cilia from ciliated cells; necrosis of type I pneumocytes; free radical formation and subsequent protein binding and lipid peroxidation

Acid formation

Sulphur dioxide, chlorine, halides

Gas dissolves in water to form acid that damages epithelial cells via oxidation; action mainly on upper airway

Alkali formation

Ammonia, calcium oxide, hydroxides

Gas dissolves in water to form alkaline solution that may cause tissue liquefaction; predominant upper airway damage, lower airway in heavy exposures

Protein binding


Reactions with amino acids lead to toxic intermediates with damage to the epithelial cell layer

Afferent nerve stimulation

Ammonia, formaldehyde

Direct nerve ending stimulation provokes symptoms


Platinum, acid anhydrides

Low molecular weight molecules serve as haptens in sensitized persons

Stimulation of host inflammatory response

Copper and zinc oxides, lipoproteins

Stimulation of cytokines and inflammatory mediators without apparent direct cellular damage

Free radical formation


Promotion of formation or retardation of clearance of superoxide radicals, leading to lipid peroxidation and oxidative damage

Delayed particle clearance

Any prolonged inhalation of mineral dust

Overwhelming of mucociliary escalators and alveolar macrophage systems with particles, leading to a non-specific inflammatory response

Workers exposed to low levels of respiratory irritants may have subclinical symptoms traceable to mucous membrane irritation, such as watery eyes, sore throat, runny nose and cough. With significant exposure, the added feeling of shortness of breath will often prompt medical attention. It is important to secure a good medical history in order to determine the likely composition of the exposure, the quantity of exposure, and the period of time during which the exposure took place. Signs of laryngeal oedema, including hoarseness and stridor, should be sought, and the lungs should be examined for signs of lower airway or parenchymal involvement. Assessment of the airway and lung function, together with chest radiography, are important in short-term management. Laryngoscopy may be indicated to evaluate the airway.

If the airway is threatened, the patient should undergo intubation and supportive care. Patients with signs of laryngeal oedema should be observed for at least 12 hours to insure that the process is self-limited. Bronchospasm should be treated with β-agonists and, if refractory, intravenous corticosteroids. Irritated oral and ocular mucosa should be thoroughly irrigated. Patients with crackles on examination or chest radiograph abnormalities should be hospitalized for observation in view of the possibility of pneumonitis or pulmonary oedema. Such patients are at risk of bacterial superinfection; nevertheless, no benefit has been demonstrated by using prophylactic antibiotics.

The overwhelming majority of patients who survive the initial insult recover fully from irritant exposures. The chances for long-term sequelae are more likely with greater initial injury. The term reactive airway dysfunction syndrome (RADS) has been applied to the persistence of asthma-like symptoms following acute exposure to respiratory irritants (Brooks, Weiss and Bernstein 1985).

This condition is thought to result from persistent inflammation with reduction of epithelial cell layer permeability or reduced conductance threshold for subepithelial nerve endings.

High-level exposures to alkalis and acids can cause upper and lower respiratory tract burns that lead to chronic disease. Ammonia is known to cause bronchiectasis (Kass et al. 1972); chlorine gas (which becomes HCl in the mucosa) is reported to cause obstructive lung disease (Donelly and Fitzgerald 1990; Das and Blanc 1993). Chronic low-level exposures to irritants may cause continued ocular and upper airway symptoms (Korn, Dockery and Speizer 1987), but deterioration of lung function has not been conclusively documented. Studies of the effects of chronic low-level irritants on airway function are hampered by a lack of long-term follow-up, confounding by cigarette smoking, the "healthy worker effect," and the minimal, if any, actual clinical effect (Brooks and Kalica 1987).

After a patient recovers from the initial injury, regular follow-up by a physician is needed. Clearly, there should be an effort to investigate the workplace and evaluate respiratory precautions, ventilation and containment of the culprit irritants.

Toxic Chemicals

Chemicals toxic to the lung include most of the respiratory irritants given enough high exposure, but there are many chemicals that cause significant parenchymal lung injury despite possessing low to moderate irritant properties. These compounds work their effects by mechanisms reviewed in table 10.3 and discussed above. Pulmonary toxins tend to be less water soluble than upper airway irritants. Examples of lung toxins and their sources of exposure are reviewed in table 10.5 .

Table 10.5 Compounds capable of lung toxicity after low to moderate exposure.


Sources of exposure



Plastics, textiles, pharmaceutical manufacturing, combustion products

Diffuse airway and parenchymal injury

Antimony trichloride; antimony  pentachloride

Alloys, organic catalysts

Pneumonitis, non-cardiogenic pulmonary oedema


Alloys with zinc and lead, electroplating, batteries, insecticides

Tracheobronchitis, pulmonary oedema (often delayed onset over 24-48 hours), kidney damage: tubule proteinuria


Chemical manufacturing, fumigant components

Upper and lower airway inflammation


Bleaching, formation of chlorinated compounds, household cleaners

Upper and lower airway inflammation, pneumonitis and non-cardiogenic pulmonary oedema

Hydrogen sulphide

Natural gas wells, mines, manure

Ocular, upper and lower airway irritation, delayed pulmonary oedema, asphyxiation from systemic tissue hypoxia

Lithium hydride

Alloys, ceramics, electronics, chemical catalysts

Pneumonitis, non-cardiogenic pulmonary oedema

Methyl isocyanate

Pesticide synthesis

Upper and lower respiratory tract irritation, pulmonary oedema


Electrolysis, ore and amalgam extraction, electronics manufacture

Ocular and respiratory tract inflammation, pneumonitis, CNS, kidney and systemic effects

Nickel carbonyl

Nickel refining, electroplating, chemical reagents

Lower respiratory irritation, pneumonitis, delayed systemic toxic effects

Nitrogen dioxide

Silos after new grain storage, fertilizer making, arc welding; combustion products

Ocular and upper airway inflammation, non-cardiogenic pulmonary oedema, delayed onset bronchiolitis

Nitrogen mustards, sulphur  mustards

Military agents, vesicants

Ocular and respiratory tract inflammation, pneumonitis


Herbicides (ingested)

Selective damage to type-2 pneumocytes leading to RADS, pulmonary fibrosis; renal failure, GI irritation


Pesticide and other chemical manufacture, arc welding, paint removal

Upper airway inflammation and pneumonitis; delayed pulmonary oedema in low doses

Zinc chloride

Smoke grenades, artillery

Upper and lower airway irritation, fever, delayed onset pneumonitis

One group of inhalable toxins are termed asphyxiants. When present in high enough concentrations, the asphyxiants, carbon dioxide, methane and nitrogen, displace oxygen and in effect suffocate the victim. Hydrogen cyanide, carbon monoxide and hydrogen sulphide act by inhibiting cellular respiration despite adequate delivery of oxygen to the lung. Non-asphyxiant inhaled toxins damage target organs, causing a wide variety of health problems and mortality.

The medical management of inhaled lung toxins is similar to the management of respiratory irritants. These toxins often do not elicit their peak clinical effect for several hours after exposure; overnight monitoring may be indicated for compounds known to cause delayed onset pulmonary oedema. Since the therapy of systemic toxins is beyond the scope of this chapter, the reader is referred to discussions of the individual toxins elsewhere in this Encyclopaedia and in further texts on the subject (Goldfrank et al. 1990; Ellenhorn and Barceloux 1988).

Inhalation Fevers

Certain inhalation exposures occurring in a variety of different occupational settings may result in debilitating flu-like illnesses lasting a few hours. These are collectively referred to as inhalation fevers. Despite the severity of the symptoms, the toxicity seems to be self-limited in most cases, and there are few data to suggest long-term sequelae. Massive exposure to inciting compounds can cause a more severe reaction involving pneumonitis and pulmonary oedema; these uncommon cases are considered more complicated than simple inhalation fever.

The inhalation fevers have in common the feature of nonspecificity: the syndrome can be produced in nearly anyone, given adequate exposure to the inciting agent. Sensitization is not required, and no previous exposure is necessary. Some of the syndromes exhibit the phenomenon of tolerance; that is, with regular repeated exposure the symptoms do not occur. This effect is thought to be related to an increased activity of clearance mechanisms, but has not been adequately studied.

Organic Dust Toxic Syndrome

Organic dust toxic syndrome (ODTS) is a broad term denoting the self-limited flu-like symptoms that occur following heavy exposure to organic dusts. The syndrome encompasses a wide range of acute febrile illnesses that have names derived from the specific tasks that lead to dust exposure. Symptoms occur only after a massive exposure to organic dust, and most individuals so exposed will develop the syndrome.

Organic dust toxic syndrome has previously been called pulmonary mycotoxicosis, owing to its putative aetiology in the action of mould spores and actinomycetes. With some patients, one can culture species of Aspergillus, Penicillium, and mesophilic and thermophilic actinomycetes (Emmanuel, Marx and Ault 1975; Emmanuel, Marx and Ault 1989). More recently, bacterial endotoxins have been proposed to play at least as large a role. The syndrome has been provoked experimentally by inhalation of endotoxin derived from Enterobacter agglomerans, a major component of organic dust (Rylander, Bake and Fischer 1989).

Endotoxin levels have been measured in the farm environment, with levels ranging from 0.01 to 100 µg/m3. Many samples had a level greater than 0.2 µg/m3, which is the level where clinical effects are known to occur (May, Stallones and Darrow 1989). There is speculation that cytokines, such as IL-1, may mediate the systemic effects, given what is already known about the release of IL-1 from alveolar macrophages in the presence of endotoxin (Richerson 1990). Allergic mechanisms are unlikely given the lack of need for sensitization and the requirement for high dust exposure.

Clinically, the patient will usually present symptoms 2 to 8 hours after exposure to (usually mouldy) grain, hay, cotton, flax, hemp or wood chips, or upon manipulation of pigs (Do Pico 1992). Often symptoms begin with eye and mucous membrane irritation with dry cough, progressing to fever, and malaise, chest tightness, myalgias and headache. The patient appears ill but otherwise normal upon physical examination. Leukocytosis frequently occurs, with levels as high as 25,000 white blood corpuscles (WBC)/mm3. The chest radiograph is almost always normal. Spirometry may reveal a modest obstructive defect. In cases where fibre optic bronchoscopy was performed and bronchial washings were obtained, an elevation of leukocytes was found in the lavage fluid. The percentage of neutrophils was significantly higher than normal (Emmanuel, Marx and Ault 1989; Lecours, Laviolette and Cormier 1986). Bronchoscopy 1 to 4 weeks after the event shows a persistently high cellularity, predominantly lymphocytes.

Depending on the nature of the exposure, the differential diagnosis may include toxic gas (such as nitrogen dioxide or ammonia) exposure, particularly if the episode occurred in a silo. Hypersensitivity pneumonitis should be considered, especially if there are significant chest radiograph or pulmonary function test abnormalities. The distinction between hypersensitivity pneumonitis (HP) and ODTS is important: HP will require strict exposure avoidance and has a worse prognosis, whereas ODTS has a benign and self-limited course. ODTS is also distinguished from HP because it occurs more frequently, requires higher levels of dust exposure, does not induce the release of serum precipitating antibodies, and (initially) does not give rise to the lymphocytic alveolitis that is characteristic of HP.

Cases are managed with antipyretics. A role for steroids has not been advocated given the self-limited nature of the illness. Patients should be educated about massive exposure avoidance. The long-term effect of repeated occurrences is thought to be negligible; however, this question has not been adequately studied.

Metal Fume Fever

Metal fume fever (MFF) is another self-limited, flu-like illness that develops after inhalation exposure, in this instance to metal fumes. The syndrome most commonly develops after zinc oxide inhalation, as occurs in brass foundries, and in smelting or welding galvanized metal. Oxides of copper and iron also cause MFF, and vapours of aluminium, arsenic, cadmium, mercury, cobalt, chromium, silver, manganese, selenium and tin have been occasionally implicated (Rose 1992). Workers develop tachyphalaxis; that is, symptoms appear only when the exposure occurs after several days without exposure, not when there are regular repeated exposures. An eight-hour TLV of 5 mg/m3 for zinc oxide has been established by the US Occupational Safety and Health Administration (OSHA), but symptoms have been elicited experimentally after a two-hour exposure at this concentration (Gordon et al. 1992).

The pathogenesis of MFF remains unclear. The reproducible onset of symptoms regardless of the individual exposed argues against a specific immune or allergic sensitization. The lack of symptoms associated with histamine release (flushing, itching, wheezing, hives) also militates against the likelihood of an allergic mechanism. Paul Blanc and co-workers have developed a model implicating cytokine release (Blanc et al. 1991; Blanc et al.1993). They measured the levels of tumour necrosis factor (TNF), and of the interleukins IL-1, IL-4, IL-6 and IL-8 in the fluid lavaged from the lungs of 23 volunteers experimentally exposed to zinc oxide fumes (Blanc et al. 1993). The volunteers developed elevated levels of TNF in their bronchoalveolar lavage (BAL) fluid 3 hours after exposure. Twenty hours later, high BAL fluid levels of IL-8 (a potent neutrophil attractant) and an impressive neutrophilic alveolitis were observed. TNF, a cytokine capable of causing fever and stimulating immune cells, has been shown to be released from monocytes in culture that are exposed to zinc (Scuderi 1990).

Accordingly, the presence of increased TNF in the lung accounts for the onset of symptoms observed in MFF. TNF is known to stimulate the release of both IL-6 and IL-8, in a time period that correlated with the peaks of the cytokines in these volunteers' BAL fluid. The recruitment of these cytokines may account for the ensuing neutrophil alveolitis and flu-like symptoms that characterize MFF. Why the alveolitis resolves so quickly remains a mystery.

Symptoms begin 3 to 10 hours after exposure. Initially, there may be a sweet metallic taste in the mouth, accompanied by a worsening dry cough and shortness of breath. Fever and shaking chills often develop, and the worker feels ill. The physical examination is otherwise unremarkable. Laboratory evaluation shows a leukocytosis and a normal chest radiograph. Pulmonary function studies may show a slightly reduced FEF25-75 and DLCO levels (Nemery 1990; Rose 1992).

With a good history the diagnosis is readily established and the worker can be treated symptomatically with antipyretics. Symptoms and clinical abnormalities resolve within 24 to 48 hours. Otherwise, bacterial and viral aetiologies of the symptoms must be considered. In cases of extreme exposure, or exposures involving contamination by toxins such as zinc chloride, cadmium or mercury, MFF may be a harbinger of a clinical chemical pneumonitis that will evolve over the next 2 days (Blount 1990). Such cases can exhibit diffuse infiltrates on a chest radiograph and signs of pulmonary oedema and respiratory failure. While this possibility should be considered in the initial evaluation of an exposed patient, such a fulminant course is unusual and not characteristic of uncomplicated MFF.

MFF does not require a specific sensitivity of the individual for the metal fumes; rather, it indicates inadequate environmental control. The exposure problem should be addressed to prevent recurrent symptoms. Although the syndrome is considered benign, the long-term effects of repeated bouts of MFF have not been adequately investigated.

Polymer Fume Fever

Polymer fume fever is a self-limited febrile illness similar to MFF, but caused by inhaled pyrolysis products of fluoropolymers, including polytetrafluoroethane (PTFE; trade names Teflon, Fluon, Halon). PTFE is widely used for its lubricant, thermal stability and electrical insulative properties. It is harmless unless heated above 300°C, when it starts to release degradation products (Shusterman 1993). This situation occurs when welding materials coated with PTFE, heating PTFE with a tool edge during high speed machining, operating moulding or extruding machines (Rose 1992) and rarely during endotracheal laser surgery (Rom 1992a).

A common cause of polymer fume fever was elicited after a period of classic public health detective work in the early 1970s (Wegman and Peters 1974; Kuntz and McCord 1974). Textile workers were developing self-limited febrile illnesses with exposures to formaldehyde, ammonia and nylon fibre; they did not have exposure to fluoropolymer fumes but handled crushed polymer. After finding that exposure levels of the other possible aetiological agents were within acceptable limits, the fluoropolymer work was examined more closely. As it turned out, only cigarette smokers working with the fluoropolymer were symptomatic. It was hypothesized that the cigarettes were being contaminated with fluoropolymer on the worker's hands, then the product was combusted on the cigarette when it was smoked, exposing the worker to toxic fumes. After banning cigarette smoking in the workplace and setting strict handwashing rules, no further illnesses were reported (Wegman and Peters 1974). Since then, this phenomenon has been reported after working with waterproofing compounds, mould-release compounds (Albrecht and Bryant 1987) and after using certain kinds of ski wax (Strom and Alexandersen 1990).

The pathogenesis of polymer fume fever is not known. It is thought to be similar to the other inhalation fevers owing to its similar presentation and apparently non-specific immune response. There have been no human experimental studies; however, rats and birds both develop severe alveolar epithelial damage on exposure to PTFE pyrolysis products (Wells, Slocombe and Trapp 1982; Blandford et al. 1975). Accurate measurement of pulmonary function or BAL fluid changes has not been done.

Symptoms appear several hours after exposure, and a tolerance or tachyphalaxis effect is not there as seen in MFF. Weakness and myalgias are followed by fever and chills. Often there is chest tightness and cough. Physical examination is usually otherwise normal. Leukocytosis is often seen, and the chest radiograph is usually normal. Symptoms resolve spontaneously in 12 to 48 hours. There have been a few cases of persons developing pulmonary oedema after exposure; in general, PTFE fumes are thought to be more toxic than zinc or copper fumes in causing MFF (Shusterman 1993; Brubaker 1977). Chronic airways dysfunction has been reported in persons who have had multiple episodes of polymer fume fever (Williams, Atkinson and Patchefsky 1974).

The diagnosis of polymer fume fever requires a careful history with high clinical suspicion. After ascertaining the source of the PTFE pyrolysis products, efforts must be made to prevent further exposure. Mandatory handwashing rules and the elimination of smoking in the workplace has effectively eliminated cases related to contaminated cigarettes. Workers who have had multiple episodes of polymer fume fever or associated pulmonary oedema should have long-term medical follow-up.


George Friedman-Jimenez and Edward L. Petsonk

Asthma is a respiratory disease characterized by airway obstruction that is partially or completely reversible, either spontaneously or with treatment; airway inflammation; and increased airway responsiveness to a variety of stimuli (NAEP 1991). Occupational asthma (OA) is asthma that is caused by environmental exposures in the workplace. Several hundred agents have been reported to cause OA. Pre-existing asthma or airway hyper-responsiveness, with symptoms worsened by work exposure to irritants or physical stimuli, is usually classified separately as work-aggravated asthma (WAA). There is general agreement that OA has become the most prevalent occupational lung disease in developed countries, although estimates of actual prevalence and incidence are quite variable. It is clear, however, that in many countries asthma of occupational aetiology causes a largely unrecognized burden of disease and disability with high economic and non-economic costs. Much of this public health and economic burden is potentially preventable by identifying and controlling or eliminating the workplace exposures causing the asthma. This article will summarize current approaches to recognition, management and prevention of OA. Several recent publications discuss these issues in more detail (Chan-Yeung 1995; Bernstein et al. 1993).

Magnitude of the Problem

Prevalences of asthma in adults generally range from 3 to 5%, depending on the definition of asthma and geographic variations, and may be considerably higher in some low-income urban populations. The proportion of adult asthma cases in the general population that is related to the work environment is reported to range from 2 to 23%, with recent estimates tending towards the higher end of the range. Prevalences of asthma and OA have been estimated in small cohort and cross-sectional studies of high-risk occupational groups. In a review of 22 selected studies of workplaces with exposures to specific substances, prevalences of asthma or OA, defined in various ways, ranged from 3 to 54%, with 12 studies reporting prevalences over 15% (Becklake, in Bernstein et al. 1993). The wide range reflects real variation in actual prevalence (due to different types and levels of exposure). It also reflects differences in diagnostic criteria, and variation in the strength of the biases, such as "survivor bias" which may result from exclusion of workers who developed OA and left the workplace before the study was conducted. Population estimates of incidence range from 14 per million employed adults per year in the United States to 140 per million employed adults per year in Finland (Meredith and Nordman 1996). Ascertainment of cases was more complete and methods of diagnosis were generally more rigorous in Finland. The evidence from these different sources is consistent in its implication that OA is often under-diagnosed and/or under-reported and is a public health problem of greater magnitude than generally recognized.

Causes of Occupational Asthma

Over 200 agents (specific substances, occupations or industrial processes) have been reported to cause OA, based on epidemiological and/or clinical evidence. In OA, airway inflammation and bronchoconstriction can be caused by immunological response to sensitizing agents, by direct irritant effects, or by other non-immunological mechanisms. Some agents (e.g., organophosphate insecticides) may also cause bronchoconstriction by direct pharmacological action. Most of the reported agents are thought to induce a sensitization response. Respiratory irritants often worsen symptoms in workers with pre-existing asthma (i.e., WAA) and, at high exposure levels, can cause new onset of asthma (termed reactive airways dysfunction syndrome (RADS) or irritant-induced asthma) (Brooks, Weiss and Bernstein 1985; Alberts and Do Pico 1996).

OA may occur with or without a latency period. Latency period refers to the time between initial exposure and development of symptoms, and is highly variable. It is often less than 2 years, but in around 20% of cases is 10 years or longer. OA with latency is generally caused by sensitization to one or more agents. RADS is an example of OA without latency.

High molecular weight sensitizing agents (5,000 daltons (Da) or greater) often act by an IgE-dependent mechanism. Low molecular weight sensitizing agents (less than 5,000 Da), which include highly reactive chemicals like isocyanates, may act by IgE-independent mechanisms or may act as haptens, combining with body proteins. Once a worker becomes sensitized to an agent, re-exposure (frequently at levels far below the level that caused sensitization) results in an inflammatory response in the airways, often accompanied by increases in airflow limitation and non-specific bronchial responsiveness (NBR).

In epidemiological studies of OA, workplace exposures are consistently the strongest determinants of asthma prevalence, and the risk of developing OA with latency tends to increase with estimated intensity of exposure. Atopy is an important and smoking a somewhat less consistent determinant of asthma occurrence in studies of agents that act through an IgE-dependent mechanism. Neither atopy nor smoking appears to be an important determinant of asthma in studies of agents acting through IgE-independent mechanisms.

Clinical Presentation

The symptom spectrum of OA is similar to non-occupational asthma: wheeze, cough, chest tightness and shortness of breath. Patients sometimes present cough-variant or nocturnal asthma. OA can be severe and disabling, and deaths have been reported. Onset of OA occurs due to a specific job environment, so identifying exposures that occurred at the time of onset of asthmatic symptoms is key to an accurate diagnosis. In WAA, workplace exposures cause a significant increase in frequency and/or severity of symptoms of pre-existing asthma.

Several features of the clinical history may suggest occupational aetiology (Chan-Yeung 1995). Symptoms frequently worsen at work or at night after work, improve on days off, and recur on return to work. Symptoms may worsen progressively towards the end of the workweek. The patient may note specific activities or agents in the workplace that reproducibly trigger symptoms. Work-related eye irritation or rhinitis may be associated with asthmatic symptoms. These typical symptom patterns may be present only in the initial stages of OA. Partial or complete resolution on weekends or vacations is common early in the course of OA, but with repeated exposures, the time required for recovery may increase to one or two weeks, or recovery may cease to occur. The majority of patients with OA whose exposures are terminated continue to have symptomatic asthma even years after cessation of exposure, with permanent impairment and disability. Continuing exposure is associated with further worsening of asthma. Brief duration and mild severity of symptoms at the time of cessation of exposure are good prognostic factors and decrease the likelihood of permanent asthma.

Several characteristic temporal patterns of symptoms have been reported for OA. Early asthmatic reactions typically occur shortly (less than one hour) after beginning work or the specific work exposure causing the asthma. Late asthmatic reactions begin 4 to 6 hours after exposure begins, and can last 24 to 48 hours. Combinations of these patterns occur as dual asthmatic reactions with spontaneous resolution of symptoms separating an early and late reaction, or as continuous asthmatic reactions with no resolution of symptoms between phases. With exceptions, early reactions tend to be IgE mediated, and late reactions tend to be IgE independent.

Increased NBR, generally measured by methacholine or histamine challenge, is considered a cardinal feature of occupational asthma. The time course and degree of NBR may be useful in diagnosis and monitoring. NBR may decrease within several weeks after cessation of exposure, although abnormal NBR commonly persists for months or years after exposures are terminated. In individuals with irritant-induced occupational asthma, NBR is not expected to vary with exposure and/or symptoms.

Recognition and Diagnosis

Accurate diagnosis of OA is important, given the substantial negative consequences of either under- or over-diagnosis. In workers with OA or at risk of developing OA, timely recognition, identification and control of the occupational exposures causing the asthma improve the chances of prevention or complete recovery. This primary prevention can greatly reduce the high financial and human costs of chronic, disabling asthma. Conversely, since a diagnosis of OA may obligate a complete change of occupation, or costly interventions in the workplace, accurately distinguishing OA from asthma that is not occupational can prevent unnecessary social and financial costs to both employers and workers.

Several case definitions of OA have been proposed, appropriate in different circumstances. Definitions found valuable for worker screening or surveillance (Hoffman et al. 1990) may not be entirely applicable for clinical purposes or compensation. A consensus of researchers has defined OA as "a disease characterized by variable airflow limitation and/or airway hyper-responsiveness due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace" (Bernstein et al. 1993). This definition has been operationalized as a medical case definition, summarized in table 10.6  (Chan-Yeung 1995).

Table 10.6 ACCP medical case definition of occupational asthma.1

Criteria for diagnosis of occupational asthma1 (requires all 4, A-D):

(A)     Physician diagnosis of asthma and/or physiological evidence of airways hyper-responsiveness

(B)     Occupational exposure preceded onset of asthmatic symptoms1 

(C)     Association between symptoms of asthma and work

(D)     Exposure and/or physiological evidence of relation of asthma to workplace environment (Diagnosis of OA requires one or more of D2-D5, likely OA requires only D1)

     (1)     Workplace exposure to agent reported to give rise to OA

     (2)     Work-related changes in FEV1 and/or PEF

     (3)     Work-related changes in serial testing for non-specific bronchial      responsiveness (e.g., Methacholine Challenge Test)

     (4)     Positive specific bronchial challenge test

     (5)     Onset of asthma with a clear association with a symptomatic exposure to an inhaled irritant in the workplace (generally RADS)

Criteria for diagnosis of RADS (should meet all 7):

     (1)     Documented absence of preexisting asthma-like complaints

     (2)     Onset of symptoms after a single exposure incident or accident

     (3)     Exposure to a gas, smoke, fume, vapour or dust with irritant properties present in high concentration

     (4)     Onset of symptoms within 24 hours after exposure with persistence of symptoms for at least 3 months

     (5)     Symptoms consistent with asthma: cough, wheeze, dyspnoea

     (6)     Presence of airflow obstruction on pulmonary function tests and/or  presence of non-specific bronchial hyper-responsiveness  (testing should be done shortly after exposure)

     (7)     Other pulmonary diseases ruled out

Criteria for diagnosis of work-aggravated asthma (WAA):

     (1)     Meets criteria A and C of ACCP Medical Case Definition of OA

     (2)     Pre-existing asthma or history of asthmatic symptoms, (with active  symptoms during the year prior to start of employment or exposure  of interest)

     (3)     Clear increase in symptoms or medication requirement, or documentation  of work-related changes in PEFR or FEV1 after start of employment or  exposure of interest

1 A case definition requiring A, C and any one of D1 to D5 may be useful in surveillance for OA,  WAA and RADS.

Source: Chan-Yeung 1995.

Thorough clinical evaluation of OA can be time consuming, costly and difficult. It may require diagnostic trials of removal from and return to work, and often requires the patient to reliably chart serial peak expiratory flow (PEF) measurements. Some components of the clinical evaluation (e.g., specific bronchial challenge or serial quantitative testing for NBR) may not be readily available to many physicians. Other components may simply not be achievable (e.g., patient no longer working, diagnostic resources not available, inadequate serial PEF measurements). Diagnostic accuracy is likely to increase with the thoroughness of the clinical evaluation. In each individual patient, decisions on the extent of medical evaluation will need to balance costs of the evaluation with the clinical, social, financial and public health consequences of incorrectly diagnosing or ruling out OA.

In consideration of these difficulties, a stepped approach to diagnosis of OA is outlined in table 10.7 . This is intended as a general guide to facilitate accurate, practical and efficient diagnostic evaluation, recognizing that some of the suggested procedures may not be available in some settings. Diagnosis of OA involves establishing both the diagnosis of asthma and the relation between asthma and workplace exposures. After each step, for each patient, the physician will need to determine whether the level of diagnostic certainty achieved is adequate to support the necessary decisions, or whether evaluation should continue to the next step. If facilities and resources are available, the time and cost of continuing the clinical evaluation are usually justified by the importance of making an accurate determination of the relationship of asthma to work. Highlights of diagnostic procedures for OA will be summarized; details can be found in several of the references (Chan-Yeung 1995; Bernstein et al. 1993). Consultation with a physician experienced in OA may be considered, since the diagnostic process may be difficult.

Table 10.7 Steps in diagnosis evaluation of asthma in the workplace.

Step 1

Thorough medical and occupational history and directed physical examination.

Step 2

Physiologic evaluation for reversible airway obstruction and/or non specific  bronchial hyper-responsiveness.

Step 3

Immunologic assessment, if appropriate.

Assess Work Status:

Currently working: Proceed to Step 4 first.

Not currently working, diagnostic trial of return to work feasible: Step 5 first,  then Step 4.

Not currently working, diagnostic trial of return to work not feasible: Step 6.

Step 4

Clinical evaluation of asthma at work or diagnostic trial of return to work.

Step 5

Clinical evaluation of asthma away from work or diagnostic trial of removal from  work.

Step 6

Workplace challenge or specific bronchial challenge testing. If available for  suspected causal exposures, this step may be performed prior to Step 4 for any patient.

This is intended as a general guide to facilitate practical and efficient diagnostic evaluation. It is recommended that physicians who diagnose and manage OA refer to current clinical  literature as well.

RADS, when caused by an occupational exposure, is usually considered a subclass of OA. It is diagnosed clinically, using the criteria in table 10.6 . Patients who have experienced significant respiratory injury due to high-level irritant inhalations should be evaluated for persistent symptoms and presence of airflow obstruction shortly after the event. If the clinical history is compatible with RADS, further evaluation should include quantitative testing for NBR, if not contra-indicated.

WAA may be common, and may cause a substantial preventable burden of disability, but little has been published on diagnosis, management or prognosis. As summarized in table 10.6 , WAA is recognized when asthmatic symptoms preceded the suspected causal exposure but are clearly aggravated by the work environment. Worsening at work can be documented either by physiological evidence or through evaluation of medical records and medication use. It is a clinical judgement whether patients with a history of asthma in remission, who have recurrence of asthmatic symptoms that otherwise meet the criteria for OA, are diagnosed with OA or WAA. One year has been proposed as a sufficiently long asymptomatic period that the onset of symptoms is likely to represent a new process caused by the workplace exposure, although no consensus yet exists.

Step 1: Thorough medical and occupational history and directed physical examination

Initial suspicion of possible OA in appropriate clinical and workplace situations is key, given the importance of early diagnosis and intervention in improving prognosis. The diagnosis of OA or WAA should be considered in all asthmatic patients in whom symptoms developed as a working adult (especially recent onset), or in whom the severity of asthma has substantially increased. OA should also be considered in any other individuals who have asthma-like symptoms and work in occupations in which they are exposed to asthma-causing agents or who are concerned that their symptoms are work-related.

Patients with possible OA should be asked to provide a thorough medical and occupational/environmental history, with careful documentation of the nature and date of onset of symptoms and diagnosis of asthma, and any potentially causal exposures at that time. Compatibility of the medical history with the clinical presentation of OA described above should be evaluated, especially the temporal pattern of symptoms in relation to work schedule and changes in work exposures. Patterns and changes in patterns of use of asthma medications, and the minimum period of time away from work required for improvement in symptoms should be noted. Prior respiratory diseases, allergies/atopy, smoking and other toxic exposures, and a family history of allergy are pertinent.

Occupational and other environmental exposures to potential asthma-causing agents or processes should be thoroughly explored, with objective documentation of exposures if possible. Suspected exposures should be compared with a comprehensive list of agents reported to cause OA (Harber, Schenker and Balmes 1996; Chan-Yeung and Malo 1994; Bernstein et al. 1993; Rom 1992b), although inability to identify specific agents is not uncommon and induction of asthma by agents not previously described is possible as well. Some illustrative examples are shown in table 10.8 . Occupational history should include details of current and relevant past employment with dates, job titles, tasks and exposures, especially current job and job held at time of onset of symptoms. Other environmental history should include a review of exposures in the home or community that could cause asthma. It is helpful to begin the exposure history in an open-ended way, asking about broad categories of airborne agents: dusts (especially organic dusts of animal, plant or microbial origin), chemicals, pharmaceuticals and irritating or visible gases or fumes. The patient may identify specific agents, work processes or generic categories of agents that have triggered symptoms. Asking the patient to describe step by step the activities and exposures involved in the most recent symptomatic workday can provide useful clues. Materials used by co-workers, or those released in high concentration from a spill or other source, may be relevant. Further information can often be obtained on product name, ingredients and manufacturer name, address and phone number. Specific agents can be identified by calling the manufacturer or through a variety of other sources including textbooks, CD ROM databases, or Poison Control Centers. Since OA is frequently caused by low levels of airborne allergens, workplace industrial hygiene inspections which qualitatively evaluate exposures and control measures are often more helpful than quantitative measurement of air contaminants.

Table 10.8 Sensitizing agents that can cause occupational asthma.



Examples of substances

Examples of jobs and industries

High-molecular-weight protein antigens

Animal-derived substances

Laboratory animals, crab/seafood, mites, insects

Animal handlers, farming and food processing


Plant-derived substances

Flour and grain dusts, natural rubber latex gloves, bacterial enzymes, castor bean dust, vegetable gums

Bakeries, health care workers, detergent making, food processing

Low-molecular-weight/chemical  sensitizers

Plasticizers, 2-part paints, adhesives, foams

Isocyanates, acid anhydrides, amines

Auto spray painting, varnishing, woodworking



Platinum salts, cobalt

Platinum refineries, metal grinding


Wood dusts

Cedar (plicatic acid), oak

Sawmill work, carpentry


Pharmaceuticals, drugs

Psyllium, antibiotics

Pharmaceutical manufacturing and packaging

Other chemicals


Chloramine T, polyvinyl chloride fumes, organophosphate insecticides

Janitorial work, meat packing

The clinical history appears to be better for excluding rather than for confirming the diagnosis of OA, and an open-ended history taken by a physician is better than a closed questionnaire. One study compared the results of an open-ended clinical history taken by trained OA specialists with a "gold standard" of specific bronchial challenge testing in 162 patients referred for evaluation of possible OA. The investigators reported that the sensitivity of a clinical history suggestive of OA was 87%, specificity 55%, predictive value positive 63% and predictive value negative 83%. In this group of referred patients, prevalence of asthma and OA were 80% and 46%, respectively (Malo et al. 1991). In other groups of referred patients, predictive values positive of a closed questionnaire ranged from 8 to 52% for a variety of workplace exposures (Bernstein et al. 1993). The applicability of these results to other settings needs to be assessed by the physician.

Physical examination is sometimes helpful, and findings relevant to asthma (e.g., wheezing, nasal polyps, eczematous dermatitis), respiratory irritation or allergy (e.g., rhinitis,  conjunctivitis) or other potential causes of symptoms should be noted.

Step 2: Physiological evaluation for reversible airway obstruction and/or  non-specific bronchial hyper-responsiveness

If sufficient physiological evidence supporting the diagnosis of asthma (NAEP 1991) is already in the medical record, Step 2 can be skipped. If not, technician-coached spirometry should be performed, preferably post-workshift on a day when the patient is experiencing asthmatic symptoms. If spirometry reveals airway obstruction which reverses with a bronchodilator, this confirms the diagnosis of asthma. In patients without clear evidence of airflow limitation on spirometry, quantitative testing for NBR using methacholine or histamine should be done, the same day if possible. Quantitative testing for NBR in this situation is a key procedure for two reasons. First, it can often identify patients with mild or early stage OA who have the greatest potential for cure but who would be missed if testing stopped with normal spirometry. Second, if NBR is normal in a worker who has ongoing exposure in the workplace environment associated with the symptoms, OA can generally be ruled out without further testing. If abnormal, evaluation can proceed to Step 3 or 4, and the degree of NBR may be useful in monitoring the patient for improvement after diagnostic trial of removal from the suspected causal exposure (Step 5). If spirometry reveals significant airflow limitation that does not improve after inhaled bronchodilator, a re-evaluation after more prolonged trial of therapy, including corticosteroids, should be considered (ATS 1995; NAEP 1991).

Step 3: Immunological assessment, if appropriate

Skin or serological (e.g., RAST) testing can demonstrate immunological sensitization to a specific workplace agent. These immunological tests have been used to confirm the work-relatedness of asthma, and, in some cases, eliminate the need for specific inhalation challenge tests. For example, among psyllium-exposed patients with a clinical history compatible with OA, documented asthma or airway hyper-responsiveness, and evidence of immunological sensitization to psyllium, approximately 80% had OA confirmed on subsequent specific bronchial challenge testing (Malo et al. 1990). In most cases, diagnostic significance of negative immunological tests is less clear. The diagnostic sensitivity of the immunological tests depends critically on whether all the likely causal antigens in the workplace or hapten-protein complexes have been included in the testing. Although the implication of sensitization for an asymptomatic worker is not well defined, analysis of grouped results can be useful in evaluating environmental controls. The utility of immunological evaluation is greatest for agents for which there are standardized in vitro tests or skin-prick reagents, such as platinum salts and detergent enzymes. Unfortunately, most occupational allergens of interest are not currently available commercially. The use of non-commercial solutions in skin-prick testing has on occasions been associated with severe reactions, including anaphylaxis, and thus caution is necessary.

If results of Steps 1 and 2 are compatible with OA, further evaluation should be pursued if possible. The order and extent of further evaluation depends on availability of diagnostic resources, work status of the patient and feasibility of diagnostic trials of removal from and return to work as indicated in table 10.7. If further evaluation is not possible, a diagnosis must be based on the information available at this point.

Step 4: Clinical evaluation of asthma at work, or diagnostic trial of return to work

Often the most readily available physiological test of airway obstruction is spirometry. To improve reproducibility, spirometry should be coached by a trained technician. Unfortunately, single-day cross-shift spirometry, performed before and after the workshift, is neither sensitive nor specific in determining work-associated airway obstruction. It is probable that if multiple spirometries are performed each day during and after several workdays, the diagnostic accuracy may be improved, but this has not yet been adequately evaluated.

Due to difficulties with cross-shift spirometry, serial PEF measurement has become an important diagnostic technique for OA. Using an inexpensive portable meter, PEF measurements are recorded every two hours, during waking hours. To improve sensitivity, measurements must be done during a period when the worker is exposed to the suspected causal agents at work and is experiencing a work-related pattern of symptoms. Three repetitions are performed at each time, and measurements are made every day at work and away from work. The measurements should be continued for at least 16 consecutive days (e.g., two five-day work weeks and 3 weekends off) if the patient can safely tolerate continuing to work. PEF measurements are recorded in a diary along with notation of work hours, symptoms, use of bronchodilator medications, and significant exposures. To facilitate interpretation, the diary results should then be plotted graphically. Certain patterns suggest OA, but none are pathognomonic, and interpretation by an experienced reader is often helpful. Advantages of serial PEF testing are low cost and reasonable correlation with results of bronchial challenge testing. Disadvantages include the significant degree of patient cooperation required, inability to definitely confirm that data are accurate, lack of standardized method of interpretation, and the need for some patients to take 1 or 2 consecutive weeks off work to show significant improvement. Portable electronic recording spirometers designed for patient self monitoring, when available, can address some of the disadvantages of serial PEF.

Asthma medications tend to reduce the effect of work exposures on measures of airflow. However, it is not advisable to discontinue medications during airflow monitoring at work. Rather, the patient should be maintained on a constant minimal safe dosage of anti-inflammatory medications throughout the entire diagnostic process, with close monitoring of symptoms and airflow, and the use of short-acting bronchodilators to control symptoms should be noted in the diary.

The failure to observe work-related changes in PEF while a patient is working routine hours does not exclude the diagnosis of OA, since many patients will require more than a two-day weekend to show significant improvement in PEF. In this case, a diagnostic trial of extended removal from work (Step 5) should be considered. If the patient has not yet had quantitative testing for NBR, and does not have a medical contra-indication, it should be done at this time, immediately after at least two weeks of workplace exposure.

Step 5: Clinical evaluation of asthma away from work or diagnostic trial of extended removal from work

This step consists of completion of the serial 2-hourly PEF daily diary for at least 9 consecutive days away from work (e.g., 5 days off work plus weekends before and after). If this record, compared with the serial PEF diary at work, is not sufficient for diagnosing OA, it should be continued for a second consecutive week away from work. After 2 or more weeks away from work, quantitative testing for NBR can be performed and compared to NBR while at work. If serial PEF has not yet been done during at least two weeks at work, then a diagnostic trial of return to work (see Step 4) may be performed, after detailed counselling, and in close contact with the treating physician. Step 5 is often critically important in confirming or excluding the diagnosis of OA, although it may also be the most difficult and expensive step. If an extended removal from work is attempted, it is best to maximize the diagnostic yield and efficiency by including PEF, FEV1, and NBR tests in one comprehensive evaluation. Weekly physician visits for counselling and to review the PEF chart can help to assure complete and accurate results. If, after monitoring the patient for at least two weeks at work and two weeks away from it, the diagnostic evidence is not yet sufficient, Step 6 should be considered next, if available and feasible.

Step 6: Specific bronchial challenge or workplace challenge testing

Specific bronchial challenge testing using an exposure chamber and standardized exposure levels has been labelled the "gold standard" for diagnosis of OA. Advantages include definitive confirmation of OA with ability to identify asthmatic response to sub-irritant levels of specific sensitizing agents, which can then be scrupulously avoided. Of all the diagnostic methods, it is the only one that can reliably distinguish sensitizer-induced asthma from provocation by irritants. Several problems with this approach have included inherent costliness of the procedure, general requirement of close observation or hospitalization for several days, and availability in only very few specialized centres. False negatives may occur if standardized methodology is not available for all suspected agents, if the wrong agents are suspected, or if too long a time has elapsed between last exposure and testing. False positives may result if irritant levels of exposure are inadvertently obtained. For these reasons, specific bronchial challenge testing for OA remains a research procedure in most localities.

Workplace challenge testing involves serial technician-coached spirometry in the workplace, performed at frequent (e.g., hourly) intervals before and during the course of a workday exposure to the suspected causal agents or processes. It may be more sensitive than specific bronchial challenge testing because it involves "real life" exposures, but since airway obstruction may be triggered by irritants as well as sensitizing agents, positive tests do not necessarily indicate sensitization. It also requires cooperation of the employer and much technician time with a mobile spirometer. Both of these procedures carry some risk of precipitating a severe asthmatic attack, and should therefore be done under close supervision of specialists experienced with the procedures.

Treatment and Prevention

Management of OA includes medical and preventive interventions for individual patients, as well as public health measures in workplaces identified as high risk for OA. Medical management is similar to that for non-occupational asthma and is well reviewed elsewhere (NAEP 1991). Medical management alone is rarely adequate to optimally control symptoms, and preventive intervention by control or cessation of exposure is an integral part of the treatment. This process begins with accurate diagnosis and identification of causative exposures and conditions. In sensitizer-induced OA, reducing exposure to the sensitizer does not usually result in complete resolution of symptoms. Severe asthmatic episodes or progressive worsening of the disease may be caused by exposures to very low concentrations of the agent and complete and permanent cessation of exposure is recommended.

Timely referral for vocational rehabilitation and job retraining may be a necessary component of treatment for some patients. If complete cessation of exposure is impossible, substantial reduction of exposure accompanied by close medical monitoring and management may be an option, although such reduction in exposure is not always feasible and the long-term safety of this approach has not been tested. As an example, it would be difficult to justify the toxicity of long-term treatment with systemic corticosteroids in order to allow the patient to continue in the same employment. For asthma induced and/or triggered by irritants, dose response may be more predictable, and lowering of irritant exposure levels, accompanied by close medical monitoring, may be less risky and more likely to be effective than for sensitizer-induced OA. If the patient continues to work under modified conditions, medical follow-up should include frequent physician visits with review of the PEF diary, well-planned access to emergency services, and serial spirometry and/or methacholine challenge testing, as appropriate.

Once a particular workplace is suspected to be high risk, due either to occurrence of a sentinel case of OA or use of known asthma-causing agents, public health methods can be very useful. Early recognition and effective treatment and prevention of disability of workers with existing OA, and prevention of new cases, are clear priorities. Identification of specific causal agent(s) and work processes is important. One practical initial approach is a workplace questionnaire survey, evaluating criteria A, B, C, and D1 or D5 in the case definition of OA. This approach can identify individuals for whom further clinical evaluation might be indicated and help identify possible causal agents or circumstances. Evaluation of group results can help decide whether further workplace investigation or intervention is indicated and, if so, provide valuable guidance in targeting future prevention efforts in the most effective and efficient manner. A questionnaire survey is not adequate, however, to establish individual medical diagnoses, since predictive positive values of questionnaires for OA are not high enough. If a greater level of diagnostic certainty is needed, medical screening utilizing diagnostic procedures such as spirometry, quantitative testing for NBR, serial PEF recording, and immunological testing can be considered as well. In known problem workplaces, ongoing surveillance and screening programmes may be helpful. However, differential exclusion of asymptomatic workers with history of atopy or other potential susceptibility factors from workplaces believed to be high risk would result in removal of large numbers of workers to prevent relatively few cases of OA, and is not supported by the current literature.

Control or elimination of causal exposures and avoidance and proper management of spills or episodes of high-level exposures can lead to effective primary prevention of sensitization and OA in co-workers of the sentinel case. The usual exposure control hierarchy of substitution, engineering and administrative controls, and personal protective equipment, as well as education of workers and managers, should be implemented as appropriate. Proactive employers will initiate or participate in some or all of these approaches, but in the event that inadequate preventive action is taken and workers remain at high risk, governmental enforcement agencies may be helpful.

Impairment and Disability

Medical impairment is a functional abnormality resulting from a medical condition. Disability refers to the total effect of the medical impairment on the patient's life, and is influenced by many non-medical factors such as age and socio-economic status (ATS 1995).

Assessment of medical impairment is done by the physician and may include a calculated impairment index, as well as other clinical considerations. The impairment index is based on (1) degree of airflow limitation after bronchodilator, (2) either degree of reversibility of airflow limitation with bronchodilator or degree of airway hyper-responsiveness on quantitative testing for NBR, and (3) minimum medication required to control asthma. The other major component of the assessment of medical impairment is the physician's medical judgement of the ability of the patient to work in the workplace environment causing the asthma. For example, a patient with sensitizer-induced OA may have a medical impairment which is highly specific to the agent to which he or she has become sensitized. The worker who experiences symptoms only when exposed to this agent may be able to work in other jobs, but permanently unable to work in the specific job for which she or he has the most training and experience.

Assessment of disability due to asthma (including OA) requires consideration of medical impairment as well as other non-medical factors affecting ability to work and function in everyday life. Disability assessment is initially made by the physician, who should identify all the factors affecting the impact of the impairment on the patient's life. Many factors such as occupation, educational level, possession of other marketable skills, economic conditions and other social factors may lead to varying levels of disability in individuals with the same level of medical impairment. This information can then be used by administrators to determine disability for purposes of compensation.

Impairment and disability may be classified as temporary or permanent, depending on the likelihood of significant improvement, and whether effective exposure controls are successfully implemented in the workplace. For example, an individual with sensitizer-induced OA is generally considered permanently, totally impaired for any job involving exposure to the causal agent. If the symptoms resolve partially or completely after cessation of exposure, these individuals may be classified with less or no impairment for other jobs. Often this is considered permanent partial impairment/disability, but terminology may vary. An individual with asthma which is triggered in a dose-dependent fashion by irritants in the workplace would be considered to have temporary impairment while symptomatic, and less or no impairment if adequate exposure controls are installed and are effective in reducing or eliminating symptoms. If effective exposure controls are not implemented, the same individual might have to be considered permanently impaired to work in that job, with recommendation for medical removal. If necessary, repeated assessment for long-term impairment/disability may be carried out two years after the exposure is reduced or terminated, when improvement of OA would be expected to have plateaued. If the patient continues to work, medical monitoring should be ongoing and reassessment of impairment/disability should be repeated as needed.

Workers who become disabled by OA or WAA may qualify for financial compensation for medical expenses and/or lost wages. In addition to directly reducing the financial impact of the disability on individual workers and their families, compensation may be necessary to provide proper medical treatment, initiate preventive intervention and obtain vocational rehabilitation. The worker's and physician's understanding of specific medico-legal issues may be important to ensuring that the diagnostic evaluation meets local requirements and does not result in compromise of the rights of the affected worker.

Although discussions of cost savings frequently focus on the inadequacy of compensation systems, genuinely reducing the financial and public health burden placed on society by OA and WAA will depend not only on improvements in compensation systems but, more importantly, on effectiveness of the systems deployed to identify and rectify, or prevent entirely, workplace exposures that are causing onset of new cases of asthma.


OA has become the most prevalent occupational respiratory disease in many countries. It is more common than generally recognized, can be severe and disabling, and is generally preventable. Early recognition and effective preventive interventions can substantially reduce the risk of permanent disability and the high human and financial costs associated with chronic asthma. For many reasons, OA merits more widespread attention among clinicians, health and safety specialists, researchers, health policy makers, industrial hygienists, and others interested in prevention of work-related diseases.


Ragnar Rylander and Richard S. F. Schilling

Organic Dust and Disease

Dusts of vegetable, animal and microbial origin have always been part of the human environment. When the first aquatic organisms moved to land some 450 million years ago, they soon developed defence systems against the many noxious substances present in the terrestrial environment, most of them of plant origin. Exposures to this environment usually cause no specific problems, even though plants contain a number of extremely toxic substances, particularly those present in or produced by moulds.

During the development of civilization, climatic conditions in some parts of the world necessitated certain activities to be undertaken indoors. Threshing in the Scandinavian countries was performed indoors during the winter, a practice mentioned by chroniclers in antiquity. The enclosure of dusty processes led to disease among the exposed persons, and one of the first published accounts of this is by the Danish bishop Olaus Magnus (1555, as cited by Rask-Andersen 1988). He described a disease among threshers in Scandinavia as follows:

In separating the grain from the chaff, care must be taken to choose a time when there is a suitable wind which will sweep away the grain dust, so that it will not damage the vital organs of the threshers. This dust is so fine that it will almost unnoticeably penetrate into the mouth and accumulate in the throat. If this is not quickly dealt with by drinking fresh ale, the thresher may never again or only for a short period eat what he has threshed.

With the introduction of machine processing of organic materials, treatment of large quantities of materials indoors with poor ventilation led to high levels of airborne dust. The descriptions by bishop Olaus Magnus and later by Ramazzini (1713) were followed by several reports on disease and organic dusts in the nineteenth century, particularly among cotton mill workers (Leach 1863; Prausnitz 1936). Later, the specific pulmonary disease common among farmers handling mouldy materials was also described (Campbell 1932).

During recent decades, a large number of reports on disease among persons exposed to organic dusts have been published. Initially, most of these were based on persons seeking medical help. The names of the diseases, when published, were often related to the particular environment where the disease was first recognized, and a bewildering array of names resulted, such as farmer's lung, mushroom grower's lung, brown lung and humidifier fever.

With the advent of modern epidemiology, more reliable figures were obtained for the incidence of occupational respiratory diseases related to organic dust (Rylander, Donham and Peterson 1986; Rylander and Peterson 1990). There was also advancement in the understanding of the pathological mechanisms underlying these diseases, particularly the inflammatory response (Henson and Murphy 1989). This paved the way for a more coherent picture of diseases caused by organic dusts (Rylander and Jacobs 1997).

The following will describe the different organic dust environments where disease has been reported, the disease entities themselves, the classical byssinosis disease and specific preventive measures.


Organic dusts are airborne particles of vegetable, animal or microbial origin. Table 10.9  lists examples of environments, work processes and agents involving the risk of exposure to organic dusts.

Table 10.9 Examples of sources of hazards of exposure to organic dust.


     Handling of grain, hay or other crops

     Sugar-cane processing




     Swine/dairy confinement buildings

     Poultry houses and processing plants

     Laboratory animals, farm animals and pets


     Sewage water and silt

     Household garbage



     Vegetable fibre processing (cotton, flax, hemp, jute, sisal)


     Timber and wood processing


     Biotechnology processing


     Contaminated water in humidifiers

     Microbial growth on structures or in ventilation ducts


It is now understood that the specific agents in the dusts are the major reason why disease develops. Organic dusts contain a multitude of agents with potential biological effects. Some of the major agents are found in table 10.10 .

Table 10.10 Major agents in organic dusts with potential biological activity.

Vegetable agents



     Plicatic acid

     Alkaloids (e.g., nicotine)


Animal agents



Microbial agents





The relative role of each of these agents, alone or in combination with others, for the development of disease, is mostly unknown. Most of the information available relates to bacterial endotoxins which are present in all organic dusts.

Endotoxins are lipopolysaccharide compounds which are attached to the outer cell surface of Gram-negative bacteria. Endotoxin has a wide variety of biological properties. After inhalation it causes an acute inflammation (Snella and Rylander 1982; Brigham and Meyrick 1986). An influx of neutrophils (leukocytes) into the lung and the airways is the hallmark of this reaction. It is accompanied by activation of other cells and secretion of inflammatory mediators. After repeated exposures, the inflammation decreases (adaptation). The reaction is limited to the airway mucosa, and there is no extensive involvement of the lung parenchyma.

Another specific agent in organic dust is (1→3)-β-D-glucan. This is a polyglucose compound present in the cell wall structure of moulds and some bacteria. It enhances the inflammatory response caused by endotoxin and alters the function of inflammatory cells, particularly macrophages and T-cells (Di Luzio 1985; Fogelmark et al. 1992).

Other specific agents present in organic dusts are proteins, tannins, proteases and other enzymes, and toxins from moulds. Very little data are available on the concentrations of these agents in organic dusts. Several of the specific agents in organic dusts, such as proteins and enzymes, are allergens.


The diseases caused by organic dusts are shown in table 10.11  with the corresponding International Classification of Disease (ICD) numbers (Rylander and Jacobs 1994).

Table 10.11 Diseases induced by organic dusts and their ICD codes.

Bronchitis and pneumonitis (ICD J40)

     Toxic pneumonitis (inhalation fever, organic dust toxic syndrome)

     Airways inflammation (mucous membrane inflammation)

     Chronic bronchitis (ICD J42)

Hypersensitivity pneumonitis (allergic alveolitis) (ICD J67)

Asthma (ICD J45)

     Rhinitis, conjunctivitis

The primary route of exposure for organic dusts is by inhalation, and consequently the effects on the lung have received the major share of attention in research as well as in clinical work. There is, however, a growing body of evidence from published epidemiological studies and case reports as well as anecdotal reports, that systemic effects also occur. The mechanism involved seems to be a local inflammation at the target site, the lung, and a subsequent release of cytokines either with systemic effects (Dunn 1992; Michel et al. 1991) or an effect on the epithelium in the gut (Axmacher et al. 1991). Non-respiratory clinical effects are fever, joint pains, neurosensory effects, skin problems, intestinal disease, fatigue and headache.

The different disease entities as described in table 10.11  are easy to diagnose in typical cases, and the underlying pathology is distinctly different. In real life, however, a worker who has a disease due to organic dust exposure, often presents a mixture of the different disease entities. One person may have airways inflammation for a number of years, suddenly develop asthma and in addition have symptoms of toxic pneumonitis during a particularly heavy exposure. Another person may have subclinical hypersensitivity pneumonitis with lymphocytosis in the airways and develop toxic pneumonitis during a particularly heavy exposure.

A good example of the mixture of disease entities that may appear is byssinosis. This disease was first described in the cotton mills, but the individual disease entities are also found in other organic dust environments. An overview of the disease follows.


The disease

Byssinosis was first described in the 1800s, and a classic report involving clinical as well as experimental work was given by Prausnitz (1936). He described the symptoms among cotton mill workers as follows:

After working for years without any appreciable trouble except a little cough, cotton mill workers notice either a sudden aggravation of their cough, which becomes dry and exceedingly irritating.... These attacks usually occur on Mondays ... but gradually the symptoms begin to spread over the ensuing days of the week; in time the difference disappears and they suffer continuously.

The first epidemiological investigations were performed in England in the 1950s (Schilling et al. 1955; Schilling 1956). The initial diagnosis was based on the appearance of a typical Monday morning chest tightness, diagnosed using a questionnaire (Roach and Schilling 1960). A scheme for grading the severity of byssinosis based on the type and periodicity of symptoms was developed (Mekky, Roach and Schilling 1967; Schilling et al. 1955). Duration of exposure was used as a measure of dose and this was related to the severity of the response. Based on clinical interviews of large numbers of workers, this grading scheme was later modified to more accurately reflect the time intervals for the decrease in FEV1 (Berry et al. 1973).

In one study, a difference in the prevalence of byssinosis in mills processing different types of cotton was found (Jones et al. 1979). Mills using high-quality cotton to produce finer yarns had a lower prevalence of byssinosis than mills producing coarse yarns and using a lower quality of cotton. Thus in addition to exposure intensity and duration, both dose-related variables, the type of dust became an important variable for assessing exposure. Later it was demonstrated that the differences in the response of workers exposed to coarse and medium cottons was dependent not only on the type of cotton but on other variables that affect exposure, including: processing variables such as carding speed, environmental variables such as humidification and ventilation, and manufacturing variables such as different yarn treatments (Berry et al. 1973).

The next refinement of the relationship between exposure to cotton dust and a response (either symptoms or objective measures of pulmonary function), was the studies from the United States, comparing those who worked in 100% cotton to workers using the same cotton but in a 50:50 blend with synthetics and workers without exposure to cotton (Merchant et al. 1973). Workers exposed to 100% cotton had the highest prevalence of byssinosis independent of cigarette smoking, one of the confounders of exposure to cotton dust. This semiquantitative relationship between dose and response to cotton dust was further refined in a group of textile workers stratified by sex, smoking, work area and mill type. A relationship was observed in each of these categories between dust concentration in the lower dust ranges and byssinosis prevalence and/or change in forced expiratory volume in one second (FEV1).

In later investigations, the FEV1 decrease over the work shift has been used to assess the effects of exposure, and it is also a part of the US Cotton Dust Standard.

Byssinosis was long regarded as a peculiar disease with a mixture of different symptoms and no knowledge of the specific pathology. Some authors suggested that it was an occupational asthma (Bouhuys 1976). A workgroup meeting in 1987 analysed the symptomatology and pathology of the disease (Rylander et al. 1987). It was agreed that the disease comprised several clinical entities, generally related to organic dust exposure.

Toxic pneumonitis may appear the first time an employee works in the mill, particularly when working in the opening, blowing and carding sections (Trice 1940). Although habituation develops, the symptoms may reappear after an unusually heavy exposure later on.

Airways inflammation is the most widespread disease, and it appears at different degrees of severity from light irritation in the nose and airways to severe dry cough and breathing difficulties. The inflammation causes constriction of airways and a reduced FEV1. Airway responsiveness is increased as measured with a methacholine or histamine challenge test. It has been discussed whether airways inflammation should be accepted as a disease entity by itself or whether it merely represents a symptom. As the clinical findings in terms of severe cough with airways narrowing can lead to a decrease in work ability, it is justified to regard it as an occupational disease.

Continued airways inflammation over several years may develop into chronic bronchitis, particularly among heavily exposed workers in the blowing and carding areas. The clinical picture would be one of chronic obstructive pulmonary disease (COPD).

Occupational asthma develops in a small percentage of the workforce, but is usually not diagnosed in cross-sectional studies as the workers are forced to leave work because of the disease. Hypersensitivity pneumonitis has not been detected in any of the epidemiological studies undertaken, nor have there been case reports relating to cotton dust exposure. The absence of hypersensitivity pneumonitis may be due to the relatively low amount of moulds in cotton, as mouldy cotton is not acceptable for processing.

A subjective feeling of chest tightness, most common on Mondays, is the classical symptom of cotton dust exposure (Schilling et al. 1955). It is not, however, a feature unique to cotton dust exposure as it appears also among persons working with other kinds of organic dusts (Donham et al. 1989). Chest tightness develops slowly over a number of years but it can also be induced in previously unexposed persons, provided that the dose level is high (Haglind and Rylander 1984). The presence of chest tightness is not directly related to a decrease in FEV1.

The pathology behind chest tightness has not been explained. It has been suggested that the symptoms are due to an increased adhesiveness of platelets which accumulate in the lung capillaries and increase the pulmonary artery pressure. It is likely that chest tightness involves some kind of cell sensitization, as it takes repeated exposures for the symptom to develop. This hypothesis is supported by results from studies on blood monocytes from cotton workers (Beijer et al. 1990). A higher ability to produce procoagulant factor, indicative of cell sensitization, was found among cotton workers as compared to controls.

The environment

The disease was originally described among workers in cotton, flax and soft hemp mills. In the first phase of cotton treatment within the mills-bale opening, blowing and carding-more than half of the workers may have symptoms of chest tightness and airways inflammation. The incidence decreases as the cotton is processed, reflecting the successive cleaning of the causative agent from the fibre. Byssinosis has been described in all countries where investigations in cotton mills have been performed. Some countries like Australia have, however, unusually low incidence figures (Gun et al. 1983).

There is now uniform evidence that bacterial endotoxins are the causative agent for toxic pneumonitis and airways inflammation (Castellan et al. 1987; Pernis et al. 1961; Rylander, Haglind and Lundholm 1985; Rylander and Haglind 1986; Herbert et al. 1992; Sigsgaard et al. 1992). Dose-response relationships have been described and the typical symptoms have been induced by inhalation of purified endotoxin (Rylander et al. 1989; Michel et al. 1995). Although this does not exclude the possibility that other agents could contribute to the pathogenesis, endotoxins can serve as markers for disease risk. It is unlikely that endotoxins are related to the development of occupational asthma, but they could act as an adjuvant for potential allergens in cotton dust.

The case

The diagnosis of byssinosis is classically made using questionnaires with the specific question "Does your chest feel tight, and if so, on which day of the week?". Persons with Monday morning chest tightness are classified as byssinotics according to a scheme suggested by Schilling (1956). Spirometry can be performed, and, according to the different combinations of chest tightness and decrease in FEV1, the diagnostic scheme illustrated in table 10.12  has evolved.

Table 10.12 Diagnostic creiteria for byssinosis.

Grade 1/2.

Chest tightness on the first day of some working weeks

Grade 1.

Chest tightness on the first day of every working week

Grade 2.

Chest tightness on the first and other days of the working week

Grade 3.

Grade 2 symptoms accompanied by evidence of permanent incapacity in the form of diminished effort intolerance and/or reduced ventilatory capacity


Treatment in the light stages of byssinosis is symptomatic, and most of the workers learn to live with the slight chest tightness and bronchoconstriction that they experience on Mondays or when cleaning machinery or carrying out similar tasks with a higher than normal exposure. More advanced stages of airways inflammation or regular chest tightness several days of the week require transfer to less dusty operations. The presence of occupational asthma mostly requires work change.


Prevention in general is dealt with in detail elsewhere in the Encyclopaedia. The basic principles for prevention in terms of product substitute, exposure limitation, worker protection and screening for disease apply also for cotton dust exposure.

Regarding product substitutes, it has been suggested that cotton with a low level of bacterial contamination be used. An inverse proof of this concept is found in reports from 1863 where the change to dirty cotton provoked an increase in the prevalence of symptoms among the exposed workers (Leach 1863). There is also the possibility of changing to other fibres, particularly synthetic fibres, although this is not always feasible from a product point of view. There is at present no production-applied technique to decrease the endotoxin content of cotton fibres.

Regarding dust reduction, successful programmes have been implemented in the United States and elsewhere (Jacobs 1987). Such programmes are expensive, and the costs for highly efficient dust removal may be prohibitive for developing countries (Corn 1987).

Regarding exposure control, the level of dust is not a sufficiently precise measure of exposure risk. Depending on the degree of contamination with Gram-negative bacteria and thus endotoxin, a given dust level may or may not be associated with a risk. For endotoxins, no official guidelines have been established. It has been suggested that a level of 200 ng/m3 is the threshold for toxic pneumonitis, 100 to 200 ng/m3 for acute airways constriction over the workshift and 10 ng/m3 for airways inflammation (Rylander and Jacobs 1997).

Knowledge about the risk factors and the consequences of exposure are important for prevention. The information basis has expanded rapidly during recent years, but much of it is not yet present in textbooks or other easily available sources. A further problem is that symptoms and findings in respiratory diseases induced by organic dust are non-specific and occur normally in the population. They may thus not be correctly diagnosed in the early stages.

Proper dissemination of knowledge concerning the effects of cotton and other organic dusts requires the establishment of appropriate training programmes. These should be directed not only towards workers with potential exposure but also towards employers and health personnel, particularly occupational health inspectors and engineers. Information must include source identification, symptoms and disease description, and methods of protection. An informed worker can more readily recognize work-related symptoms and communicate more effectively to a health care provider. Regarding health surveillance and screening, questionnaires are a major instrument to be used. Several versions of questionnaires specifically designed for diagnosing diseases induced by organic dust have been reported in the literature (Rylander, Peterson and Donham 1990; Schwartz et al. 1995). Lung function testing is also a useful tool for surveillance and diagnosis. Measurements of airway responsiveness have been found to be useful (Rylander and Bergström 1993; Carvalheiro et al. 1995). Other diagnostic tools such as measurements of inflammatory mediators or cell activity are still in the research phase.


Homayoun Kazemi

*This article is based in part on an article on beryllium disease by H.L.Hardy, L.B. Tepper and R.I. Chamberlin published in the 3rd edition of the Encyclopaedia of Occupational Health and Safety.

Beryllium disease is a systemic disorder involving multiple organs, with pulmonary manifestations being most prominent and common. It occurs on exposure to beryllium in its alloy form or in one of its various chemical compounds. Route of exposure is by inhalation and the disease can be either acute or chronic. Acute disease is extremely rare currently, and none has been reported since the first widespread industrial use of beryllium in the 1940s after industrial hygiene measures had been implemented to limit high-dose exposures. Chronic beryllium disease continues to be reported.

Beryllium, Alloys and Compounds

Beryllium, an industrial substance suspected of having carcinogenic potential, is notable for its lightness in weight, high tensile strength and corrosion resistance. Table 10.13  outlines the properties of beryllium and its compounds.

Table 10.13 Properties of beryllium and its compounds.


Formula  weight

Specific  gravity

Melting/boiling point (ºC)



Beryllium (Be)

9.01 (a.w.)




Grey to silver metal

Beryllium oxide (BeO)




Soluble in acids and alkalis; insoluble in water

White amorphous powder

Beryllium fluoride1 (BeF2 )



Sublimes 800 °C

Readily soluble in water; sparingly soluble in ethyl alcohol

Hygroscopic solid

Beryllium chloride2 (BeCl2 )




Very soluble in water; soluble in ethyl alcohol, benzene, ethyl ether and carbon disulphide

White or slightly yellow deliquescent crystals

Beryllium nitrate3; (Be(NO3 )2 ·3H2 O)




Soluble in water and ethyl alcohol

White to faintly yellow deliquescent crystals

Beryllium nitride4 (Be3 N2 )





Hard, refractory white crystals

Beryllium sulphate hydrate5 (BeSO4·4H2 O)




Soluble in water; insoluble in ethyl alcohol

Colourless crystals

1 Beryllium fluoride is made by the decompensation at 900-950 ºC of ammonium beryllium fluoride.  Its main use is in the production of beryllium metal by reduction with magnesium. 2 Beryllium chloride is manufactured by passing chlorine over a mixture of beryllium oxide and carbon. 3 Beryllium nitrate is produced by the action of nitric acid on beryllium oxide. It is used as a  chemical reagent and as a gas mantle hardener. 4 Beryllium nitride is prepared by heating beryllium metal powder in an oxygen-free, nitrogen atmosphere at 700-1,400 ºC. It is used in atomic energy reactions, including the production of the radioactive carbon isotope carbon-14. 5 Beryllium sulphate hydrate is produced by treating the fritted ore with concentrated suphuric acid.  It is used in the production of metallic beryllium by the sulphate process.


Beryl (3BeO·Al2O3·6SiO2) is the chief commercial source of beryllium, the most abundant of the minerals containing high concentrations of beryllium oxide (10 to 13%). Major sources of beryl are to be found in Argentina, Brazil, India, Zimbabwe and the Republic of South Africa. In the United States, beryl is found in Colorado, South Dakota, New Mexico and Utah. Bertrandite, a low-grade ore (0.1 to 3%) with an acid-soluble beryllium content, is now being mined and processed in Utah.


The two most important methods of extracting beryllium from the ore are the sulphate process and the fluoride process.

In the sulphate process, crushed beryl is melted in an arc furnace at 1,650°C and poured through a high-velocity water stream to form a frit. After heat treatment, the frit is ground in a ball mill and mixed with concentrated sulphuric acid to form a slurry, which is sprayed in the form of a jet into a directly heated, rotating sulphating mill. The beryllium, now in a water-soluble form, is leached from the sludge, and ammonium hydroxide is added to the leach liquor, which is then fed to a crystallizer where ammonium alum is crystallized out. Chelating agents are added to the liquor to hold iron and nickel in solution, sodium hydroxide is then added, and the sodium beryllate thus formed is hydrolyzed to precipitate beryllium hydroxide. The latter product may be converted to beryllium fluoride for reduction by magnesium to metallic beryllium, or to beryllium chloride for electrolytic reduction.

In the fluoride process (figure 10.11) a briquetted mixture of ground ore, sodium silicofluoride and soda ash is sintered in a rotating hearth furnace. The sintered material is crushed, milled and leached. Sodium hydroxide is added to the solution of beryllium fluoride thus obtained and the precipitate of beryllium hydroxide is filtered in a rotary filter. Metallic beryllium is obtained as in the previous process by the magnesium reduction of beryllium fluoride or by electrolysis of beryllium chloride.

Figure 10.11 Production of beryllium oxide by the fluoride process


Beryllium is used in alloys with a number of metals including steel, nickel, magnesium, zinc and aluminium, the most widely used alloy being beryllium-copper-properly called "a bronze"-which has a high tensile strength and a capacity for being hardened by heat treatment. Beryllium bronzes are used in non-spark tools, electrical switch parts, watch springs, diaphragms, shims, cams and bushings.

One of the largest uses of the metal is as a moderator of thermal neutrons in nuclear reactors and as a reflector to reduce the leakage of neutrons from the reactor core. A mixed uranium-beryllium source is often used as a neutron source. As a foil, beryllium is used as window material in x-ray tubes. Its lightness, high elastic modulus and heat stability make it an attractive material for the aircraft and aerospace industry.

Beryllium oxide is made by heating beryllium nitrate or hydroxide.

It is used in the manufacture of ceramics, refractory materials and other beryllium compounds. It was used for the manufacture of phosphors for fluorescent lamps until the incidence of beryllium disease in the industry caused its use for this purpose to be abandoned (in 1949 in the United States).


Fire and health hazards are associated with processes involving beryllium. Finely divided beryllium powder will burn, the degree of combustibility being a function of particle size. Fires have occurred in dust filtration units and during the welding of ventilation ducting in which finely divided beryllium was present.

Beryllium and its compounds are highly toxic substances. Beryllium can affect all organ systems, although the primary organ involved is the lung. Beryllium causes systemic disease by inhalation and can distribute itself widely throughout the body after absorption from the lungs. Little beryllium is absorbed from the gastro-intestinal tract. Beryllium can cause skin irritation and its traumatic introduction into subcutaneous tissue can cause local irritation and granuloma formation.


Beryllium in all its forms, except for beryl ore, has been associated with disease. The route of entry is by inhalation and in the acute disease there is a direct toxic effect on both the nasopharyngeal mucosa and that of the entire tracheobronchial tree as well, causing oedema and inflammation. In the lung it causes an acute chemical pneumonitis. The major form of beryllium toxicity at this point in time is chronic beryllium disease. A beryllium-specific delayed type of hypersensitivity is the major pathway of chronic disease. The entry of beryllium into the system through the lungs leads to proliferation of specific CD4+ lymphocytes, with beryllium acting as a specific antigen, either alone or as a hapten through an interleukin-2 (IL2) receptor pathway. Individual susceptibility to beryllium thus can be explained on the basis of the individual CD4+ response. Release of lymphokines from the activated lymphocytes then can lead to granuloma formation and macrophage recruitment. Beryllium can be transported to sites outside the lung where it can cause granuloma formation. Beryllium is released slowly from different sites and it is excreted by the kidneys. This slow release can occur over a span of 20 to 30 years. The chronicity and latency of disease can probably be explained on the basis of the slow metabolism and release phenomenon. The immune mechanisms involved in the pathogenesis of beryllium disease also allow for specific approaches to diagnosis, which will be discussed below.


The primary pathological finding in beryllium disease is the formation of non-caseating granulomas in the lungs, lymph nodes and at other sites. Histopathological studies of lungs in patients with acute beryllium disease have shown a non-specific pattern of acute and subacute bronchitis and pneumonitis. In chronic beryllium disease, there are varying degrees of lymphocytic infiltration of the lung interstitium and non-caseating granuloma formation (figure 10.12).

Figure 10.12 Lung tissue in a patient with chronic beryllium disease

Both granulomas and round cell infiltration are visible

Many of the granulomas are located in the peribronchiolar areas. In addition, there can be histiocytes, plasma cells and giant cells with calcific inclusion bodies. If it is a case solely of granuloma formation, the long-term prognosis is better. The histology of the lung in chronic beryllium disease is indistinguishable from that of sarcoidosis. Non-caseating granulomas are also found in lymph nodes, liver, spleen, muscle and skin.

Clinical Manifestations

Skin injuries

Acid salts of beryllium cause allergic contact dermatitis. Such lesions may be erythematous, papular or papulovesicular, are commonly pruritic, and are found on exposed parts of the body. There is usually a delay of 2 weeks from first exposure to occurrence of the dermatitis, except in the case of heavy exposures, when an irritant reaction may be immediate. This delay is regarded as the time required to develop the hypersensitive state.

Accidental implantation of beryllium metal or crystals of a soluble beryllium compound in an abrasion, a crack in the skin or under the nail may cause an indurated area with central suppuration. Granulomas can also form at such sites.

Conjunctivitis and dermatitis may occur alone or together. In cases of conjunctivitis, periorbital oedema may be severe.

Acute disease

Beryllium nasopharyngitis is characterized by swollen and hyperaemic mucous membranes, bleeding points, fissures and ulceration. Perforation of the nasal septum has been described. Removal from exposure results in reversal of this inflammatory process within 3 to 6 weeks.

Involvement of the trachea and bronchial tree following exposure to higher levels of beryllium causes non-productive cough, substernal pain and moderate shortness of breath. Rhonchi and/or rales may be audible, and the x ray of the chest may show increased bronchovascular markings. The character and speed of onset and the severity of these signs and symptoms depend on the quality and quantity of exposure. Recovery is to be expected within 1 to 4 weeks if the worker is removed from further exposure.

The use of steroids is quite useful in countering the acute disease. No new cases of acute disease have been reported to the US Beryllium Case Registry in over 30 years. The Registry, which was started by Harriet Hardy in 1952, has almost 1,000 case records, among which are listed 212 acute cases. Almost all of these occurred in the fluorescent lamp manufacturing industry. Forty-four subjects with the acute disease subsequently developed chronic disease.

Chronic beryllium disease

Chronic beryllium disease is a pulmonary and systemic granulomatous disease caused by inhalation of beryllium. The latency of the disease can be from 1 to 30 years, most commonly occurring 10 to 15 years after first exposure. Chronic beryllium disease has a variable course with exacerbations and remissions in its clinical manifestations. However, the disease is usually progressive. There have been a few cases with chest x-ray abnormalities with a stable clinical course and without significant symptoms.

Exertional dyspnoea is the most common symptom of chronic beryllium disease. Other symptoms are cough, fatigue, weight loss, chest pain and arthralgias. Physical findings may be entirely normal or may include bibasilar crackles, lymphadenopathy, skin lesions, hepatosplenomegaly and clubbing. Signs of pulmonary hypertension may be present in severe, long-standing disease.

Renal stones and hyperuricaemia can occur in some patients and there have been rare reports of parotid gland enlargement and central nervous system involvement. The clinical manifestations of chronic beryllium disease are very similar to those of sarcoidosis.

Roentgenologic features

The x-ray pattern in chronic beryllium disease is non-specific and is similar to that which may be observed in sarcoidosis, idiopathic pulmonary fibrosis, tuberculosis, mycoses and dust disease (figure 10.13). Early in the course of the disease films may show granular, nodular or linear densities. These abnormalities may increase, decrease or remain unchanged, with or without fibrosis. Upper-lobe involvement is common. Hilar adenopathy, seen in approximately one-third of patients, is usually bilateral and accompanied by mottling of the lung fields. The absence of lung changes in the presence of adenopathy is a relative but not an absolute differential consideration in favour of sarcoidosis as opposed to chronic beryllium disease. Unilateral hilar adenopathy has been reported, but is quite rare.

Figure 10.13 Chest roentgenograph of a patient with chronic beryllium disease, showing diffuse  fibronodular infiltrates and prominent hila

The x-ray picture does not correlate well with clinical status and does not reflect particular qualitative or quantitative aspects of the causal exposure.

Pulmonary function tests

Data from the Beryllium Case Registry show that 3 patterns of impairment may be found in chronic beryllium disease. Of 41 patients studied over a period of an average of 23 years after initial beryllium exposure, 20% had a restrictive defect, 36% had an interstitial defect (normal lung volumes and air flow rates but reduced diffusing capacity for carbon monoxide), 39% had an obstructive defect and 5% were normal. The obstructive pattern, which occurred in both smokers and non-smokers, was associated with granulomas in the peribronchial region. This study indicated that the pattern of impairment affects prognosis. Patients with interstitial defect fared best, with the least deterioration over a five-year interval. Patients with obstructive and restrictive defects experienced worsening of their impairment in spite of corticosteroid therapy.

Studies of lung function in beryllium extraction workers who were asymptomatic showed the presence of mild arterial hypoxaemia. This occurred usually within the first 10 years of exposure. In workers exposed to beryllium for 20 years or more there was a reduction in the forced vital capacity (FVC) and the forced expiratory volume in one second (FEV1). These findings suggest that the initial mild hypoxaemia could be due to the early alveolitis and that with further exposure and elapse of time the reduction in FEV1 and FVC could represent fibrosis and granuloma formation.

Other laboratory tests

Non-specific abnormal laboratory tests have been reported in chronic beryllium disease and include elevated sedimentation rate, erythrocytosis, increased gammaglobulin levels, hyperuricaemia and hypercalcaemia.

The Kveim skin test is negative in beryllium disease, whereas it may be positive in sarcoidosis. The angiotensin converting enzyme (ACE) level is usually normal in beryllium disease, but can be increased in 60% or more of patients with active sarcoidosis.


Diagnosis of chronic beryllium disease for many years was based on the criteria developed through the Beryllium Case Registry, which included:

1.     a history of significant beryllium exposure

2.     evidence of lower respiratory tract disease

3.     abnormal chest x ray with interstitial fibronodular disease

4.     abnormal lung function tests with decreased carbon monoxide diffusing capacity (DLCO)

5.     pathological changes consistent with beryllium exposure in lung or thoracic lymph nodes

6.     the presence of beryllium in tissue.

Four of the six criteria had to be met and should have included either (1) or (6). Since the 1980s, advances in immunology have made it possible to make the diagnosis of beryllium disease without requiring tissue specimens for histological examination or beryllium analysis. The transformation of lymphocytes in blood in response to beryllium exposure (as in the lymphocyte transformation test, LTT) or lymphocytes from bronchoalveolar lavage (BAL) have been proposed by Newman et al. (1989) as useful diagnostic tools in making the diagnosis of beryllium disease in exposed subjects. Their data suggest that a positive blood LTT is indicative of sensitization. However, recent data show that the blood LTT does not correlate well with pulmonary disease. The BAL lymphocyte transformation correlates much better with abnormal pulmonary function and does not correlate well with concurrent abnormalities in the blood LTT. Thus, to make a diagnosis of beryllium disease, one needs a combination of clinical, radiological and lung function abnormalities and a positive LTT in the BAL. A positive blood LTT by itself is not diagnostic. Microprobe analysis of small tissue samples for beryllium is another recent innovation which could help in diagnosis of disease in small lung tissue samples obtained by transbronchial lung biopsy.

Sarcoidosis is the disorder most closely resembling chronic beryllium disease, and the differentiation may be difficult. Thus far, no cystic bone disease or involvement of the eye or tonsil has appeared in chronic beryllium disease. Similarly, the Kveim test is negative in beryllium disease. Skin testing to demonstrate beryllium sensitization is not recommended, in that the test itself is sensitizing, may possibly trigger systemic reactions in sensitized people and does not of itself establish that the presenting disease is necessarily beryllium related.

More sophisticated immunological approaches in differential diagnosis should allow for better differentiation from sarcoidosis in the future.


The prognosis of chronic beryllium disease has altered favourably during the years; it has been suggested that the longer delays in onset observed among beryllium workers may reflect lower exposure or lower beryllium body burden, resulting in a milder clinical course. Clinical evidence is that steroid therapy, if used when measurable disability first appears, in adequate doses for long enough periods, has improved the clinical status of many patients, allowing some of them to return to useful jobs. There is no clear evidence that steroids have cured chronic beryllium poisoning.

Beryllium and cancer

In animals, experimentally administered beryllium is a carcinogen, causing osteogenic sarcoma after intravenous injection in rabbits and lung cancer after inhalation in rats and monkeys. Whether beryllium may be a human carcinogen is a controversial issue. Some epidemiological studies have suggested an association, particularly after acute beryllium disease. This finding has been disputed by others. One can conclude that beryllium is carcinogenic in animals and there may be a link between lung cancer and beryllium in humans, particularly in those with the acute disease.

Safety and Health Measures

Safety and health precautions must cover the fire hazard as well as the much more serious toxicity danger.

Fire prevention

Arrangements must be made to prevent possible sources of ignition, such as the sparking or arcing of electrical apparatus, friction, and so forth, in the vicinity of finely divided beryllium powder. Equipment in which this powder has been present should be emptied and cleaned before acetylene or electrical welding apparatus is used on it. Oxide-free, ultrafine beryllium powder that has been prepared in inert gas is liable to ignite spontaneously on exposure to air.

Suitable dry powder-not water-should be used to extinguish a beryllium fire. Full personal protective equipment, including respiratory protective equipment, should be worn and firefighters should bathe afterwards and arrange for their clothing to be laundered separately.

Health protection

Beryllium processes must be conducted in a carefully controlled manner to protect both the worker and the general population. The main risk takes the form of airborne contamination and the process and plant should be designed to give rise to as little dust or fume as possible. Wet processes should be used instead of dry processes, and the ingredients of beryllium-containing preparations should be unified as aqueous suspensions instead of as dry powders; whenever possible the plant should be designed as groups of separate enclosed units. The permissible concentration of beryllium in the atmosphere is so low that enclosure must be applied even to wet processes, otherwise escaping splashes and spills can dry out and the dust can enter the atmosphere.

Operations from which dust may be evolved should be conducted in areas with maximum degree of enclosure consistent with the needs of manipulation. Some operations are performed in glove boxes, but many more are conducted in enclosures provided with exhaust ventilation similar to that installed in chemical fume cupboards. Machining operations may be ventilated by high-velocity, low-volume local exhaust systems or by hooded enclosures with exhaust ventilation.

To check the effectiveness of these precautionary measures atmosphere monitoring should be done in such a manner that the daily average exposure of workers to respirable beryllium can be calculated. The work area should be cleaned regularly by means of a proper vacuum cleaner or a wet mop. Beryllium processes should be segregated from the other operations in the factory.

Personal protective equipment should be provided for workers engaged in beryllium processes. Where they are fully employed in processes involving the manipulation of beryllium compounds or in processes associated with the extraction of the metal from the ore, provision should be made for a complete change of clothing so that the workers do not go home wearing clothing in which they have been working. Arrangements should be made for the safe laundering of such working clothes, and protective overalls should be provided even to laundry workers to ensure that they too are not exposed to risk. These arrangements should not be left to normal home laundering procedures. Cases of beryllium poisoning in the families of workers have been attributed to workers taking contaminated clothing home or wearing them in the home.

An occupational health standard of 2 µg/m3, proposed in 1949 by a committee operating under the auspices of the US Atomic Energy Commission, continues to be widely observed. Existing interpretations generally permit fluctuations to a "ceiling" of 5 µg/m3 as long as the time-weighted average is not exceeded. Additionally, an "acceptable maximum peak above the ceiling concentration for an eight-hour shift" of 25 µg/m3 for up to 30 min is also permissible. These operational levels are achievable in current industrial practice, and there is no evidence of adverse health experience among persons working in an environment thus controlled. Because of a possible link between beryllium and lung cancer it has been suggested that the allowable limit be reduced to 1 µg/m3, but no official action has been taken on this suggestion in the United States.

The population at risk for developing beryllium disease is that which in some manner deals with beryllium in its extraction or subsequent use. However, a few "neighbourhood" cases have been reported from a distance 1 to 2 km from beryllium extraction plants.

Pre-employment and periodical medical examinations of workers exposed to beryllium and its compounds are compulsory in a number of countries. Recommended evaluation includes an annual respiratory questionnaire, a chest x ray and lung function tests. With advances in immunology, the LTT may also become a routine evaluation, although at this time not enough data are available to recommend its use routinely. With evidence of beryllium disease, it is unwise to allow a worker to be exposed to beryllium further, even though the workplace meets the threshold criteria for beryllium concentration in the air.


The major step in therapy is avoidance of further exposure to beryllium. Corticosteroids are the primary mode of therapy in chronic beryllium disease. Corticosteroids appear to alter the course of disease favourably but do not "cure" it.

Corticosteroids should be started on a daily basis with a relatively high dose of Prednisone of 0.5 to 1 mg per kg or more, and continued until improvement occurs or no further deterioration in clinical or lung function tests occurs. Usually this takes 4 to 6 weeks. Slow reduction of steroids is recommended, and eventually alternate-day therapy may be possible. Steroid therapy ordinarily becomes a lifelong necessity.

Other supportive measures such as supplemental oxygen, diuretics, digitalis and antibiotics (when infection exists) are indicated as the clinical condition of the patient would dictate. Immunization against influenza and pneumococcus should also be considered, as with any patient with chronic respiratory disease.


Alois David

The expression pneumoconiosis, from the Greek pneuma (air, wind) and konis (dust) was coined in Germany by Zenker in 1867 to denote changes in the lungs caused by the retention of inhaled dust. Gradually, the need for distinction between the effects of various types of dust became evident. It was necessary to discriminate among mineral or vegetable dust and their microbiological component. Consequently, the Third International Conference of Experts on Pneumoconiosis, organized by the ILO in Sydney in 1950, adopted the following definition: "Pneumoconiosis is a diagnosable disease of the lungs produced by the inhalation of dust, the term 'dust' being understood to refer to particulate matter in the solid phase, but excluding living organisms."

However, the word disease seems to imply some degree of health impairment which may not be the case with pneumoconioses not connected with the development of lung fibrosis/scarring. In general, the reaction of lung tissue to the presence of dust varies with different dusts. Non-fibrogenic dusts evoke a tissue reaction in lungs characterized by minimal fibrotic reaction and absence of lung function impairment. Such dusts, examples of which are finely divided dusts of kaolinite, titanium dioxide, stannous oxide, barium sulphate and ferric oxide, are frequently referred to as biologically inert.

Fibrogenic dust such as silica or asbestos causes a more pronounced fibrogenic reaction resulting in scars in the lung tissue and obvious disease. The division of dusts into fibrogenic and non-fibrogenic varieties is by no means sharp because there are many minerals, notably silicates, which are intermediate in their ability to produce fibrotic lesions in the lungs. Nevertheless, it proved useful for clinical purposes and is reflected in the classification of pneumoconioses.

A new definition of pneumoconioses was adopted at the Fourth International Conference on Pneumoconiosis, Bucharest, 1971: "Pneumoconiosis is the accumulation of dust in the lungs and the tissue reactions to its presence. For the purpose of this definition, 'dust' is meant to be an aerosol composed of solid inanimate particles."

In order to avoid any misinterpretation, the expression non-neoplastic is sometimes added to the words "tissue reaction".

The Working Group at the Conference made the following comprehensive statement:

     The Definition of Pneumoconiosis

Earlier on, in 1950, a definition of pneumoconiosis was established at the 3rd International Conference of Experts on Pneumoconiosis and this has continued to be used until the present time.

In the meantime, the development of new technologies has resulted in more occupational risks, particularly those related to the inhalation of airborne contaminants.

Increased knowledge in the field of occupational medicine has enabled new pulmonary diseases of occupational origin to be recognized but has also demonstrated the necessity for a re-examination of the definition of pneumoconiosis established in 1950.

The ILO therefore arranged for a Working Group to be convened within the framework of the IVth International Pneumoconiosis Conference in order to examine the question of the definition of pneumoconiosis.

The Working Group held a general discussion on the matter and proceeded to examine a number of proposals submitted by its members. It finally adopted a new definition of pneumoconiosis which was prepared together with a commentary. This text is reproduced below.

In recent years a number of countries have included under pneumoconiosis, because of socio-economic reasons, conditions which are manifestly not pneumoconiosis, but are nevertheless occupational pulmonary diseases. Under the term "disease" are included for preventive reasons the earliest manifestations which are not necessarily disabling or life shortening.

Therefore the Working Group has undertaken to redefine pneumoconiosis as the accumulation of dust in the lungs and the tissue reactions to its presence. For the purpose of this definition, "dust" is meant to be an aerosol composed of solid inanimate particles.

From a pathological point of view pneumoconiosis may be divided for the sake of convenience into collagenous or non-collagenous forms.

A non-collagenous pneumoconiosis is caused by a non-fibrogenic dust and has the following characteristics:

i. the alveolar architecture remains intact

ii. the stromal reaction is minimal and consists mainly of reticulin fibres

iii. the dust reaction is potentially reversible.

Examples of non-collagenous pneumoconiosis are those caused by pure dusts of tin oxide (stannosis) and barium sulphate (barytosis).

Collagenous pneumoconiosis is characterised by:

i. permanent alteration or destruction of alveolar architecture

ii. collagenous stromal reaction of moderate to maximal degree, and

iii. permanent scarring of lung.

Such collagenous pneumoconiosis may be caused by fibrogenic dusts or by an altered tissue response to a non-fibrogenic dust.

Examples of collagenous pneumoconiosis caused by fibrogenic dusts are silicosis and asbestosis, whereas complicated coalworkers' pneumoconiosis or progressive massive fibrosis (PMF) is an altered tissue response to a relatively non-fibrogenic dust.

In practice, the distinction between collagenous and non-collagenous pneumoconiosis is difficult to establish. Continued exposure to the same dust, such as coal dust, may cause transition from a non-collagenous to a collagenous form. Furthermore, exposure to a single dust is now becoming less common and exposures to mixed dusts having different degrees of fibrogenic potential may result in pneumoconiosis which can range from the non-collagenous to the collagenous forms.

There are in addition occupational chronic pulmonary diseases which, although they develop from the inhalation of dust are excluded from the pneumoconiosis because the particles are not known to accumulate in the lungs.

The following are examples of potentially disabling occupational chronic pulmonary diseases: byssinosis, berylliosis, farmers' lung, and related diseases. They have one common denominator, namely the aetiologic component of dust has sensitized the pulmonary or bronchial tissue so that if the lung tissue responds, the inflammation tends to be granulomatous and if the bronchial tissue responds, there is apt to be bronchial constriction.

Exposures to noxious inhaled materials in certain industries are associated with an increased risk of mortality from carcinoma of the respiratory tract. Examples of such materials are radioactive ores, asbestos and chromates.

Adopted at the IVth ILO International Conference on Pneumoconiosis. Bucharest, 1971.


Michel Lesage

Despite all the national and international energies devoted to their prevention, pneumoconioses are still very present both in industrialized and developing countries, and are responsible for the disability and impairment of many workers. This is why the International Labour Office (ILO), the World Health Organization (WHO) and many national institutes for occupational health and safety continue their fight against these diseases and to propose sustainable programmes for preventing them. For instance, the ILO, the WHO and the US National Institute for Occupational Safety and Health (NIOSH) have proposed in their programmes to work in cooperation on a global fight against silicosis. Part of this programme is based on medical surveillance which includes the reading of thoracic radiographs to help diagnose this pneumoconiosis. This is one example which explains why the ILO, in cooperation with many experts, has developed and updated on a continuous basis a classification of radiographs of pneumoconioses that provides a means for recording systematically the radiographic abnormalities in the chest provoked by the inhalation of dust. The scheme is designed for classifying the appearances of posterio-anterior chest radiographs.

The object of the classification is to codify the radiographic abnormalities of pneumoconioses in a simple, reproducible manner. The classification does not define pathological entities, nor take into account working capacity. The classification does not imply legal definitions of pneumoconioses for compensation purposes, nor imply a level at which compensation is payable. Nevertheless, the classification has been found to have wider uses than anticipated. It is now extensively used internationally for epidemiological research, for the surveillance of those industry occupations and for clinical purposes. Use of the scheme may lead to better international comparability of pneumoconioses statistics. It is also used for describing and recording, in a systematic way, part of the information needed for assessing compensation.

The most important condition for using this system of classification with full value from a scientific and ethical point of view is to read, at all times, films to be classified by systematically referring to the 22 standard films provided in the ILO International Classification set of standard films. If the reader attempts to classify a film without referring to any of the standard films, then no mention of reading according to the ILO International Classification of Radiographs should be made. The possibility of deviating from the classification by over or under reading is so risky that his or her reading should not be used at least for epidemiological research or international comparability of pneumoconioses statistics.

The first classification was proposed for silicosis at the First International Conference of Experts on Pneumoconioses, held in Johannesburg in 1930. It combined both radiographic appearances and impairment of lung functions. In 1958, a new classification based purely on radiographic changes was established (Geneva classification 1958). Since, it has been revised several times, the last time in 1980, always with the objective of providing improved versions to be extensively used for clinical and epidemiological purposes. Each new version of the classification promoted by the ILO has brought modifications and changes based on international experience gained in the use of earlier classifications.

In order to provide clear instructions for the use of the classification, the ILO issued in 1970 a publication entitled International Classification of Radiographs of Pneumoconioses/1968 in the Occupational Safety and Health Series (No. 22). This publication was revised in 1972 as ILO U/C International Classification of Radiographs of Pneumoconioses/1971 and again in 1980 as Guidelines for the use of ILO International Classification of Radiographs of Pneumoconioses, revised edition 1980. The description of standard radiographs is given in table 10.14 .

Table 10.14 Description of standard radiographs.


Small opacities


Pleural thickening










Chest wall






1980 Standard radiographs showing

Technical quality


Shape- size


Large opacities

Circum- scribed (plaques)



Costo- phrenic  angle  obliteration

Pleural calcification



0/0 (example 1)












Vascular pattern is well illustrated

0/0 (example 2)












Also shows vascular pattern, but not as clearly as example 1

1/1; p/p




R   L

x   x

x   x

x   x








Rheumatoid pneumoconiosis in left lower zone. Small opacities are present in all zones, but the profusion in the right-upper zone is typical of (some would say a little more profuse than) that classifiable as category 1/1

2/2; p/p




R   L

x   x

x   x

x   x







pi; tb.

Quality defect: radiograph is too light

3/3; p/p




R   L

x   x

x   x

x   x






R   L

x   -




1/1; q/q




R   L

x   x

x   x

-   -








Illustrates profusion 1/1 better than shape or size

2/2; q/q




R   L

x   x

x   x

x   x




     R  L

     x  x


     a  a


     1  1



R   L

x   x




3/3; q/q




R    L

x   x

x   x

x   x








Quality defects: poor definition of pleura and cut basal angles

1/1; r/r




R   L

x   x

x   x

-   -






R   L

-   x



Quality defect: subject movement. Profusion of small opacities is more marked in right lung

2/2; r/r




R   L

x   x

x   x

x   x








Quality defects: radiograph too light and contrast too high. The heart shadow is slightly displaced to the left

3/3; r/r




R   L

x   x

x   x

x   x







ax; ih.


1/1; s/t




R   L

x   -

x   x

x   x








Quality defect: cut bases. Kerley lines in lower right zone

2/2; s/s




R   L

-   -

x   x

x   x








Quality defect: distortion of bases due to shrinking. Emphysema in upper zones

3/3; s/s




R   L

x   x

x   x

x   x




     R  L

     x  x


     a  a


     3  3




ho; ih; pi.

Quality defect: radiograph is too light. Honeycomb lung appearance is not marked

1/1; t/t Costophrenic  angle obliteration




R    L

-   -

x   x

x   x




     R  L

     x  x


     a  a


     2  2



R   L

x   -


R   L

-   x

extent: 2


This radiograph defines the lower limit for costophrenic angle obliteration. Note shrinkage in lower lung fields

2/2; t/t




R   L

x   x

x   x

x   x




     R  L

     x  x


     a  a

extent:      1  1





Pleural thickening is present in the apices of the lung

3/3; t/t




R   L

x   x

x   x

x   x







hi; ho; id; ih; tb.


1/1; u/u

2/2; u/u

3/3; u/u












This composite radiograph illustrates the mid-categories of profusion of small opacities classifiable for shape and size as u/u.





R   L

x   x

x   x

x   x








Quality defects: radiograph is too light and pleural definition is poor





R   L

x   x

x   x

x   x







ax; co.

Definition of pleura is slightly imperfect





R   L

x   x

x   x

x   x







bu; di; em; es; hi; ih.

The small opacities are difficult to classify because of the presence of the large opacities. Note the left costophrenic angle obliteration. This is not classifiable because it does not reach the lower limit defined by the standard radiograph 1/1; t/t

Pleural thickening (circumscribed)












The pleural thickening present face on, is of indeterminate width, and extent 2

Pleural thickening (diffuse)












The pleural thickening present in profile, is of width a, and extent 2. Not associated small calcifications

Pleural thickening (calcification) diaphragm












Circumscribed, calcified pleural thickening of extent 2

Pleural thickening (calcification) chest wall












Calcified and uncalcified pleural thickening present face on, is of indeterminate width, and extent 2

ILO 1980 Classification

The 1980 revision was carried out by the ILO with the cooperation of the Commission of the European Communities, NIOSH and the American College of Radiology. The summary of the classification is given in table 10.15 . It retained the principle of former classifications (1968 and 1971).

Table 10.15 ILO 1980 International Classification of Radiographs of Pneumoconioses: Summary of details of classification. 




Technical quality






Acceptable, with no technical defect likely to impair classification of the radiograph of pneumoconiosis.



Poor, with some technical defect but still acceptable for classification purposes.




Parenchymal abnormalities

Small opacities



The category of profusion is based on assessment of the concentration of opacities by comparison with the standard radiographs.



0/-     0/0      0/1
1/0     1/1     1/2
2/1     2/2     2/3
3/2     3/3      3/+

Category O-small opacities absent or less profuse than the lower limit of category 1.
Categories 1, 2 and 3-increasing profusion of small opacities as defined by the corresponding standard radiographs.



RU     RM     RL
LU     LM     LL

The zones in which the opacities are seen are recorded. The right (R) and left (L) thorax are both divided into three zones-upper (U), middle (M) and lower (L).
The category of profusion is determined by considering the profusion as a whole over the affected zones of the lung and by comparing this with the standard radiographs.


Shape and Size





p/p     q/q      r/r

The letters p, q and r denote the presence of small, rounded opacities. Three sizes are defined by the appearances on standard radiographs:
p = diameter up to about 1.5mm
q = diameter exceeding about 1.5mm and up to about 3mm
r = diameter exceeding about 3mm and up to about 10mm



s/s     t/t      u/u

The letters s, t and u denote the presence of small, irregular opacities. Three sizes are defined by the appearances on standard radiographs:
s = width up to about 1.5mm
t = width exceeding about 1.5mm and up to about 3mm
u = width exceeding 3mm and up to about 10mm



p/s     p/t    p/u     p/q      p/r
q/s     q/t     q/u     q/p     q/r
r/s     r/t     r/u     r/p     r/q
s/p     s/q     s/r     s/t     s/u
t/p     t/q     t/r     t/s     t/u
u/p     u/q     u/r     u/s     u/t

For mixed shapes (or sizes) of small opacities, the predominant shape and size is recorded first. The presence of a significant number of another shape and size is recorded after the oblique stroke.

Large opacities


A     B     C

The categories are defined in terms of the dimensions of the opacities.
Category A - an opacity having a greatest diameter exceeding about 10mm and up to and including 50mm, or several opacities each greater than about 10mm, the sum of whose greatest diameters does not exceed about 50mm.
Category B - one or more opacities larger or more numerous than those in category A whose combined area does not exceed the equivalent of the right upper zone.
Category C - one or more opacities whose combined area exceeds the equivalent of the right upper zone.

Pleural abnormalities

Pleural thickening

Chest wall



Two types of pleural thickening of the chest wall are recognized: circumscribed (plaques) and diffuse. Both types may occur together



R           L

Pleural thickening of the chest wall is recorded separately for the right (R) and left (L) thorax.



a     b     c

For pleural thickening seen along the lateral chest wall the measurement of maximum width is made from the inner line of the chest wall to the inner margin of the shadow seen most sharply at the parenchymal-pleural boundary. The maximum width usually occurs at the inner margin of the rib shadow at its outermost point.
a = maximum width up to abut 5mm
b = maximum width over about 5mm and up to about 10mm
c = maximum width over about 10mm


Face on

Y     N

The presence of pleural thickening seen face-on is recorded even if it can be seen also in profile. If pleural thickening is seen face-on only, width cannot usually be measured.



1     2     3

Extent of pleural thickening is defined in terms of the maximum length of pleural involvement, or as the sum of maximum lengths, whether seen in profile or face-on.
1 = total length equivalent up to one quarter of the projection of the lateral chest wall
2 = total length exceeding one quarter but not one half of the projection of the lateral chest wall
3 = total length exceeding one half of the projection of the lateral chest wall



Y      N

A plaque involving the diaphragmatic pleura is recorded as present (Y) or absent (N), separately for the right (R) and left (L) thorax.



R      L


Costrophrenic angle  obliteration


Y      N

The presence (Y) or absence (N) of costophrenic angle obliteration is recorded separately from thickening over other areas, for the right (R) and left (L) thorax. The lower limit for this obliteration is defined by a standard radiograph



R      L

If the thickening extends up the chest wall, then both costophrenic angle obliteration and pleural thickening should be recorded.

Pleural calcification



The site and extent of pleural calcification are recorded separately for the two lungs, and the extent defined in terms of dimensions.


Chest wall

R      L




R      L




R     L

"Other" includes calcification of the mediastinal and pericardial pleura.



1     2     3

1 = an area of calcified pleura with greatest diameter up to about 20mm, or a number of such areas the  sum of whose greatest diameters does not exceed about 20mm.
2 = an area of calcified pleura with greatest diameter exceeding about 20mm and up to about 100mm, or a number of such areas the sum of whose greatest diameters exceeds about 20mm but does not exceed about 100mm.
3 = an area of calcified pleura with greatest diameter exceeding about 100mm, or a number of such areas whose sum of greatest diameters exceeds about 100mm.




It is to be taken that the definition of each of the symbols is preceded by an appropriate word or phrase such as "suspect", "changes suggestive of", or "opacities suggestive of", etc.



Coalescence of small pneumoconiotic opacities






Cancer of lung or pleura



Calcification in small pneumoconiotic opacities



Abnormality of cardiac size or shape



Cor pulmonale






Marked distortion of the intrathoracic organs






Definite emphysema



Eggshell calcification of hilar or mediastinal lymph nodes



Fractured rib(s)



Enlargement of hilar or mediastinal lymph nodes



Honeycomb lung



Ill-defined diaphragm



Ill-defined heart outline



Septal (Kerley) lines



Other significant abnormality



Pleural thickening in the interlobar fissure of mediastinum






Rheumatoid pneumoconiosis







Y      N

Comments should be recorded pertaining to the classification of the radiograph, particularly if some other cause is thought to be responsible for a shadow which could be thought by others to have been due to pneumoconiosis; also to identify radiographs for which the technical quality may have affected the reading materially.

The Classification is based on a set of standard radiographs, a written text and a set of notes (OHS No. 22). There are no features to be seen in a chest radiograph which are pathognomonic of dust exposure. The essential principle is that all appearances which are consistent with those defined and represented in the standard radiographs and the guideline for the use of the ILO International Classification, are to be classified. If the reader believes that any appearance is probably or definitively not dust related, the radiograph should not be classified but an appropriate comment must be added. The 22 standard radiographs have been selected after international trials, in such a way as to illustrate the mid-categories standards of profusion of small opacities and to give examples of category A, B and C standards for large opacities. Pleural abnormalities (diffuse pleural thickening, plaques and obliteration of costophrenic angle) are also illustrated on different radiographs.

Discussion in particular at the Seventh International Pneumoconioses Conference, held in Pittsburgh in 1988, indicated the need for improvement of some parts of the classification, in particular those concerning pleural changes. A discussion group meeting on the revision of the ILO International Classification of Radiographs of Pneumoconioses was convened in Geneva by the ILO in November 1989. The experts made the suggestion that the short classification is of no advantage and can be deleted. As regards pleural abnormalities, the group agreed that this classification would now be divided into three parts: "Diffuse pleural thickening"; "Pleural plaques"; and "Costophrenic angle obliteration". Diffuse pleural thickening might be divided into chest wall and diaphragm. They were identified according to the six zones-upper, middle and lower, of both right and left lungs. If a pleural thickening is circumscribed, it could be identified as a plaque. All plaques should be measured in centimetres. The obliteration of the costophrenic angle should be systematically noted (whether it exists or not). It is important to identify whether the costophrenic angle is visible or not. This is because of its special importance in relation to pleural diffuse thickening. Whether plaques are classified or not should be merely indicated by a symbol. The flattening of the diaphragm should be recorded by an additional symbol since it is a very important feature in asbestos exposure. The presence of plaques should be recorded in these boxes using the appropriate symbol "c" (calcified) or "h" (hyaline).

A full description of the classification, including its applications and limitation is found in the publication (ILO 1980). The revision of the classification of radiographs is a continuous ILO process, and a revised guideline should be published in the near future (1997-98) taking into account the recommendations of these experts.


Patrick Sébastien and Raymond Bégin

Pneumoconioses have been recognized as occupational diseases for a long time. Substantial efforts have been directed to research, primary prevention and medical management. But physicians and hygienists report that the problem is still present in both industrialized and industrializing countries (Valiante, Richards and Kinsley 1992; Markowitz 1992). As there is strong evidence that the three main industrial minerals responsible for the pneumoconioses (asbestos, coal and silica) will continue to have some economical importance, thus further entailing possible exposure, it is expected that the problem will continue to be of some magnitude throughout the world, particularly among underserved populations in small industries and small mining operations. Practical difficulties in primary prevention, or insufficient understanding of the mechanisms responsible for the induction and the progression of the disease are all factors which could possibly explain the continuing presence of the problem.

The aetiopathogenesis of pneumoconioses can be defined as the appraisal and understanding of all the phenomena occurring in the lung following the inhalation of fibrogenic dust particles. The expression cascade of events is often found in the literature on the subject. The cascade is a series of events that first exposure and at its farthest extent progresses to the disease in its more severe forms. If we except the rare forms of accelerated silicosis, which can develop after only a few months of exposure, most of the pneumoconioses develop following exposure periods measured in decades rather than years. This is especially true nowadays in workplaces adopting modern standards of prevention. Aetiopathogenesis phenomena should thus be analysed in terms of its long-term dynamics.

In the last 20 years, a large amount of information has become available on the numerous and complex pulmonary reactions involved in interstitial lung fibrosis induced by several agents, including mineral dusts. These reactions were described at the biochemical and cellular level (Richards, Masek and Brown 1991). Contributions were made by not only physicists and experimental pathologists but also by clinicians who used bronchoalveolar lavage extensively as a new pulmonary technique of investigation. These studies pictured aetiopathogenesis as a very complex entity, which can nonetheless be broken down to reveal several facets: (1) the inhalation itself of dust particles and the consequent constitution and significance of the pulmonary burden (exposure-dose-response relationships), (2) the physicochemical characteristics of the fibrogenic particles, (3) biochemical and cellular reactions inducing the fundamental lesions of the pneumoconioses and (4) the determinants of progression and complication. The later facet must not be ignored, since the more severe forms of pneumoconioses are the ones which entail impairment and disability.

A detailed analysis of the aetiopathogenesis of the pneumoconioses is beyond the scope of this article. One would need to distinguish the several types of dust and to go deeply into numerous specialized areas, some of which are still the subject of active research. But interesting general notions emerge from the currently available amount of knowledge on the subject. They will be presented here through the four "facets" previously mentioned and the bibliography will refer the interested reader to more specialized texts. Examples will be essentially given for the three main and most documented pneumoconioses: asbestosis, coal workers' pneumoconioses (CWP) and silicosis. Possible impacts on prevention will be discussed.

Exposure-Dose-Response Relationships

Pneumoconioses result from the inhalation of certain fibrogenic dust particles. In the physics of aerosols, the term dust has a very precise meaning (Hinds 1982). It refers to airborne particles obtained by mechanical comminution of a parent material in a solid state. Particles generated by other processes should not be called dust. Dust clouds in various industrial settings (e.g., mining, tunnelling, sand blasting and manufacturing) generally contain a mixture of several types of dust. The airborne dust particles do not have a uniform size. They exhibit a size distribution. Size and other physical parameters (density, shape and surface charge) determine the aerodynamic behaviour of the particles and the probability of their penetration and deposition in the several compartments of the respiratory system.

In the field of pneumoconioses, the site compartment of interest is the alveolar compartment. Airborne particles small enough to reach this compartment are referred to as respirable particles. All particles reaching the alveolar compartments are not systematically deposited, some being still present in the exhaled air. The physical mechanisms responsible for deposition are now well understood for isometric particles (Raabe 1984) as well as for fibrous particles (Sébastien 1991). The functions relating the probability of deposition to the physical parameters have been established. Respirable particles and particles deposited in the alveolar compartment have slightly different size characteristics. For non-fibrous particles, size-selective air sampling instruments and direct reading instruments are used to measure mass concentrations of respirable particles. For fibrous particles, the approach is different. The measuring technique is based upon filter collection of "total dust" and counting of fibres under the optical microscope. In this case, the size selection is made by excluding from the count the "non-respirable" fibres with dimensions exceeding predetermined criteria.

Following the deposition of particles on the alveolar surfaces there starts the so-called alveolar clearance process. Chemotactic recruitment of macrophages and phagocytosis constitute its first phases. Several clearance pathways have been described: removal of dust-laden macrophages toward the ciliated airways, interaction with the epithelial cells and transfer of free particles through the alveolar membrane, phagocytosis by interstitial macrophages, sequestration into the interstitial area and transportation to the lymph nodes (Lauweryns and Baert 1977). Clearance pathways have specific kinetics. Not only the exposure regimen, but also the physicochemical characteristics of the deposited particles, trigger the activation of the different pathways responsible for the lung's retention of such contaminants.

The notion of a retention pattern specific to each type of dust is rather new, but is now sufficiently established to be integrated into aetiopathogenesis schemes. For example, this author has found that after long term exposure to asbestos, fibres will accumulate in the lung if they are of the amphibole type, but will not if they are of the chrysotile type (Sébastien 1991). Short fibres have been shown to be cleared more rapidly than longer ones. Quartz is known to exhibit some lymph tropism and readily penetrates the lymphatic system. Modifying the surface chemistry of quartz particles has been shown to affect alveolar clearance (Hemenway et al. 1994; Dubois et al. 1988). Concomitant exposure to several dust types may also influence alveolar clearance (Davis, Jones and Miller 1991).

During alveolar clearance, dust particles may undergo some chemical and physical changes. Examples of theses changes include coating with ferruginous material, the leaching of some elemental constituents and the adsorption of some biological molecules.

Another notion recently derived from animal experiments is that of "lung overload" (Mermelstein et al. 1994). Rats heavily exposed by inhalation to a variety of insoluble dusts developed similar responses: chronic inflammation, increased numbers of particle-laden macrophages, increased numbers of particles in the interstitium, septal thickening, lipoproteinosis and fibrosis. These findings were not attributed to the reactivity of the dust tested (titanium dioxide, volcanic ash, fly ash, petroleum coke, polyvinyl chloride, toner, carbon black and diesel exhaust particulates), but to an excessive exposure of the lung. It is not known if lung overload must be considered in the case of human exposure to fibrogenic dusts.

Among the clearance pathways, the transfer towards the interstitium would be of particular importance for pneumoconioses. Clearance of particles having undergone sequestration into the interstitium is much less effective than clearance of particles engulfed by macrophages in the alveolar space and removed by ciliated airways (Vincent and Donaldson 1990). In humans, it was found that after long-term exposure to a variety of inorganic airborne contaminants, the storage was much greater in interstitial than alveolar macrophages (Sébastien et al. 1994). The view was also expressed that silica-induced pulmonary fibrosis involves the reaction of particles with interstitial rather than alveolar macrophages (Bowden, Hedgecock and Adamson 1989). Retention is responsible for the "dose", a measure of the contact between the dust particles and their biological environment. A proper description of the dose would require that one know at each point in time the amount of dust stored in the several lung structures and cells, the physicochemical states of the particles (including the surface states), and the interactions between the particles and the pulmonary cells and fluids. Direct assessment of dose in humans is obviously an impossible task, even if methods were available to measure dust particles in several biological samples of pulmonary origin such as sputum, bronchoalveolar lavage fluid or tissue taken at biopsy or autopsy (Bignon, Sébastien and Bientz 1979). These methods were used for a variety of purposes: to provide information on retention mechanisms, to validate certain exposure information, to study the role of several dust types in pathogenic developments (e.g., amphiboles versus chrysotile exposure in asbestosis or quartz versus coal in CWP) and to assist in diagnosis.

But these direct measurements provide only a snapshot of retention at the time of sampling and do not allow the investigator to reconstitute dose data. New dosimetric models offer interesting perspectives in that regard (Katsnelson et al. 1994; Smith 1991; Vincent and Donaldson 1990). These models aim at assessing dose from exposure information by considering the probability of deposition and the kinetics of the different clearance pathways. Recently there was introduced into these models the interesting notion of "harmfulness delivery" (Vincent and Donaldson 1990). This notion takes into account the specific reactivity of the stored particles, each particle being considered as a source liberating some toxic entities into the pulmonary milieu. In the case of quartz particles for example, it could be hypothesized that some surface sites could be the source of active oxygen species. Models developed along such lines could also be refined to take into account the great interindividual variation generally observed with alveolar clearance. This was experimentally documented with asbestos, "high retainer animals" being at greater risk of developing asbestosis (Bégin and Sébastien 1989).

So far, these models were exclusively used by experimental pathologists. But they could also be useful to epidemiologists (Smith 1991). Most epidemiological studies looking at exposure response relationships relied on "cumulative exposure", an exposure index obtained by integrating over time the estimated concentrations of airborne dust to which workers had been exposed (product of intensity and duration). The use of cumulative exposure has some limitations. Analyses based on this index implicitly assume that duration and intensity have equivalent effects on risk (Vacek and McDonald 1991).

Maybe the use of these sophisticated dosimetric models could provide some explanation for a common observation in the epidemiology of pneumoconioses: "the considerable between-work force differences" and this phenomenon was clearly observed for asbestosis (Becklake 1991) and for CWP (Attfield and Morring 1992). When relating the prevalence of the disease to the cumulative exposure, great differences-up to 50-fold-in risk were observed between some occupational groups. The geological origin of the coal (coal rank) provided partial explanation for CWP, mining deposits of high rank coal (a coal with high carbon content, like anthracite) yielding greater risk. The phenomenon remains to be explained in the case of asbestosis. Uncertainties on the proper exposure response curve have some bearings-at least theoretically-on the outcome, even at current exposure standards.

More generally, exposure metrics are essential in the process of risk assessment and the establishment of control limits. The use of the new dosimetric models may improve the process of risk assessment for pneumoconioses with the ultimate goal of increasing the degree of protection offered by control limits (Kriebel 1994).

Physicochemical Characteristics of Fibrogenic Dust Particles

A toxicity specific to each type of dust, related to the physicochemical characteristics of the particles (including the more subtle ones such as the surface characteristics), constitutes probably the most important notion to have emerged progressively during the last 20 years. In the very earliest stages of research, no differentiation was made among "mineral dusts". Then generic categories were introduced: asbestos, coal, artificial inorganic fibres, phyllosilicates and silica. But this classification was found to be not precise enough to account for the variety in observed biological effects. Nowadays a mineralogical classification is used. For example, the several mineralogical types of asbestos are distinguished: serpentine chrysotile, amphibole amosite, amphibole crocidolite and amphibole tremolite. For silica, a distinction is generally made between quartz (by far the most prevalent), other crystalline polymorphs, and amorphous varieties. In the field of coal, high rank and low rank coals should be treated separately, since there is strong evidence that the risk of CWP and especially the risk of progressive massive fibrosis is much greater after exposure to dust produced in high rank coal mines.

But the mineralogical classification has also some limits. There is evidence, both experimental and epidemiological (taking into account "between-workforce differences"), that the intrinsic toxicity of a single mineralogical type of dust can be modulated by acting on the physicochemical characteristics of the particles. This raised the difficult question of the toxicological significance of each of the numerous parameters which can be used to describe a dust particle and a dust cloud. At the single particle level, several parameters can be considered: bulk chemistry, crystalline structure, shape, density, size, surface area, surface chemistry and surface charge. Dealing with dust clouds adds another level of complexity because of the distribution of these parameters (e.g., size distribution and the composition of mixed dust).

The size of the particles and their surface chemistry were the two parameters most studied to explain the modulation effect. As seen before, retention mechanisms are size related. But size may also modulate the toxicity in situ, as demonstrated by numerous animal and in vitro studies.

In the field of mineral fibres, the size was considered of so much importance that it constituted the basis of a pathogenesis theory. This theory attributed the toxicity of fibrous particles (natural and artificial) to the shape and size of the particles, leaving no role for the chemical composition. In dealing with fibres, size must be broken down into length and diameter. A two-dimensional matrix should be used to report size distributions, the useful ranges being 0.03 to 3.0 mm for diameter and 0.3 to 300 mm for length (Sébastien 1991). Integrating the results of the numerous studies, Lippman (1988) assigned a toxicity index to several cells of the matrix. There is a general tendency to believe that long and thin fibres are the most dangerous ones. Since the standards currently used in industrial hygiene are based upon the use of the optical microscope, they ignore the thinnest fibres. If assessing the specific toxicity of each cell within the matrix has some academic interest, its practical interest is limited by the fact that each type of fibre is associated with a specific size distribution that is relatively uniform. For compact particles, such as coal and silica, there is unclear evidence about a possible specific role for the different size sub-fractions of the particles deposited in the alveolar region of the lung.

More recent pathogenesis theories in the field of mineral dust imply active chemical sites (or functionalities) present at the surface of the particles. When the particle is "born" by separation from its parent material, some chemical bonds are broken in either a heterolytic or a homolytic way. What occurs during breaking and subsequent recombinations or reactions with ambient air molecules or biological molecules makes up the surface chemistry of the particles. Regarding quartz particles for example, several chemical functionalities of special interest have been described: siloxane bridges, silanol groups, partially ionized groups and silicon-based radicals.

These functionalities can initiate both acid-base and redox reactions. Only recently has attention been drawn to the latter (Dalal, Shi and Vallyathan 1990; Fubini et al. 1990; Pézerat et al. 1989; Kamp et al. 1992; Kennedy et al. 1989; Bronwyn, Razzaboni and Bolsaitis 1990). There is now good evidence that particles with surface-based radicals can produce reactive oxygen species, even in a cellular milieu. It is not certain if all the production of oxygen species should be attributed to the surface-based radicals. It is speculated that these sites may trigger the activation of lung cells (Hemenway et al. 1994). Other sites may be involved in the membranolytic activity of the cytotoxic particles with reactions such as ionic attraction, hydrogen bonding and hydrophobic bonding (Nolan et al. 1981; Heppleston 1991).

Following the recognition of surface chemistry as an important determinant of dust toxicity, several attempts were made to modify the natural surfaces of mineral dust particles to reduce their toxicity, as assessed in experimental models.

Adsorption of aluminium on quartz particles was found to reduce their fibrogenicity and to favour alveolar clearance (Dubois et al. 1988). Treatment with polyvinylpyridine-N-oxide (PVPNO) had also some prophylactic effect (Goldstein and Rendall 1987; Heppleston 1991). Several other modifying processes were used: grinding, thermal treatment, acid etching and adsorption of organic molecules (Wiessner et al. 1990). Freshly fractured quartz particles exhibited the highest surface activity (Kuhn and Demers 1992; Vallyathan et al. 1988). Interestingly enough, every departure from this "fundamental surface" led to a decrease in quartz toxicity (Sébastien 1990). The surface purity of several naturally occurring quartz varieties could be responsible for some observed differences in toxicity (Wallace et al. 1994). Some data support the idea that the amount of uncontaminated quartz surface is an important parameter (Kriegseis, Scharman and Serafin 1987).

The multiplicity of the parameters, together with their distribution in the dust cloud, yields a variety of possible ways to report air concentrations: mass concentration, number concentration, surface area concentration and concentration in various size categories. Thus, numerous indices of exposure can be constructed and the toxicological significance of each has to be assessed. The current standards in occupational hygiene reflect this multiplicity. For asbestos, the standards are based on the numerical concentration of fibrous particles in a certain geometrical size category. For silica and coal, the standards are based on the mass concentration of respirable particles. Some standards have also been developed for exposure to mixtures of particles containing quartz. No standard is based upon surface characteristics.

Biological Mechanisms Inducing the Fundamental Lesions

Pneumoconioses are interstitial fibrous lung diseases, the fibrosis being diffuse or nodular. The fibrotic reaction involves the activation of the lung fibroblast (Goldstein and Fine 1986) and the production and metabolism of the connective tissue components (collagen, elastin and glycosaminoglycans). It is considered to represent a late healing stage after lung injury (Niewoehner and Hoidal 1982). Even if several factors, essentially related to the characteristics of exposure, can modulate the pathological response, it is interesting to note that each type of pneumoconiosis is characterized by what could be called a fundamental lesion. The fibrosing alveolitis around the peripheral airways constitutes the fundamental lesion of asbestos exposure (Bégin et al. 1992). The silicotic nodule is the fundamental lesion of silicosis (Ziskind, Jones and Weil 1976). Simple CWP is composed of dust macules and nodules (Seaton 1983).

The pathogenesis of the pneumoconioses is generally presented as a cascade of events whose sequence runs as follows: alveolar macrophage alveolitis, signalling by inflammatory cell cytokines, oxidative damage, proliferation and activation of fibroblasts and the metabolism of collagen and elastin. Alveolar macrophage alveolitis is a characteristic reaction to retention of fibrosing mineral dust (Rom 1991). The alveolitis is defined by increased numbers of activated alveolar macrophages releasing excessive quantities of mediators including oxidants, chemotaxins, fibroblast growth factors and protease. Chemotaxins attract neutrophils and, together with macrophages, may release oxidants capable of injuring alveolar epithelial cells. Fibroblast growth factors gain access to the interstitium, where they signal fibroblasts to replicate and increase the production of collagen.

The cascade starts at the first encounter of particles deposited in the alveoli. With asbestos for example, the initial lung injury occurs almost immediately after exposure at the alveolar duct bifurcations. After only 1 hour of exposure in animal experiments, there is active uptake of fibres by type I epithelial cells (Brody et al. 1981). Within 48 hours, increased numbers of alveolar macrophages accumulate at sites of deposition. With chronic exposure, this process may lead to peribronchiolar fibrosing alveolitis.

The exact mechanism by which deposited particles produce primary biochemical injury to the alveolar lining, a specific cell, or any of its organelles, is unknown. It may be that extremely rapid and complex biochemical reactions result in free radical formation, lipid peroxidation, or a depletion in some species of vital cell protectant molecule. It has been shown that mineral particles can act as catalytic substrates for hydroxyl and superoxide radical generation (Guilianelli et al. 1993).

At the cellular level, there is slightly more information. After deposition at the alveolar level, the very thin epithelial type I cell is readily damaged (Adamson, Young and Bowden 1988). Macrophages and other inflammatory cells are attracted to the damage site and the inflammatory response is amplified by the release of arachidonic acid metabolites such as prostaglandins and leukotrienes together with exposure of the basement membrane (Holtzman 1991; Kuhn et al. 1990; Engelen et al. 1989). At this stage of primary damage, the lung architecture becomes disorganized, showing an interstitial oedema.

During the chronic inflammatory process, both the surface of the dust particles and the activated inflammatory cells release increased amounts of reactive oxygen species in the lower respiratory tract. The oxidative stress in the lung has some detectable effects on the antioxidant defense system (Heffner and Repine 1989), with expression of antioxidant enzymes like superoxide dismutase, glutathione peroxidases and catalase (Engelen et al. 1990). These factors are located in the lung tissue, the interstitial fluid and the circulating erythrocytes. The profiles of antioxidant enzymes may depend on the type of fibrogenic dust (Janssen et al. 1992). Free radicals are known mediators of tissue injury and disease (Kehrer 1993).

Interstitial fibrosis does result from a repair process. There are numerous theories to explain how the repair process takes place. The macrophage/fibroblast interaction has received the greatest attention. Activated macrophages secrete a network of proinflammatory fibrogenic cytokines: TNF, IL-1, transforming growth factor and platelet-derived growth factor. They also produce fibronectin, a cell surface glycoprotein which acts as a chemical attractant and, under some conditions, as a growth stimulant for mesenchymal cells. Some authors consider that some factors are more important than others. For example, special importance was ascribed to TNF in the pathogenesis of silicosis. In experimental animals, it was shown that collagen deposition after silica instillation in mice was almost completely prevented by anti-TNF antibody (Piguet et al. 1990). The release of platelet-derived growth factor and transforming growth factor was presented as playing an important role in the pathogenesis of asbestosis (Brody 1993).

Unfortunately, many of the macrophage/fibroblast theories tend to ignore the potential balance between the fibrogenic cytokines and their inhibitors (Kelley 1990). In fact, the resulting imbalance between oxidizing and antioxidizing agents, proteases and antiproteases, the arachidonic acid metabolites, elastases and collagenases, as well as the imbalances between the various cytokines and growth factors, would determine the abnormal remodelling of the interstitium component towards the several forms of pneumoconioses (Porcher et al. 1993). In pneumoconioses, the balance is clearly directed towards an overwhelming effect of the damaging cytokine activities.

Because type I cells are incapable of division, after the primary insult, the epithelial barrier is replaced with type II cells (Lesur et al. 1992). There is some indication that if this epithelial repair process is successful and that the regenerating type II cells are not damaged further, the fibrogenesis is not likely to proceed. Under some conditions, the repair by the type II cell is taken to excess, resulting in alveolar proteinosis. This process was clearly demonstrated after silica exposure (Heppleston 1991). To what extent the alterations in epithelial cells influence the fibroblasts is uncertain. Thus, it would seem that fibrogenesis is initiated in areas of extensive epithelial damage, as fibroblasts replicate, then differentiate and produce more collagen, fibronectin and other components of the extracelluar matrix.

There is abundant literature on the biochemistry of the several types of collagen formed in pneumoconioses (Richards, Masek and Brown 1991). The metabolism of such collagen and its stability in the lung are important elements of the fibrogenesis process. The same probably holds for the other components of the damaged connective tissue. The metabolism of collagen and elastin is of particular interest in the healing phase since these proteins are so important to lung structure and function. It has been very nicely shown that alterations in the synthesis of these proteins might determine whether emphysema or fibrosis evolves after lung injury (Niewoehner and Hoidal 1982). In the disease state, mechanisms such as an increase in transglutaminase activity could favour the formation of stable protein masses. In some CWP fibrotic lesions, the protein components account for one-third of the lesion, the rest being dust and calcium phosphate.

Considering only collagen metabolism, several stages of fibrosis are possible, some of which are potentially reversible while others are progressive. There is experimental evidence that unless a critical exposure is exceeded, the early lesions can regress and irreversible fibrosis is an unlikely outcome. In asbestosis for example, several types of lung reactions were described (Bégin, Cantin and Massé 1989): a transient inflammatory reaction without lesion, a low retention reaction with fibrotic scar limited to the distal airways, a high inflammatory reaction sustained by the continuous exposure and the weak clearance of the longest fibres.

It can be concluded from these studies that exposure to fibrotic dust particles is able to trigger several complex biochemical and cellular pathways involved in lung injury and repair. Exposure regimen, physicochemical characteristics of the dust particles, and possibly individual susceptibility factors seem to be the determinants of the fine balance among the several pathways. Physicochemical characteristics will determine the type of the ultimate fundamental lesion. Exposure regimen seems to determine the time course of events. There is some indication that sufficiently low exposure regimens can in most cases limit the lung reaction to non-progressive lesions with no disability or impairment.

Medical surveillance and screening always have been part of the strategies for the prevention of pneumoconioses. In that context, the possibility of detecting some early lesions is advantageous. Increased knowledge of pathogenesis paved the way to the development of several biomarkers (Borm 1994) and to the refinement and use of "non-classical" pulmonary investigation techniques such as the measurement of the clearance rate of deposited 99 technetium diethylenetriamine-penta-acetate (99 Tc-DTPA) to assess pulmonary epithelial integrity (O'Brodovich and Coates 1987), and quantitative gallium-67 lung scan to assess inflammatory activity (Bisson, Lamoureux and Bégin 1987).

Several biomarkers were considered in the field of pneumoconioses: sputum macrophages, serum growth factors, serum type III procollagen peptide, red blood cell antioxidants, fibronectin, leucocyte elastase, neutral metalloendopeptidase and elastin peptides in plasma, volatile hydrocarbons in exhaled air and TNF release by peripheral blood monocytes. Biomarkers are conceptually quite interesting, but many more studies are necessary to assess their significance precisely. This validation effort will be quite demanding, since it will require investigators to conduct prospective epidemiological studies. Such an effort was carried out recently for TNF release by peripheral blood monocytes in CWP. TNF was found to be an interesting marker of CWP progression (Borm 1994). Besides the scientific aspects of the significance of biomarkers in the pathogenesis of pneumoconioses, other issues related to the use of biomarkers must be examined carefully (Schulte 1993), namely, opportunities for prevention, impact on occupational medicine and ethical and legal problems.

Progression and Complication of Pneumoconioses

In the early decades of this century, pneumoconiosis was regarded as a disease that disabled the young and killed prematurely. In industrialized countries, it is now generally regarded as no more than a radiological abnormality, without impairment or disability (Sadoul 1983).

However, two observations should be set against this optimistic statement. First, even if under limited exposure, pneumoconiosis remains a relatively silent and asymptomatic disease, it should be known that the disease may progress towards more severe and disabling forms. Factors affecting this progression are definitely important to consider as part of the aetiopathogenesis of the condition. Secondly, there is now evidence that some pneumoconioses can affect general health outcome and can be a contributing factor for lung cancer.

The chronic and progressive nature of asbestosis has been documented from the initial subclinical lesion to clinical asbestosis (Bégin, Cantin and Massé 1989). Modern pulmonary investigation techniques (BAL, CT scan, gallium-67 lung uptake) revealed that inflammation and injury was continuous from the time of exposure, through the latent or subclinical phase, to the development of the clinical disease. It has been reported (Bégin et al. 1985) that 75% of subjects who initially had a positive gallium-67 scan but did not have clinical asbestosis at that time, did progress to "full-blown" clinical asbestosis over a four-year period. In both humans and experimental animals, asbestosis may progress after disease recognition and exposure cessation. It is highly probable that exposure history prior to recognition is an important determinant of progression. Some experimental data support the notion of non-progressive asbestosis associated with light induction exposure and exposure cessation at recognition (Sébastien, Dufresne and Bégin 1994). Assuming that the same notion applies to humans, it would be of the first importance to establish precisely the metrics of "light induction exposure". In spite of all the efforts at screening working populations exposed to asbestos, this information is still lacking.

It is well-known that asbestos exposure can yield to an excessive risk of lung cancer. Even if it is admitted that asbestos is a carcinogen per se, it has long been debated whether the risk of lung cancer among asbestos workers was related to the exposure to asbestos or to the lung fibrosis (Hughes and Weil 1991). This issue is not resolved yet.

Owing to continuous improvement of working conditions in modern mining facilities, nowadays, CWP is a disease affecting essentially retired miners. If simple CWP is a condition without symptoms and without demonstrable effect on lung function, progressive massive fibrosis (PMF) is a much more severe condition, with major structural alterations of the lung, deficits of lung function and reduced life expectancy. Many studies have aimed at identifying the determinants of progression towards PMF (heavy retention of dust in the lung, coal rank, mycobacterial infection or immunological stimulation). A unifying theory was proposed (Vanhee et al. 1994), based upon a continuous and severe alveolar inflammation with activation of the alveolar macrophages and substantial production of reactive oxygen species, chemotactic factors and fibronectin. Other complications of CWP include mycobacterial infection, Caplan's syndrome and scleroderma. There is no evidence of elevated risk of lung cancer among coal miners.

The chronic form of silicosis follows exposure, measured in decades rather than years, to respirable dust containing generally less than 30% quartz. But in case of uncontrolled exposure to quartz-rich dust (historical exposures with sand blasting, for example), acute and accelerated forms can be found after only several months. Cases of acute and accelerated disease are particularly at risk of complication by tuberculosis (Ziskind, Jones and Weil 1976). Progression may also occur, with the development of large lesions that obliterate lung structure, called either complicated silicosis or PMF.

A few studies examined the progression of silicosis in relation to exposure and yielded diverging results about the relationships between progression and exposure, before and after onset (Hessel et al. 1988). Recently, Infante-Rivard et al. (1991) studied the prognostic factors influencing the survival of compensated silicotic patients. Patients with small opacities alone on their chest radiograph and who did not have dyspnoea, expectoration or abnormal breath sounds had a survival similar to that of the referents. Other patients had a poorer survival. Finally, one should mention the recent concern about silica, silicosis and lung cancer. There is some evidence for and against the proposition that silica per se is carcinogenic (Agius 1992). Silica may synergize potent environmental carcinogens, such as those in tobacco smoke, through a relatively weak promoting effect on carcinogenesis or by impairing their clearance. Moreover, the disease process associated with or leading to silicosis might carry an increased risk of lung cancer.

Nowadays, progression and complication of pneumoconioses could be considered as a key issue for medical management. The use of classical pulmonary investigation techniques has been refined for early recognition of the disease (Bégin et al. 1992), at a stage where pneumoconiosis is limited to its radiological manifestation, without impairment or disability. In the near future, it is probable that a battery of biomarkers will be available to document even earlier stages of the disease. The question of whether a worker diagnosed with pneumoconiosis-or documented to be in its earlier stages-should be allowed to continue with his or her job has puzzled occupational health decision makers for some time. It is a rather difficult question which entails ethical, social and scientific considerations. If an overwhelming scientific literature is available on the induction of pneumoconiosis, the information on progression usable by decision makers is rather sparse and somewhat confusing. A few attempts were made to study the roles of variables such as exposure history, dust retention and medical condition at onset. The relationships between all these variables do complicate the issue. Recommendations are made for health screening and surveillance of workers exposed to mineral dust (Wagner 1996). Programmes are already-or will be-put in place accordingly. Such programmes would definitely benefit from better scientific knowledge on progression, and especially on the relation between exposure and retention characteristics.


The information brought by many scientific disciplines to bear upon the aetiopathogenesis of the pneumoconioses is overwhelming. The major difficulty now is to reassemble the scattered elements of the puzzle into unifying mechanistic pathways leading to the fundamental lesions of the pneumoconioses. Without this necessary integration, we would be left with the contrast between a few fundamental lesions, and very numerous biochemical and cellular reactions.

Our knowledge of aetiopathogenesis has so far influenced the practices of occupational hygiene only to a limited extent, in spite of the strong intention of hygienists to operate according to standards having some biological significance. Two main notions were incorporated in their practices: the size selection of respirable dust particles and the dust type dependence of toxicity. The latter yielded some limits specific to each type of dust. The quantitative risk assessment, a necessary step in defining exposure limits, constitutes a complicated exercise for several reasons, such as the variety of possible exposure indices, poor information on past exposure, the difficulty one has with epidemiological models in dealing with multiple indices of exposure and the difficulty in estimating dose from exposure information. The current exposure limits, embodying sometimes considerable uncertainty, are probably low enough to offer good protection. The between-workforce differences observed in exposure-response relationships however, reflect our incomplete control of the phenomenon.

The impact of newer understanding of the cascade of events in the pathogenesis of the pneumoconioses has not modified the traditional approach to workers' surveillance, but has significantly helped physicians in their capacity of recognizing the disease (pneumoconiosis) early, at a time when the disease has had only a limited impact on lung function. It is indeed subjects at the early stage of disease that should be recognized and withdrawn from further significant exposure if prevention of disability is to be achieved by medical surveillance.


John E. Parker and Gregory R. Wagner

Silicosis is a fibrotic disease of the lungs caused by the inhalation, retention and pulmonary reaction to crystalline silica. Despite knowledge of the cause of this disorder-respiratory exposures to silica containing dusts-this serious and potentially fatal occupational lung disease remains prevalent throughout the world. Silica, or silicon dioxide, is the predominant component of the earth's crust. Occupational exposure to silica particles of respirable size (aerodynamic diameter of 0.5 to 5 µm) is associated with mining, quarrying, drilling, tunnelling and abrasive blasting with quartz containing materials (sandblasting). Silica exposure also poses a hazard to stonecutters, and pottery, foundry, ground silica and refractory workers. Because crystalline silica exposure is so widespread and silica sand is an inexpensive and versatile component of many manufacturing processes, millions of workers throughout the world are at risk of the disease. The true prevalence of the disease is unknown.


Silicosis is an occupational lung disease attributable to the inhalation of silicon dioxide, commonly known as silica, in crystalline forms, usually as quartz, but also as other important crystalline forms of silica, for example, cristobalite and tridymite. These forms are also called "free silica" to distinguish them from the silicates. The silica content in different rock formations, such as sandstone, granite and slate, varies from 20 to nearly 100%.

Workers in High-Risk Occupations and Industries

Although silicosis is an ancient disease, new cases are still reported in both the developed and developing world. In the early part of this century, silicosis was a major cause of morbidity and mortality. Contemporary workers are still exposed to silica dust in a variety of occupations-and when new technology lacks adequate dust control, exposures may be to more hazardous dust levels and particles than in non-mechanized work settings. Whenever the earth's crust is disturbed and silica-containing rock or sand is used or processed, there are potential respiratory risks for workers. Reports continue of silicosis from industries and work settings not previously recognized to be at risk, reflecting the nearly ubiquitous presence of silica. Indeed, due to the latency and chronicity of this disorder, including the development and progression of silicosis after exposure has ceased, some workers with current exposures may not manifest disease until the next century. In many countries throughout the world, mining, quarrying, tunnelling, abrasive blasting and foundry work continue to present major risks for silica exposure, and epidemics of silicosis continue to occur, even in developed nations.

Forms of Silicosis-Exposure History and Clinicopathologic Descriptions

Chronic, accelerated and acute forms of silicosis are commonly described. These clinical and pathologic expressions of the disease reflect differing exposure intensities, latency periods and natural histories. The chronic or classic form usually follows one or more decades of exposure to respirable dust containing quartz, and this may progress to progressive massive fibrosis (PMF). The accelerated form follows shorter and heavier exposures and progresses more rapidly. The acute form may occur after short-term, intense exposures to high levels of respirable dust with high silica content for periods that may be measured in months rather than years.

Chronic (or classic) silicosis may be asymptomatic or result in insidiously progressive exertional dyspnoea or cough (often mistakenly attributed to the ageing process). It presents as a radiographic abnormality with small (<10 mm), rounded opacities predominantly in the upper lobes. A history of 15 years or more since onset of exposure is common. The pathologic hallmark of the chronic form is the silicotic nodule. The lesion is characterized by a cell-free central area of concentrically arranged, whorled hyalinized collagen fibers, surrounded by cellular connective tissue with reticulin fibers. Chronic silicosis may progress to PMF (sometimes referred to as complicated silicosis), even after exposure to silica-containing dust has ceased.

Progressive massive fibrosis is more likely to present with exertional dyspnoea. This form of disease is characterized by nodular opacities greater than 1 cm on chest radiograph and commonly will involve reduced carbon monoxide diffusing capacity, reduced arterial oxygen tension at rest or with exercise, and marked restriction on spirometry or lung volume measurement. Distortion of the bronchial tree may also lead to airway obstruction and productive cough. Recurrent bacterial infection not unlike that seen in bronchiectasis may occur. Weight loss and cavitation of the large opacities should prompt concern for tuberculosis or other mycobacterial infection. Pneumothorax may be a life-threatening complication, since the fibrotic lung may be difficult to re-expand. Hypoxaemic respiratory failure with cor pulmonale is a common terminal event.

Accelerated silicosis may appear after more intense exposures of shorter (5 to 10 years) duration. Symptoms, radiographic findings and physiological measurements are similar to those seen in the chronic form. Deterioration in lung function is more rapid, and many workers with accelerated disease may develop mycobacterial infection. Auto-immune disease, including scleroderma or systemic sclerosis, is seen with silicosis, often of the accelerated type. The progression of radiographic abnormalities and functional impairment can be very rapid when auto-immune disease is associated with silicosis.

Acute silicosis may develop within a few months to 2 years of massive silica exposure. Dramatic dyspnoea, weakness, and weight loss are often presenting symptoms. The radiographic findings of diffuse alveolar filling differ from those in the more chronic forms of silicosis. Histologic findings similar to pulmonary alveolar proteinosis have been described, and extrapulmonary (renal and hepatic) abnormalities are occasionally reported. Rapid progression to severe hypoxaemic ventilatory failure is the usual course.

Tuberculosis may complicate all forms of silicosis, but people with acute and accelerated disease may be at highest risk. Silica exposure alone, even without silicosis may also predispose to this infection. M. tuberculosis is the usual organism, but atypical mycobacteria are also seen.

Even in the absence of radiographic silicosis, silica-exposed workers may also have other diseases associated with occupational dust exposure, such as chronic bronchitis and the associated emphysema. These abnormalities are associated with many occupational mineral dust exposures, including dusts containing silica.

Pathogenesis and the Association with Tuberculosis

The precise pathogenesis of silicosis is uncertain, but an abundance of evidence implicates the interaction between the pulmonary alveolar macrophage and silica particles deposited in the lung. Surface properties of the silica particle appear to promote macrophage activation. These cells then release chemotactic factors and inflammatory mediators that result in a further cellular response by polymorphonuclear leukocytes, lymphocytes and additional macrophages. Fibroblast-stimulating factors are released that promote hyalinization and collagen deposition. The resulting pathologic silicotic lesion is the hyaline nodule, containing a central acellular zone with free silica surrounded by whorls of collagen and fibroblasts, and an active peripheral zone composed of macrophages, fibroblasts, plasma cells, and additional free silica as shown in figure 10.14 .

Figure 10.14 Typical silicotic nodule, microscopic section

Courtesy of Dr. V. Vallyathan

The precise properties of silica particles that evoke the pulmonary response described above are not known, but surface characteristics may be important. The nature and the extent of the biological response are in general related to the intensity of the exposure; however, there is growing evidence that freshly fractured silica may be more toxic than aged dust containing silica, an effect perhaps related to reactive radical groups on the cleavage planes of freshly fractured silica. This may offer a pathogenic explanation for the observation of cases of advanced disease in both sandblasters and rock drillers where exposures to recently fractured silica are particularly intense.

The initiating toxic insult may occur with minimal immunological reaction; however, a sustained immunological response to the insult may be important in some of the chronic manifestations of silicosis. For example, antinuclear antibodies may occur in accelerated silicosis and scleroderma, as well as other collagen diseases in workers who have been exposed to silica. The susceptibility of silicotic workers to infections, such as tuberculosis and Nocardia asteroides, is likely related to the toxic effect of silica on pulmonary macrophages.

The link between silicosis and tuberculosis has been recognized for nearly a century. Active tuberculosis in silicotic workers may exceed 20% when community prevalence of tuberculosis is high. Again, people with acute silicosis appear to be at considerably higher risk.

Clinical Picture of Silicosis

The primary symptom is usually dyspnoea, first noted with activity or exercise and later at rest as the pulmonary reserve of the lung is lost. However, in the absence of other respiratory disease, shortness of breath may be absent and the presentation may be an asymptomatic worker with an abnormal chest radiograph. The radiograph may at times show quite advanced disease with only minimal symptoms. The appearance or progression of dyspnoea may herald the development of complications including tuberculosis, airways obstruction or PMF. Cough is often present secondary to chronic bronchitis from occupational dust exposure, tobacco use, or both. Cough may at times also be attributed to pressure from large masses of silicotic lymph nodes on the trachea or mainstem bronchi.

Other chest symptoms are less common than dyspnoea and cough. Haemoptysis is rare and should raise concern for complicating disorders. Wheeze and chest tightness may occur usually as part of associated obstructive airways disease or bronchitis. Chest pain and finger clubbing are not features of silicosis. Systemic symptoms, such as fever and weight loss, suggest complicating infection or neoplastic disease. Advanced forms of silicosis are associated with progressive respiratory failure with or without cor pulmonale. Few physical signs may be noted unless complications are present.

Radiographic Patterns and Functional Pulmonary Abnormalities

The earliest radiographic signs of uncomplicated silicosis are generally small rounded opacities. These can be described by the ILO International Classification of Radiographs of Pneumoconioses by size, shape and profusion category. In silicosis, "q" and "r" type opacities dominate. Other patterns including linear or irregular shadows have also been described. The opacities seen on the radiograph represent the summation of pathologic silicotic nodules. They are usually found predominantly in the upper zones and may later progress to involve other zones. Hilar lymphadenopathy is also noted sometimes in advance of nodular parenchymal shadows. Egg shell calcification is strongly suggestive of silicosis, although this feature is seen infrequently. PMF is characterized by the formation of large opacities. These large lesions can be described by size using the ILO classification as categories A, B or C. Large opacities or PMF lesions tend to contract, usually to the upper lobes, leaving areas of compensatory emphysema at their margins and often in the lung bases. As a result, previously evident small rounded opacities may disappear at times or be less prominent. 

Pleural abnormalities may occur but are not a frequent radiographic feature in silicosis. Large opacities may also pose concern regarding neoplasm and radiographic distinction in the absence of old films may be difficult. All lesions that cavitate or change rapidly should be evaluated for active tuberculosis. Acute silicosis may present with a radiologic alveolar filling pattern with rapid development of PMF or complicated mass lesions. See figure 10.15 and figure 10.16 .

Figure 10.15 Chest radiograph, acute silico-proteinosis in a surface coal mine driller

Courtesy of Dr. NL Lapp and Dr. DE Banks

Figure 10.16 Chest radiograph, complicated silicosis demonstrating progressive massive fibrosis

Pulmonary function tests, such as spirometry and diffusing capacity, are helpful for the clinical evaluation of people with suspected silicosis. Spirometry may also be of value in early recognition of the health effects from occupational dust exposures, as it may detect physiologic abnormalities that may precede radiologic changes. No solely characteristic pattern of ventilatory impairment is present in silicosis. Spirometry may be normal, or when abnormal, the tracings may show obstruction, restriction or a mixed pattern. Obstruction may indeed be the more common finding. These changes tend to be more marked with advanced radiologic categories. However, poor correlation exists between radiographic abnormalities and ventilatory impairment. In acute and accelerated silicosis, functional changes are more marked and progression is more rapid. In acute silicosis, radiologic progression is accompanied by increasing ventilatory impairment and gas exchange abnormalities, which leads to respiratory failure and eventually to death from intractable hypoxaemia.

Complications and Special Diagnostic Issues

With a history of exposure and a characteristic radiograph, the diagnosis of silicosis is generally not difficult to establish. Challenges arise only when the radiologic features are unusual or the history of exposure is not recognized. Lung biopsy is rarely required to establish the diagnosis. However, tissue samples are helpful in some clinical settings when complications are present or the differential diagnosis includes tuberculosis, neoplasm or PMF. Biopsy material should be sent for culture, and in research settings, dust analysis may be a useful additional measure. When tissue is required, open lung biopsy is generally necessary for adequate material for examination.

Vigilance for infectious complications, especially tuberculosis, cannot be overemphasized, and symptoms of change in cough or hemoptysis, and fever or weight loss should trigger a work-up to exclude this treatable problem.

Substantial concern and interest about the relationship between silica exposure, silicosis and cancer of the lung continues to stimulate debate and further research. In October of 1996, a committere of The International Agency for Research on Cancer (IARC) classified crystalline silica as a Group I carcinogen, reaching this conclusion based on "sufficient evidence of carcinogenicity in humans". Uncertainty over the pathogenic mechanisms for the development of lung cancer in silica-exposed populations exists, and the possible relationship between silicosis (or lung fibrosis) and cancer in exposed workers continues to be studied. Regardless of the mechanism that may be responsible for neoplastic events, the known association between silica exposures and silicosis dictates controlling and reducing exposures to workers at risk for this disease.

Prevention of Silicosis

Prevention remains the cornerstone of eliminating this occupational lung disease. The use of improved ventilation and local exhaust, process enclosure, wet techniques, personal protection including the proper selection of respirators, and where possible, industrial substitution of agents less hazardous than silica all reduce exposure. The education of workers and employers regarding the hazards of silica dust exposure and measures to control exposure is also important.

If silicosis is recognized in a worker, removal from continuing exposure is advisable. Unfortunately, the disease may progress even without further silica exposure. Additionally, finding a case of silicosis, especially the acute or accelerated form, should prompt a workplace evaluation to protect other workers also at risk.

Screening and Surveillance

Silica and other mineral-dust exposed workers should have periodic screening for adverse health effects as a supplement to, but not a substitute for, dust exposure control. Such screening commonly includes evaluations for respiratory symptoms, lung function abnormalities, and neoplastic disease. Evaluations for tuberculosis infection should also be performed. In addition to individual worker screening, data from groups of workers should be collected for surveillance and prevention activities. Guidance for these types of studies is included in the list of suggested readings.

Therapy, Management of Complications and Control of Silicosis

When prevention has been unsuccessful and silicosis has developed, therapy is directed largely at complications of the disease. Therapeutic measures are similar to those commonly used in the management of airway obstruction, infection, pneumothorax, hypoxaemia, and respiratory failure complicating other pulmonary disease. Historically, the inhalation of aerosolized aluminium has been unsuccessful as a specific therapy for silicosis. Polyvinyl pyridine-N-oxide, a polymer that has protected experiment animals, is not available for use in humans. Recent laboratory work with tetrandrine has shown in vivo reduction in fibrosis and collagen synthesis in silica exposed animals treated with this drug. However, strong evidence of human efficacy is currently lacking, and there are concerns about the potential toxicity, including the mutagenicity, of this drug. Because of the high prevalence of disease in some countries, investigations of combinations of drugs and other interventions continue. Currently, no successful approach has emerged, and the search for a specific therapy for silicosis to date has been unrewarding.

Further exposure is undesirable, and advice on leaving or changing the current job should be given with information about past and present exposure conditions.

In the medical management of silicosis, vigilance for complicating infection, especially tuberculosis, is critical. The use of BCG in the tuberculin-negative silicotic patient is not recommended, but the use of preventive isoniazid (INH) therapy in the tuberculin-positive silicotic subject is advised in countries where the prevalence of tuberculosis is low. The diagnosis of active tuberculosis infection in patients with silicosis can be difficult. Clinical symptoms of weight loss, fever, sweats and malaise should prompt radiographic evaluation and sputum acid-fast bacilli strains and cultures. Radiographic changes, including enlargement or cavitation in conglomerate lesions or nodular opacities, are of particular concern. Bacteriological studies on expectorated sputum may not always be reliable in silicotuberculosis. Fiberoptic bronchoscopy for additional specimens for culture and study may often be helpful in establishing a diagnosis of active disease. The use of multidrug therapy for suspected active disease in silicotics is justified at a lower level of suspicion than in the non-silicotic subject, due to the difficulty in firmly establishing evidence for active infection. Rifampin therapy appears to have enhanced the success rate of treatment of silicosis complicated by tuberculosis, and in some recent studies response to short-term therapy was comparable in cases of silicotuberculosis to that in matched cases of primary tuberculosis.

Ventilatory support for respiratory failure is indicated when precipitated by a treatable complication. Pneumothorax, spontaneous and ventilator-related, is usually treated by chest tube insertion. Bronchopleural fistula may develop, and surgical consultation and management should be considered.

Acute silicosis may rapidly progress to respiratory failure. When this disease resembles pulmonary alveolar proteinosis and severe hypoxaemia is present, aggressive therapy has included massive whole-lung lavage with the patient under general anaesthesia in an attempt to improve gas exchange and remove alveolar debris. Although appealing in concept, the efficacy of whole lung lavage has not been established. Glucocorticoid therapy has also been used for acute silicosis; however, it is still of unproven benefit.

Some young patients with end-stage silicosis may be considered candidates for lung or heart-lung transplantation by centres experienced with this expensive and high-risk procedure. Early referral and evaluation for this intervention may be offered to selected patients.

The discussion of an aggressive and high-technology therapeutic intervention such as transplantation serves dramatically to underscore the serious and potentially fatal nature of silicosis, as well as to emphasize the crucial role for primary prevention. The control of silicosis ultimately depends upon the reduction and control of workplace dust exposures. This is accomplished by rigorous and conscientious application of fundamental occupational hygiene and engineering principles, with a commitment to the preservation of worker health.


Michael D. Attfield, Edward L. Petsonk and Gregory R. Wagner

Coal miners are subject to a number of lung diseases and disorders arising from their exposure to coal mine dust. These include pneumoconiosis, chronic bronchitis and obstructive lung disease. The occurrence and severity of disease depends on the intensity and duration of dust exposure. The specific composition of the coal mine dust also has a bearing on some health outcomes.

In the developed countries, where high prevalences of lung disease existed in the past, reductions in dust levels brought about by regulation have led to substantial drops in disease prevalence since the 1970s. In addition, major reductions in the mining work force in most of those countries over recent decades, partly brought about by changes in technology and resulting improvements in productivity, will result in further reductions in overall disease levels. Miners in other countries, where coal mining is a more recent phenomenon and dust controls are less aggressive, have not been so fortunate. This problem is exacerbated by the high cost of modern mining technology, forcing the employment of large numbers of workers, many of whom are at high risk of disease development.

In the following text, each disease or disorder is considered in turn. Those specific to coal mining, such as coal workers' pneumoconiosis are described in detail; the description of others, such as obstructive lung disease, is restricted to those aspects that relate to coal miners and dust exposure.

Coal Workers' Pneumoconiosis

Coal workers' pneumoconiosis (CWP) is the disease most commonly associated with coal mining. It is not a fast-developing disease, usually taking at least ten years to be manifested, and often much longer when exposures are low. In its initial stages it is an indicator of excessive lung dust retention, and may be associated with few symptoms or signs in itself. However, as it advances, it puts the miner at increasing risk of development of the much more serious progressive massive fibrosis (PMF).


The classic lesion of CWP is the coal macule, a collection of dust and dust-laden macrophages around the periphery of the respiratory bronchioles. The macules contain minimal collagen and are thus usually not palpable. They are about 1 to 5 mm in size, and are frequently accompanied by an enlargement of the adjacent air spaces, termed focal emphysema. Though often very numerous, they are not usually evident on a chest radiograph.

Another lesion associated with CWP is the coal nodule. These larger lesions are palpable and contain a mixture of dust-laden macrophages, collagen and reticulin. The presence of coal nodules, with or without silicotic nodules (see below), indicates lung fibrosis, and is largely responsible for the opacities seen on chest radiographs. Macronodules (7 to 20 mm) in size may coalesce to form progressive massive fibrosis (see below), or PMF may develop from a single macronodule.

Silicotic nodules (described under silicosis) have been found in a significant minority of underground coal miners. For most, the cause may rest simply with the silica present in the coal dust, although exposure to pure silica in some jobs is certainly an important factor (e.g., among surface drillers, underground motormen and roof bolters).


The most useful indicator of CWP in miners during life is obtained using the routine chest radiograph. Dust deposits and the nodular tissue reactions attenuate the x-ray beam and result in opacities on the film. The profusion of these opacities can be assessed systematically by using a standardized method of radiograph description such as that disseminated by the ILO and described elsewhere in this chapter. In this method, individual posterior-anterior films are compared to standard radiographs showing increasing profusion of small opacities, and the film classified into one of four major categories (0, 1, 2, 3) based on its similarity to the standard. A secondary classification is also made, depending on the reader's assessment of the film's similarity to adjacent ILO categories. Other aspects of the opacities, such as size, shape and region of occurrence in the lung are also noted. Some countries, such as China and Japan, have developed similar systems for systematic radiograph description or interpretation that are particularly suited to their own needs.

Traditionally, small rounded types of opacity have been associated with coal mining. However, more recent data indicate that irregular types can also result from exposure to coal mine dust. The opacities of CWP and silicosis are often indistinguishable on the radiograph. However, there is some evidence that larger sized opacities (type r) more often indicate silicosis.

It is important to note that a substantial amount of pathologic abnormality related to pneumoconiosis may be present in the lung before it can be detected on the routine chest x ray. This is particularly true for macular deposition, but it becomes progressively less true with greater profusion and size of nodules. Concomitant emphysema may also reduce the visibility of lesions on the chest x ray. Computerized tomography (CT)-particularly high-resolution computerized tomography (HRCT)-may permit visualization of abnormalities not clearly evident on routine chest x rays, although CT is not necessary for routine clinical diagnosis of miners' lung diseases and is not indicated for medical surveillance of miners.

Clinical aspects

The development of CWP, although a marker of excessive lung dust retention, in itself is often unaccompanied by any overt clinical signs. This should not, however, be taken to imply that the inhalation of coal mine dust is without risk, for it is now well known that other lung diseases can arise from dust exposure. Pulmonary hypertension is more often noted in miners who develop airflow obstruction in association with CWP. Moreover, once CWP has developed, it usually progresses unless dust exposure ceases, and may progress thereafter. It also puts the miner at greatly increased risk of development of the clinically ominous PMF, with the likelihood of subsequent impairment, disability and premature mortality.

Disease mechanisms

Development of the earliest change of CWP, the dust macule, represents the effects of dust deposition and accumulation. The subsequent stage, that is, the development of nodules, results from the lung's inflammatory and fibrotic reaction to the dust. In this, the roles of silica and non-silica dust have long been debated. On the one hand, silica dust is known to be considerably more toxic than coal dust. Yet, on the other hand, epidemiological studies have shown no strong evidence implicating silica exposure in CWP prevalence or incidence. Indeed, it seems that almost an inverse relationship exists, in that disease levels tend to be elevated where silica levels are lower (e.g., in areas where anthracite is mined). Recently, some understanding of this paradox has been gained through studies of particle characteristics. These studies indicate that not only the quantity of silica present in the dust (as measured conventionally using infrared spectrometry or x-ray diffraction), but also the bioavailability of the surface of the silica particles may be related to toxicity. For example, clay coating (occlusion) may play an important modifying role. Another important factor under current investigation concerns surface charge in the form of free radicals and the effects of "freshly fractured" versus "aged" silica-containing dusts.

Surveillance and epidemiology

The prevalence of CWP among underground miners varies with the kind of job, tenure and age. A recent study of US coal miners revealed that from 1970 to 1972 about 25 to 40% of working coal miners had category 1 or greater small rounded opacities after 30 or more years in mining. This prevalence reflects exposure to levels of 6 mg/m3 or more of respirable dust among coal face workers prior to that time. The introduction of a dust limit of 3 mg/m3 in 1969, with a reduction to 2 mg/m3 in 1972 has led to a decline in disease prevalence to about half of the former levels. Declines related to dust control have been noted elsewhere, for example, in the United Kingdom and Australia. Unfortunately, these gains have been counterbalanced by temporal increases in prevalence elsewhere.

An exposure-response relationship for prevalence or incidence of CWP and dust exposure has been demonstrated in a number of studies. These have shown that the primary significant dust exposure variable is exposure to mixed mine dust. Intensive studies by British researchers failed to disclose any major influence of silica exposure, as long as the percentage of silica was less than about 5%. Coal rank (percentage carbon) is another important predictor of CWP development. Studies in the United States, the United Kingdom, Germany and elsewhere have given clear indications that the prevalence and incidence of CWP increases markedly with coal rank, these being substantially greater where anthracite (high rank) coal is mined. No other environmental variables have been found to exert any major effects on CWP development. Miner age appears to have some bearing on disease development, since older miners appear to be at increased risk. However, it is not entirely clear whether this implies that older miners are more susceptible, whether it is a residence time effect, or is simply an artefact (the age effect might reflect underestimation of exposure estimates for older miners, for example). Cigarette smoking does not appear to increase the risk of CWP development.

Research in which miners were followed-up with chest radiographs every five years shows that the risk of developing PMF over the five years is clearly related to the category of CWP as revealed on the initial chest x ray. Since the risk at category 2 is much greater than that at category 1, conventional wisdom at one time was that miners should be prevented from reaching category 2 if at all possible. However, in most mines there are usually many more miners with category 1 CWP compared to category 2. Thus, the lower risk for category 1 compared to category 2 is offset somewhat by the larger numbers of miners with category 1. On this showing, it has become clear that all pneumoconiosis should be prevented.


Miners as a group have been observed to have increased risk of death from non-malignant respiratory diseases, and there is evidence that the mortality among miners with CWP is somewhat increased over those of similar age without the disease. However, the effect is smaller than the excess seen for miners with PMF (see below).


The only protection against CWP is minimization of dust exposure. If possible, this should be achieved by dust suppression methods, such as ventilation and water sprays, rather than by respirator use or administrative controls, for example, worker rotation. In this respect, there is now good evidence that regulatory actions in some countries to reduce the level of dust, taken around the 1970s, has resulted in greatly reduced levels of disease. Transfer of workers with early signs of CWP to less dusty jobs is a prudent action, although there is little practical evidence that such programmes have succeeded in preventing disease progression. For this reason, dust suppression must remain the primary method of disease prevention.

Ongoing, aggressive monitoring of dust exposure and the conscious exertion of control efforts can be supplemented by health screening surveillance of miners. If miners are found to develop dust-related diseases, efforts at exposure control should be intensified throughout the workplace and miners with dust effects should be offered work in low-dust areas of the mine environment.


Although several forms of treatment have been tried, including aluminium powder inhalation, and the administration of tetrandine, no treatment is known that effectively reverses or slows the fibrotic process in the lung. Currently, primarily in China, but elsewhere also, whole-lung lavage is being tried with the intent of reducing the total lung dust burden. Although the procedure can result in the removal of a considerable amount of dust, its risks, benefits and role in the management of miners' health are unclear.

In other respects, treatment should be directed towards preventing complications, maximizing the miners' functional status and alleviating their symptoms, whether due to CWP or to other, concomitant respiratory diseases. In general, miners who develop dust-induced lung diseases should evaluate their current dust exposures and utilize the resources of government and labour organizations to find the avenues available to reduce all adverse respiratory exposures. For miners who smoke, smoking cessation is an initial step in personal exposure management. Prevention of infectious complications of chronic lung disease with available pneumococcal and yearly influenza vaccines is suggested. Early investigation of symptoms of lung infection, with particular attention to mycobacterial disease, is also recommended. The treatments for acute bronchitis, bronchospasm and congestive heart failure among miners are similar to those for patients without dust-related disease.

Progressive Massive Fibrosis

PMF, sometimes referred to as complicated pneumoconiosis, is diagnosed when one or more large fibrotic lesions (whose definition depends on the mode of detection) are present in one or both lungs. As its name implies, PMF often becomes more severe over time, even in the absence of additional dust exposure. It can also develop after dust exposure has ceased, and may often cause disability and premature mortality.


PMF lesions may be unilateral or bilateral, and are most often found in the upper or middle lobes of the lung. The lesions are formed of collagen, reticulin, coal mine dust and dust-laden macrophages, while the centre may contain a black liquid which cavitates on occasion. US pathology standards require the lesions to be 2 cm in size or larger to be identified as PMF entities in surgical or autopsy specimens.


Large opacities (>1 cm) on the radiograph, coupled with a history of extensive coal mine dust exposure, are taken to imply the presence of PMF. However, it is important that other diseases such as lung cancer, tuberculosis and granulomas be considered. Large opacities are usually seen on a background of small opacities, but development of PMF from a category 0 profusion has been noted over a five-year period.

Clinical aspects

Diagnostic possibilities for each individual miner with large chest opacities must be appropriately evaluated. Clinically stable miners with bilateral lesions in the typical upper-lung distribution and with pre-existing simple CWP may present little diagnostic challenge. However, miners with progressive symptoms, risk factors for other disorders (e.g., tuberculosis), or atypical clinical features should undergo a thorough appropriate examination before the diagnostician attributes the lesions to PMF.

Dyspnoea and other respiratory symptoms often accompany PMF, but may not necessarily be due to the disease itself. Congestive heart failure (due to pulmonary hypertension and cor pulmonale) is a not infrequent complication.

Disease mechanisms

Despite extensive research, the actual cause of PMF development remains unclear. Over the years, various hypotheses have been proposed, but none is fully satisfactory. One prominent theory was that tuberculosis played a role. Indeed, tuberculosis is often present in miners with PMF, particularly in the developing countries. However, PMF has been found to develop in miners in whom there was no sign of tuberculosis, and tuberculin reactivity has not been found to be elevated in miners with pneumoconiosis. Despite investigation, consistent evidence of the role of the immune system in PMF development is lacking.

Surveillance and epidemiology

As with CWP, PMF levels have been declining in countries which have strict dust control regulations and programmes. A recent study of US miners revealed that about 2% of coal miners working underground had PMF after 30 or more years in mining (although this figure may have been biased by affected miners leaving the work force).

Exposure-response investigations of PMF have shown that exposure to coal mine dust, category of CWP, coal rank and age are the primary determinants of disease development. As with CWP, epidemiological studies have found no major effect of silica dust. Although it was thought at one time that PMF developed only on a background of the small opacities of CWP, recently this has been found not to be the case. Miners with an initial chest x ray showing category 0 CWP have been shown to develop PMF over five years, with the risk increasing with their cumulative dust exposure. Also, miners may develop PMF after cessation of dust exposure.


PMF leads to premature mortality, the prognosis worsening with increasing stage of the disease. A recent study showed that miners with category C PMF had only one-fourth the rate of survival over 22 years compared to miners with no pneumoconiosis. This effect was manifested over all age groups.


Avoidance of dust exposure is the only way to prevent PMF. Since the risk of its development increases sharply with increasing category of simple CWP, a strategy for secondary prevention of PMF is for miners to undergo periodic chest x rays and to terminate or reduce their exposure if simple CWP is detected. Although this approach appears valid and has been adopted in certain jurisdictions, its effectiveness has not been evaluated systematically.


There is no known treatment for PMF. Medical care should be organized around ameliorating the condition and associated lung illnesses, while protecting against infectious complications. Although maintaining functional stability may be more difficult in patients with PMF, in other respects, management is similar to simple CWP.

Obstructive Lung Disease

There is now consistent and convincing evidence of a relationship between lung function loss and dust exposure. Various studies in different countries have looked at the influence of dust exposure on absolute values of, and temporal changes in, measurements of ventilatory function, such as forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and flow rates. All have found evidence that dust exposure leads to a reduction in lung function, and the results have been strikingly similar for several recent British and US investigations. These indicate that over the course of a year, dust exposure at the coal face brings about, on average, a reduction in lung function equivalent to smoking half a pack of cigarettes each day. The studies also demonstrate that effects vary, and a given miner may develop effects equal to, or worse than, those expected from cigarette smoking, particularly if the individual has experienced higher dust exposures.

The effects of dust exposure have been found in both those who have never smoked and in current smokers. Moreover, there is no evidence that smoking exacerbates the dust exposure effect. Rather, studies have generally shown a slightly smaller effect in current smokers, a result that may be due to healthy worker selection. It is important to note that the relationship between dust exposure and ventilatory decline appears to exist independently of pneumoconiosis. That is, it is not a requirement that pneumoconiosis be present for there to be reduced lung function. To the contrary, it appears rather that the inhaled dust can act along multiple pathways, leading to pneumoconiosis in some miners, to obstruction in others and to multiple outcomes in yet others. In contrast to miners with CWP alone, miners with respiratory symptoms have significantly lower lung function, after standardization for age, smoking, dust exposure and other factors.

Recent work on ventilatory function changes has involved the exploration of longitudinal changes. The results indicate that there may be a non-linear trend of decline over time in new miners, a high initial rate of loss being followed by a more moderate decline with continued exposure. Furthermore, there is evidence that miners who react to the dust may choose, if possible, to remove themselves from the heavier exposures.

Chronic Bronchitis

Respiratory symptoms, such as chronic cough and phlegm production, are a frequent consequence of work in coal mining, most studies showing an excess prevalence compared to non-exposed control groups. Moreover, the prevalence and incidence of respiratory symptoms has been shown to increase with cumulative dust exposure, after taking into account age and smoking. The presence of symptoms appears to be associated with a reduction in lung function over and above that due to dust exposure and other putative causes. This suggests that dust exposure may be instrumental in initiating certain disease processes that then progress regardless of further exposure. A relationship between bronchial gland size and dust exposure has been demonstrated pathologically, and it has been found that mortality from bronchitis and emphysema increases with increasing cumulative dust exposure.


Pathological studies have repeatedly found an excess of emphysema in coal miners compared to control groups. Moreover, the degree of emphysema has been found to be related both to the amount of dust in the lungs and to pathological assessments of pneumoconiosis. Furthermore, it is important to recognize that there is evidence that the presence of emphysema is related to dust exposure and to the percentage of predicted FEV1. Hence, these results are consistent with the view that dust exposure can lead to disability through causing emphysema.

The form of emphysema most clearly associated with coal mining is focal emphysema. This consists of zones of enlarged air spaces, 1 to 2 mm in size, adjacent to dust macules surrounding the respiratory bronchioles. The current thinking is that the emphysema is formed from tissue destruction, rather than from distension or dilation. Apart from focal emphysema, there is evidence that centriacinar emphysema has an occupational origin, and that total emphysema, (i.e., the extent of all types) is correlated with tenure in mining, in those who have never smoked as well as in smokers. There is no evidence that smoking potentiates the dust exposure/emphysema relationship. However, there are indications of an inverse relationship between the silica content of lungs and the presence of emphysema.

The issue of emphysema has long been controversial, with some stating that selection bias and smoking make interpretation of pathological studies difficult. In addition, some consider that focal emphysema has only trivial effects on lung function. However, pathological studies undertaken since the 1980s have been responsive to earlier criticisms, and indicate that the effect of dust exposure may be more significant for miners' health than previously thought. This point of view is supported by recent findings that mortality from bronchitis and emphysema is related to cumulative dust exposure.


Silicosis, though associated more with industries other than coal mining, can occur in coal miners. In underground mines, it is found most frequently in workers in certain jobs where exposure to pure silica typically occurs. Such workers include roof bolters, who drill into the ceiling rock, which can often be sandstone or other rock with high silica content; motormen, drivers of rail transport who are exposed to the dust generated by sand placed on the tracks to lend traction; and rock drillers, who are involved in mine development. Rock drillers at surface coal mines have been shown to be at particular risk in the United States, with some developing acute silicosis after only a few years of exposure. Based on pathological evidence, as noted below, some degree of silicosis may afflict many more coal miners than just those working the jobs noted above.

Silicotic nodules in coal miners are similar in nature to those observed elsewhere, and consist of a whorled pattern of collagen and reticulin. One large autopsy study has revealed that about 13% of coal miners had silicotic nodules in their lungs. Although one job, (that of motorman) was notable for having a much higher prevalence of silicotic nodules (25%), there was little variation in the prevalence among miners in other jobs, suggesting that the silica in the mixed mine dust was responsible.

Silicosis cannot be reliably differentiated from coal workers' pneumoconiosis on a radiograph. However, there is some evidence that the larger type of small opacities (type r) are indicative of silicosis.

Rheumatoid Pneumoconiosis

Rheumatoid pneumoconiosis, one variant of which is called Caplan's syndrome, is the term used for a condition affecting dust-exposed workers who develop multiple large radiographic shadows. Pathologically, these lesions resemble rheumatoid nodules rather than PMF lesions, and often arise over a short time interval. Active arthritis or the presence of circulating rheumatoid factor are generally found, but occasionally are absent.

Lung Cancer

Included in the occupational exposures suffered by coal miners are a number of substances that are potential carcinogens. Some of these are silica and benzo(a)pyrenes. Yet, there is no clear evidence of an excess of deaths from lung cancer in coal miners. One obvious explanation for this is that coal miners are forbidden to smoke underground because of the danger of fires and explosions. However, the fact that no exposure-response relationship between lung cancer and dust exposure has been detected suggests that coal mine dust is not a major cause of lung cancer in the industry.

Regulatory Limits on Dust Exposure

The World Health Organization (WHO) has recommended a "tentative health-based exposure limit" for respirable coal mine dust (with less than 6% respirable quartz) ranging from 0.5 to 4 mg/m3. WHO suggests a 2 in 1,000 risk of PMF over a working lifetime as a criterion, and recommends that mine-based environmental factors, including coal rank, percentage of quartz and particle size should be taken into account when setting limits.

Currently, among the major coal-producing countries, limits are based on regulating coal dust alone (e.g., 3.8 mg/m3 in the United Kingdom, 5 mg/m3 in Australia and Canada) or on regulating a mixture of coal and silica as in the United States (2 mg/m3 when the per cent quartz is 5 or less, or (10 mg/m3)/per cent SiO2), or in Germany (4 mg/m3 when the per cent quartz is 5 or less, or 0.15 mg/m3 otherwise), or on regulating pure quartz (e.g., Poland, with a 0.05 mg/m3 limit).


Margaret R. Becklake

Historical Perspective

Asbestos is a term used to describe a group of naturally occurring fibrous minerals which are very widely distributed in rock outcrops and deposits throughout the world. Exploitation of the tensile and heat-resistant properties of asbestos for human use dates from ancient times. For instance, in the third century BC asbestos was used to strengthen clay pots in Finland. In classic times, shrouds woven from asbestos were used to preserve the ashes of the famous dead. Marco Polo returned from his travels in China with descriptions of a magic material which could be manufactured into a flame resistant cloth. By the early years of the nineteenth century, deposits were known to exist in several parts of the world, including the Ural Mountains, northern Italy and other Mediterranean areas, in South Africa and in Canada, but commercial exploitation only started in the latter half of the nineteenth century. By this time, the industrial revolution created not only the demand (such as that of insulating the steam engine) but also facilitated production, with mechanization replacing hand cobbing of fibre from the parent rock. The modern industry began in Italy and the United Kingdom after 1860 and was boosted by the development and exploitation of the extensive deposits of chrysotile (white) asbestos in Quebec (Canada) in the 1880s. Exploitation of the also extensive deposits of chrysotile in the Ural mountains was modest until the 1920s. The long thin fibres of chrysotile were particularly suitable for spinning into cloth and felts, one of the early commercial uses for the mineral. The exploitation of the deposits of crocidolite (blue) asbestos of the northwest Cape, South Africa, a fibre more water-resistant than chrysotile and better suited to marine use, and of the amosite (brown) asbestos deposits, also found in South Africa, started in the early years of this century. Exploitation of the Finnish deposits of anthophyllite asbestos, the only important commercial source of this fibre, took place between 1918 and 1966, while the deposits of crocidolite in Wittenoom, Western Australia, were mined from 1937 to 1966.

Fibre Types

The asbestos minerals fall into two groups, the serpentine group which includes chrysotile, and the amphiboles, which include crocidolite, tremolite, amosite and anthophyllite (figure 10.17). Most ore deposits are heterogeneous mineralogically, as are most of the commercial forms of the mineral (Skinner, Roos and Frondel 1988). Chrysotile and the various amphibole asbestos minerals differ in crystalline structure, in chemical and surface characteristics and in the physical characteristics of their fibres, usually described in terms of the length-to-diameter (or aspect) ratio. They also differ in characteristics which distinguish commercial use and grade. Pertinent to the current discussion is the evidence that the different fibres differ in their biological potency (as considered below in the sections on various diseases).

Figure 10.17 Asbestos fibre types

Seen on election microscopy together with energy dispersive x-ray spectra which enables  identification of individual fibres

Courtesy of A. Dufresne and M. Harrigan, McGill University

Commercial Production

The growth of commercial production, illustrated in figure 10.18 , was slow in the early years of this century. For instance, Canadian production exceeded 100,000 short tons per annum for the first time in 1911 and 200,000 tons in 1923. Growth between the two World Wars was steady, increased considerably to meet the demands of the Second World War and spectacularly to meet peacetime demands (including those of the cold war) to reach a peak in 1976 of 5,708,000 short tons (Selikoff and Lee 1978). After this, production faltered as the ill-health effects of exposure became a matter of increasing public concern in North America and Europe and remain at approximately 4,000,000 short tons per annum up to 1986, but decreased further in the 1990s.

Figure 10.18 World production of asbestos in thousands of tons 1900-92

There was also a shift in the uses and sources of fibre in the 1980s; in Europe and North America demand declined as substitutes for many applications were introduced, while on the African, Asian and South American continents, demand for asbestos increased to meet the needs of a cheap durable material for use in construction and in water reticulation. By 1981, Russia had become the world's major producer, with an increase in the commercial exploitation of large deposits in China and Brazil. In 1980, it was estimated that a total of over 100 million tons of asbestos had been mined worldwide, 90% of which was chrysotile, approximately 75% of which came from 4 chrysotile mining areas, located in Quebec (Canada), Southern Africa and the central and southern Ural Mountains. Two to three per cent of the world's total production was crocidolite, from the Northern Cape, South Africa, and from Western Australia, and another 2 to 3% was amosite, from the Eastern Transvaal, South Africa (Skinner, Ross and Frondel 1988).

Asbestos-Related Diseases and Conditions

Like silica, asbestos has the capability of evoking scarring reactions in all biological tissue, human and animal. In addition, asbestos evokes malignant reactions, adding a further element to the concern for human health, as well as a challenge to science as to how asbestos exerts its ill effects. The first asbestos-related disease to be recognized, diffuse interstitial pulmonary fibrosis or scarring, later called asbestosis, was the subject of case reports in the United Kingdom in the early 1900s. Later, in the 1930s, case reports of lung cancer in association with asbestosis appeared in the medical literature though it was only over the next several decades that the scientific evidence was gathered establishing that asbestos was the carcinogenic factor. In 1960, the association between asbestos exposure and another much less common cancer, malignant mesothelioma, which involves the pleura (a membrane that covers the lung and lines the chest wall) was dramatically brought to attention by the report of a cluster of these tumours in 33 individuals, all of whom worked or lived in the asbestos mining area of the Northwest Cape (Wagner 1996). Asbestosis was the target of the dust control levels introduced and implemented with increasing rigour in the 1960s and 1970s, and in many industrialized countries, as the frequency of this disease decreased, asbestos-related pleural disease emerged as the most frequent manifestation of exposure and the condition which most frequently brought exposed subjects to medical attention. Table 10.16  lists diseases and conditions currently recognized as asbestos-related. The diseases in bold type are those most frequently encountered and for which a direct causal relationship is well established, while for the sake of completeness, certain other conditions, for which the relationship is less well established, are also listed (see footnote to table 10.16) and the sections which follow in the text below that expand upon the various disease headings).

Table 10.16 Asbestos-related diseases and conditions.1


Organ(s) affected




Asbestosis (diffuse interstitial fibrosis)

Small airway disease2 (fibrosis limited to the  peri-bronchiolar region)

Chronic airways disease3



Pleural plaques

Viscero-parietal reactions, including benign pleural  effusion, diffuse pleural fibrosis and rounded  atelectasis



Asbestos corns4



Lung cancer (all cell types)

Cancer of larynx



Mesothelioma of pleura


Other mesothelium-lined cavities

Mesothelioma of the peritoneum, pericardium and scrotum (in decreasing frequency of occurrence)


Gastrointestinal tract5

Cancer of stomach, oesophagus, colon, rectum



Ovary, gall bladder, bile ducts, pancreas, kidney

1 The diseases or conditions indicated in bold type are those most frequently encountered and  the ones for which a causal relationship is well established and/or generally recognized.

2 Fibrosis in the walls of the small airways of the lung (including the membranous and respiratory  bronchioles) is thought to represent the early lung parenchymal response to retained asbestos  (Wright et al. 1992) which will progress to asbestosis if exposure continues and/or is heavy,  but if exposure is limited or light, the lung response may be limited to these areas  (Becklake in Liddell & Miller 1991).

3 Included are bronchitis, chronic obstructive pulmonary disease (COPD) and emphysema.  All have been shown to be associated with work in dusty environments. The evidence for causality  is reviewed in the section Chronic Airways Diseases and Becklake (1992).

4 Related to direct handling of asbestos and of historical rather than current interest.

5 Data not consistent from all studies (Doll and Peto 1987); some of the highest risks were reported  in a cohort of over 17,000 American and Canadian asbestos insulation workers (Selikoff 1990),  followed from January 1, 1967 to December 31, 1986 in whom exposure had been particularly heavy.

Sources: Becklake 1994; Liddell and Miller 1992; Selikoff 1990; Doll and Peto in Antman and  Aisner 1987; Wright et al. 1992.


Table 10.17  lists the major sources, products and uses of the asbestos minerals. Though necessarily incomplete, this table emphasizes that:

1.     Deposits are found in many parts of the world, most of which have been exploited non-commercially or commercially in the past, and some of which are currently commercially exploited.

2.     There are many manufactured products in current or past use which contain asbestos, particularly in the construction and transport industries.

3.     Disintegration of these products or their removal carries with it the risk of the resuspension of fibres and of renewed human exposure.

Table 10.17 Main commercial sources, products and uses of asbestos.

Fibre type

Location of major deposits

Commercial products and/or uses

Chrysotile (white)

Russia, Canada (Québec, also British Columbia, Newfoundland), China (Szechwan province); Mediterranean countries (Italy, Greece, Corsica, Cyprus); Southern Africa (South Africa, Zimbabwe, Swaziland); Brazil; smaller deposits in United States (Vermont, Arizona, California) and in Japan

Construction materials (tiles, shingles, gutters and cisterns; roofing, sheeting, and siding)

Pressure and other pipes

Fire proofing (marine and other)

Insulation and sound proofing

Reinforced plastic products (fan blades, switch gear)

Friction materials usually in combination with resins in brakes, clutches, other

Textiles (used in belts, clothing, casing, fire barriers, autoclaves, yarns and packing)

Paper products (used in millboard, insulators, gaskets, roof felt, wall coverings, etc.)

Floats in paints, coatings and welding rods

Crocidolite (blue)

South Africa (Northwest Cape, Eastern Transvaal), Western Australia1

Used mainly in combination in cement products (in particular pressure pipes) but also in many of the other products listed above

Amosite (brown)

South Africa (Northern Transvaal)1

Used mainly in cement, thermal insulation and roofing products particularly in the United States2 , but also in combination in many of the products listed under chrysotile



Filler in the rubber, plastics and chemical industries


Italy, Korea and some Pacific Islands; mined on a small scale in Turkey, China and elsewhere; contaminates the ore bearing rock in some asbestos, iron, talc and vermiculite mines; also found in agricultural soils in the Balkan Peninsula and in Turkey

Used as a filler in talc; may or may not be removed in processing the ore so it may appear in end products


Contaminates amosite, and less often, chrysotile, talc and vermiculite deposits

Not usually exploited commercially

1 A list such as this is obviously not comprehensive and the readers should consult the sources cited and other chapters in this Encyclopedia for more complete information.

2 No longer in operation.

Sources: Asbestos Institute (1995); Browne (1994); Liddell and Miller (1991);  Selikoff and Lee (1978); Skinner et al (1988).

A figure of over 3,000 has been commonly quoted for the number of uses of asbestos and no doubt led to asbestos being dubbed the "magic mineral" in the 1960s. A 1953 industry list contains as many as 50 uses for raw asbestos, in addition to its use in the manufacture of the products listed in table 10.17 , each of which has many other industrial applications. In 1972, the consumption of asbestos in an industrialized country like the United States was attributed to the following categories of product: construction (42%); friction materials, felts, packings and gaskets (20%); floor tiles (11%); paper (9%); insulation and textiles (3%) and other uses (15%) (Selikoff and Lee 1978). By contrast, a 1995 industry list of the main product categories shows major redistribution on a worldwide basis as follows: asbestos cement (84%); friction materials (10%); textiles (3%); seals and gaskets (2%); and other uses (1%) (Asbestos Institute 1995).

Occupational Exposures, Past and Current

Occupational exposure, certainly in industrialized countries, has always been and is still the most likely source of human exposure (see table 10.17  and the references cited in its footnote; other sections of this Encyclopaedia contain further information). There have, however, been major changes in industrial processes and procedures aimed at diminishing the release of dust into the working environment (Browne 1994; Selikoff and Lee 1978). In countries with mining operations, milling usually takes place at the minehead. Most chrysotile mines are open cast, while amphibole mines usually involve underground methods which generate more dust. Milling involves separating fibre from rock by means of mechanized crushing and screening, which were dusty processes until the introduction of wet methods and/or enclosure in most mills during the 1950s and 1960s. The handling of waste was also a source of human exposure, as was transporting bagged asbestos, whether it involved loading and unloading trucks and railcars or work on the dockside. These exposures have diminished since the introduction of leak-proof bags and the use of sealed containers.

Workers have had to use raw asbestos directly in packing and lagging, particularly in locomotives, and in spraying walls, ceilings and airducts, and in the marine industry, deckheads and bulkheads. Some of these uses have been phased out voluntarily or have been banned. In the manufacture of asbestos cement products, exposure occurs in receiving and opening bags containing raw asbestos, in preparing the fibre for mixing in the slurry, in machining end-products and in dealing with waste. In the manufacture of vinyl tiles and flooring, asbestos was used as a reinforcing and filler agent to blend with organic resins, but has now largely been replaced by organic fibre in Europe and North America. In the manufacture of yarns and textiles, exposure to fibre occurs in receiving, preparing, blending, carding, spinning, weaving and calendaring the fibre-processes which were until recently dry and potentially very dusty. Dust exposure has been considerably reduced in modern plants through use of a colloidal suspension of fibre extruded through a coagulant to form wet strands for the last-mentioned three processes. In the manufacture of asbestos paper products, human exposure to asbestos dust is also most likely to occur in the reception and preparation of the stock mix and in cutting the final products which in the 1970s contained from 30 to 90% asbestos. In the manufacture of asbestos friction products (dry mix-moulded, roll-formed, woven or endless wound) human exposure to asbestos dust is also most likely to occur during the initial handling and blending processes as well as in finishing the end product, which in the 1970s contained from 30 to 80% of asbestos. In the construction industry, prior to regular use of appropriate exhaust ventilation (which came in the 1960s), the high-speed power sawing, drilling and sanding of asbestos-containing boards or tiles led to the release of fibre-containing dust close to the operator's breathing zone, particularly when such operations were conducted in closed spaces (for instance in high-rise buildings under construction). In the period after the Second World War, a major source of human exposure was in the use, removal or replacement of asbestos-containing materials in the demolition or refurbishing of buildings or ships. One of the chief reasons for this state of affairs was the lack of awareness, both of the composition of these materials (i.e., that they contained asbestos) and that exposure to asbestos could be harmful to health.

Improved worker education, better work practices and personal protection have reduced the risk in the 1990s in some countries. In the transport industry, sources of exposure were the removal and replacement of lagging in locomotive engines and of braking material in trucks and cars in the automobile repair industry. Other sources of past exposure leading to, in particular, pleural disease, continue to attract notice, even in the 1990s, usually on the basis of case reports, for instance those describing workers using asbestos string in the manufacture of welding rods, in the formation of asbestos rope for grouting furnaces and maintaining underground mine haulage systems.

Other Sources of Exposure

Exposure of individuals engaged in trades which do not directly involve use or handling of asbestos but who work in the same area as those who do deal with it directly is called para-occupational (bystander) exposure. This has been an important source of exposure not only in the past but also for cases presenting for diagnosis in the 1990s. Workers involved include electricians, welders and carpenters in the construction and in the ship building or repair industries; maintenance personnel in asbestos factories; fitters, stokers and others in power stations and ships and boiler houses where asbestos lagging or other insulation is in place, and maintenance personnel in post-war high-rise buildings incorporating various asbestos-containing materials. In the past, domestic exposure occurred primarily from dust-laden workclothes being shaken or laundered at home, the dust so released becoming entrapped in carpets or furnishings and resuspended into the air with the activities of daily living. Not only could levels of airborne fibre reach levels as high as 10 fibre per millilitre (f/ml), that is, ten times the occupational exposure limit proposed by a WHO consultation (1989) of 1.0 f/ml but the fibres tended to remain airborne for several days. Since the 1970s, the practice of retaining all work clothes at the worksite for laundering has been widely but not universally adopted. In the past also, residential exposure occurred from contamination of air from industrial sources. For instance, increased levels of airborne asbestos have been documented in the neighbourhood of mines and asbestos plants and are determined by production levels, emission controls and weather. Given the long lag time for, in particular, asbestos-related pleural disease, such exposures are still likely to be responsible for some cases presenting for diagnosis in the 1990s. In the 1970s and 1980s, with the increase in public awareness of both the ill-health consequences of asbestos exposure and of the fact that asbestos containing materials are used extensively in modern construction (particularly in the friable form used for spray-on applications to walls, ceilings and ventilation ducts), a major cause of concern centred on whether, as such buildings age and are subject to daily wear and tear, asbestos fibres may be released into the air in sufficient numbers to become a threat to the health of those working in modern high-rise buildings (see below for risk estimates). Other sources of contamination of the air in urban areas include the release of fibre from brakes of vehicles and rescattering of fibres released by passing vehicles (Bignon, Peto and Saracci 1989).

Non-industrial sources of environmental exposure include naturally occurring fibres in soils, for instance in eastern Europe, and in rock outcrops in the Mediterranean region, including Corsica, Cyprus, Greece and Turkey (Bignon, Peto and Saracci 1989). An additional source of human exposure results from the use of tremolite for whitewash and stucco in Greece and Turkey, and according to more recent reports, in New Caledonia in the South Pacific (Luce et al. 1994). Furthermore, in several rural villages in Turkey, a zeolite fibre, erionite, has been found to be used both in stucco and in domestic construction and has been implicated in mesothelioma production (Bignon, Peto and Saracci 1991). Finally, human exposure may occur through drinking water, mainly from natural contamination, and given the widespread natural distribution of the fibre in outcrops, most water sources contain some fibre, levels being highest in mining areas (Skinner, Roos and Frondel 1988).

Aetiopathology of Asbestos-Related Disease

Fate of inhaled fibres

Inhaled fibres align themselves with the airstream and their capability of penetrating into the deeper lung spaces depends on their dimension, fibres of 5 µm or less in aerodynamic diameter showing an over 80% penetration, but also less than 10 to 20% retention. Larger particles may impact in the nose and in major airways at bifurcations, where they tend to collect. Particles deposited in the major airways are cleared by the action of ciliated cells and are transported up the mucus escalator. Individual differences associated with what appears to be the same exposure are due, at least in part, to differences between individuals in the penetration and retention of inhaled fibres (Bégin, Cantin and Massé 1989). Small particles deposited beyond the major airways are phagocytosed by alveolar macrophages, scavenger cells which ingest foreign material. Longer fibres, that is, those over 10 µm, often come under attack by more than one macrophage, are more likely to become coated and to form the nucleus of an asbestos body, a characteristic structure recognized since the early 1900s as a marker of exposure (see figure 10.19).

Figure 10.19 Asbestos body

Magnification x 400, seen on microscopic section of the lung as a slightly curved elongated  structure with a finely beaded iron protein coat. The asbestos fibre itself can be identified as the  thin line near one end of the asbestos body (arrow).

Source: Fraser et al. 1990

Coating a fibre is considered to be part of the lungs' defense to render it inert and non-immunogenic. Asbestos bodies are more likely to form on amphibole than on chrysotile fibres, and their density in biological material (sputum, bronchoalveolar lavage, lung tissue) is an indirect marker of lung burden. Coated fibres may persist in the lung for long periods, to be recovered from sputum or bronchoalveolar lavage fluid up to 30 years after last exposure. Clearance of non-coated fibres deposited in the lung's parenchyma is towards the lung periphery and subpleural regions, and then to lymph nodes at the root of the lung. Theories to explain how fibres evoke the various pleural reactions associated with asbestos exposure include:

1.     direct penetration into the pleural space and drainage with the pleural fluid to pores in the pleura lining the chest wall

2.     release of mediators into the pleural space from subpleural lymphatic collections3.     retrograde flow from lymph nodes at the root of the lung to the parietal pleura (Browne 1994)

There may also be retrograde flow via the thoracic duct to the abdominal lymph nodes to explain the occurrence of peritoneal mesothelioma.

Cellular effects of inhaled fibres

Animal studies indicate that the initial events which follow asbestos retention in the lung include:

1.     an inflammatory reaction, with accumulation of white blood cells followed by a macrophagic alveolitis with release of fibronectin, growth factor and various neutrophil chemotactic factors and, over time, the release of superoxide ion and

2.     proliferation of alveolar, epithelial, interstitial and endothelial cells (Bignon, Peto and Saracci 1989).

These events are reflected in the material recovered by bronchoalveolar lavage in animals and humans (Bégin, Cantin and Massé 1989). Both fibre dimensions and their chemical characteristics appear to determine biological potency for fibrogenesis, and these characteristics, in addition to surface properties, are also thought to be important for carcinogenesis. Long, thin fibres are more active than short ones, although the activity of the latter cannot be discounted, and amphiboles are more active than chrysotile, a property attributed to their greater biopersistence (Bégin, Cantin and Massé 1989). Asbestos fibres may also affect the human immune system and change the circulating population of blood lymphocytes. For instance, human cell mediated immunity to cell antigens (such as is exhibited in a tuberculin skin test) may be impaired (Browne 1994). In addition, since asbestos fibres appear to be capable of inducing chromosome abnormality, the view has been expressed that they can also be considered capable of inducing as well as promoting cancer (Jaurand in Bignon, Peto and Saracci 1989).

Dose versus exposure response relationships

In biological sciences such as pharmacology or toxicology in which dose-response relationships are used to estimate the probability of desired effects or the risk of undesired effects, a dose is conceptualized as the amount of agent delivered to and remaining in contact with the target organ for sufficient time to evoke a reaction. In occupational medicine, surrogates for dose, such as various measures of exposure, are usually the basis for risk estimates. However, exposure-response relationships can usually be demonstrated in workforce-based studies; the most appropriate exposure measure may, however, differ between diseases. Somewhat disconcerting is the fact that although exposure-response relationships will differ between workforces, these differences can be explained only in part by the fibre, particle size and industrial process. Nevertheless, such exposure-response relationships have formed the scientific basis for risk assessment and for setting permissible exposure levels, which were originally focused on controlling asbestosis (Selikoff and Lee 1978). As the prevalence and/or incidence of this condition has decreased, concern has switched to assure protection of human health against asbestos-related cancers. Over the last decade, techniques have been developed for the quantitative measurement of lung dust burden or biological dose directly in terms of fibres per gram of dry lung tissue. In addition, energy dispensive x-ray analysis (EDXA) permits precise characterization of each fibre by fibre type (Churg 1991). Though standardization of results between laboratories has not yet been achieved, comparisons of results obtained within a given laboratory are useful, and lung burden measurements have added a new tool for case evaluation. In addition, the application of these techniques in epidemiological studies has

1.     confirmed the biopersistence of amphibole fibres in the lung compared to chrysotile fibres

2.     identified fibre burden in the lungs of some individuals in whom exposure was forgotten, remote or thought to be unimportant

3.     demonstrated a gradient in lung burden associated with rural and urban residence and with occupational exposure and

4.     confirmed a fibre gradient in the lung dust burden associated with the major asbestos-related diseases (Becklake and Case 1994).


Definition and history

Asbestosis is the name given to the pneumoconiosis consequent on exposure to asbestos dust. The term pneumoconiosis is used here as defined in the article "Pneumoconioses: Definitions", of this Encyclopaedia as a condition in which there is "accumulation of dust in the lungs and tissue responses to the dust". In the case of asbestosis, the tissue reaction is collagenous, and results in permanent alteration of the alveolar architecture with scarring. As early as 1898, the Annual Report of Her Majesty's Chief Inspector of Factories contained reference to a lady factory inspector's report on the adverse health consequences of asbestos exposure, and the 1899 Report contained details of one such case in a man who had worked for 12 years in one of the recently established textile factories in London, England. Autopsy revealed diffuse severe fibrosis of the lung and what subsequently came to be known as asbestos bodies were seen on subsequent histologic re-examination of the slides. Since fibrosis of the lung is an uncommon condition, the association was thought to be causal and the case was presented in evidence to a committee on compensation for industrial disease in 1907 (Browne 1994). Despite the appearance of reports of a similar nature filed by inspectors from the United Kingdom, Europe and Canada over the next decade, the role of exposure to asbestos in the genesis of the condition was not generally recognized until a case report was published in the British Medical Journal in 1927. In this report, the term pulmonary asbestosis was first used to describe this particular pneumoconiosis, and comment was made on the prominence of the associated pleural reactions, in contrast, for instance, to silicosis, the main pneumoconiosis recognized at the time (Selikoff and Lee 1978).

In the 1930s, two major workforce-based studies carried out among textile workers, one in the United Kingdom and one in the United States, provided evidence of an exposure-response (and therefore likely causal) relationship between level and duration of exposure and radiographic changes indicative of asbestosis. These reports formed the basis of the first control regulations in the United Kingdom, promulgated in 1930, and the first threshold limit values for asbestos published by the American Conference of Government and Industrial Hygienists in 1938 (Selikoff and Lee 1978).


The fibrotic changes which characterize asbestosis are the consequence of an inflammatory process set up by fibres retained in the lung. The fibrosis of asbestosis is interstitial, diffuse, tends to involve the lower lobes and peripheral zones preferentially and, in the advanced case, is associated with obliteration of the normal lung architecture. Fibrosis of the adjacent pleura is common. Nothing in the histological features of asbestosis distinguish it from interstitial fibrosis due to other causes, except the presence of asbestos in the lung either in the form of asbestos bodies, visible to light microscopy, or as uncoated fibres, most of which are too fine to be seen except by means of electron microscopy. Thus, the absence of asbestos bodies in images derived from light microscopy does not rule out either exposure or the diagnosis of asbestosis. At the other end of the spectrum of disease severity, the fibrosis may be limited to relatively few zones and affect mainly the peribronchiolar regions (see figure 10.20), giving rise to what has been called asbestos-related small airways disease. Again, except perhaps for more extensive involvement of membranous small airways, nothing in the histologic changes of this condition distinguishes it from small airways disease due to other causes (such as cigarette smoking or exposure to other mineral dusts) other than the presence of asbestos in the lung. Small airways disease may be the only manifestation of asbestos-related lung fibrosis or it may coexist with varying degrees of interstitial fibrosis, that is, asbestosis (Wright et al. 1992). Carefully considered criteria have been published for the pathological grading of asbestosis (Craighead et al. 1982). In general, the extent and intensity of the lung fibrosis relates to the measured lung dust burden (Liddell and Miller 1991).

Figure 10.20 Asbestos-related small airways disease

Peribronchiolar fibrosis and infiltration by inflammatory cells is seen on a histologic section of  a respiratory bronchiole (R) and its distal divisions or alveolar ducts (A). The surrounding lung is  mostly normal but with focal thickening of the interstitial tissue (arrow), representing early asbestosis

Source: Fraser et al. 1990

Clinical features

Shortness of breath, the earliest, most consistently reported and most distressing complaint, has led to asbestosis being called a monosymptomatic disease (Selikoff and Lee 1978). Shortness of breath precedes other symptoms which include a dry, often distressing cough, and chest tightness-which is thought to be associated pleural reactions. Late inspiratory rales or crackles which persist after coughing are heard, first in the axilla and over the lung bases, before becoming more generalized as the condition advances, and are thought to be due to the explosive opening of airways which close on expiration. Coarse rales and rhonchi, if present, are thought to reflect bronchitis either in response to working in a dusty environment, or due to smoking.

Chest imaging

Traditionally, the chest radiograph has been the most important single diagnostic tool for establishing the presence of asbestosis. This has been facilitated by the use of the ILO (1980) radiological classification, which grades the small irregular opacities that are characteristic of asbestosis on a continuum from no disease to the most advanced disease, both for severity (described as profusion on a 12-point scale from -/0 to 3/+) and extent (described as the number of zones affected). Despite between reader differences, even among those who have completed training courses in reading, this classification has proved particularly useful in epidemiological studies, and has also been used clinically. However, pathological changes of asbestosis can be present on lung biopsy in up to 20% of subjects with a normal chest radiograph. In addition, small irregular opacities of low profusion (e.g., 1/0 on the ILO scale) are not specific for asbestosis but can be seen in relation to other exposures, for instance to cigarette smoking (Browne 1994).

Computer tomography (CT) has revolutionized the imaging of interstitial lung disease, including asbestosis, with high resolution computer tomography (HRCT) adding increased sensitivity to the detection of interstitial and pleural disease (Fraser et al. 1990). Characteristics of asbestosis which can be identified by HRCT include thickened interlobular (septal) and intralobular core lines, parenchymal bands, curvilinear subpleural lines and subpleural dependent densities, the first two being the most distinctive for asbestosis (Fraser et al. 1990). HRCT can also identify these changes in cases with pulmonary function deficit in whom the chest radiograph is inconclusive. Based on postmortem HRCT, thickened intralobular lines have been shown to correlate with peribronchiolar fibrosis, and thickened interlobular lines with interstitial fibrosis (Fraser et al. 1990). As yet, no standardized reading method has been developed for the use of HRCT in asbestos-related disease. In addition to its cost, the fact that a CT device is a hospital installation makes it unlikely that it will replace the chest radiograph for surveillance and epidemiological studies; its role will likely remain limited to individual case investigation or to planned studies intended to address specific issues. Figure 10.21 illustrates the use of chest imaging in the diagnosis of asbestos-related lung disease; the case shown exhibits asbestosis, asbestos-related pleural disease and lung cancer. Large opacities, a complication of other pneumoconioses, in particular silicosis, are unusual in asbestosis and are usually due to other conditions such as lung cancer (see the case described in figure 10.21) or rounded atelectasis.

Figure 10.21 Chest imaging in asbestos-related lung diseaseA posteroanterior chest radiograph

(A) shows asbestosis involving both lungs and assessed as ILO  category 1/1, associated with bilateral pleural thickening (open arrows) and a vaguely defined  opacity (arrow heads) in the left upper lobe. On HRCT scan (B), this was shown to be a dense mass  (M) abutting onto the pleura and transthoracic needle biopsy revealed an adenocarcinoma of the  lung. Also on CT scan (C), at high attenuation pleural plaques can be seen (arrow heads) as well as  a thin curvilinear opacity in the parenchyma underlying the plaques with interstitial abnormality in  the lung between the opacity and the pleuraSource: Fraser et al. 1990

Lung function tests

Established interstitial lung fibrosis due to asbestos exposure, like established lung fibrosis due to other causes, is usually but not invariably associated with a restrictive lung function profile (Becklake 1994). Its features include reduced lung volumes, in particular vital capacity (VC) with preservation of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC%), reduced lung compliance, and impaired gas exchange. Air flow limitation with reduced FEV1/FVC may, however, also be present as a response to a dusty work environment or to cigarette smoke. In the earlier stages of asbestosis, when the pathological changes are limited to peribronchiolar fibrosis and even before small irregular opacities are evident on the chest radiograph, impairment of tests reflecting small airway dysfunction such as the Maximum Mid-expiratory Flow Rate may be the only sign of respiratory dysfunction. Responses to the stress of exercise may also be impaired early in the disease, with increased ventilation in relation to the oxygen requirement of the exercise (due to an increased breathing frequency and shallow breathing) and impaired O2 exchange. As the disease progresses, less and less exercise is required to compromise O2 exchange. Given that the asbestos-exposed worker may exhibit features of both a restrictive and an obstructive lung function profile, the wise physician interprets the lung function profile in the asbestos worker for what it is, as a measure of impairment, rather than as an aid to diagnosis. Lung functions, in particular vital capacity, provide a useful tool for the follow-up of subjects individually, or in epidemiological studies, for instance after exposure has ceased, to monitor the natural history of asbestosis or asbestos-related pleural disease.

Other laboratory tests

Bronchoalveolar lavage is increasingly used as a clinical tool in the investigation of asbestos-related lung disease:

1.     to rule out other diagnoses

2.     to assess the activity of the pulmonary reactions under study such as fibrosis or

3.     to identify the agent in the form of asbestos bodies or fibres.

It is also used to study disease mechanisms in humans and animals (Bégin, Cantin and Massé 1989). The uptake of Gallium-67 is used as a measure of the activity of the pulmonary process, and serum antinuclear antibodies (ANA) and rheumatoid factors (RF), both of which reflect the immunological status of the individual, have also been investigated as factors influencing disease progression, and/or accounting for between individual differences in response to what appears to be the same level and dose of exposure.

Epidemiology including natural history

The prevalence of radiological asbestosis documented in workforce-based surveys varies considerably and, as might be expected, these differences relate to differences in exposure duration and intensity rather than differences between workplaces. However, even when these are taken into account by restricting comparison of exposure response relationships to those studies in which exposure estimates were individualized for each cohort member and based on job history and industrial hygiene measurements, marked fibre and process related gradients are evident (Liddell and Miller 1991). For instance, a 5% prevalence of small irregular opacities (1/0 or more on the ILO classification) resulted from a cumulative exposure to approximately 1,000 fibre years in Quebec chrysotile miners, to approximately 400 fibre years in Corsican chrysotile miners, and to under 10 fibre years in South African and Australian crocidolite miners. By contrast, for textile workers exposed to Quebec chrysotile, a 5% prevalence of irregular small opacities resulted from a cumulative exposure to under 20 fibre years. Lung dust burden studies are also consistent with a fibre gradient for evoking asbestosis: in 29 men in Pacific shipyard trades with asbestosis associated with mainly amosite exposure, the average lung burden found in autopsy material was 10 million amosite fibres per gram of dry lung tissue compared to an average chrysotile burden of 30 million fibres per gram of dry lung tissue in 23 Quebec chrysotile miners and millers (Becklake and Case 1994). Fibre size distribution contributes to but does not fully explain these differences, suggesting that other plant-specific factors, including other workplace contaminants, may play a role.

Asbestosis may remain stable or progress, but probably does not regress. Progression rates increase with age, with cumulative exposure, and with the extent of existing disease, and are more likely to occur if exposure was to crocidolite. Radiological asbestosis can both progress and appear long after exposure ceases. Deterioration of lung functions may also occur after exposure has ceased (Liddell and Miller 1991). An important issue (and one on which the epidemiological evidence is not consistent) is whether continued exposure increases the chance of progression once radiological changes have developed (Browne 1994; Liddell and Miller 1991). In some jurisdictions, for example in the United Kingdom, the number of cases of asbestosis presenting for worker's compensation have decreased over the last decades, reflecting the workplace controls put in place in the 1970s (Meredith and McDonald 1994). In other countries, for instance in Germany (Gibbs, Valic and Browne 1994), rates of asbestosis continue to rise. In the United States, age-adjusted asbestos-related mortality rates (based on mention of asbestosis on the death certificate as either the cause of death or as playing a contributory role) for age 15+ increased from under 1 per million in 1960 to over 2.5 in 1986, and to 3 in 1990 (US Dept. of Health and Human Services, 1994).

Diagnosis and case management

Clinical diagnosis depends on:

1.     establishing the presence of disease

2.     establishing whether exposure occurred and

3.     evaluating whether the exposure was likely to have caused the disease.

The chest radiograph remains the key tool to establish the presence of disease, supplemented by HRCT if available in cases where there is doubt. Other objective features are the presence of basal crackles, while lung function level, including exercise challenge, is useful in establishing impairment, a step required for compensation evaluation. Since neither the pathology, radiological changes, nor the symptoms and lung function changes associated with asbestosis are different from those associated with interstitial lung fibrosis due to other causes, establishing exposure is key to diagnosis. In addition, the many uses of asbestos products whose content is often not known to the user makes an exposure history a much more daunting exercise in interrogation than was previously thought. If the exposure history appears inadequate, identification of the agent in biological specimens (sputum, bronchoalveolar lavage and when indicated, biopsy) can corroborate exposure; dose in the form of lung burden can be assessed quantitatively by autopsy or in surgically removed lungs.

Evidence of disease activity (from a gallium-67 scan or bronchoalveolar lavage) may assist in estimating prognosis, a key issue in this irreversible condition. Even in the absence of consistent epidemiological evidence that progression is slowed once exposure ceases, such a course may be prudent and certainly desirable. It is not, however, a decision easy to take or recommend, particularly for older workers with little opportunity for job retraining. Certainly exposure should not continue in any workplace not in conformity with current permissible exposure levels. Criteria for the diagnosis of asbestosis for epidemiological purposes are less demanding, particularly for cross-sectional workforce-based studies which include those well enough to be at work. These usually address issues of causality and often use markers that indicate minimal disease, based either on lung function level or on changes in the chest radiograph. By contrast, criteria for diagnosis for medicolegal purposes are considerably more stringent and vary according to the legal administrative systems under which they operate, varying between states within countries as well as between countries.

Asbestos-Related Pleural Disease

Historical perspective

Early descriptions of asbestosis mention fibrosis of the visceral pleura as part of the disease process (see "Pathology", above). In the 1930s there were also reports of circumscribed pleural plaques, often calcified, in the parietal pleura (which lines the chest wall and covers the surface of the diaphragm), and occurring in those with environmental, not occupational, exposure. A 1955 workforce-based study of a German factory reported a 5% prevalence of pleural changes on the chest radiograph, thereby drawing attention to the fact that pleural disease might be the primary if not the only manifestation of exposure. Visceroparietal pleural reactions, including diffuse pleural fibrosis, benign pleural effusion (reported first in the 1960s) and rounded atelectasis (first reported in the 1980s) are now all considered interrelated reactions which are usefully distinguished from pleural plaques on the basis of pathology and probably pathogenesis, as well as clinical features and presentation. In jurisdictions in which the prevalence and/or incidence rates of asbestosis are decreasing, pleural manifestations, increasingly common in surveys, are increasingly the basis of detection of past exposure, and increasingly the reason for an individual seeking medical attention.

Pleural plaques

Pleural plaques are smooth, raised, white irregular lesions covered with mesothelium and found on the parietal pleura or diaphragm (figure 10.22).

Figure 10.22 Asbestos-related pleural disease

A diaphragmatic pleural plaque (A) is seen in an autopsy specimen as a smooth well defined focus  of fibrosis on the diaphragm of a construction worker with incidental exposure to asbestos and  asbestos bodies in the lung. Visceral pleural fibrosis (B) is seen on an inflated autopsy lung  specimen, and radiates from two central foci on the visceral pleura of the lung of a construction  worker with asbestos exposure who also exhibited several parietal pleural plaques.

Source: Fraser et al. 1990.

They vary in size, are often multiple, and tend to calcify with increasing age (Browne 1994). Only a small proportion of those detected at autopsy are seen on the chest radiograph, though most can be detected by HRCT. In the absence of pulmonary fibrosis, pleural plaques may cause no symptoms and may be detected only in screening surveys using chest radiography. Nevertheless, in workforce surveys, they are consistently associated with modest but measurable lung function impairment, mainly in VC and FVC (Ernst and Zejda 1991). In radiological surveys in the United States, rates of 1% are reported in men without known exposure, and 2.3% in men which include those in urban populations, with occupational exposure. Rates are also higher in communities with asbestos industries or high usage rates, while in some workforces, such as sheet metal workers, insulators, plumbers and railroad workers, rates may exceed 50%. In a 1994 Finnish autopsy survey of 288 men aged 35 to 69 years who died suddenly, pleural plaques were detected in 58%, and exhibited the tendency to increase with age, with the probability of exposure (based on history), with the concentration of asbestos fibres in lung tissue, and with smoking (Karjalainen et al. 1994). The aetiologic fraction of plaques attributable to a lung dust burden of 0.1 million fibres per gram of lung tissue was estimated at 24%, (this value is considered to be an underestimate). Lung dust burden studies are also consistent with fibre gradient in potency for evoking pleural reactions; in 103 men with amosite exposure in Pacific shipyard trades, all with pleural plaques, the average autopsy lung burden was 1.4 million fibres per gram of lung tissue, compared to 15.5 and 75 million fibres per gram of lung tissue for chrysotile and tremolite respectively in 63 Quebec chrysotile miners and millers examined in the same way (Becklake and Case 1994).

Visceroparietal pleural reactions

Though the pathology and pathogenesis of the different forms of visceroparietal reaction to asbestos exposure are almost certainly interrelated, their clinical manifestations and how they come to attention differs. Acute exudative pleural reactions may occur in the form of effusions in subjects whose lungs do not manifest other asbestos-related disease, or as an exacerbation in the severity and extent of existing pleural reactions. Such pleural effusions are called benign by way of distinguishing them from effusions associated with malignant mesothelioma. Benign pleural effusions occur typically 10 to 15 years after first exposure (or after limited past exposure) in individuals in their 20s and 30s. They are usually transient but may reoccur, may involve one or both sides of the chest simultaneously or sequentially, and may be either silent or associated with symptoms including chest tightness and/or pleural pain and dyspnoea. The pleural fluid contains leucocytes, often blood, and is albumin-rich; only rarely does it contain asbestos bodies or fibres which may, however, be found in biopsy material of the pleura or underlying lung. Most benign pleural effusions clear spontaneously, though in a small proportion of subjects (of the order of 10% in one series) these effusions may evolve into diffuse pleural fibrosis (see figure 10.22), with or without the development of lung fibrosis. Local pleural reactions may also fold in upon themselves, trapping lung tissue and causing well defined lesions called rounded atelectasis or pseudotumour because they may have the radiological appearance of lung cancer. In contrast to pleural plaques, which seldom cause symptoms, visceroparietal pleural reactions are usually associated with some shortness of breath as well as lung function impairment, particularly when there is obliteration of the costophrenic angle. In one study, for instance, average FVC deficit was 0.07 l when the chest wall was involved and 0.50 l when the costophrenic angle was involved (Ernst and Zejda in Liddell and Miller 1991). As already indicated, the distribution and determinants of pleural reactions vary considerably between workforces, with prevalence rates increasing with:

1.     estimated residence time of fibre in the lung (measured as time since first exposure)

2.     exposures primarily to or including amphibole and

3.     possibly intermittence of exposure, given the high rates of contamination in occupations in which use of asbestos materials is intermittent, but exposure probably heavy.

Lung Cancer

Historical perspective

The 1930s saw the publication of a number of clinical case reports from the United States, the United Kingdom and Germany of lung cancer (a condition much less common then than it is today) in asbestos workers, most of whom also had asbestosis of varying degrees of severity. Further evidence of the association between the two conditions was provided in the 1947 Annual Report of His Majesty's Chief Inspector of Factories, which noted that lung cancer had been reported in 13.2% of male deaths attributed to asbestosis in the period 1924 to 1946 and in only 1.3% of male deaths attributed to silicosis. The first study to address the causal hypothesis was a cohort mortality study of a large United Kingdom asbestos textile plant (Doll 1955), one of the first such workforce-based studies, and by 1980, after at least eight such studies in as many workforces had confirmed an exposure-response relationship, the association was generally accepted as causal (McDonald and McDonald in Antman and Aisner 1987).

Clinical features and pathology

In the absence of other associated asbestos disease, the clinical features and criteria for the diagnosis of asbestos-associated lung cancer are no different from those for lung cancer not associated with asbestos exposure. Originally, asbestos-associated lung cancers were considered to be scar cancers, similar to lung cancer seen in other forms of diffuse lung fibrosis such as scleroderma. Features which favoured this view were their location in the lower lung lobes (where asbestosis is usually more marked), their sometimes multicentric origin and a preponderance of adenocarcinoma in some series. However, in most reported workforce-based studies, the distribution of cell types was no different from that seen in studies of non-asbestos-exposed populations, supporting the view that asbestos itself may be a human carcinogen, a conclusion reached by the International Agency for Research on Cancer (World Health Organization: International Agency for Research on Cancer 1982). Most but not all asbestos-related lung cancers occur in association with radiologic asbestosis (see below).


Cohort studies confirm that lung cancer risk increases with exposure, though the fractional rate of increase for each fiber per milliliter per year exposed varies, and is related both to fibre type and to industrial process (Health Effects Institute-Asbestos Research 1991). For instance, for mainly chrysotile exposures in mining, milling and friction product manufacture, the increase ranged from approximately 0.01 to 0.17%, and in textile manufacture from 1.1 to 2.8%, while for exposure to amosite insulation products and some cement product exposures involving mixed fibre, rates of as high as 4.3 and 6.7% have been recorded (Nicholson 1991). Cohort studies in asbestos workers also confirm that cancer risk is demonstrable for non-smokers and that risk is increased (closer to multiplicative than additive) by cigarette smoking (McDonald and McDonald in Antman and Aisner 1987). The relative risk for lung cancer declines after exposure ceases, although the decline appears slower than that which occurs after quitting smoking. Lung dust burden studies are also consistent with a fibre gradient in lung cancer production; 32 men in Pacific shipyard trades with mainly amosite exposure had a lung dust burden of 1.1 million amosite fibres per gram of dry lung tissue compared to 36 Quebec chrysotile miners with an average lung dust burden of 13 million chrysotile fibres per gram of lung tissue (Becklake and Case 1994).

Relationship to asbestosis

In the 1955 autopsy study of causes of death in 102 workers employed in the United Kingdom asbestos textile factory referred to above (Doll 1955), lung cancer was found in 18 individuals, 15 of whom also had asbestosis. All subjects in whom both conditions were found had worked for at least 9 years before 1931, when national regulations for asbestos dust control were introduced. These observations suggested that as exposure levels decreased, the competing risk of death from asbestosis also decreased and workers lived long enough to exhibit the development of cancer. In most workforce-based studies, older workers with long service have some pathological evidence of asbestosis (or asbestos-related small airways disease) at autopsy even though this may be minimal and not detectable on the chest radiograph in life (McDonald and McDonald in Antman and Aisner 1987). Several but not all cohort studies are consistent with the view that not all excess lung cancers in populations exposed to asbestos are related to asbestosis. More than one pathogenetic mechanism may in fact be responsible for lung cancers in individuals exposed to asbestos depending on the site and deposition of the fibres. For instance, long thin fibres, which are deposited preferentially at airway bifurcations, are thought to become concentrated and to act as inducers of the process of cancerogenesis through chromosomal damage. Promoters of this process may include continued exposure to asbestos fibres or to tobacco smoke (Lippman 1995). Such cancers are more likely to be squamous cell in type. By contrast, in lungs which are the site of fibrosis, cancerogenesis may result from the fibrotic process: such cancers are more likely to be adenocarcinomas.

Implications and attributability

While determinants of excess cancer risk can be derived for exposed populations, attributability in the individual case cannot. Obviously, attributability to asbestos exposure is more likely and credible in an exposed individual with asbestosis who has never smoked than in an exposed individual without asbestosis who smokes. Nor can this probability be modelled reasonably. Lung dust burden measurements may supplement a careful clinical assessment but each case must be evaluated on its merits (Becklake 1994).

Malignant Mesothelioma

Pathology, diagnosis, ascertainment and clinical features

Malignant mesotheliomas arise from the serous cavities of the body. Approximately two-thirds arise in the pleura, about one-fifth in the peritoneum, while the pericardium and tunica vaginalis are much less frequently affected (McDonald and McDonald in Lidell and Miller 1991). Since mesothelial cells are pluripotential, the histological features of mesothelial tumours may vary; in most series, epithelial, sarcomatous and mixed forms account for approximately 50, 30 and 10% of cases respectively. Diagnosis of this rare tumour, even in the hands of experienced pathologists, is not easy, and mesothelioma panel pathologists often confirm only a small percentage, in some studies less than 50% of cases submitted for review. A variety of cytological and immunohistochemical techniques have been developed to assist in differentiating malignant mesothelioma from the main alternative clinical diagnoses, namely, secondary cancer or reactive mesothelial hyperplasia; this remains an active research field in which expectations are high but findings inconclusive (Jaurand, Bignon and Brochard 1993). For all these reasons, ascertainment of cases for epidemiological surveys is not straightforward, and even when based on cancer registries, may be incomplete. In addition, confirmation by expert panels using specified pathological criteria is necessary to assure comparability in criteria for registration.

Clinical features

Pain is usually the presenting feature. For pleural tumours, this starts in the chest and/or shoulders, and may be severe. Breathlessness follows, associated with pleural effusion and/or progressive encasement of the lung by tumour, and weight loss. With peritoneal tumours, abdominal pain is usually accompanied by swelling. Imaging features are illustrated in figure 10.23 . The clinical course is usually rapid and median survival times, six months in a 1973 report and eight months in a 1993 report, have changed little over the last two decades, despite the greater public and medical awareness which often leads to earlier diagnosis and despite advances in diagnostic techniques and an increase in the number of treatment options for cancer.

Figure 10.23 Malignant mesothelioma

Seen on an overpenetrated chest roetngenogram (A) as a large mass in the axillary region.  Note the associated reduction in volume of the right haemothorax with marked irregular nodular  thickening of the pleura of the whole right lung. CT scan (B) confirms the extensive pleural  thickening involving parietal and mediastinal pleura (closed arrows) in and around the ribs.

Source: Fraser et al. 1990


In the 15 years which followed the 1960 report of the mesothelioma case series from the Northwest Cape, South Africa (Wagner 1996), international confirmation of the association came from reports of other case series from Europe (United Kingdom, France, Germany, Holland), the United States (Illinois, Pennsylvania and New Jersey) and Australia, and of case control studies from the United Kingdom (4 cities), Europe (Italy, Sweden, Holland) and from the United States and Canada. Odds ratios in these studies ranged from 2 to 9. In Europe in particular, the association with shipyard occupations was strong. In addition, proportional mortality studies in asbestos-exposed cohorts suggested that risk was associated both with fibre type and with industrial process, with rates attributable to mesothelioma ranging from 0.3% in chrysotile mining to 1% in chrysotile manufacturing, compared with 3.4% in amphibole mining and manufacturing and as high as 8.6% for exposure to mixed fibre in insulation (McDonald and McDonald in Liddell and Miller 1991). Similar fibre gradients are shown in cohort mortality studies which, given the short survival times of these tumours, are a reasonable reflection of incidence. These studies also show longer latent periods when exposure was to chrysotile compared to amphiboles. 

Geographical variation in incidence has been documented using Canadian age-and sex-specific rates for 1966 to 1972 to calculate expected rates (McDonald and McDonald in Liddell and Miller 1991); rate ratios (values actually observed over expected) were 0.8 for the United States (1972), 1.1 for Sweden (1958 to 1967), 1.3 for Finland (1965 to 1969), 1.7 for United Kingdom (1967 to 1968), and 2.1 for the Netherlands (1969 to 1971). While technical factors including ascertainment may obviously contribute to the variation recorded, the results do suggest higher rates in Europe than in North America.

Time trends and gender differences in mesothelioma incidence have been used as a measure of the health impact of asbestos exposure on populations. The best estimates for overall rates in industrialized countries before 1950 are under 1.0 per million for men and women (McDonald and McDonald in Jaurand and Bignon 1993). Subsequently, rates increased steadily in men and either not at all or less in women. For instance, overall rates in men and women per million were reported at 11.0 and under 2.0 in the United States in 1982, 14.7 and 7.0 in Denmark for 1975-80, 15.3 and 3.2 in the United Kingdom for 1980-83, and 20.9 and 3.6 in the Netherlands for 1978-87. Higher rates in men and women, but excluding younger subjects, were reported for crocidolite mining countries: 28.9 and 4.7 respectively in Australia (aged 20+) for 1986, and 32.9 and 8.9 respectively in South African Whites (aged 15+) for 1988 (Health Effects Institute-Asbestos Research 1991). The rising rates in men are likely to reflect occupational exposure, and if so, they should level off or decrease within the 20-to 30-year "incubation" period following the introduction of workplace controls and reduction of exposure levels in most workplaces in most industrialized countries in the 1970s. In countries in which the rates in women are rising, this increase may reflect their increasing engagement in occupations with risk exposure, or the increasing environmental or indoor contamination of urban air (McDonald 1985).


Environmental factors are clearly the main determinants of mesothelioma risk, exposure to asbestos being the most important, though the occurrence of family clusters maintains interest in the potential role of genetic factors. All asbestos fibre types have been implicated in mesothelioma production, including anthophyllite for the first time in a recent report from Finland (Meurman, Pukkala and Hakama 1994). However, there is a substantial body of evidence, from proportional and cohort mortality studies and lung burden studies, which suggests the role of a fibre gradient in mesothelioma production, risk being higher for exposures to mainly amphiboles or amphibole chrysotile mixtures, compared with mainly chrysotile exposures. In addition, there are rate differences between workforces for the same fibre at what appears to be the same exposure level; these remain to be explained, though fibre size distribution is a likely contributing factor.

The role of tremolite has been widely debated, a debate sparked by the evidence of its biopersistence in lung tissue, animal and human, compared to that of chrysotile. A plausible hypothesis is that the many short fibres which reach and are deposited in peripheral lung airways and alveoli are cleared to subpleural lymphatics where they collect; their potency in mesothelioma production depends on their biopersistence in contact with pleural surfaces (Lippmann 1995). In human studies, mesothelioma rates are lower for populations exposed at work to chrysotile relatively uncontaminated by tremolite (for instance, in Zimbabwean mines) compared to those exposed to chrysotile which is so contaminated (for instance, in Quebec mines), and these findings have been replicated in animal studies (Lippmann 1995). Also, in a multivariate analysis of lung fibre burden in material from a Canada-wide mesothelioma case control study (McDonald et al. 1989), the results suggested that most if not all mesotheliomas could be explained by tremolite lung fibre burden. Finally, a recent analysis of the mortality in the cohort of over 10,000 Quebec chrysotile miners and millers born between 1890 and 1920, and followed to 1988 (McDonald and McDonald 1995), supports this view: in almost 7,300 deaths, the 37 mesothelioma deaths were concentrated in certain mines from the Thetford area, yet the lung burden of 88 cohort members from the mines implicated did not differ from that of miners from other mines in terms of chrysotile fibre burden, only in terms of tremolite burden (McDonald et al. 1993).

What has been called the tremolite question is perhaps the most important of the currently debated scientific issues, and it also has public health implications. Note must also be made of the important fact that in all series and jurisdictions, a certain proportion of cases occur without reported asbestos exposure, and that only in some of these cases do lung dust burden studies point to previous environmental or occupational exposure. Other occupational exposures have been implicated in mesothelioma production, for instance in talc, vermiculite and possibly mica mining, but in these, the ore contained either tremolite or other fibres (Bignon, Peto and Saracci 1989). An open search for other exposures, occupational or non-occupational, to fibres, inorganic and organic, and to other agents which may be associated with mesothelioma production, should continue.

Other Asbestos-Related Diseases

Chronic airways disease

Usually included under this rubric are chronic bronchitis and chronic obstructive pulmonary disease (COPD), both of which can be diagnosed clinically, and emphysema, until recently diagnosed only by pathological examination of lungs removed at autopsy or otherwise (Becklake 1992). A major cause is smoking, and, over the past decades, mortality and morbidity due to chronic airways disease has increased in most industrialized countries. However, with the decline of pneumoconiosis in many workforces, evidence has emerged to implicate occupational exposures in the genesis of chronic airways disease, after taking into account the dominant role of smoking. All forms of chronic airways disease have been shown to be associated with work in a variety of dusty occupations, including those occupations in which an important component of the dust contaminating the workplace was asbestos (Ernst and Zejda in Liddell and Miller 1991). Total pollutant burden, rather than exposure to any of its particular components, in this case asbestos dust, is thought to be implicated, in much the same way as the effect of smoking exposure on chronic airways diseases is viewed, that is, in terms of total exposure burden (e.g., as pack-years), not exposure to any one of the over 4,000 constituents of tobacco smoke. (see elsewhere in this volume for a further discussion of the relationship between occupational exposures and chronic airways disease).

Other cancers

In several of the earlier cohort studies of asbestos exposed workers, mortality attributable to all cancers exceeded that expected, based on national or regional vital statistics. While lung cancer accounted for most of the excess, other cancers implicated were gastro-intestinal cancers, laryngeal cancer and cancer of the ovaries, in that order of frequency. For gastro-intestinal cancers, (including those affecting the oesophagus, the stomach, the colon and the rectum), the relevant exposure in occupational cohorts is presumed to be via swallowing asbestos-laden sputum raised from the major airways in the lung, and in earlier times, (before protection measures were taken against exposure at lunch sites) direct contamination of food in workplaces which had no lunch areas separate from working areas of plants and factories. Retrograde flow via the thoracic duct from lymph nodes draining the lung might also occur (see "Fate of inhaled fibres", above). Because the association was inconsistent in the different cohorts studied, and because exposure response relationships were not always seen, there has been a reluctance to accept the evidence of the association between occupational exposure and asbestos exposure as causal (Doll and Peto 1987; Liddell and Miller 1991).

Cancer of the larynx is much less common than gastro-intestinal or lung cancer. As early as the 1970s, there were reports of an association between cancer of the larynx and asbestos exposure. Like lung cancer, a major risk factor and cause of laryngeal cancer is smoking. Laryngeal cancer is also strongly associated with alcohol consumption. Given the location of the larynx (an organ exposed to all the inhaled pollutants to which the lungs are exposed) and given the fact that it is lined by the same epithelium that lines the major bronchi, it is certainly biologically plausible that cancer of the larynx occurs as a result of asbestos exposure. However, the overall evidence available to date is inconsistent, even from large cohort studies such as the Quebec and Balangero (Italy) chrysotile miners, possibly because it is a rare cancer and there is still reluctance to regard the association as causal (Liddell and Miller 1991) despite its biological plausibility. Cancer of the ovaries has been recorded in excess of expected in three cohort studies (WHO 1989). Misdiagnosis, in particular as peritoneal mesothelioma, may explain most of the cases (Doll and Peto 1987).

Prevention, Surveillance and Assessment

Historical and current approaches

Prevention of any pneumoconiosis, including asbestosis, has traditionally been through:

1.     engineering and work practices to maintain airborne fibre levels as low as possible, or at least in conformity with permissible exposure levels usually set by law or regulation

2.     surveillance, conducted to record trends of markers of disease in exposed populations and monitor the results of control measures

3.     education and product labelling aimed at assisting workers as well as the general public in avoiding non-occupational exposure.

Permissible exposure levels were originally directed at controlling asbestosis and were based on industrial hygiene measurements in million particles per cubic foot, gathered using the same methods as were used for the control of silicosis. With the shift in biological focus to fibres, in particular long thin ones, as the cause of asbestosis, methods more appropriate to their identification and measurement in air were developed and, given these methods, the focus on the more abundant short fibres which contaminate most workplaces was minimized. Aspect (length to diameter) ratios for most particles of milled chrysotile asbestos fall within the range 5:1 to 20:1, going up to 50:1, in contrast to most particles of milled amphibole asbestos (including cleavage fragments) whose values fall below 3:1. The introduction of the membrane filter for fibre counting of air samples led to an arbitrary industrial hygiene and medical definition of a fibre as a particle at least 5 µm long, 3 µm or less thick, and with a length to width ratio of at least 3:1. This definition, used for many of the studies of exposure-response relationships, forms the scientific basis for setting environmental standards.

For instance, it was used in a meeting sponsored by the World Health Organization (1989) to propose occupational exposure limits and has been adopted by agencies such as the US Occupational Safety and Health Administration; it is retained mainly for reasons of comparability. The WHO meeting, chaired by Sir Richard Doll, while recognizing that the occupational exposure limit in any country can only be set by the appropriate national body, recommended that countries having high limits should take urgent steps to lower the occupational exposure for an individual worker to 2 f/ml (eight-hour time-weighted average) and that all countries should move as quickly as possible to 1 f/ml (eight-hour time-weighted average) if they had not already done so. With the decrease in asbestosis rates in some industrialized countries, and concern over asbestos-related cancers in all, attention has now shifted to determining whether the same fibre parameters-that is, at least 5 µm long, 3 µm or less thick, and with a length to width ratio of at least 3:1-are also appropriate for controlling carcinogenesis (Browne 1994). A current theory of asbestos carcinogenesis implicates short as well as long fibres (Lippmann 1995). In addition, given the evidence for a fibre gradient in mesothelioma and lung cancer production, and to a lesser extent, for asbestosis production, an argument could be made for permissible exposure levels taking fibre type into account. Some countries have addressed the issue by banning the use (and thus the import) of crocidolite, and setting more stringent exposure levels for amosite, namely 0.1 f/l (McDonald and McDonald 1987).

Exposure levels in the workplace

Permissible exposure levels embody the hypothesis, based on all available evidence, that human health will be preserved if exposure is maintained within those limits. Revision of permissible exposure levels, when it occurs, is invariably towards greater stringency (as described in the paragraph above). Nevertheless, despite good compliance with workplace controls, cases of disease continue to occur, for reasons of personal susceptibility (for instance, higher-than-average fibre retention rates) or because of failure of workplace controls for certain jobs or processes. Engineering controls, improved workplace practices and the use of substitutes, described elsewhere in the chapter, have been implemented internationally (Gibbs, Valic and Browne 1994) in larger establishments through industry, union and other initiatives. For instance, according to a 1986 worldwide industry review, compliance with the current recommended standard of 1 f/ml had been achieved at 83% of production sites (mines and mills) covering 13,499 workers in 6 countries; in 96% of 167 cement factories operating in 23 countries; in 71% of 40 textile factories covering over 2,000 workers operating in 7 countries; and in 97% of 64 factories manufacturing friction materials, covering 10,190 workers in 10 countries (Bouige 1990). However, a not unimportant proportion of such workplaces still do not comply with regulations, not all manufacturing countries participated in this survey, and the anticipated health benefits are evident only in some national statistics, not in others ("Diagnosis and case management", above). Control in demolition processes and small enterprises using asbestos continues to be less than successful, even in many industrialized countries.


The chest radiograph is the main tool for asbestosis surveillance, cancer registries and national statistics for asbestos-related cancers. A commendable initiative in international surveillance of mining, tunnelling and quarrying, undertaken by the ILO through voluntary reporting from governmental sources, focuses on coal and hard-rock mining but could include asbestos. Unfortunately, follow-through has been poor, with the last report, which was based on data for 1973-77, being published in 1985 (ILO 1985). Several countries issue national mortality and morbidity data, an excellent example being the Work-related Lung Disease Surveillance Report for the United States, a report referred to above (USDHSS 1994). Such reports provide information to interpret trends and evaluate the impact of control levels at a national level. Larger industries should (and many do) keep their own surveillance statistics, as do some unions. Surveillance of smaller industries may require specific studies at appropriate intervals. Other sources of information include programmes such as the Surveillance of Work-related Respiratory Diseases (SWORD) in the United Kingdom, which gathers regular reports from a sample of the country's chest and occupational physicians (Meredith and McDonald 1994), and reports from compensation boards (which often, however, do not provide information on workers at risk).

Product labelling, education and the information highway

Mandatory product labelling together with worker education and education of the general public are powerful tools in prevention. While in the past, this took place within the context of worker organizations, worker management committees, and union education programmes, future approaches could exploit electronic highways to make available databases on health and safety in toxicology and medicine.

Exposure in buildings and from water supplies

In 1988, a review of potential health risks associated with working in buildings constructed using asbestos-containing materials was mandated by the US Congress (Health Effects Institute-Asbestos Research 1991). The results of a large number of indoor sampling studies from Europe, the United States and Canada were used in risk estimates. The lifetime risk for premature cancer death was estimated to be 1 per million for those exposed for 15 years in schools (for estimated exposure levels ranging from .0005 to .005 f/ml) and 4 per million for those exposed for 20 years working in office buildings (for estimated exposure levels ranging from .0002 to .002 f/ml). For comparison, the risk for occupational exposure to 0.1 f/ml (i.e., in compliance with the permissible exposure limit proposed by the US Occupational Safety and Health Administration) for 20 years was estimated at 2,000 per million exposed. Measurements in drinking water in urban communities show considerable variation, from undetectable levels to high levels ranging from 0.7 million f/l in Connecticut, USA, to levels ranging from 1.1 million to 1.3 billion f/l in the mining areas of Quebec (Bignon, Peto and Saracci 1989). Some contamination may also occur from the asbestos cement pipes which must service most urban water reticulation services in the world. However, a working group which reviewed the evidence in 1987 did not discount the potential associated hazard, but did not regard the health risks associated with asbestos ingestion as "one of the most pressing public health hazards" (USDHHS 1987), a view concordant with the concluding remarks in an IARC (WHO) monograph on non-occupational exposure to mineral fibres (Bignon, Peto and Saracci 1989).

Asbestos and other fibres in the 21st century

The first half of the twentieth century was characterized by what could be described as gross neglect of asbestos-related ill health. Before the Second World War, the reasons for this are not clear; the scientific basis for control was there but perhaps not the will and not the worker militancy. During the war, there were other national and international priorities, and after the war, pressures of urbanization by a rapidly increasing world population took precedence, and perhaps fascination in an industrial age with the versatility of the "magic" mineral diverted attention from its dangers. Following the first International Conference on the Biological Effects of Asbestos in 1964 (Selikoff and Churg 1965), asbestos-related disease became a cause célèbre, not only on its own account, but also because it marked a period of labour-management confrontation concerning the rights of the worker to knowledge about workplace hazards, health protection and fair compensation for injury or illness. In countries with no-fault worker's compensation, asbestos-related disease on the whole received fair recognition and handling. In countries where product liability and class action suits were more usual, large awards have been made to some affected workers (and their lawyers) while others have been left destitute and without support. While the need for fibres in modern societies is unlikely to diminish, the role of the mineral fibres vis-à-vis other fibres may change. There has already been a shift in uses both within and between countries (see "Other sources of exposure", above). Though the technology exists to diminish workplace exposures, there remain workplaces in which it has not been applied. Given the current knowledge, given international communication and product labelling, and given worker education and industry commitment, it should be possible to use this mineral to provide cheap and durable products for use in construction and water reticulation on an international basis without risk to user, worker, manufacturer or miner, or to the general public at large.


Gerolamo Chiappino

Shortly after the end of the First World War, while doing research to find a material able to replace diamond in metal-drawing nozzles, Karl Schoeter patented in Berlin a sintering process (pressurization plus heating at 1,500 °C) of a mixture of fine tungsten carbide (WC) powder with 10% of cobalt to produce "hard metal". The main characteristics of this sinter are the extreme hardness, only slightly inferior to that of diamond, and the maintenance of its mechanical properties at high temperatures; these characteristics make it suitable for use in drawing metal, for welded inserts, and for high-speed tools for machining of metals, stone, wood and materials with high resistance to wear or to heat, in the mechanical, aeronautical and ballistic fields. The use of hard metal is continually expanding all over the world. In 1927 Krupp extended the use of hard metal into the cutting tools field, calling it "Widia" (wie Diamant-like diamond), a name still in use today.

Sintering remains the basis of all hard metal production: techniques are improved by the introduction of other metallic carbides-titanium carbide (TiC) and tantalum carbide (TaC)-and by treatment of hard metal parts for mobile cutting inserts with one or more layers of titanium nitride or aluminium oxide and of other very hard compounds applied with chemical vapour deposition (CVD) or physical vapour deposition (PVD). The fixed inserts welded to the tools cannot be plated, but are repeatedly sharpened by a diamond grinding wheel (figure 10.24 and figure 10.25 ).

Figure 10.24 (A) Examples of some hard metal drawing mobile inserts, plated with golden-yellow tungsten nitride; (B) insert welded to the tool and working in steel drawing.

Figure 10.25 Fixed inserts welded to (A) stone drill and (B) saw disk

The hard metal sinter is formed by particles of metallic carbides incorporated in a matrix formed by cobalt, which melts during sintering, interacting and occupying the interstices. Cobalt is therefore the structure gluing material, which assumes metal-ceramic characteristics (figure 10.26, figure 10.27 and figure 10.28).

Figure 10.26 Microstructure of a WC/Co sintering; WC particles are incorporated into the Co light matrix (1,500x).

Figure 10.27 Microstructure of a WC + TiC + TaC + Co sintering. Along with WC prismatic particles, globular particles formed by a solid solution of TiC + TaC are observed. The light matrix is formed by Co (1,500x)

Figure 10.28 Sintering microstructure plated by multiple very hard layers (2,000x)

The sintering process uses very fine metallic carbide powders (average diameters from 1 to 9 µm) and cobalt powders (average diameter from 1 to 4 µm) which are mixed, treated with paraffin solution, die-pressed, de-waxed at low temperature, pre-sintered at 700 to 750 °C and sintered at 1,500 °C (Brookes 1992).

When sintering is done with inadequate methods, improper techniques and poor industrial hygiene, the powders can pollute the atmosphere of the work environment: workers are therefore exposed to the risk of inhalation of metallic carbide powders and cobalt powders. Along with the primary process there are other activities which can expose the workers to the risk of aerosol inhalation of hard metal. Sharpening of fixed inserts welded to tools is normally carried out by dry diamond grinding or, more frequently, cooled with liquids of different kinds, producing powders or mists formed by very small drops containing metallic particles. Particles of hard metal are also used in the production of a high-resistance layer on steel surfaces subjected to wear, applied through methods (plasma coating process and others) based on the combination of a powder spray with an electric arc or a controlled explosion of a gas mixture at high temperature. The electric arc or the explosive flow of the gas determines the fusion of the metallic particles and their impact on the surface being plated.

First observations on "hard metal diseases" were described in Germany in the 1940s. They reported a diffuse, progressive pulmonary fibrosis, called Hartmetallungenfibrose. During the next 20 years parallel cases were observed and described in all industrial countries. The workers affected were in the majority of cases in charge of the sintering. From 1970 to the present, several studies indicate that the pathology to the breathing apparatus is caused by the inhalation of hard metal particles. It affects only susceptible subjects, and consists of the following symptoms:

·     acute: rhinitis, asthma

·     subacute: fibrosant alveolitis

·     chronic: diffuse and progressive interstitial fibrosis.

It affects not only workers in charge of sintering, but anyone inhaling aerosol containing hard metal and particularly cobalt. It is mainly and perhaps exclusively caused by cobalt.

The definition of hard metal disease now includes a group of pathologies of the breathing apparatus, different from each other in clinical gravity and prognosis, but having in common a variable individual reactivity to the aetiological factor, cobalt.

More recent epidemiological and experimental information agree on the causal role of cobalt for acute symptoms in the upper respiratory tract (rhinitis, asthma) and for subacute and chronic symptoms in the bronchial parenchyma (fibrosing alveolitis and chronic interstitial fibrosis).

The pathogenic mechanism is based on the induction by Co of a hypersensitive immunoreaction: in fact, only some of the subjects present pathologies after short exposures to relatively low concentration, or even after longer and more intense exposures. Co concentrations in biological samples (blood, urine, skin) are not significantly different in those who have the pathology and those who do not; there is no correlation of dose and response at the tissue level; specific antibodies have been individuated (immunoglobins IgE and IgG) against a Co-albumin compound in asthmatics, and the Co patch test is positive in the subjects with alveolitis or fibrosis; the cytological aspects of the giant-cellular alveolitis are compatible with immunoreaction, and acute or subacute symptoms tend to regress when the subjects are removed from exposure to Co (Parkes 1994).

The immunological basis of hypersensitivity to Co has not yet been satisfactorily explained; it is not possible, therefore, to identify a reliable marker of individual susceptibility.

Identical pathologies to those found in the subjects exposed to hard metals were also observed in diamond cutters, who use disks formed by microdiamonds cemented with Co and who therefore inhale only Co and diamond particles.

It is not yet fully demonstrated that pure Co (all other inhaled particles excluded) is capable alone of producing the pathologies and above all the diffused interstitial fibrosis: the particles inhaled with Co could have a synergistic as well as modulating effect. Experimental studies seem to demonstrate that the biological reactivity to a mixture of Co particles and of tungsten is stronger than that caused by Co alone, and significant pathologies are not to be observed in the workers in charge of the production of pure Co powder (Science of the Total Environment 1994).

Clinical symptoms of hard metal disease, which, on the basis of current aetiopathogenic knowledge should be more precisely called "cobalt disease", are, as mentioned before, acute, subacute and chronic.

Acute symptoms include a specific respiratory irritation (rhinitis, laryngo-tracheitis, pulmonary oedema) caused by exposure to high concentrations of Co powder or Co smoke; they are observable only in exceptional cases. Asthma is observed more frequently. It appears in 5 to 10% of the workers exposed to cobalt concentrations of 0.05 mg/m3, the current US threshold limit value (TLV). Symptoms of thoracic constriction with dyspnoea and cough tend to appear at the end of the work shift or during the night. The diagnosis of occupational allergic bronchial asthma due to cobalt can be suspected on the basis of case history criteria, but it is confirmed by a specific bronchial stimulation test which determines the appearance of an immediate, delayed or dual bronchospastic response. Even respiratory capacity tests carried out at the beginning and at the end of the work shift can help the diagnosis. Asthmatic symptoms due to cobalt tend to disappear when the subject is removed from exposure, but, similarly to all other forms of occupational allergic asthma, symptoms can become chronic and irreversible when the exposure continues for a long time (years), despite the presence of respiratory disturbances. Highly bronchoreactive subjects can present non-allergic aetiological asthmatic symptoms, with a non-specific response to inhalation of cobalt and other irritating powders. In a high percentage of cases with allergic bronchial asthma, specific reaction towards a human Co-seroalbumin compound was found in the IgE serum. The radiological finding does not vary: only in rare cases can mixed forms of asthma plus alveolitis with radiological alteration specifically caused by alveolitis be found. Bronchodilator therapy, along with an immediate end of the work exposure, leads to complete recovery for cases that are of recent onset, not yet chronic.

Subacute and chronic symptoms include fibrosant alveolitis and chronic diffuse and progressive interstitial fibrosis (DIPF). The clinical experience seems to indicate that the transition from alveolitis to interstitial fibrosis is a process which evolves gradually and slowly in time: one can find cases of pure initial alveolitis reversible with withdrawal from the exposure plus corticosteroid therapy; or cases with an already present fibrosis component, which can improve but not reach complete recovery by removing the subject from exposure, even with additional therapy; and finally, cases in which the predominant situation is that of an irreversible DIPF. The occurrence of such cases is low in the exposed workers, very much lower than the percentage of allergic asthma cases.

Alveolitis is easy to study today in its cytological components through broncho-alveolar lavage (BAL); it is characterized by a large increase of the total cell number, mainly formed by macrophages, with numerous multinuclear giant cells and the typical aspect of foreign-body giant cells containing at times cytoplasmic cells (figure 10.29); even an absolute or relative increase of lymphocytes is frequent, with a decreased CD4/CD8 ratio, associated with a large increase of eosinophiles and mast cells. Rarely, alveolitis is mainly lymphocytic, with CD4/CD8 ratio inverted, as it occurs in the pneumopathies due to hypersensitivity.

Figure 10.29 Cytological BAL in a macrophagic mononuclear giant-cellular alveolitis case caused by hard metal. Between the mononuclear macrophages and the lymphocyte, a giant foreigh-body type of cell (400x) is observed.

Subjects with alveolitis report dyspnoea linked with fatigue, loss of weight and dry cough. Crepitation is present in the lower lung with functional alteration of a restrictive kind and diffused round or irregular radiological opacity. The patch test for cobalt is positive in the majority of cases. In the susceptible subjects, alveolitis is revealed after a relatively short period of workplace exposure, of one or a few years. In its initial phases this form is reversible up to complete recovery with the simple removal from exposure, with better results if this is combined with cortisone therapy.

The development of diffuse interstitial fibrosis aggravates the clinical symptoms with a worsening of the dyspnoea, which appears even after minimal strain and then even at rest, with worsening of the restrictive ventilatory impairment which is linked to a reduction of the capillary-alveolar diffusion, and with appearance of radiographic opacities of a linear type and of honeycombing (figure 10.30). The histological situation is that of a fibrosing alveolitis of a "mural type".

Figure 10.30 Thoracic radiograph of a subject affected by interstitial fibrosis caused by hard metal.  Linear and diffused opacity and honeycombing aspects are observed

The evolution is rapidly progressive; therapies are ineffective and the prognosis doubtful. One of the cases diagnosed by the author eventually required a lung transplant.

The occupational diagnosis is based on case history, BAL cytological pattern and cobalt patch test.

Prevention of hard metal disease, or, more precisely, of cobalt disease, is now mainly technical: protecting the workers through the elimination of powder, smokes or mists with adequate ventilation of the work areas. In fact, the lack of knowledge about the factors which determine individual hypersensitivity to cobalt makes the identification of susceptible people impossible, and the maximum effort must be made to reduce the atmospheric concentrations.

The number of people at risk is underestimated because many sharpening activities are carried out in small industries or by craftspeople. In such workplaces, the US TLV of 0.05 mg/m3 is frequently exceeded. There is also some question as to the adequacy of the TLV for protecting workers against cobalt disease since dose-effect relationships for disease mechanisms involving hypersensitivity are not completely understood.

Routine surveillance must be accurate enough to identify cobalt pathologies in their earliest stages. An annual questionnaire aimed mainly at temporary symptoms must be administered, along with a medical examination that includes pulmonary function testing and other appropriate medical examinations. Since it has been demonstrated that there is a good correlation between cobalt concentrations in the work environment and the urinary excretion of the metal, it is appropriate to carry out semi-annual measurement of cobalt in urine (CoU) on samples taken at the end of the work week. When the exposure is at the level of the TLV, the biological exposure index (BEI) is estimated to be equal to 30 µg Co/litre urine.

Pre-exposure medical examinations for the presence of pre-existing respiratory disease and bronchial hypersensitivity can be useful in the counselling and placement of workers. Metacholine tests are a useful indicator of non-specific bronchial hyperreactivity and may be useful in some settings.

International standardization of environmental and medical surveillance methods for workers exposed to cobalt is highly recommended.


Steven R. Short and Edward L. Petsonk

This article is devoted to a discussion of pneumoconioses related to a variety of specific non-fibrous substances; exposures to these dusts are not covered elsewhere in this volume. For each material capable of engendering a pneumoconiosis upon exposure, a brief discussion of the mineralogy and commercial importance is followed by information related to the lung health of exposed workers.


Aluminium is a light metal with many commercial uses in both its metallic and combined states. (Abramson et al. 1989; Kilburn and Warshaw 1992; Kongerud et al. 1994.) Aluminium-containing ores, primarily bauxite and cryolite, consist of combinations of the metal with oxygen, fluorine and iron. Silica contamination of the ores is common. Alumina (Al2O3) is extracted from bauxite, and may be processed for use as an abrasive or as a catalyst. Metallic aluminium is obtained from alumina by electrolytic reduction in the presence of fluoride. Electrolysis of the mixture is carried out by using carbon electrodes at a temperature of about 1,000 °C in cells known as pots. The metallic aluminium is then drawn off for casting. Dust, fume and gas exposures in pot rooms, including carbon, alumina, fluorides, sulphur dioxide, carbon monoxide and aromatic hydrocarbons, are accentuated during crust breaking and other maintenance operations. Numerous products are manufactured from aluminium plate, flake, granules and castings-resulting in extensive potential for occupational exposures. Metallic aluminium and its alloys find use in the aircraft, boat and automobile industries, in the manufacture of containers and of electrical and mechanical devices, as well as in a variety of construction and structural applications. Small aluminium particles are used in paints, explosives and incendiary devices. To maintain particle separation, mineral oils or stearin are added; increased lung toxicity of aluminium flakes has been associated with the use of mineral oil.

Lung health

Inhalation of aluminium-containing dusts and fumes may occur in workers involved in the mining, extraction, processing, fabrication and end-use of aluminium-containing materials. Pulmonary fibrosis, resulting in symptoms and radiographic findings, has been described in workers with several differing exposures to aluminium-containing substances. Shaver's disease is a severe pneumoconiosis described among workers involved in the manufacture of alumina abrasives. A number of deaths from the condition have been reported. The upper lobes of the lung are most often affected and the occurrence of pneumothorax is a frequent complication. High levels of silicon dioxide have been found in the pot room environment as well as in workers' lungs at autopsy, suggesting silica as a potential contributor to the clinical picture in Shaver's disease. High concentrations of aluminium oxide particulate have also been observed. Lung pathology may show blebs and bullae, and pleural thickening is seen occasionally. The fibrosis is diffuse, with areas of inflammation in the lungs and associated lymph nodes.

Aluminium powders are used in making explosives, and there have been a number of reports of a severe and progressive fibrosis in workers involved in this process. Lung involvement has also occasionally been described in workers employed in the welding or polishing of aluminium, and in bagging cat litter containing aluminium silicate (alunite). However, there has been considerable variation in the reporting of lung diseases in relation to exposures to aluminium. Epidemiological studies of workers exposed to aluminium reduction have generally shown low prevalence of pneumoconiotic changes and slight mean reductions in ventilatory lung function. In various work environments, alumina compounds can occur in several forms, and in animal studies these forms appear to have differing lung toxicities. 

Silica and other mixed dusts may also contribute to this varying toxicity, as may the materials used to coat the aluminium particles. One worker, who developed a granulomatous lung disease after exposure to oxides and metallic aluminium, showed transformation of his blood lymphocytes upon exposure to aluminium salts, suggesting that immunologic factors might play a role.

An asthmatic syndrome has frequently been noted among workers exposed to fumes in aluminium reduction pot rooms. Fluorides found in the pot room environment have been implicated, although the specific agent or agents associated with the asthmatic syndrome has not been determined. As with other occupational asthmas, symptoms are often delayed 4 to 12 hours after exposure, and include cough, dyspnoea, chest tightness and wheeze. An immediate reaction may also be noted. Atopy and a family history of asthma do not appear to be risk factors for development of pot room asthma. After cessation of exposure, symptoms may be expected to disappear in most cases, although two-thirds of the affected workers show persistent non-specific bronchial responsiveness and, in some workers, symptoms and airway hyperresponsiveness continue for years even after exposure is terminated. The prognosis for pot room asthma appears to be best in those who are immediately removed from exposure when the asthmatic symptoms become manifest. Fixed airflow obstruction has also been associated with pot room work.

Carbon electrodes are used in the aluminium reduction process, and known human carcinogens have been identified in the pot room environment. Several mortality studies have revealed lung cancer excesses among exposed workers in this industry.

Diatomaceous Earth

Deposits of diatomaceous earth result from the accretion of skeletons of microscopic organisms. (Cooper and Jacobson 1977; Checkoway et al. 1993.) Diatomaceous earth may be utilized in foundries and in the maintenance of filters, abrasives, lubricants and explosives. Certain deposits comprise up to 90% free silica. Exposed workers may develop lung changes involving simple or complicated pneumoconiosis. The risk of death from both nonmalignant respiratory diseases and lung cancer has been related to the workers' tenure in dusty work as well as to cumulative crystalline silica exposures during the mining and processing of diatomaceous earth.

Elemental Carbon

Aside from coal, the two common forms of elemental carbon are graphite (crystalline carbon) and carbon black. (Hanoa 1983; Petsonk et al. 1988.) Graphite is used in the manufacture of lead pencils, foundry linings, paints, electrodes, dry batteries and crucibles for metallurgical purposes. Finely ground graphite has lubricant properties. Carbon black is a partially decomposed form used in automotive tires, pigments, plastics, inks and other products. Carbon black is manufactured from fossil fuels through a variety of processes involving partial combustion and thermal decomposition.

Inhalation of carbon, as well as associated dusts, may occur during the mining and milling of natural graphite, and during the manufacture of artificial graphite. Artificial graphite is produced by the heating of coal or petroleum coke, and generally contains no free silica.

Lung health

Pneumoconiosis results from worker exposure to both natural and artificial graphite. Clinically, workers with carbon or graphite pneumoconiosis show radiographic findings similar to those for coal workers. Severe symptomatic cases with massive pulmonary fibrosis were reported in the past, particularly related to the manufacture of carbon electrodes for metallurgy, although recent reports emphasize that the materials implicated in exposures leading to this sort of condition are likely to be mixed dusts.


Gilsonite, also known as uintaite, is a solidified hydrocarbon. (Keimig et al. 1987.) It occurs in veins in the western United States. Current uses include the manufacture of automotive body seam sealers, inks, paints and enamels. It is an ingredient of oil-well drilling fluids and cements; it is an additive in sand moulds in the foundry industry; it is to be found as a component of asphalt, building boards and explosives; and it is employed in the production of nuclear grade graphite. Workers exposed to gilsonite dust have reported symptoms of cough and phlegm production. Five of ninety-nine workers surveyed showed radiographic evidence of pneumoconiosis. No abnormalities in pulmonary function have been defined in relation to gilsonite dust exposures.


Gypsum is hydrated calcium sulphate (CaSO4·2H2O) (Oakes et al. 1982). It is used as a component of plasterboard, plaster of Paris and Portland cement. Deposits are found in several forms and are often associated with other minerals such as quartz. Pneumoconiosis has been observed in gypsum miners, and has been attributed to silica contamination. Ventilatory abnormalities have not been associated with gypsum dust exposures.

Oils and Lubricants

Liquids containing hydrocarbon oils are used as coolants, cutting oils and lubricants (Cullen et al. 1981). Vegetable oils are found in some commercial products and in a variety of foodstuffs. These oils may be aerosolized and inhaled when metals that are coated with oils are milled or machined, or if oil-containing sprays are used for purposes of cleaning or lubrication. Environmental measurements in machine shops and mills have documented airborne oil levels up to 9 mg/m3. One report implicated airborne oil exposure from the burning of animal and vegetable fats in an enclosed building.

Lung health

Workers exposed to these aerosols have occasionally been reported to develop evidence of a lipoid pneumonia, similar to that noted in patients who have aspirated mineral oil nose drops or other oily materials. The condition is associated with symptoms of cough and dyspnoea, inspiratory lung crackles, and impairments in lung function, generally mild in severity. A few cases have been reported with more extensive radiographic changes and severe lung impairments. Exposure to mineral oils has also been associated in several studies with an increased risk of respiratory tract cancers.

Portland Cement

Portland cement is made from hydrated calcium silicates, aluminium oxide, magnesium oxide, iron oxide, calcium sulphate, clay, shale and sand (Abrons et al. 1988; Yan et al. 1993). The mixture is crushed and calcined at high temperatures with the addition of gypsum. Cement finds numerous uses in road and building construction.

Lung health

Silicosis appears to be the greatest risk in cement workers, followed by a mixed dust pneumoconiosis. (In the past, asbestos was added to cement to improve its characteristics.) Abnormal chest radiographic findings, including small rounded and irregular opacities and pleural changes, have been noted. Workers have occasionally been reported to have developed pulmonary alveolar proteinosis after the inhalation of cement dust. Airflow obstructive changes have been noted in some, but not all, surveys of cement workers.

Rare Earth Metals

Rare earth metals or "lanthanides" have atomic numbers between 57 and 71. Lanthanum (atomic number 57), cerium (58), and neodymium (60) are the commonest of the group. The other elements in this group include praseodymium (59), promethium (61), samarium (62), europium (63), gadolinium (64), terbium (65), dysprosium (66), holmium (67), erbium (68), thulium (69), ytterbium (70) and lutetium (71). (Hussain, Dick and Kaplan 1980; Sabbioni, Pietra and Gaglione 1982; Vocaturo, Colombo and Zanoni 1983; Sulotto, Romano and Berra 1986; Waring and Watling 1990; Deng et al. 1991.) The rare earth elements are found naturally in monazite sand, from which they are extracted. They are used in a variety of alloy metals, as abrasives for polishing mirrors and lenses, for high-temperature ceramics, in fireworks and in cigarette lighter flints. In the electronics industry they are used in electrowelding and are to be found in various electronic components, including television phosphors, radiographic screens, lasers, microwave devices, insulators, capacitors and semiconductors.

Carbon arc lamps are used widely in the printing, photoengraving and lithography industries and were used for floodlighting, spotlighting and movie projection before the wide-scale adoption of argon and xenon lamps. The rare earth metal oxides were incorporated into the central core of carbon arc rods, where they stabilize the arc stream. Fumes which are emitted from the lamps are a mixture of gaseous and particulate material composed of approximately 65% rare earth oxides, 10% fluorides and unburnt carbon and impurities.

Lung health

Pneumoconiosis in workers exposed to rare earths has been exhibited primarily as bilateral nodular chest radiographic infiltrates. Lung pathology in cases of rare earth pneumoconiosis has been described as an interstitial fibrosis accompanied by an accumulation of fine granular dust particles, or granulomatous changes.

Variable pulmonary function impairments have been described, from restrictive to mixed restrictive-obstructive. However, the spectrum of pulmonary disease related to inhalation of rare earth elements is still to be defined, and data regarding the pattern and progression of disease and histological changes is available primarily only from a few case reports.

A neoplastic potential of the rare earth isotopes has been suggested by a case report of lung cancer, possibly related to ionizing radiation from the naturally occurring rare earth radioisotopes.

Sedimentary Compounds

Sedimentary rock deposits form through the processes of physical and chemical weathering, erosion, transport, deposition and diagenesis. These may be characterized into two broad classes: Clastics, which include mechanically deposited erosion debris, and chemical precipitates, which include carbonates, shells of organic skeletons and saline deposits. Sedimentary carbonates, sulphates and halides provide relatively pure minerals that have crystallized from concentrated solutions. Due to the high solubility of many of the sedimentary compounds, they are rapidly cleared from the lungs and are generally associated with little pulmonary pathology. In contrast, workers exposed to certain sedimentary compounds, primarily clastics, have shown pneumoconiotic changes.


Phosphate ore, Ca5(F,Cl)(PO4)3, is used in the production of fertilizers, dietary supplements, toothpaste, preservatives, detergents, pesticides, rodent poisons and ammunitions (Dutton et al. 1993). Extraction and processing of the ore may result in a variety of irritant exposures. Surveys of workers in phosphate mining and extraction have documented increased symptoms of cough and phlegm production, as well as radiographic evidence of pneumoconiosis, but little evidence of abnormal lung function.


Shale is a mixture of organic material composed mainly of carbon, hydrogen, oxygen, sulphur and nitrogen (Rom, Lee and Craft 1981; Seaton et al. 1981). The mineral component (kerogen) is found in the sedimentary rock called marlstone, which is of a grey-brown colour and a layered consistency. Oil shale has been used as an energy source since the 1850s in Scotland. Major deposits exist in the United States, Scotland and Estonia. Dust in the atmosphere of underground oil shale mines is of relatively fine dispersion, with up to 80% of the dust particles under 2 mm in size.

Lung health

Pneumoconiosis related to the deposition of shale dust in the lung is termed shalosis. The dust creates a granulomatous and fibrotic reaction in the lungs. This pneumoconiosis is similar clinically to coal workers' pneumoconiosis and silicosis, and may progress to massive fibrosis even after the worker has left the industry.

Pathologic changes identified in lungs with shalosis are characterized by vascular and bronchial deformation, with irregular thickening of interalveolar and interlobular septa. In addition to interstitial fibrosis, lung specimens with shale pneumoconiosis have shown enlarged hilar shadows, related to the transport of shale dust and subsequent development of well-defined sclerotic changes in the hilar lymph nodes.

Shale workers have been found to have a prevalence of chronic bronchitis two and one-half times that of age-matched controls. The effect of shale dust exposures on lung function has not been studied systematically.


Slate is a metamorphic rock, made up of various minerals, clays and carbonaceous matter (McDermott et al. 1978). The major constituents of slate include muscovite, chlorite, calcite and quartz, along with graphite, magnetite and rutile. These have undergone metamorphosis to form a dense crystalline rock that possesses strength but is easily cleaved, characteristics which account for its economic importance. Slate is used in roofing, dimension stone, floor tile, flagging, structural shapes such as panels and window sills, blackboards, pencils, billiard tables and laboratory bench tops. Crushed slate is used in highway construction, tennis court surfaces and lightweight roofing granules.

Lung health

Pneumoconiosis has been found in a third of workers studied in the slate industry in North Wales, and in 54% of slate pencil makers in India. Various lung radiographic changes have been identified in slateworkers. Because of the high quartz content of some slates and the adjacent rock strata, slateworkers' pneumoconiosis may have features of silicosis. The prevalence of respiratory symptoms in slateworkers is high, and the proportion of workers with symptoms increases with pneumoconiosis category, irrespective of smoking status. Diminished values of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are associated with increasing pneumoconiosis category.

The lungs of miners exposed to slate dust reveal localized areas of perivascular and peribronchial fibrosis, extending to macule formation and extensive interstitial fibrosis. Typical lesions are fibrotic macules of variable configuration intimately associated with small pulmonary blood vessels.


Talc is composed of magnesium silicates, and is found in a variety of forms. (Vallyathan and Craighead 1981; Wegman et al. 1982; Stille and Tabershaw 1982; Wergeland, Andersen and Baerheim 1990; Gibbs, Pooley and Griffith 1992.)

Deposits of talc are frequently contaminated with other minerals, including both fibrous and non-fibrous tremolite and quartz. Lung health effects of talc-exposed workers may be related to both the talc itself as well as the other associated minerals.

Talc production occurs primarily in Australia, Austria, China, France and the United States. Talc is used as a component in hundreds of products, and is used in the manufacture of paint, pharmaceuticals, cosmetics, ceramics, automobile tires and paper.

Lung health

Diffuse rounded and irregular parenchymal lung opacities and pleural abnormalities are seen on the chest radiographs of talc workers in association with the talc exposure. Depending on the specific exposures experienced, the radiographic shadows may be ascribed to talc itself or to contaminants in the talc. Talc exposure has been associated with symptoms of cough, dyspnoea and phlegm production, and with evidence of airflow obstruction in pulmonary function studies. Lung pathology has revealed various forms of pulmonary fibrosis: granulomatous changes and ferruginous bodies have been reported, and dust-laden macrophages collected around the respiratory bronchioles intermingled with bundles of collagen. Mineralogical examination of lung tissue from talc workers is also variable and may show silica, mica or mixed silicates.

Since talc deposits may be associated with asbestos and other fibres, it is not surprising that an increased risk of bronchogenic carcinoma has been reported in talc miners and millers. Recent investigations of workers exposed to talc without associated asbestos fibres revealed trends for higher mortality from non-malignant respiratory disease (silicosis, silico-tuberculosis, emphysema and pneumonia), but the risk for bronchogenic cancer was not found to be elevated.


Exposure to hairsprays occurs in the home environment as well as in commercial hairdressing establishments (Rom 1992b). Environmental measurements in beauty salons have indicated the potential for respirable aerosol exposures. Several case reports have implicated hairspray exposure in the occurrence of a pneumonitis, thesaurosis, in heavily exposed individuals. Clinical symptoms in the cases were generally mild, and resolved with termination of exposure. Histology usually showed a granulomatous process in the lung and enlarged hilar lymph nodes, with thickening of alveolar walls and numerous granular macrophages in the airspaces. Macromolecules in hairsprays, including shellacs and polyvinylpyrrolidone, have been suggested as potential agents. In contrast to the clinical case reports, increased lung parenchymal radiographic shadows observed in radiological surveys of commercial hairdressers have not been conclusively related to hairspray exposure. Although the results of these studies do not allow definitive conclusions to be drawn, clinically important lung disease from typical hairspray exposures does appear to be an unusual occurrence.


Kazimierz Marek and Jan E. Zejda

Chronic respiratory disorders characterized by differing grades of dyspnoea, cough, phlegm expectoration and functional respiratory impairment are included in the general category of chronic non-specific lung disease (CNSLD). The original definition of CNSLD, accepted at the Ciba Symposium in 1959, covered chronic bronchitis, emphysema and asthma. Subsequently, the diagnostic terminology of chronic bronchitis was redefined according to the concept that disabling airflow limitation represents the final stage of the ever-progressing process which starts as a benign expectoration caused by prolonged or recurrent inhalation of bronchial irritants (the "British Hypothesis"). The concept was thrown into question in 1977 and since then hypersecretion and airflow obstruction are regarded as unrelated processes. The alternative hypothesis, known as the "Dutch Hypothesis," while accepting the role of smoking and air pollution in the aetiology of chronic airflow limitation, points to the key and possibly causative role of susceptibility of the host, manifesting itself as, for instance, an asthmatic tendency. Subsequent studies have shown that both hypotheses can contribute to the understanding of the natural history of chronic airways disease. Although the conclusion about the insignificant prognostic value of hypersecretory syndrome has generally been accepted as well-grounded, the recent studies have shown a significant association between hypersecretory disorder and the increased risk of the development of airflow limitation and respiratory mortality.

Currently, the term CNSLD combines two major categories of chronic respiratory disorders, asthma (discussed in a separate article of this chapter) and chronic obstructive pulmonary disease (COPD).


In a document published by the American Thoracic Society (ATS) (1987), COPD is defined as a disorder characterized by abnormal tests of expiratory flow that do not change markedly over periods of several months' observation. Taking into account functional and structural causes of airflow limitation, the definition includes the following non-asthmatic airways disorders: chronic bronchitis, emphysema and peripheral airways disease. The important common characteristics of COPD are pronounced pathophysiological abnormalities mostly exhibited as a varying degree of chronic airflow limitation (CAL). Chronic airflow limitation can be found in a subject with any disease included under the rubric of COPD.

Chronic bronchitis is defined as an abnormal condition of the respiratory tract, characterized by persistent and excessive productive cough, which reflects the mucous hypersecretion within the airways. For epidemiological purposes, the diagnosis of chronic bronchitis has been based on answers to the set of standard questions included in the Medical Research Council (MRC) or ATS questionnaire on respiratory symptoms. The disorder is defined as cough and phlegm expectoration occurring on most days for at least three months of the year, during at least two successive years.

Emphysema is defined as an anatomical alteration of the lung characterized by abnormal enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of acinar architecture. Emphysema often coexists with chronic bronchitis.

The term peripheral airways disease or small airways disease is used to describe the abnormal condition of airways less than 2 to 3 mm in diameter. Inflammation, obstruction and excess mucus production in this part of the bronchial tree has been observed in a variety of clinical entities, including chronic bronchitis and emphysema. The pathological evidence of local structural abnormalities and the concept that the observed changes can represent an early stage in the natural history of chronic disease of airways, have stimulated in the late 1960s and the 1970s a rapid development of functional tests designed to examine physiological properties of peripheral airways. Consequently, the term peripheral airways disease is generally understood to refer to structural abnormalities or functional defect.

CAL is a functional hallmark of COPD. The term refers to an increased resistance to airflow, resulting in a persistent slowing during forced expiration. The definition thereof and the underlying clinical and pathophysiological knowledge imply two important diagnostic clues. First, the condition must be shown to have a chronic course, and the early recommendation of 1958 required the presence of CAL for more than one year to fulfil the diagnostic criteria. The time frame suggested recently is less rigorous and refers to the demonstration of a defect over the period of three months. In surveillance of work-related CAL, the standard spirometric evaluation provides sufficient means of identification of CAL, based on the reduction in the forced expiratory volume in one second (FEV1) and/or in the ratio of FEV1 to forced vital capacity (FVC).

Usually, CAL is diagnosed when the FEV1 value is reduced below 80% of the predicted value. According to the functional classification of CAL recommended by the American Thoracic Society:

1.     mild impairment occurs when the value of FEV1 is below 80% and above 60% of the predicted value

2.     moderate impairment occurs when FEV1 is in the range of 40% to 59% of the predicted value

3.     severe impairment occurs when FEV1 is below 40% of the predicted value.

When the degree of impairment is assessed by the value of the FEV1/FVC ratio, a mild defect is diagnosed if the ratio falls between 60% and 74%; moderate impairment if the ratio ranges from 41% to 59%; and severe impairment if the ratio is 40% or less.

Prevalence of COPD

Accumulated evidence indicates that COPD is a common problem in many countries. Its prevalence is higher in men than in women and increases with age. Chronic bronchitis, a well-standardized diagnostic form of COPD, is two to three times more prevalent in men than in women. Large surveys document that usually between 10% and 20% of adult men in the general population meet the diagnostic criteria of chronic bronchitis (table 10.18). The disease is much more frequent among smokers, both in men and in women. Occurrence of COPD in occupational populations is discussed below.

Table 10.18 Prevalence of COPD in selected countries - results of large surveys.







SMK (%)

CB (%)


SMK (%)

CB (%)










































































Legend: SMK = smoking habit; CB = chronic bronchitis; COPD/CAL = chronic obstructive pulmonary disease/chronic airways limitation; n.r. = not reported.

Modified with permission from: Woolcock 1989.

Risk factors of COPD, including effect of occupational exposures

COPD is a disorder of multifactorial aetiology. Numerous studies have provided evidence for a causative dependence of COPD on many risk factors, categorized as host and environmental factors. The role of occupational exposures among environmental risk factors in the genesis of COPD has been recognized following accumulation of epidemiological evidence published in the period 1984 to 1988. Recently independent effects of smoking and occupational exposures have been confirmed, based on the results of the studies published from 1966 to 1991. Table 10.19  summarizes the current state of knowledge on multifactorial aetiology of COPD.

Table 10.19 Risk factors implicated in COPD.

Factor related to






Antitrypsin deficiency


Familial factors

Increased airway reactivity

Past health


Tobacco smoke (personal)

Tobacco smoke (environmental)

Air pollution

Occupational exposure

Reproduced with permission from: Becklake et al. 1988.

The occurrence of chronic bronchitis in occupational populations is a potential marker of significant exposure to occupational irritants. A significant effect of exposure to industrial dust on the development of chronic bronchitis has been documented in workers employed in coal mining, the iron and steel industry, as well as in textile, construction and agricultural industries. In general, more dusty environments are associated with higher prevalence of the symptoms of chronic expectoration. The prevalence studies, however, are subject to "healthy worker effect", a bias that results in underestimation of health impact of harmful occupational exposures. More conclusive, yet less available, are data on the disease's incidence. In certain occupations the incidence rate of chronic bronchitis is high and ranges from 197-276/10,000 in farmers to 380/10,000 in engineering workers and 724/10,000 in miners and quarryworkers, compared with 108/10,000 in white-collar workers.

This pattern, and the causative effect of smoking as well, are in line with a concept that chronic bronchitis presents a common response to chronic inhalation of respiratory irritants.

A deleterious effect of lung dust burden is thought to result in chronic non-specific bronchial wall inflammation. This type of inflammatory response has been documented in workers exposed to organic dust and its constituents, such as for example grain and endotoxin, both responsible for neutrophillic inflammation. The role of individual susceptibility cannot be ruled out and known host-related factors include past respiratory infections, the efficiency of clearance mechanisms and poorly determined genetic factors, whereas cigarette smoking remains a single most potent environmental cause of chronic bronchitis.

The contribution of occupational exposures to the aetiology of emphysema is not clearly understood. The putative causative factors include nitrogen oxide, ozone and cadmium, as suggested by experimental observations. The data provided by occupational epidemiology are less convincing and may be difficult to obtain because of usually low levels of occupational exposures and a predominant effect of smoking. This is particularly important in case of so-called centriacinar emphysema. The other pathological form of the disease, panacinar emphysema, is considered hereditary and related to alpha1-antitrypsin deficiency.

Bronchiolar and peribronchiolar inflammation, accompanied by progressive narrowing of the affected segment of the bronchial tree (peripheral airways disease or constrictive bronchiolitis) can be seen in a variety of conditions underlying symptoms of COPD, at different stages of natural history. In the occupational setting, the disease usually follows acute lung injury due to inhalation of toxic fumes, such as sulphur dioxide, ammonia, chlorine and nitrogen oxides. However, the occupational epidemiology of constrictive bronchiolitis largely remains unclear. Apparently, its early stages are difficult to identify because of non-specific symptomatology and limitation of diagnostic procedure. More is known about the cases following industrial accidents. Otherwise, the disease can go undetected until the development of overt symptomatology and objective respiratory impairment (i.e., chronic airflow limitation).

CAL is not infrequently found in various occupational groups and, as documented by controlled studies, its prevalence in blue-collar workers can exceed that of white-collar workers. Due to the complex aetiology of CAL, including the effect of smoking and host-related risk factors, early studies on the association of chronic airflow limitation with occupational exposure were inconclusive. Modern occupational epidemiology, employing goal-oriented design and modelling of exposure-response relationships, has provided evidence on association of airflow capacity with exposure to both mineral and organic dusts, fumes and gases.

Workforce-based longitudinal studies conducted in workers exposed to mineral and organic dusts, and to fumes and gases show that lung function loss is associated with occupational exposures. The results summarized in table 10.20 prove a significant effect of exposures to dust in coal and iron mining, the asbestos-cement industry, steel and smelter workers and pulp mill workers. A number of analysed exposures is composed of exposure to dust and fumes (such as non-halogenated hydrocarbons, paints, resins or varnishes) as well as gases (such as sulphur dioxide or the oxides of nitrogen). According to the results of a comprehensive review, restricted to the most valid and systematically analysed articles on COPD and occupational dust exposure, it can be estimated that 80 of 1,000 non-smoking coalminers could be expected to develop at least 20% loss of FEV1 following 35 years of work with a mean respirable dust concentration of 2 mg/m3, and for non-smoking gold miners the respective risk could be three times as large.

Table 10.20 Loss of ventilatory function in relation to occupational exposures: results from selected longitudinal workforce-based studies.

Country (year)

Subjects and exposures

Test used

Annual loss of function*








UK (1982)

1,677 coalminers

FEV ml


41 (av) 57 (max)



USA (1985)

1,072 coalminers

FEV ml





Italy (1984)

65 asbestos cement workers

FEV ml



Not given

Not given

Sweden (1985)

70 asbestos cement workers






France (1986)

871 iron miners






France (1979)

159 steel-workers




Not given

Not given

Canada (1984)

179 mine and smelter workers






France (1982)

556 workers in factories

FEV ml



52 (dust)

47 (gases)

55 (heat)



Finland (1982)

659 pulp mill workers

FEV ml

No effect

No effect



Canada (1987)

972 mine and smelter workers

FEV ml


69 (roaster)

49 (furnace)

33 (mining)



* Table shows the average annual loss of lung function in the exposed (E) compared to the  non-exposed (NE), and in smokers (S) compared to non-smokers (NS). Independent effects of  smoking (S) and/or exposure (E) shown to be significant in the analyses carried out by the  authors in all studies except for the Finnish study.

Modified with permission from: Becklake 1989.

Selected studies performed with grain workers show the effect of occupational exposure to organic dust on longitudinal changes in lung function. Although limited in number and the duration of follow-up, the findings document an independent relationship of smoking with annual lung function loss (vis à vis exposure to grain dust).


The central pathophysiological disorder of COPD is chronic airflow limitation. The disorder results from narrowing of the airways-a condition that has a complex mechanism in chronic bronchitis-whereas in emphysema the airways obstruction results mainly from low elastic recoil of the lung tissue. Both mechanisms often coexist.

The structural and functional abnormalities seen in chronic bronchitis include hypertrophy and hyperplasia of submucosal glands associated with mucous hypersecretion. The inflammatory changes lead to smooth muscle hyperplasia and mucosal swelling. The mucous hypersecretion and airways narrowing favour bacterial and viral infections of the respiratory tract, which may further increase the airways obstruction.

The airflow limitation in emphysema reflects the loss of elastic recoil as a consequence of the destruction of elastin fibres and collapsing bronchiolar wall due to high lung compliance. The destruction of elastin fibres is considered to result from an imbalance in the proteolytic-antiproteolytic system, in a process known also as protease inhibitor-deficiency. Alpha1-antitrypsin is the most potent protease inhibiting the elastase effect on alveoli in humans. Neutrophils and macrophages that release elastase accumulate in response to local inflammatory mediators and inhalation of various respiratory irritants, including tobacco smoke. The other, less powerful inhibitors are α2-macroglobulin and low-weight elastase inhibitor, released from submucosal glands.

Recently, the antioxidant-deficiency hypothesis has been examined for its role in the pathogenetic mechanisms of emphysema. The hypothesis contends that oxidants, if not inhibited by antioxidants, cause damage to the lung tissue, leading to emphysema. Known oxidants include exogenous factors (ozone, chlorine, nitrogen oxides and tobacco smoke) and endogenous factors such as free radicals. The most important antioxidant factors include natural antioxidants such as vitamins E and C, catalase, superoxide dysmutase, glutathion, ceruloplasmin, and synthetic antioxidants such as N-acetylcysteine and allopurinol. There is an increasing body of evidence about synergism regarding antioxidant-deficiency and protease inhibitor-deficiency mechanisms in the pathogenesis of emphysema.


Pathologically, chronic bronchitis is characterized by hypertrophy and hyperplasia of the glands in the submucosa of large airways. As a result, the ratio of the bronchial gland thickness to the bronchial wall thickness (the so-called Reid index) increases. Other pathological abnormalities include metaplasia of the cilliary epithelium, smooth muscle hyperplasia and neutrophillic and lymphocytic infiltrations. The changes in large airways are often accompanied by pathological abnormalities in small bronchioles.

Pathological changes in small bronchioles have been consistently documented as varying degrees of the inflammatory process of airway walls. After the introduction of the concept of small airways disease, the focus has been on the morphology of separate segments of bronchioles. The histological evaluation of the membranous bronchioles, expanded subsequently to the respiratory bronchioles, displays wall inflammation, fibrosis, muscle hypertrophy, pigment deposition, epithelial goblet and squamous metaplasia and intraluminal macrophages. Pathological abnormalities of the type described above have been termed "mineral dust induced airway disease". An associated condition demonstrated in this segment of the respiratory tract is peribronchiolar fibrosing alveolitis, which is thought to represent the early reaction of pulmonary tissue to inhalation of mineral dust.

Pathological changes in emphysema can be categorized as centriacinar emphysema or panacinar emphysema. The former entity is largely limited to the centre of the acinus whereas the latter form involves changes in all structures of the acinus. Although panacinar emphysema is thought to reflect a hereditary protease inhibitor deficiency, both forms may coexist. In emphysema, terminal bronchioles show signs of inflammation and distal airspaces are abnormally enlarged. The structural destruction involves alveoli, capillaries and may lead to the formation of large abnormal airspaces (emphysema bullosum). Centriacinar emphysema tends to be located in the upper lung lobes whereas panacinar emphysema is usually found in the lower lung lobes.

Clinical Symptoms

Chronic cough and phlegm expectoration are two major symptoms of chronic bronchitis, whereas dyspnoea (shortness of breath) is a clinical feature of emphysema. In advanced cases, the symptoms of chronic expectoration and dyspnoea usually coexist. The onset and progress of dyspnoea suggest the development of chronic airflow limitation. According to the symptoms and the physiological status, clinical presentation of chronic bronchitis includes three forms of the disease: simple, mucopurulent and obstructive bronchitis.

In chronic bronchitis, the results of chest auscultation may reveal normal breath sounds. In advanced cases there may be a prolonged expiratory time, wheezes and rales, heard during expiration. Cyanosis is common in advanced obstructive bronchitis.

Clinical diagnosis of emphysema is difficult in its early stage. Dyspnoea may be a single finding. The patient with advanced emphysema may have the barrel-chest and signs of hyperventilation. As a result of lung hyperinflation, other findings include hyperresonance, decrease in diaphragmatic excursion and diminished breath sounds. Cyanosis is rare.

Because of similar causative factors (predominantly the effect of tobacco smoke) and similar presentation diagnosis of chronic bronchitis vis-à-vis emphysema may be difficult, especially if chronic airflow limitation dominates the picture. Table 10.21 provides some clues that are helpful for diagnosis. The advanced form of COPD can take two extreme types: predominant bronchitis ("blue bloater") or predominant emphysema ("pink puffer").

Table 10.21 Diagnostic classification of two clinical types of COPD, chronic bronchitis and emphysema.


Predominant bronchitis  ("Blue Bloater")

Predominant emphysema  ("Pink Puffer")

Body mass







Predominant symptom



Large quantity



Usually marked during exercise

Predominant symptom

Breath sounds

Normal or slightly decreased, adventitious lung sounds


Cor Pulmonale



Respiratory infections



Chest radiology has a limited diagnostic value in chronic bronchitis and early stages of emphysema. Advanced emphysema shows a radiological pattern of increased radiolucency (hyperinflation). Computerized tomography provides better insight into the location and magnitude of emphysematous changes, including differentiation between centriacinar and panacinar emphysema.

Lung function testing has a well-established position in diagnostic evaluation of COPD (table 10.22) . The battery of tests that are of practical importance in functional assessment of chronic bronchitis and emphysema includes functional residual capacity (FRC), residual volume (RV), total lung capacity (TLC), FEV1 and FEV1/VC, airways resistance (Raw), static compliance (Cst), elastic recoil (PL,el), blood gases (PaO2, PaCO2) and diffusing capacity (DLCO).

Table 10.22 Lung function testing in differential diagnosis of two clinical types of COPD, chronic bronchitis and emphysema.

Lung function test

Predominant bronchitis ("Blue Bloater")

Predominant emphysema ("Pink Puffer")


Normal or slightly increased

Markedly increased





Markedly increased

Slightly increased



Markedly increased



Markedly increased


Markedly increased

Slightly decreased





Normal or slightly decreased


RV = residual volume; FRC = functional residual capacity; TLC = total lung capacity;  FEV1 = forced expiratory volume in the first second and VC = vital capacity;  RAW =airways resistance; Cst =static compliance; PL,el = elastic recoil; PaO2 and  PaCO2 = blood gases; DLCO = diffusing capacity.

Clinical diagnosis of peripheral airways disease is not possible. Very often the disease accompanies chronic bronchitis or emphysema or even precedes clinical presentation of both latter forms or COPD. Isolated form of peripheral airways disease can be investigated by means of lung function testing, although the functional status of peripheral airways is difficult to assess. This part of the bronchial tree contributes to less than 20% of the total airflow resistance and isolated, mild abnormalities in small airways are considered to be below the level of detectability of conventional spirometry. More sensitive methods designed to measure the function of peripheral airways include a number of tests, among which the following are in most frequent use: maximal midexpiratory flow rate (FEF25-75), flow rates at low lung volumes (MEF50, MEF25), single breath nitrogen index (SBN2/l), closing capacity (CC), upstream airflow conductance (Gus) and frequency dependent compliance (Cfd). In general, these tests are thought to have a low specificity. On theoretical grounds FEF25-75 and MEF50,25 should reflect calibre-limiting mechanisms first of all, whereas SBN2/l is thought to be more specific to the mechanical properties of airspaces. The former indices are used most frequently in occupational epidemiology.

Differential diagnosis

Basic differences between chronic bronchitis and emphysema are shown in table 10.21 and table 10.22 . However, in individual cases the differential diagnosis is difficult and sometimes impossible to conduct with a fair degree of confidence. In some cases it is also difficult to differentiate between COPD and asthma. In practice, asthma and COPD are not clear-cut entities and there is a large degree of overlap between the two diseases. In asthma, the airway obstruction is usually intermittent, while in COPD it is constant. The course of airflow limitation is more variable in asthma than in COPD.

Case Management

The clinical management of COPD involves cessation of a smoking habit, the single most effective measure. Occupational exposure to respiratory irritants should be discontinued or avoided. The clinical management should focus on the proper treatment of respiratory infections and should involve regular influenza vaccinations. Bronchodilator therapy is justified in patients with airflow limitation and should comprise β2-adrenergic agonists and anticholinergics, given as monotherapy or in combination, preferably as an aerosol. Theophylline is still in use although its role in the management of COPD is controversial. Long-term corticosteroid therapy may be effective in some cases. Bronchial hypersecretion is often dealt with by mucoactive drugs affecting mucus production, mucus structure or mucocilliary clearance. The assessment of the effects of mucolytic therapy is difficult because these drugs are not used as monotherapy of COPD. Patients with hypoxaemia (PaO2 equal to or less than 55 mm Hg) qualify for long-term oxygen therapy, a treatment that is facilitated by access to portable oxygenators. Augmentation therapy with alpha1-antitrypsin can be considered in emphysema with confirmed alpha1-antitrypsin deficiency (phenotype PiZZ). The effect of antioxidant drugs (such as vitamin E and C) on the progress of emphysema is under investigation.


Prevention of COPD should begin with anti-smoking campaigns targeting both the general population and occupational groups at risk. In the occupational setting, the control and prevention of exposures to respiratory irritants are essential and always constitute a priority. These activities should aim at effective reduction of air pollution to safe levels, usually defined by so-called permissible exposure levels. Since the number of air pollutants is not regulated or not adequately regulated, every effort to reduce exposure is justified. In circumstances where such a reduction is impossible to achieve, personal respiratory protection is required to diminish the risk of individual exposure to harmful agents.

Medical prevention of COPD in the occupational setting incorporates two important steps: a respiratory health surveillance programme and an employee education programme.

The respiratory health surveillance programme involves regular evaluation of respiratory health; it starts with initial assessment (history, physical examination, chest x ray and standard lung function testing) and continues to be performed periodically over the period of employment. The programme is meant to assess the baseline respiratory health of workers (and to identify workers with subjective and/or objective respiratory impairment) prior to the commencement of work, and to detect early signs of respiratory impairment during ongoing surveillance of workers. Workers with positive findings should be withdrawn from exposure and referred for further diagnostic evaluation.

The employee education programme should be based on the reliable recognition of respiratory hazards present in the work environment and should be designed by health professionals, industrial hygienists, safety engineers and the management. The programme should provide workers with proper information on respiratory hazards in the workplace, potential respiratory effects of exposures, and pertinent regulations. It should also involve promotion of safe work practices and a healthy lifestyle.


James E. Lockey and Clara S. Ross

The industrial use of various types of man-made fibres has been increasing, particularly since restrictions were placed on the use of asbestos in view of its known health hazards. The potential for adverse health effects related to the production and use of man-made fibres is still being studied. This article will provide an overview of the general principles regarding the potential for toxicity related to such fibres, an overview of the various types of fibres in production (as listed in table 10.23) and an update regarding existing and ongoing studies of their potential health effects.

Table 10.23 Synthetic fibres.

Man-made fibres

Aluminium oxide





Kevlar® para-aramid


Silicon carbide fibres and  whiskers


Man-made vitreous fibres

Glass fibre

Glass wool


Continuous glass filament


Special-purpose glass fibre


Mineral wool

Rock wool


Slag wool


Refractory ceramic fibre


Toxicity Determinants

The primary factors related to potential for toxicity due to exposure to fibres are:

1.     fibre dimension

2.     fibre durability and

3.     dose to the target organ.

Generally, fibres that are long and thin (but of a respirable size) and are durable have the greatest potential for causing adverse effects if delivered to the lungs in sufficient concentration. Fibre toxicity has been correlated in short-term animal inhalation studies with inflammation, cytotoxicity, altered macrocyte function and biopersistence. Carcinogenic potential is most likely related to cellular DNA damage via formation of oxygen-free radicals, formation of clastogenic factors, or missegregation of chromosomes in cells in mitosis-alone or in combination. Fibres of a respirable size are those less than 3.0 to 3.5 µm in diameter and less than 200 µm in length. According to the "Stanton hypothesis," the carcinogenic potential of fibres (as determined by animal pleural implantation studies) is related to their dimension (the greatest risk is associated with fibres less than 0.25 µm in diameter and greater than 8 µm in length) and durability (Stanton et al. 1981). Naturally occurring mineral fibres, such as asbestos, exist in a polycrystalline structure that has the propensity to cleave along longitudinal planes, creating thinner fibres with higher length-to-width ratios, which have a greater potential for toxicity. The vast majority of man-made fibres are non-crystalline or amorphous and will fracture perpendicularly to their longitudinal plane into shorter fibres. This is an important difference between asbestos and non-asbestos fibrous silicates and man-made fibres. The durability of fibres deposited in the lung is dependent upon the lung's ability to clear the fibres, as well as the fibres' physical and chemical properties. The durability of man-made fibres can be altered in the production process, according to end-use requirements, through the addition of certain stabilizers such as Al2O3. Because of this variability in the chemical constituents and size of man-made fibres, their potential toxicity has to be evaluated on a fibre-type by fibre-type basis.

Man-made Fibres

Aluminium oxide fibres

Crystalline aluminium oxide fibre toxicity has been suggested by a case report of pulmonary fibrosis in a worker employed in aluminium smelting for 19 years (Jederlinic et al. 1990). His chest radiograph revealed interstitial fibrosis. Analysis of the lung tissue by electron microscopy techniques demonstrated 1.3 x 109 crystalline fibres per gram of dry lung tissue, or ten times more fibres than the number of asbestos fibres found in lung tissue from chrysotile asbestos miners with asbestosis. Further study is needed to determine the role of crystalline aluminium oxide fibres (figure 10.31) and pulmonary fibrosis.

Figure 10.31 Scanning electron micrograph (SEM) of aluminium oxide fibres

Courtesy of T. Hesterberg.

This case report, however, suggests a potential for fibrization to take place when proper environmental conditions coexist, such as increased air flow across molten materials. Both phase-contrast light microscopy and electron microscopy with energy dispersion x-ray analysis should be used to identify potential airborne fibres in the work environment and in lung tissue samples in cases where there are clinical findings consistent with fibre-induced pneumoconiosis.

Carbon/Graphite Fibres

Carbonaceous pitch, rayon or polyacrylonitrile fibres heated to 1,200 °C form amorphous carbon fibres, and when heated above 2,200 °C form crystalline graphite fibres (figure 10.32).

Figure 10.32 SEM of carbon fibres

Resin binders can be added to increase the strength and to allow moulding and machining of the material. Generally, these fibres have a diameter of 7 to 10 µm, but variations in size occur due to the manufacturing process and mechanical manipulation. Carbon/graphite composites are used in the aircraft, automobile and sporting goods industries. Exposure to respirable-sized carbon/graphite particles can occur during the manufacturing process and with mechanical manipulation. Furthermore, small quantities of respirable-sized fibres can be produced when composites are heated to 900 to 1,100 °C. The existing knowledge regarding these fibres is inadequate to provide definite answers as to their potential for causing adverse health effects. Studies involving intratracheal injection of different graphite fibre composite dusts in rats produced heterogeneous results. Three of the dust samples tested produced minimal toxicity, and two of the samples produced consistent toxicity as manifested by cytotoxicity for alveolar macrophages and differences in the total number of cells recovered from the lung (Martin, Meyer and Luchtel 1989). Clastogenic effects have been observed in mutagenicity studies of pitch-based fibres, but not of polyacrylonitrile-based carbon fibres. A ten-year study of carbon fibre production workers, manufacturing fibres 8 to 10 µm in diameter, did not reveal any abnormalities (Jones, Jones and Lyle 1982). Until further studies are available, it is recommended that exposure to respirable-sized carbon/graphite fibres be 1 fibre/ml (f/ml) or lower, and that exposure to respirable-sized composite particulates be maintained below the current respirable dust standard for nuisance dust.

Kevlar para-aramid fibres

Kevlar para-aramid fibres are approximately 12 µm in diameter and the curved ribbon-like fibrils on the surface of the fibres are less than 1 mm in width (figure 10.33).

Figure 10.33 SEM of Kevlar para-aramid fibres

The fibrils partially peel off the fibres and interlock with other fibrils to form clumps which are non-respirable in size. The physical properties of Kevlar fibres include substantial heat resistance and tensile strength. They have many different uses, serving as a reinforcing agent in plastics, fabrics and rubber, and as an automobile brake friction material. The eight-hour time-weighted average (TWA) of fibril levels during manufacturing and end-use applications ranges from 0.01 to 0.4 f/ml (Merriman 1989). Very low levels of Kevlar aramid fibres are generated in dust when used in friction materials. The only available health effects data is from animal studies. Rat inhalation studies involving one- to two-year time periods and exposures to fibrils at 25, 100 and 400 f/ml revealed alveolar bronchiolarization which was dose-related. Slight fibrosis and alveolar duct fibrotic changes also were noted at the higher exposure levels. The fibrosis may have been related to overloading of pulmonary clearance mechanisms. A tumour type unique to rats, cystic keratinizing squamous cell tumour, developed in a few of the study animals (Lee et al. 1988). Short-term rat inhalation studies indicate that the fibrils have low durability in lung tissue and are rapidly cleared (Warheit et al. 1992). There are no studies available regarding the human health effects of exposure to Kevlar para-aramid fibre. However, in view of the evidence of decreased biopersistence and given the physical structure of Kevlar, the health risks should be minimal if exposures to fibrils are maintained at 0.5 f/ml or less, as is now the case in commercial applications.

Silicon carbide fibres and whiskers

Silicon carbide (carborundum) is a widely used abrasive and refractory material that is manufactured by combining silica and carbon at 2,400 °C. Silicon carbide fibres and whiskers - figure 10.34  (Harper et al. 1995)-can be generated as by-products of the manufacture of silicon carbide crystals or can be purposely produced as polycrystalline fibres or monocrystalline whiskers. The fibres generally are less than 1 to 2 µm in diameter and range from 3 to 30 µm in length. The whiskers average 0.5 µm in diameter and 10 µm in length. Incorporation of silicon carbide fibres and whiskers adds strength to products such as metal matrix composites, ceramics and ceramic components. Exposure to fibres and whiskers can occur during the production and manufacturing processes and potentially during the machining and finishing processes. For example, short-term exposure during handling of recycled materials has been shown to reach levels up to 5 f/ml. Machining of metal and ceramic matrix composites have resulted in eight-hour TWA exposure concentrations of 0.031 f/ml and up to 0.76 f/ml, respectively (Scansetti, Piolatto and Botta 1992; Bye 1985).

Figure 10.34 SEMs of silicon carbide fibres (A) and whiskers (B)



Existing data from animal and human studies indicate a definite fibrogenic and possible carcinogenic potential. In vitro mouse cell culture studies involving silicon carbide whiskers revealed cytotoxicity equal to or greater than that resulting from crocidolite asbestos (Johnson et al. 1992; Vaughan et al. 1991). Persistent adenomatous hyperplasia of rat lungs was demonstrated in a subacute inhalation study (Lapin et al. 1991). Sheep inhalation studies involving silicon carbide dust revealed that the particles were inert. However, exposure to silicon carbide fibres resulted in fibrosing alveolitis and increased fibroblast growth activity (Bégin et al. 1989). Studies of lung tissue samples from silicon carbide manufacturing workers revealed silicotic nodules and ferruginous bodies and indicated that silicon carbide fibres are durable and can exist in high concentrations in lung parenchyma. Chest radiographs also have been consistent with nodular and irregular interstitial changes and pleural plaques.

Silicon carbide fibres and whiskers are respirable in size, durable, and have definite fibrogenic potential in lung tissue. A manufacturer of silicon carbide whiskers has set an internal standard at 0.2 f/ml as an eight-hour TWA (Beaumont 1991). This is a prudent recommendation based on currently available health information.

Man-made Vitreous Fibres

Man-made vitreous fibres (MMVFs) generally are classified as:

1.     glass fibre (glass wool or fibreglass, continuous glass filament and special-purpose glass fibre)

2.     mineral wool (rock wool and slag wool) and

3.     ceramic fibre (ceramic textile fibre and refractory ceramic fibre).

The manufacturing process begins with melting raw materials with subsequent rapid cooling, resulting in the production of non-crystalline (or vitreous) fibres. Some manufacturing processes allow for large variations in terms of fibre size, the lower limit being 1 mm or less in diameter (figure 10.35). Stabilizers (such as Al2O3, TiO2 and ZnO) and modifiers (such as MgO, Li2O, BaO, CaO, Na2O and K2O) can be added to alter the physical and chemical properties such as tensile strength, elasticity, durability and thermal non-transference.

Figure 10.35 SEM of slag wool

Rock wool, glass fibres and refractory ceramic fibres are identical in appearance

Glass fibre is manufactured from silicon dioxide and various concentrations of stabilizers and modifiers. Most glass wool is produced through use of a rotary process resulting in 3 to 15 µm average diameter discontinuous fibres with variations to 1 µm or less in diameter. The glass wool fibres are bound together, most commonly with phenolic formaldehyde resins, and then put through a heat-curing polymerization process. Other agents, including lubricants and wetting agents, may also be added, depending on the production process. The continuous glass filament production process results in less variation from the average fibre diameter in comparison to glass wool and special-purpose glass fibre. Continuous glass filament fibres range from 3 to 25 µm in diameter. Special-purpose glass fibre production involves a flame attenuation fibrization process that produces fibres with an average diameter of less than 3 µm.

Slag wool and rock wool production involves melting and fibrizing slag from metallic ore and igneous rock, respectively. The production process includes a dish shaped wheel and wheel centrifuge process. It produces 3.5 to 7 µm average diameter discontinuous fibres whose size may range well into the respirable range. Mineral wool can be manufactured with or without binder, depending on end-use applications.

Refractory ceramic fibre is manufactured through a wheel centrifuge or steam jet fibrization process using melted kaolin clay, alumina/silica, or alumina/silica/zirconia. Average fibre diameters range from 1 to 5 µm. When heated to temperatures above 1,000 °C, refractory ceramic fibres can undergo conversion to cristobalite (a crystalline silica).

MMVFs with different fibre diameters and chemical composition are used in over 35,000 applications. Glass wool is used in residential and commercial acoustical and thermal insulation applications, as well as in air handling systems. Continuous glass filament is used in fabrics and as reinforcing agents in plastics such as are employed in automobile parts. Special-purpose glass fibre is used in specialty applications, for instance in aircraft, that require high heat and acoustical insulation properties. Rock and slag wool without binder is used as blown insulation and in ceiling tiles. Rock and slag wool with a phenolic resin binder is used in insulation materials, such as insulation blankets and batts. Refractory ceramic fibre constitutes 1 to 2% of the worldwide production of MMVF. Refractory ceramic fibre is used in specialized high-temperature industrial applications, such as furnaces and kilns. Glass wool, continuous glass filament and mineral wool are manufactured in the greatest amounts.

MMVFs are thought to have less potential than naturally occurring fibrous silicates (such as asbestos) for producing adverse health effects because of their non-crystalline state and their propensity to fracture into shorter fibres. Existing data suggests that the most commonly utilized MMVF, glass wool, has the lowest risk of producing adverse health effects, followed by rock and slag wool, and then both special-purpose glass fibre with increased durability and refractory ceramic fibre. Special-purpose glass fibre and refractory ceramic fibre have the greatest potential for existing as respirable-sized fibres as they are generally less than 3 µm in diameter. Special-purpose glass fibre (with increased concentration of stabilizers such as Al2O3) and refractory ceramic fibre are also durable in physiologic fluids. Continuous glass filaments are non-respirable in size and therefore do not represent a potential pulmonary health risk.

Available health data is gathered from inhalation studies in animals and morbidity and mortality studies of workers involved with MMVF manufacturing. Inhalation studies involving exposure of rats to two commercial glass wool insulation materials averaging 1 µm in diameter and 20 µm in length revealed a mild pulmonary cellular response which partly reversed following discontinuation of exposure. Similar findings resulted from an animal inhalation study of a type of slag wool. Minimal fibrosis has been demonstrated with animal inhalation exposure to rock wool. Refractory ceramic fibre inhalation studies resulted in lung cancer, mesothelioma and pleural and pulmonary fibrosis in rats and in mesothelioma and pleural and pulmonary fibrosis in hamsters at a maximum tolerated dose of 250 f/ml. At 75 f/ml and 120 f/ml, one mesothelioma and minimal fibrosis was demonstrated in rats, and at 25 f/ml, there was a pulmonary cellular response (Bunn et al. 1993).

Skin, eye, and upper and lower respiratory tract irritation can occur and depends on exposure levels and job duties. Skin irritation has been the most common health effect noted and can cause up to 5% of new MMVF manufacturing plant workers to leave their employment within a few weeks. It is caused by mechanical trauma to the skin from fibres greater than 4 to 5 µm in diameter. It can be prevented with appropriate environmental control measures including avoiding direct skin contact with the fibres, wearing loose fitting, long-sleeved clothing, and washing work clothing separately. Upper and lower respiratory symptoms can occur in unusually dusty situations, particularly in MMVF product fabrication and end-use applications and in residential settings when MMVFs are not handled, installed or repaired correctly.

Studies of respiratory morbidity, as measured by symptoms, chest radiographs and pulmonary function tests among manufacturing plant workers generally have not found any adverse effects. However, an ongoing study of refractory ceramic fibre manufacturing plant workers has revealed an increased prevalence of pleural plaques (Lemasters et al. 1994). Studies in secondary production workers and end-users of MMVF are limited and have been hampered by the likelihood of the confounding factor of previous asbestos exposures.

Mortality studies of workers in glass fibre and mineral wool manufacturing plants are continuing in Europe and the United States. The data from the study in Europe revealed an overall increase in lung cancer mortality based upon national, but not local, mortality rates. There was an increasing trend of lung cancer in the glass and mineral wool cohorts with time since first employment but not with duration of employment. Using local mortality rates, there was an increase in lung cancer mortality for the earliest phase of mineral wool production (Simonato, Fletcher and Cherrie 1987; Boffetta et al. 1992). The data from the study in the United States demonstrated a statistically significant increased risk of respiratory cancer but failed to find an association between the development of cancer and various fibre exposure indices (Marsh et al. 1990). This is in accord with other case-control studies of slag wool and glass fibre manufacturing plant workers which have revealed an increased risk of lung cancer associated with cigarette smoking but not to the extent of MMVF exposure (Wong, Foliart and Trent 1991; Chiazze, Watkins and Fryar 1992). A mortality study of continuous glass filament manufacturing workers did not reveal an increased risk of mortality (Shannon et al. 1990). A mortality study involving refractory ceramic fibre workers is under way in the United States. Mortality studies of workers involved with product fabrication and end-users of MMVF are very limited.

In 1987, the International Agency for Research on Cancer (IARC) classified glass wool, rock wool, slag wool, and ceramic fibres as possible human carcinogens (group 2B). Ongoing animal studies and morbidity and mortality studies of workers involved with MMVF will help to further define any potential human health risk. Based on available data, the health risk from exposure to MMVF is substantially lower than what has been associated with asbestos exposure both from a morbidity and mortality perspective. The vast majority of the human studies, however, are from MMVF manufacturing facilities where exposure levels have generally been maintained below a 0.5 to 1 f/ml level over an eight-hour work day. The lack of morbidity and mortality data on secondary and end-users of MMVF makes it prudent to control respirable fibre exposure at or below these levels through environmental control measures, work practices, worker training and respiratory protection programmes. This is especially applicable with exposure to durable refractory ceramic and special purpose glass MMVF and any other type of respirable man-made fibre that is durable in biological media and that can therefore be deposited and retained in the pulmonary parenchyma.


Paolo Boffetta and Elisabete Weiderpass

Lung Cancer

Lung cancer is the most common cancer worldwide. In 1985, it is estimated that worldwide 676,500 cases occurred in males and 219,300 cases in females, accounting for 11.8% of all new cancers, and this figure is increasing at a rate of about 0.5% per year (Parkin, Pisani and Ferlay 1993). About 60% of these cases occur in industrialized countries, in many of which lung cancer is the leading cancer cause of death among males. In both industrialized and developing countries, males have a higher incidence than females, the sex ratio ranging from two- to ten-fold. The international intergender variations in lung cancer incidence are largely explained by the variation in current and past smoking patterns.

A higher lung cancer risk has been consistently observed in urban compared to rural areas. In industrialized countries, a clear, inverse relationship is evident in males in lung cancer incidence and mortality by social class, while women show less clear and consistent patterns. Differences in social class in males principally reflect a different smoking pattern. In developing countries, however, there seems to be a higher risk in men from the upper social class than in other men: this pattern probably reflects the earlier adoption of Western habits by affluent groups in the population.

Incidence data from the United States National Cancer Institute's SEER Program for the period 1980-86 indicate, similarly to previous years, that Black males have a higher incidence than White males, while incidence for females does not differ by race. These differences among ethnic groups in the United States can actually be attributed to socio-economic differences between Blacks and Whites (Baquet et al. 1991).

Lung cancer incidence increases almost linearly with age, when plotted in a log-log scale; only in the oldest age groups can a downward curve be observed. Lung cancer incidence and mortality have increased rapidly during this century, and continue to increase in most countries.

There are four principal histological types of lung cancer: squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma (SCLC). The first three are also referred to as non-small cell lung cancer (NSCLC). The proportions of each histological type change according to sex and age.

Squamous cell carcinoma is very strongly associated with smoking and represents the most common type of lung cancer in many populations. It arises most frequently in the proximal bronchi.

Adenocarcinoma is less strongly associated with smoking. This tumour is peripheral in origin and may present as a solitary peripheral nodule, a multifocal disease or a rapidly progressive pneumonic form, spreading from lobe to lobe.

Large cell carcinoma represents a smaller proportion of all lung cancers and has a similar behaviour as adenocarcinoma.

SCLC represents a small proportion (10 to 15%) of all lung cancers; it typically arises in the central endobronchial location and tends to develop early metastases.

The signs and symptoms of lung cancer depend on the location of the tumour, the spread and the effects of metastatic growth. Many patients present with an asymptomatic lesion discovered incidentally on x ray. Among NSCLC patients, fatigue, decreased activity, persistent cough, dyspnoea, decreased appetite and weight loss are common. Wheeze or stridor may also develop in advanced stages. Continuous growth may result in atelectasia, pneumonia and abscess formation. Clinical signs among SCLC patients are less pronounced than among those with NSCLC, and are usually related to the endobronchial location.

Lung cancer can metastasize to virtually any organ. The most common locations of metastatic lesions are pleura, lymph nodes, bone, brain, adrenals, pericardium and liver. At the moment of diagnosis, the majority of patients with lung cancer have metastases.

The prognosis varies with the stage of the disease. Overall five-year survival for lung cancer patients in Europe (in 1983-85) was between 7% and 9% (Berrino et al. 1995).

No population screening method is currently available for lung cancer.

Nasopharyngeal Cancer

Nasopharyngeal cancer is rare in most populations, but is frequent in both sexes in areas such as South-East Asia, Southern China and North Africa. Migrants from South China retain the high risk to a large extent, but second- and third-generation Chinese migrants to the United States have less than half the risk of first generation migrants.

Cancers of the nasopharynx are predominantly of squamous epithelial origin. According to WHO, these tumours are classified as: type 1, keratinizing squamous cell carcinoma; type 2, non-keratinizing carcinoma; and type 3, undifferentiated carcinoma, which is the most frequent histological type. Type 1 has an uncontrolled local growth, and metastatic spread is found in 60% of the patients. Types 2 and 3 have metastatic spread in 80 to 90% of the patients.

A mass in the neck is noticed in approximately 90% of nasopharyngeal carcinoma patients. Alterations in the hearing, serous otitis media, tinnitus, nasal obstruction, pain and symptoms related to the growth of the tumour into adjacent anatomical structures may be noticed.

The overall five-year survival for nasopharyngeal cancer patients in Europe between 1983 and 1985 was around 35%, varying according to the stage of the tumour and its location (Berrino et al. 1995).

Consumption of Chinese-style salted fish is a risk factor of nasopharyngeal cancer; the role of other nutritional factors and of viruses, in particular Epstein-Barr virus, although suspected, has not been confirmed. No occupational factors are known to cause nasopharyngeal cancer. No preventive measures are available at present (Higginson, Muir and Muñoz 1992).

Sinonasal Cancer

Neoplasms of the nose and nasal cavities are relatively rare. Together, cancer of the nose and nasal sinus-including maxillary, ethmoidal, sphenoid and frontal sinuses-account for less than 1% of all cancers. In most cases these tumours are classified as squamous carcinomas. In Western countries, cancers of the nose are more common than cancers of the nasal sinus (Higginson, Muir and Muñoz 1992).

They occur more frequently in men and among Black populations. The highest incidence is seen in Kuwait, Martinique and India. The peak of development of the disease occurs during the sixth decade of life. The major known cause of sinonasal cancer is exposure to wood dust, in particular from hardwood species. Tobacco smoking does not seem to be associated with this type of cancer.

Most tumours of the nasal cavity and para-nasal sinus are well differentiated and slow growing. Symptoms may include non-healing ulcer, bleeding, nasal obstruction and symptoms related to the growth into the oral cavity, orbit and pterygoid fossa. The disease is usually advanced at the time of diagnosis.

Overall five-year survival for nose and nasal sinus cancer patients in Europe between 1983 and 1985 was around 35%, varying according to the size of the lesion at diagnosis (Berrino et al. 1995).

Laryngeal Cancer

The highest incidence of laryngeal cancer is reported in Sao Paolo (Brazil), Navarra (Spain) and Varese (Italy). High mortality has also been reported in France, Uruguay, Hungary, Yugoslavia, Cuba, the Middle East and North Africa. Laryngeal cancer is predominantly a male cancer: an estimated 120,500 cases among males and 20,700 cases among females occurred in 1985 (Parkin, Pisani and Ferlay 1993). In general, incidence is higher among Black populations as compared to Whites, and in urban areas compared to rural.

Almost all cancers of the larynx are squamous carcinomas. The majority are located in the glottis, but they may also develop in the supraglottis or, rarely, in the subglottis.

Symptoms may not occur or be very subtle. Pain, a scratchy sensation, alteration of tolerance for hot or cold foods, a tendency to aspirate liquids, airway alteration, a slight change in the voice during several weeks and cervical adenopathy may be present, according to the location and stage of the lesion.

Most larynx cancers are visible with laryngeal inspection or endoscopy. Pre-neoplastic lesions can be identified in the larynx of smokers (Higginson, Muir and Muñoz 1992).

The overall five-year survival for laryngeal cancer patients in Europe between 1983 and 1985 was around 55% (Berrino et al. 1995).

Pleural Mesothelioma

Mesotheliomas may arise from the pleura, peritoneum and pericardium. Malignant mesothelioma represents the most important pleural tumour; it occurs mainly between the fifth and seventh decade of life.

Pleural mesothelioma was once a rare tumour and remains so in most female populations, while in men in industrialized countries it has increased by 5 to 10% per year during the last decades. In general, men are affected five times as much as women. Precise estimates of incidence and mortality are problematic because of difficulties in the histological diagnosis and changes in the International Classification of Diseases (ICD) (Higginson, Muir and Muñoz 1992). However, incidence rates seem to present very important local variations: they are very high in areas where asbestos mining is present (e.g., North West Cape Province of South Africa), in major naval dockyard cities, and in regions with environmental fibre contamination, such as certain areas of central Turkey.

Patients may be asymptomatic and have their disease diagnosed incidentally on chest radiographs, or they may have dyspnoea and chest pain.

Mesotheliomas tend to be invasive. The median survival is 4 to 18 months in various series.

Occupational Risk Factors of Respiratory Cancer

Apart from tobacco smoke, a causal association with respiratory cancer has been demonstrated according to the International Agency for Research on Cancer (IARC) for 13 agents or mixtures and nine exposure circumstances (see table 10.24). Furthermore, there are eight agents, mixtures or exposure circumstances which according to IARC are probably carcinogenic to one or more organs in the respiratory tract (table 10.25). All but azathioprine, an immunosuppressant drug, are primarily occupational exposures (IARC 1971-94).

Table 10.24 Establishing human respiratory carcinogens according to IARC.


Target sites

Individual agents



Lung, larynx, pleura

Arsenic and arsenic compounds


Beryllium and beryllium compounds


Bis (chloromethyl) ether


Cadmium and cadmium compounds


Chloromethyl methyl ether (technical-grade)


Chromium (VI) compounds

Nose, lung

Mustard gas

Lung, larynx

Nickel compounds

Nose, lung

Talc containing asbestiform fibres

Lung, pleura

Complex mixtures




Coal-tar pitches




Tobacco smoke

Nose, lung, larynx

Exposure circumstances


Aluminium production


Boot and shoe manufacture and repair


Coal gasification


Coke production


Iron and steel founding


Furniture and cabinet-making


Strong inorganic acid mists containing sulphuric acid (occupational exposures to)


Painters (occupational exposure as)


Radon and its decay products


Underground haematite mining (with exposure to radon)


Source: IARC, 1971-1994.

Table 10.25 Probable human respiratory carcinogens according to IARC.


Suspected target sites

Individual agents







Nose, larynx

Silica (crystalline)


Complex mixtures


Diesel engine exhaust


Welding fumes


Exposure circumstances


Rubber industry


Spraying and application of insecticides (occupational exposures in)


Source: IARC, 1971-1994.

Occupational groups demonstrating an increased risk of lung cancer following exposure to arsenic compounds include non-ferrous smeltery workers, fur handlers, manufacturers of sheep-dip compounds and vineyard workers (IARC 1987).

A large number of epidemiological studies have been carried out on the association between chromium (VI) compounds and the occurrence of lung and nasal cancer in the chromate, chromate pigment and chromium plating industries (IARC 1990a). The consistency of findings and the magnitude of the excesses have demonstrated the carcinogenic potential of chromium (VI) compounds.

Nickel refinery workers from many countries have shown substantial increased risks of lung and nasal cancers; other occupational groups exposed to nickel among which an increased risk of lung cancer has been detected include sulphide nickel ore miners and high nickel alloy manufacture workers (IARC 1990b).

Workers exposed to beryllium are at elevated risk of lung cancer (IARC 1994a). The most informative data are those derived from the US Beryllium Case Registry, in which cases of beryllium-related lung diseases were collected from different industries.

An increase in lung cancer occurrence has been found in cohorts of cadmium smelters and nickel-cadmium battery workers (IARC 1994b). Concurrent exposure to arsenic among smelters and to nickel among battery workers, cannot explain such an increase.

Asbestos is an important occupational carcinogen. Lung cancer and mesothelioma are the major asbestos-related neoplasms, but cancers at other sites, such as the gastro-intestinal tract, larynx and kidney, have been reported in asbestos workers. All forms of asbestos have been causally related to lung cancer and mesothelioma. In addition, talc-containing asbestiform fibres have been shown to be carcinogenic to the human lung (IARC 1987). A distinctive characteristic of asbestos-induced lung cancer is its synergistic relationship with cigarette smoking.

A number of studies among miners, quarry workers, foundry workers, ceramic workers, granite workers and stone cutters have shown that individuals diagnosed as having silicosis after exposure to dust containing crystalline silica have an increased risk of lung cancer (IARC 1987).

Polynuclear aromatic hydrocarbons (PAHs) are formed mainly as a result of pyrolytic processes, especially the incomplete combustion of organic materials. However, humans are exposed exclusively to mixtures of PAHs, such as soots, coal-tars and coal-tar pitches. Cohort studies of mortality among chimney-sweeps have shown an increased risk of lung cancer, which has been attributed to soot exposure. Several epidemiological studies have shown excesses of respiratory cancer among workers exposed to pitch fumes in aluminium production, calcium carbide production and roofing. In these industries, exposure to tar, and particularly coal tar, does also occur. Other industries in which an excess of respiratory cancer is due to exposure to coal-tar fumes are coal gasification and coke production (IARC 1987). An increased risk of respiratory (mainly lung) cancer was found in some, but not all the studies tried to analyse diesel engine exhaust exposure separately from other combustion products; the occupational groups which were studied include railroad workers, dockers, bus garage workers, bus company employees and professional lorry drivers (IARC 1989a). Other mixtures of PAHs that have been studied for their carcinogenicity to humans include carbon blacks, gasoline engine exhaust, mineral oils, shale oils, and bitumens. Shale oils and untreated and mildly treated mineral oils are carcinogenic to humans, whereas gasoline engine exhaust is possibly carcinogenic and highly refined mineral oils, bitumens and carbon blacks are not classifiable as to their carcinogenicity to humans (IARC 1987, 1989a). Although these mixtures do contain PAHs, a carcinogenic effect on the human lung has not been demonstrated for any of them, and the evidence of carcinogenicity for untreated and mildly treated mineral oils and for shale oils is based on increased risk of cancers from sites other than respiratory organs (mainly skin and scrotum) among exposed workers.

Bis(b-chloroethyl)sulphide, known as mustard gas, was widely used during the First World War, and the studies of soldiers exposed to mustard gas as well as of workers employed in its manufacture have revealed a subsequent development of lung and nasal cancer (IARC 1987).

Numerous epidemiological studies have demonstrated that workers exposed to chloromethyl methyl ether and/or bis(chloromethyl)-ether have an increased risk of lung cancer, primarily of SCLC (IARC 1987).

Workers exposed to acrylonitrile have been found to be at higher risk of lung cancer in some but not all studies which have been conducted among workers in textile fibre manufacture, acrylonitrile polymerization and the rubber industry (IARC 1987).

Excess occurrence has been reported for workers exposed to formaldehyde, including chemical workers, wood workers, and producers and users of formaldehyde (IARC 1987). The evidence is strongest for nasal and nasopharyngeal cancer: the occurrence of these cancers showed a dose-response gradient in more than one study, although the number of exposed cases was often small. Other neoplasms at possible increased risk are lung and brain cancer and leukaemia.

An increased risk of laryngeal cancer has been found in several studies of workers exposed to mists and vapours of sulphuric and other strong inorganic acids, such as workers in steel pickling operations, and in soap manufacture and petrochemical workers (IARC 1992). Lung cancer risk was also increased in some, but not all, of these studies. Furthermore, an excess of sinonasal cancer was found in a cohort of workers in isopropanol manufacture using the strong-acid process.

Woodworkers are at increased risk of nasal cancer, in particular adenocarcinoma (IARC 1987). The risk is confirmed for furniture and cabinet-makers; studies on workers in carpentry and joinery suggested a similar excess risk, but some studies produced negative results. Other wood industries, such as sawmills and pulp and paper manufacture, were not classifiable as to their carcinogenic risk. Although carcinogenicity of wood dust was not evaluated by IARC, it is plausible to consider that wood dust is responsible for at least part of the increased risk of nasal adenocarcinoma among woodworkers. Woodworkers do not seem to be at increased risk of cancer in other respiratory organs.

Nasal adenocarcinoma has been caused also by employment in boot and shoe manufacture and repair (IARC 1987). No clear evidence is available, on the other hand, that workers employed in the manufacture of leather products and in leather tanning and processing are at increased risk of respiratory cancer. It is not known at present whether the excess of nasal adenocarcinoma in the boot and shoe industry is due to leather dust or to other exposures. Carcinogenicity of leather dust has not been evaluated by IARC.

Lung cancer has been common among uranium miners, underground hematite miners and several other groups of metal miners (IARC 1988; BEIR IV Committee on the Biological Effects of Ionizing Radiation 1988). A common factor among each of these occupational groups is exposure to α-radiation emitted by inhaled radon particles. The main source of data on cancer following exposure to ionizing radiation is derived from the follow-up of atomic bomb survivors (Preston et al. 1986; Shimizu et al. 1987). The risk of lung cancer is elevated among the atomic bomb survivors as well as among people who have received radiation therapy (Smith and Doll 1982). No convincing evidence, however, is currently available on the existence of an elevated lung cancer risk among workers exposed to low-level ionizing radiation, such as those occurring in the nuclear industry (Beral et al. 1987; BEIR V, Committee on the Biological Effects of Ionizing Radiation 1990). Carcinogenicity of ionizing radiation has not been evaluated by IARC.

An elevated risk of lung cancer among painters was found in three large cohort studies and in eight small cohort and census-based studies, as well as eleven case-control studies from various countries. On the other hand, little evidence of an increase in lung cancer risk was found among workers involved in the manufacture of paint (IARC 1989b).

A number of other chemicals, mixtures, occupations and industries which have been evaluated by IARC to be carcinogenic to humans (IARC Group 1) do not have the lung as the primary target organ. Nonetheless, the possibility of an increased risk of lung cancer has been raised for some of these chemicals, such as vinyl chloride (IARC 1987), and occupations, such as spraying and application of insecticides (IARC 1991a), but the evidence is not consistent.

Furthermore, several agents which have the lung as one of the main targets, have been considered to be possible human carcinogens (IARC Group 2B), on the basis of carcinogenic activity in experimental animals and/or limited epidemiological evidence. They include inorganic lead compounds (IARC 1987), cobalt (IARC 1991b), man-made vitreous fibres (rockwool, slagwool and glasswool) (IARC 1988b), and welding fumes (IARC 1990c).


Anthony A. Marfin, Ann F. Hubbs, Karl J. Musgrave, and John E. Parker

Although epidemiological studies of occupationally acquired pneumonia (OAP) are limited, work-related lung infections are thought to be declining in frequency worldwide. In contrast, OAPs in developed nations may be increasing in occupations associated with biomedical research or healthcare. OAP in hospital workers largely reflects the prevalent community-acquired pathogens, but the re-emergence of tuberculosis, measles and pertussis in health care settings presents additional risk for health-based occupations. In developing nations, and in specific occupations in developed nations, unique infectious pathogens that do not commonly circulate in the community cause many OAPs.

Attributing infection to occupational rather than community exposure can be difficult, especially for hospital workers. In the past, occupational risk was documented with certainty only in situations where workers were infected with agents that occurred in the workplace but were not present in the community. In the future, the use of molecular techniques to track specific microbial clones through the workplace and communities will make risk determinations more clear.

Like community-acquired pneumonia, OAP results from microaspiration of bacteria that colonize the oropharynx, inhalation of respirable infectious particles, or haematogenous seeding of the lungs. Most community-acquired pneumonia results from microaspiration, but OAP is usually due to inhalation of infectious 0.5 to 10 µm airborne particles in the workplace. Larger particles fail to reach the alveoli because of impaction or sedimentation onto the walls of the large airways and are subsequently cleared. Smaller particles remain suspended during inspiratory and expiratory flow and are rarely deposited in the alveoli. For some diseases, such as the haemorrhagic fever with renal syndrome associated with hantavirus infection, the principal mode of transmission is inhalation but the primary focus of disease may not be the lungs. Occupationally acquired pathogens that are not transmitted by inhalation may secondarily involve the lungs but will not be discussed here.

This review briefly discusses some of the most important occupationally acquired pathogens. A more extensive list of occupationally acquired pulmonary disorders, classified by specific aetiologies, is presented in table 10.26 .

Table 10.26 Occupationally acquired infectious diseases contracted via microaspiration or inhalation of infectious particles.

Disease (pathogen)


At-risk populations

Bacteria, chlamydia, mycoplasma and rickettsia

Brucellosis (Brucella spp.)

Livestock (cattle, goats, pigs)

Veterinary care workers, agricultural workers, laboratory workers, abattoir workers

Inhalation anthrax (Bacillus anthracis)

Animal products (wools, hides)

Agricultural workers, tanners, abattoir workers, textile workers, laboratory workers

Pneumonic plague (Yersinia pestis)

Wild rodents

Veterinary care workers, hunters/trappers, laboratory workers

Pertussis (Bordatella pertussis)


Employees of nursing homes, health care workers

Legionnaire's disease (Legionella spp.)

Contaminated water sources (e.g., cooling towers, evaporator condensers)

Health care workers, laboratory workers, industrial laboratory workers, water well excavators

Melioidosis (Pseudomonas pseudomallei)

Soil, stagnant water, rice fields

Military personnel, agricultural workers

Streptococcus pneumoniae


Health care workers, agricultural workers, subterranean miners

Neisseria meningitidis


Health care workers, laboratory workers, military personnel

Pasteurellosis (Pasteurella multocida)

Variety of domesticated (cats, dogs) and wild animals

Agricultural workers, veterinary care workers

Respiratory tularaemia (Francisella tularensis)

Wild rodents and rabbits

Manual labourers, military personnel, laboratory workers, hunters/trappers, agricultural workers

Ornithosis (Chlamydia psittaci)


Pet shop workers, poultry production workers, veterinary care workers, laboratory workers

TWAR pneumonia (Chlamydia pneumoniae)


Health care workers, military personnel

Q Fever (Coxiella burnetii)

Domesticated animals (cattle, sheep, goats)

Laboratory workers, textile workers, abattoir workers, dairy cattle workers, veterinary care workers

Atypical pneumonia (Mycoplasma pneumoniae)


Military personnel, health care workers, institutional workers


Histoplasmosis (Histoplasma capsulatum)

Soil; bird or bat excrement (endemic to eastern North America)

Agricultural workers, laboratory workers, manual labourers

Coccidioidomycosis (Coccidioides immitis)

Soil (endemic to western North America)

Military personnel, agricultural workers, manual labourers, textile workers, laboratory workers

Blastomycosis (Blastomyces dermatitidis)

Soil (endemic to eastern North America)

Laboratory workers, agricultural workers, manual labourers, forestry workers

Paracoccidioidomycosis (Paracoccidioides brasiliensis)

Soil (endemic to Venezuela, Colombia, Brazil)

Agricultural workers

Sporotrichosis (Sporothrix schenkii)

Plant debris, tree and garden plant bark

Gardeners, florists, miners

Tuberculosis (Mycobacterium tuberculosis, M. bovis, M. africanum)

Human and non-human primates, cattle

Hard rock miners, foundry workers, health care and laboratory workers, abattoir workers, veterinary care workers, military personnel, tavern workers

Mycobacteriosis other than tuberculosis  (Mycobacterium spp.)


Silica-exposed workers, including sandblasters




Agricultural workers, herders, rodent control workers



Health care and laboratory workers



Health care and laboratory workers



Health care and laboratory workers

Varicella zoster


Health care and laboratory workers, military personnel

Respiratory syncytial virus


Health care and laboratory workers



Health care and laboratory workers, military personnel

Parainfluenza virus


Health care and laboratory workers

Lymphocytic choriomeningitis virus (arenavirus)


Laboratory workers, veterinary care workers

Lassa Fever (arenavirus)


Health care workers

Marburg and Ebola viruses (filovirus)

Human and non-human primates, possibly bats

Laboratory workers, veterinary care workers, health care workers, cotton factory workers

Occupationally Acquired Infections in Agricultural Workers

In addition to gases and organic dusts that affect the respiratory tract and mimic infectious diseases, several zoonotic (pathogens common to animals and humans) and other infectious diseases associated with rural living uniquely affect agricultural workers. These diseases are acquired by inhalation of infectious aerosols, and are rarely transmitted from one person to another. Such illnesses that occur in agricultural workers include anthrax, brucellosis, Q fever, ornithosis, tuberculosis and plague (table 10.26). Fungal pathogens include histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis and cryptococcosis (table 10.26). Except for the hantaviral diseases, viral diseases are not an important cause of occupational lung disease in agricultural workers.

Some of these infections are thought to be more common but their incidence is difficult to determine because: (1) most infections are subclinical, (2) clinical illness is mild or difficult to diagnose because of non-specific symptoms, (3) medical and diagnostic services are rarely available for most agricultural workers, (4) there is no organized system for reporting many of these diseases and (5) many of these are rare diseases in the general community and are not recognized by medical personnel. For example, although epidemic nephritis due to Puumala virus, a hantavirus, is rarely reported in western Europe, serosurveys of agricultural workers have shown a 2 to 7% prevalence of antibody to hantaviruses.

Zoonotic infections in developed nations are decreasing due to active disease control programmes directed at the animal populations. Despite these controls, agricultural workers and persons working in agriculturally related fields (such as veterinarians, meat-packers, poultry-processors and hair/hide workers) remain at risk for many diseases.

Hantavirus Infection

Hantavirus infection resulting in haemorrhagic fever with renal syndrome (HFRS) or epidemic nephritis (EN) has been clinically described among agricultural workers, military personnel and laboratory workers in endemic areas of Asia and Europe for more than 50 years. Infection results from inhalation of aerosols of urine, saliva and faeces from infected rodents. Haemorrhagic illness and decreased renal function develop during most hantavirus illnesses rather than pneumonia, but pulmonary oedema due to increased vascular permeability has been reported in HFRS and EN. The profound pulmonary consequences of hantavirus infections were not fully appreciated until a recent outbreak of Hantavirus Pulmonary Syndrome (HPS) associated with infection with a recently isolated hantavirus in the western United States (Muerto Canyon virus, Four Corners virus, or Sin Nombre virus).

Hantaviruses are members of the Bunyaviridae, a family of RNA viruses. Five hantaviruses have been associated with human disease. HFRS has been associated with Hantaan virus in eastern Asia, Dobrava virus in the Balkans, and Seoul virus, which has a worldwide distribution. EN has been associated with Puumala virus in western Europe. HPS has been associated with a newly isolated hantavirus in the western United States. From 1951 to 1983, 12,000 cases of HFRS were reported from the Republic of Korea. Disease incidence in China is reported to be increasing with epidemics in rural and urban centres, and in 1980, 30,500 cases with 2,000 deaths were attributed to HFRS.

Clinical presentation

With the viruses causing HFRS or EN, infection usually results in asymptomatic development of anti-hantavirus antibodies. In people who become ill, signs and symptoms of the early phase are non-specific, and hantavirus infection can be diagnosed only with serologic testing. Slow recovery is common, but a few persons progress to HFRS or EN developing proteinuria, microscopic haematuria, azotaemia and oliguria. Persons with HFRS also develop profound haemorrhage due to disseminated intravascular coagulation, increased vascular permeability, and shock. Mortality in persons with the full HFRS syndrome varies from 5 to 20%.

HPS is characterized by diffuse interstitial pulmonary infiltrates and the abrupt onset of acute respiratory distress and shock. Marked leukocytosis may occur as a result of increased cytokines that characterize hantaviral illnesses. In HPS, mortality may be more than 50%. The incidence of asymptomatic infection or unrecognized HPS is incompletely investigated.

Diagnostic tests

Diagnosis is made by demonstrating the presence of immunoglobulin M or rising titre of immunoglobulin G using highly specific and sensitive indirect immunofluorescence and neutralizing antibody assays. Other diagnostic methods include polymerase chain reaction for viral ribonucleic acid and immunohistochemistry for viral antigen.


Infection results from inhalation of aerosols of urine, saliva and faeces from infected rodents. Infected rodents do not have any apparent illness. Transmission may occur by percutaneous inoculation of urine, saliva or faeces from infected rodents, but there is no evidence of human-to-human transmission.

Seroepidemiological surveys of humans and rodents have shown that hantaviruses are endemic with a worldwide distribution in rural and urban settings. In endemic rural settings, rodent-human interactions increase when rodents seasonally invade homes or human activity increases in areas with high rodent density. Persons in rural occupations are at greatest risk of infection. In surveys of asymptomatic rural populations in Italy, 4 to 7% of forestry workers, rangers, farmers and hunters had anti-hantavirus antibody, compared to 0.7% of soldiers. In asymptomatic agricultural workers in Ireland and Czechoslovakia, the prevalence of anti-hantavirus antibody was 1 to 2% and 20 to 30%, respectively. Planting, harvesting, threshing, herding and forestry are risk factors for virus infection. Serosurveys in the western United States to determine the occupational risk of hantavirus infection are in progress, but in a study of health care workers (HCWs) caring for HPS patients, no infections were identified. From the first 68 persons with HPS, it appears that agricultural activities in habitats of infected rodents are risk factors for infection. Patients were more likely to hand plow, clean food storage areas, plant, clean animal sheds and be herders. The major reservoir for HPS is the deer mouse, Peromyscus maniculatus.

Other affected occupations

In urban settings, the rodent reservoir for Seoul virus is the house rat. Urban workers, such as dockworkers, workers at grain storage facilities, zoo workers and rodent-control workers may be at risk for hantavirus infection. Research laboratories using rodents for research other than hantavirus research have occasionally been unsuspected sources for hantavirus infections of laboratory workers. Other occupations, such as military personnel and field biologists, are at risk for hantavirus infection.


Ribavirin has demonstrated in vitro activity against several hantaviruses and clinical efficacy against Hantaan virus infection, and has been used to treat persons with HPS.

Public health controls

No vaccine is available for use although there are ongoing efforts to develop live and killed vaccines. Minimizing human contact with rodents and reducing rodent populations in human environments reduces the risk of disease. In hantavirus research laboratories, high-level biosafety facilities limit the risk from virus propagation in cell culture or handling materials with high concentrations of virus. In other research laboratories using rodents, periodic serologic surveillance for hantavirus infection of rodent colonies may be considered.

Lymphocytic Choriomeningitis (LCM)

LCM, like the hantaviral infections, is naturally an infection of wild rodents which occasionally spreads to man. The LCM virus is an arenavirus, but transmission usually occurs by aerosolization. The natural hosts include wild mice, but persistent infection of domestic Syrian hamsters is well documented. Infection is, therefore, possible in most occupations involving the aerosolization of rodent urine. The most recent documented occupational outbreak of this disease occurred in laboratory personnel exposed to T-cell deficient nude mice persistently infected as a result of inoculation of contaminated tumour cell lines.

Clinical presentation

Most cases of LCM are asymptomatic or associated with non-specific flu-like illness and are, therefore, not recognized. While the respiratory tract is the site of entry, respiratory symptoms tend to be non-specific and self-limited. Meningitis or meningoencephalitis develops in a small percentage of the patients and may lead to a specific diagnosis.

Diagnostic tests

Diagnosis is usually by serologic demonstration of a rising titre to the virus in the presence of appropriate clinical signs. Virus isolation and tissue immunofluorescence are also occasionally used.


Approximately 20% of wild mice are infected with this virus. Transplacental transmission of the virus in susceptible rodents leads to T-cell tolerance and congenitally infected mice (or hamsters) who remain persistently infected throughout their lives. Similarly, T-cell deficient mice, such as nude mice, may become persistently infected with the virus. Humans are infected by aerosol transmission. In addition, rodent cell lines can be contaminated with and propagate the virus. Humans usually become infected by aerosols, although transmission may be direct or via insect vectors.

Other affected occupations

Any occupation involving exposure to dusts contaminated with the excreta of wild rodents confers risk of LCM infection. Animal caretakers in laboratory animal facilities, workers in the pet store industry, and laboratory workers working with rodent cell lines may become infected.


LCM infection is usually self-limited. Supportive treatment may be necessary in severe cases.

Public health controls

No vaccine is available. Screening of research mice, hamsters and cell lines has limited most laboratory-acquired infections. For T-cell deficient mice, serologic testing requires the use of immunocompetent sentinel mice. The use of routine laboratory safety precautions such as gloves, eye protection and laboratory coats is appropriate. Reducing the number of wild rodents in the human environment is important in the control of LCM, hantavirus and plague.

Respiratory Chlamydiosis

Respiratory chlamydiosis due to Chlamydia psittaci is the most frequently reported cause of OAP associated with animal (poultry) slaughter and meat processing. Chlamydiosis and other illnesses are often associated with exposure to ill animals, which may be the only clue to the source and type of infection. Processing infected animals creates aerosols that infect persons who are remote from meat processing, and working near meat-processing plants may be a clue to the type of infection. Respiratory chlamydiosis may be associated with exposure to parrots (psittacosis) or non-psittacine birds (ornithosis). Non-avian sources of Chlamydia psittaci are usually not considered potential zoonoses, although spontaneous abortion and conjunctivitis have been reported in humans exposed to sheep and goat strains. Pneumonia due to C. pneumoniae is a recently described common cause of community acquired pneumonia distinct from C. psittaci infections. Because of its recent discovery, the role of C. pneumoniae in OAPs is incompletely investigated and will not be further discussed in this review.

Clinical presentation

Ornithosis varies from mild influenza-like illness to severe pneumonia with encephalitis which, in the preantibiotic era, had a case-fatality rate (CFR) greater than 20%. Prodromal fever, chills, myalgia, headache and non-productive cough may last up to three weeks prior to the diagnosis of pneumonia. Neurologic, hepatic and renal changes are common. Roentgenographic findings include lower lobe consolidation with hilar lymphadenopathy. Clinical suspicion after determining work-related or other exposures to birds is crucial to the diagnosis because there are no pathognomonic findings.

Diagnostic tests

Ornithosis usually results in a high titre of complement fixation (CF) antibody, although early treatment with tetracyclines may suppress antibody formation. A single acute serum titre ≥1:16 dilution of CF antibody with a compatible clinical presentation or four-fold change in CF antibody titre can be used to make the diagnosis. Inappropriately paired serum samples and the high background of Chlamydia antibodies in at-risk groups undermine the utility of antibody assays to diagnose most chlamydial diseases.


C. psittaci is present in virtually all avian species and is common in mammals. Infection usually results from zoonotic transmission but person-to-person transmission has been reported. Asymptomatic infection is common and up to 11% of agricultural workers without a history of illness have antibodies to C. psittaci. Limited outbreaks remain intermittent but pandemics associated with the exotic bird trade most recently occurred in 1930. In the United States, 70 to 100 cases of ornithosis are reported annually, and nearly one-third of these illnesses are occupationally acquired. Most occupationally acquired infections occur in workers in the pet-bird or poultry-processing industries and are related to aerosolization of avian tissue or faeces. In countries where birds are commonly kept as pets and importation quarantines are poorly enforced, outbreaks are more common but occupation is less of a risk factor.

Other affected occupations

Disease most frequently occurs in poultry processing workers, but workers in exotic bird distribution and avian quarantine facilities, breeding aviaries and veterinary clinics are at risk.


Tetracycline or erythromycin for 10 to 14 days should be adequate treatment, but clinical relapse is common when treatment is given for an inadequate duration.

Public health controls

In the United States, exotic birds are quarantined for chemoprophylaxis with tetracyclines. Similar methods are used in other countries where an exotic bird trade exists. No vaccine has been developed for ornithosis. Programmes to increase ventilation to dilute aerosol concentration, reduce aerosolization or inhalation of infectious particles, or treat ill birds in commercial processing plants have been instituted, but their efficacy has not been demonstrated.


Annually, approximately 500,000 cases of Brucellosis occur worldwide, caused by several Brucella species. The pathogenicity of Brucella infections is dependent upon the infecting species, which tend to have different reservoir hosts. The reservoirs for Brucella abortus, B. suis, B. melitensis, B. ovis, B. canis, and B. neotomae tend to be cattle, swine, goats, sheep, dogs and rats, respectively.

Brucellosis can result from infection by different routes, including aerosolization. However, most illness results from ingestion of non-pasteurized dairy products from goats. The resulting systemic illness is caused by B. melitensis but not associated with specific occupations. Pneumonia occurs in 1% of cases, although cough is a frequent finding.

In developed countries, occupational brucellosis is usually caused by Brucella abortus and results from ingestion or inhalation of infectious aerosols associated with placentas of swine and cattle. Subclinical infection is common; up to 1% of agricultural workers have antibodies to B. abortus. Illness develops in approximately 10% of infected persons. Unlike illness due to B. melitensis, illness associated with B. abortus is usually occupationally acquired and is less severe. Persons with acute brucellosis develop high daily fevers, arthralgia and hepatosplenomegaly. In primary brucella pneumonia, pneumonic consolidation is actually rare, and pulmonary findings may include hoarseness or wheezing, hilar adenopathy, peribronchial infiltrates, parenchymal nodules or a miliary pattern. Isolation can be made from bone marrow in 90% of acute cases and from blood in 50 to 80% of cases. Diagnosis can be made serologically with a variety of antibody assays. Tetracyclines should be used for four to six weeks, and rifampin may be added for synergy. Cattle, goat, sheep and swine raisers, dairy workers, slaughterhouse workers, veterinarians and butchers are the primary populations at risk. Brucella testing and eradication programmes have greatly reduced the number of infected animals and have identified those herds which pose the greatest risk for disease transmission. When working with Brucella-infected animals, avoidance or personal protection, especially after abortion or parturition, are the only effective disease control methods.

Inhalation Anthrax

Inhalation anthrax occurs worldwide but is less common than cutaneous anthrax. Anthrax is a systemic illness in many animals and is usually transmitted to humans by percutaneous infection from processing or by eating contaminated meat. Inhalation anthrax is caused by inhalation of spores of Bacillus anthracis from the bone, hair or hide of sheep, goats or cattle ("woolsorter's disease") or rarely while processing infected meat. Spores undergo phagocytosis by alveolar macrophages and are transported to mediastinal lymph nodes, where they germinate. This results in a haemorrhagic mediastinitis but rarely presents as primary pneumonia. Illness is characterized by a widened mediastinum, pulmonary oedema, pleural effusions, splenomegaly and rapid progression to respiratory failure. The case fatality rate is 50% or greater despite antibiotics and ventilatory support. Positive blood cultures are common but serologic testing using a blotting immunoassay may be used. Ill persons are treated with high-dose penicillin, or intravenous ciprofloxacin as an alternative in persons allergic to penicillin. Animal breeders, veterinarians, veterinary care workers, hair and hide processors, and slaughterhouse workers are at increased risk. Annual vaccination is available for animals in endemic areas and humans at high risk for disease. Specific control measures against inhalation anthrax include formaldehyde decontamination, steam sterilization or irradiation of hair and hides; prohibiting hide importation from endemic areas; and personal respiratory protection for workers.

Pneumonic Plague

Plague, caused by Yersinia pestis, is predominantly a flea-borne disease enzootic in wild rodents. Humans usually become infected when bitten by an infected flea and often develop septicaemia. In the United States from 1970 through 1988, secondary pneumonia from haematogenous spread developed in approximately 10% of septicaemic persons. Animals and humans with pneumonic plague produce infectious aerosols. Primary pneumonia in humans can occur from inhalation of an infectious aerosol created around dying animals with secondary pneumonia. Despite the potential for pneumonic spread, person-to-person transmission is rare and has not occurred in the United States in nearly 50 years. Disease controls include the isolation of persons with pneumonic plague and the use of personal respiratory protection by HCWs. Aerosol transmission to hospital workers is possible, and tetracycline prophylaxis should be considered for anyone in contact with humans or animals with pneumonic plague. A number of occupations are at risk for aerosol transmission, including biomedical and hospital laboratory workers and, in endemic areas, a number of rural occupations, including veterinarians, rodent-control workers, hunter/trappers, mammologists, wildlife biologists and agricultural workers. A killed vaccine is recommended for persons in high-risk occupations.

Q Fever

Caused by inhalation of Coxiella burnetii, Q fever is a systemic disease that presents as atypical pneumonia in 10 to 60% of infected persons. Many different isolates of C. burnetii produce disease, and theories of plasmid-dependent virulence are controversial. C. burnetii infects many domestic animals (e.g., sheep, cattle, goats, cats) worldwide; is aerosolized from urine, faeces, milk, placenta or uterine tissues; forms a highly resistant endospore that remains infectious for years; and is extremely infectious.

Clinical presentation

After a 4- to 40-day incubation period, acute Q fever presents as an influenza-like illness that progresses to an atypical pneumonia similar to Mycoplasma. Acute illness lasts about two weeks but may persist up to nine weeks. Chronic illness, predominantly an endocarditis and hepatitis, may develop up to 20 years following acute illness.

Diagnostic tests

Primary isolation of C. burnetii is rarely performed because it requires a high level of biosafety containment. Diagnosis is made serologically by demonstrating a CF antibody titre of 1:8 or greater in an appropriate clinical setting or a four-fold change in CF titre.

Other affected occupations

Agricultural (especially dairy and wool), hospital laboratory, and biomedical research workers are at risk for infection.


No effective vaccine exists for C. burnetii. A two-week course of tetracyclines or ciprofloxacin is used to treat acute illness.

Public health controls

Because of its widespread geographic distribution, numerous animal reservoirs, and resistance to inactivation, personal respiratory protection and engineering controls to contain infectious aerosols are the only effective preventive measures. However, these control methods are difficult to implement in many agricultural settings (e.g., sheep and cattle herding). The early diagnosis of Q fever by medical personnel can be facilitated by education of workers at high risk for contracting this rare disease. Transmission to hospital personnel may occur, and isolation may limit the spread of Q fever pneumonia in hospitals.

Miscellaneous Bacterial OAPS of Agricultural Workers

Pseudomonas pseudomallei is a soil- and rodent-associated organism principally of Southeast Asia which causes melioidosis. The disease is associated with soil exposure and a potentially long latency. Military personnel during and after the Vietnam War have been the major victims of melioidosis in the United States. Multifocal, nodular, suppurative or granulomatous pneumonia characterizes the pulmonary form of melioidosis.

Francisella tularensis, the aetiologic agent of tularaemia, is a zoonosis associated with wild rodents and lagomorphs. This is a potential occupational disease of wildlife biologists, mammologists, rodent-control workers, hunters, trappers and veterinarians. Tularaemia may result from inhalation, direct inoculation, cutaneous contact or ingestion, or it may be vector borne. Pulmonary disease results from either direct inhalation exposure or haematogenous spread of septicaemic disease. The pulmonary lesions of tularaemia are acute, multifocal, suppurative and necrotizing.


Histoplasmosis is caused by Histoplasma capsulatum, a free-living mould in the soil associated with the faeces of birds or bats. Histoplasmosis is the most important cause of fungal OAPs in agricultural workers. The miscellaneous fungal pneumonias of agricultural workers are described in the next section.

Clinical presentation

Following exposure, attack rates and severity of histoplasmosis vary as a result of the infecting inoculum and the host's antibody levels conferred by prior infection. Following heavy exposure, up to 50% of persons develop self-limited respiratory illness, while others remain asymptomatic. The least severe of the symptomatic syndromes includes "flu-like" symptoms, non-productive cough, and chest pain. Physical examination may be remarkable for erythema nodosum or erythema multiforme. Chest x rays show patchy, segmental infiltrates but no x ray findings can specifically differentiate histoplasmosis from other pulmonary infections. Hilar or mediastinal lymphadenopathy is common in all stages of primary histoplasmosis.

Progressive primary pneumonic histoplasmosis is characterized by profound systemic complaints, cough productive of purulent sputum, and haemoptysis. Progressive x-ray changes include multiple nodules, lobar consolidation and dense, multilobar interstitial infiltrates. Greater exposures increase the severity of the illness and result in severe respiratory disease, the acute respiratory distress syndrome (ARDS) or atelectasis due to obstruction by mediastinal lymphadenopathy.

Approximately 20% of ill persons develop other histoplasmosis syndromes which are idiosyncratic and not the result of greater exposure or progression of primary disease. Syndromes include arthritis-erythema nodosum, pericarditis, and chronic pulmonary histoplasmosis (fibrotic apical lung infiltrates with cavitation). Disseminated histoplasmosis develops in a small percentage of patients, particularly the immunosuppressed.

Diagnostic tests

Definitive diagnosis is made by isolating or histopathologically demonstrating the organism in an appropriate clinical specimen. Unfortunately, the organism is present in low concentrations and the sensitivities of these methods are low. Presumptive diagnoses are often made on the basis of geographic location, exposure history and x-ray findings of the lungs or calcifications in the spleen.


H. capsulatum is found worldwide associated with specific soil conditions, but illness is reported primarily from the Ohio and Mississippi River valleys of the United States. High concentrations of spores are found in bird roosts, old buildings, poultry houses, caves or schoolyards; they are disrupted by work activity. Microconidia concentration is higher in disrupted, enclosed areas (e.g., building demolition) and results in higher inoculum for workers there than in most outdoor sites. In endemic areas, persons who clean bird roosts, demolish older contaminated buildings or perform excavations for road or building construction are at greater risk than the general population. In the United States, 15,000 to 20,000 persons are hospitalized each year with histoplasmosis, and approximately 3% of them die.

Other affected occupations

Attributing occupational risk for Histoplasma infection is difficult because the organism is free-living in soil and the concentration of aerosolized spores is increased by wind and dusty conditions. Infection is predominantly due to geographic location. In endemic areas, rural persons, regardless of occupation, have a 60 to 80% prevalence of positive skin test to H. capsulatum antigens. Actual illness results from a large infecting inoculum and is usually restricted to workers involved in the disruption of soil or destruction of contaminated buildings.


Antifungal treatment for histoplasmosis and other occupationally acquired fungal infections is not indicated for acute self-limited pulmonary disease. Therapy with amphotericin B (30 to 35 mg/kg total dose) or ketoconazole (400 mg/day for six months) or treatment regimens using both agents is indicated for disseminated histoplasmosis, chronic pulmonary histoplasmosis, acute pulmonary histoplasmosis with ARDS, or mediastinal granuloma with symptomatic obstruction, and may be useful for prolonged, moderately severe primary illness. Treatment results in an 80 to 100% response rate, but relapses are common and may be as high as 20% with amphotericin B and 50% with ketoconazole. Efficacy of newer azole drugs (i.e., itraconazole and fluconazole) for occupational fungal infections has not been defined.

Public health controls

No effective vaccine has been developed. Chemical decontamination with 3% formaldehyde, prewetting the ground or contaminated surfaces to reduce aerosolization, and personal respiratory protection to reduce inhalation of aerosolized spores may reduce infection, but the efficacy of these methods has not been determined.

Miscellaneous Fungal Pneumonias

The miscellaneous fungal pneumonias of agricultural workers include aspergillosis, blastomycosis, cryptococcosis, coccidioidomycosis and paracoccidioidomycosis (table 10.26). These diseases are caused by Aspergillus spp., Blastomyces dermatitidis, Cryptococcus neoformans, Coccidioides immitis and Paracoccidioides brasiliensis, respectively. Although these fungi have a widespread geographic distribution, disease is usually reported from endemic areas. Relative to viral and bacterial causes of pneumonia, these disorders are rare and are often initially unsuspected. T-cell disorders enhance susceptibility to histoplasmosis, blastomycosis, cryptococcosis, coccidioidomycosis and paracoccidioidomycosis. However, a large initial exposure may result in disease in the immunocompetent worker. Infections with Aspergillus and related fungi tend to occur in neutropenic patients. Aspergillosis is most frequently an OAP of the immunosuppressed and will be discussed in the section on infections in the immunosuppressed.

Cr. neoformans, like H. capsulatum, is a common inhabitant of soil contaminated by avian faeces, and occupational exposure to such dusts or other dusts contaminated with Cr. neoformans may result in disease. Occupational blastomycosis is associated with outside occupations, especially in the eastern and central United States. Coccidioidomycosis results from exposure to contaminated dusts in endemic areas of the south-western United States (hence the synonym San Joaquin valley fever). Occupational exposure to contaminated soils of South and Central America is often associated with paracoccidioidomycosis. Because of the potentially long latency with paracoccidioidomycosis, this exposure may long precede the appearance of symptoms.

Clinical presentation

The clinical presentation of coccidioidomycosis, blastomycosis, or paracoccidioidomycosis is similar to histoplasmosis. Aerosol exposures to these fungi can produce OAP if the initial inoculum is high enough. However, host factors, such as prior exposure, limit disease in most individuals. In coccidioidomycosis, pulmonary and systemic signs of disease are apparent in a small percentage of those infected; progressive disease with dissemination to multiple organs is rare in the absence of immunosuppression. Although the source of infection is usually the lung, blastomycosis may present as pulmonary disease, cutaneous disease, or systemic disease. The most common clinical presentation of blastomycosis is a chronic cough with pneumonia indistinguishable from tuberculosis. However, the majority of patients with clinically apparent blastomycosis will have extra-pulmonary lesions involving the skin, bones or genitourinary system. Paracoccidioidomycosis is a disease of Mexico, Central and South America which most frequently presents as reactivation of prior infection after a long but variable latency period. The disease may be associated with ageing of infected individuals, and reactivation may be induced by immunosuppression. The pulmonary presentation is similar to other fungal pneumonias, but extrapulmonary disease, particularly of the mucous membranes, is common in paracoccidioidomycosis.

The lung is the usual site for primary infection with Cryptococcus neoformans. As with the previously discussed fungi, pulmonary infections may be asymptomatic, self-limited or progressive. However, dissemination of the organism, particularly to the meninges and brain, may occur without symptomatic respiratory disease. Cryptococcal meningoencephalitis without evidence of pulmonary cryptococcosis, while rare, is the most common clinical manifestation of Cr. neoformans infection.

Diagnostic tests

Direct demonstration of the tissue form of the organism permits a definitive diagnosis in biopsies and cytologic preparations. Immunofluorescence can be a useful confirmatory procedure if morphologic details are insufficient for establishing the aetiologic agent. These organisms can also be cultured from suspicious lesions. A positive latex cryptococcal agglutinin test in cerebrospinal fluid is consistent with cryptococcal meningoencephalitis. However, demonstration of organisms may not be sufficient for the diagnosis of disease. For example, saprophytic growth of Cr. neoformans is possible in airways.

Other affected occupations

Laboratory workers isolating these fungi are at risk for infection.


Antifungal therapy is similar to that for histoplasmosis.

Public health controls

Engineering controls are indicated to reduce the risk to laboratory workers. Respiratory protection when working with soils heavily contaminated with avian faeces will reduce exposure to Cr. neoformans.

Occupationally Acquired Infections in Health Care and Laboratory Workers

Inhalation of infectious aerosols is the most common source of infection in hospital workers, and many types of viral and bacterial pneumonias have been attributed to work-related transmission (table 10.26). The majority of infections are viral and self-limited. However, potentially serious outbreaks of tuberculosis, measles, pertussis and pneumococcal pneumonia have been reported in hospital workers. Infections in immunocompromised workers are discussed at the end of this section.

Diagnostic laboratory workers are at risk for occupationally acquired infections resulting from airborne transmission. Transmission occurs when pathogens are aerosolized during the initial processing of clinical specimens from patients with uncertain infectious diseases, and is rarely recognized. For example, in a recent community outbreak of brucellosis, one-third of the laboratory technicians developed brucellosis. Employment in the laboratory was the only identified risk factor. Person-to-person transmission between laboratory employees, food or waterborne transmission, or contact with a particular clinical specimen could not be shown to be risk factors. Rubella, tuberculosis, varicella-zoster and respiratory syncytial virus are occupational illnesses similarly acquired in the laboratory by technicians.

Despite rigorous veterinary care, biosafety containment procedures and the use of commercially reared, pathogen-free laboratory animals, inhalation remains the principal mode of infectious disease transmission associated with biomedical research workers. In addition, newly discovered micro-organisms or previously unrecognized zoonotic reservoirs may be encountered and undermine these disease control strategies.


Measles, as an occupationally acquired illness, has become an increasing problem among hospital workers in developed nations. Since 1989, there has been a resurgence of measles in the United States due to poor compliance with vaccine recommendations and the failure of primary immunization in vaccine recipients. Because of the high morbidity and potential mortality associated with measles in susceptible workers, special consideration should be given to measles in any occupational health programme. From 1985 to 1989, more than 350 cases of occupationally acquired measles were reported in the United States, representing 1% of all reported cases. Nearly 30% of hospital workers with occupationally acquired measles were hospitalized. The largest groups of hospital workers with measles were nurses and physicians, and 90% of them acquired measles from patients. Although 50% of these ill persons were eligible for vaccination, none had been vaccinated. The increased measles morbidity and mortality in adults has increased the concern that infected workers may infect patients and co-workers.

In 1989, the Immunization Practices Advisory Committee recommended two doses of measles vaccine or evidence of measles immunity at the time of employment in a health care setting. Serologic and vaccination status of workers should be documented. In addition, when patients with measles present, re-evaluation of the immune status of HCWs is appropriate. Implementing these recommendations and appropriate isolation of patients with known and suspected measles curtails the transmission of measles in medical settings.

Clinical presentation

In addition to the common presentation of measles seen in non-immune adults, atypical and modified presentations of measles must be considered because many hospital workers had previously received killed vaccines or have partial immunity. In classic measles, a two-week incubation period with mild upper respiratory symptoms follows infection. During this period, the worker is viremic and infectious. This is followed by a seven- to ten-day course of cough, coryza and conjunctivitis and the development of a morbilliform rash and Koplik spots (raised white lesions on the buccal mucosa), which are pathognomonic for measles. Diffuse reticulonodular infiltrates with bilateral hilar lymphadenopathy, often with a superimposed bacterial bronchopneumonia, are noted on x ray. These signs occur well after the person has had the opportunity to infect other susceptible persons. Pulmonary complications account for 90% of the measles deaths in adults. No specific antiviral treatment is effective for any form of measles, although high-titre anti-measles immunoglobulin may ameliorate some symptoms in adults.

In atypical measles, which occurs in persons vaccinated with a killed vaccine developed in the 1960s, severe pulmonary involvement is common. The rash is atypical and Koplik spots are rare. In modified measles, which occurs in persons previously receiving a live vaccine but developing partial immunity, signs and symptoms are similar to classic measles but milder, and often go unnoticed. Persons with atypical and modified measles are viremic and can spread measles virus.


Measles in hospital workers is often modified or atypical, and is rarely suspected. Measles should be considered in a person with an erythematous maculopapular rash preceded by a three- to four-day febrile prodrome. In persons with a first time infection and without previous immunization, viral isolation or antigen detection is difficult, but enzyme-linked immunosorbent or fluorescent antibody assays may be used for rapid diagnosis. In persons with previous immunizations, interpreting these assays is difficult, but immunofluorescent antibody stains of exfoliated cells may be helpful.


Susceptible nurses and physicians are nearly nine times more likely to acquire measles than persons of the same age who are not HCWs. As with all measles infections, person-to-person transmission occurs via inhalation of an infectious aerosol. Hospital workers acquire measles from patients and co-workers and, in turn, transmit measles to susceptible patients, co-workers and family members.

Other affected occupations

Epidemic measles has occurred in academic institutions in developed nations and among agricultural workers restricted to collective lodgings on plantations.

Public health controls

Public health intervention strategies include immunization programmes as well as infection control programmes to monitor measles illness and antibody status of workers. If natural infection or an appropriate two-dose vaccination cannot be documented, antibody assays should be performed. Vaccination of pregnant workers is contraindicated. Vaccination of other at-risk workers is an important aid in disease prevention. After exposure to measles, removal of susceptible workers from patient contact for 21 days may reduce the spread of disease. Restricted activity of workers with measles for 7 days after the appearance of the rash may also curtail disease transmission. Unfortunately, appropriately vaccinated workers have developed measles despite protective antibody levels that were documented prior to illness. As a result, many recommend personal respiratory protection when caring for patients with measles.

Miscellaneous viral respiratory tract infections

A variety of viruses which are not unique to the health care environment are the most common cause of OAPs in health care workers. The aetiological agents are those which cause community-acquired OAPs, including adenovirus, cytomegalovirus, influenza virus, parainfluenza virus and respiratory syncytial virus. Because these organisms are also present in the community, establishing these as the cause of an individual OAP is difficult. However, serologic studies suggest that health care and day care workers are at increased risk for exposure to these respiratory pathogens. These viruses are also responsible for disease outbreaks in many situations where workers are brought together in a confined space. For example, outbreaks of adenoviral infection are common in military recruits.


Pertussis, like measles, has been increasingly reported in hospital workers in developed nations. In 1993, nearly 6,000 cases of pertussis were reported in the United States, an 80% increase over 1992. Unlike previous years, 25% of the reported cases occurred in persons over ten years old. The number of occupationally acquired illnesses in hospital workers is unknown but is felt to be underreported in developed nations. Because of waning immunity in adults and the potential for hospital workers to infect susceptible infants, there is greater emphasis on diagnosis and surveillance of pertussis.

Clinical presentation

Pertussis may persist for six to ten weeks without intervention. In the first week, when the ill person is most contagious, dry cough, coryza, conjunctivitis and fever develop. In previously vaccinated adults, the persistent, productive cough may last several weeks and pertussis is rarely considered. Clinical diagnosis is difficult, and clinical suspicion should be aroused when one encounters any worker with a cough that lasts for more than seven days. A white count greater than 20,000 with a predominance of lymphocytes may be the only laboratory abnormality, but this is rarely noted in adults. Chest radiographs show confluent bronchopneumonia in the lower lobes that radiate from the heart to give the characteristic "shaggy heart" sign, and atelectasis is present in 50% of cases.

Because of the extreme infectiousness of this agent, strict respiratory isolation is necessary until treatment with erythromycin or trimethoprim/sulphamethoxazole has continued for five days. Close contacts of infected person and hospital workers who were not using respiratory precautions should receive 14 days of antibiotic prophylaxis regardless of immunization status.


Isolation of Bordetella pertussis, direct immunofluorescent staining of nasal secretions, or development of a B. pertussis antibody response is used to make a definitive diagnosis.


B. pertussis is highly contagious, transmitted person-to-person via inhalation of infectious aerosols, and has an attack rate of 70 to 100%. In the past, it has not been a disease of adults and has not been appreciated as an OAP. During a community outbreak of pertussis in the western United States, many hospital workers were exposed at work and developed pertussis despite antibiotic prophylaxis. Because of waning protective antibody levels in adults who have never had clinical disease but received cellular vaccine after 1940, there is a growing population of pertussis-susceptible hospital workers in developed nations.

Public health controls

Identification, isolation and treatment are the main disease control strategies in hospitals. The role of acellular pertussis vaccine for hospital workers without adequate levels of protective antibody is unclear. During the recent outbreak in the western United States, one-third of vaccinated hospital workers reported mild to moderate side effects to the vaccine but 1% had "severe" systemic symptoms. Although these more severely affected workers missed days of work, no neurologic symptoms were reported.


During the 1950s, it was generally recognized that health care workers in developed nations were at greater risk for tuberculosis (TB-granulomatous disease due to Mycobacterium tuberculosis or closely related organisms M. bovis) than the general population. From the 1970s through the early 1980s, surveys suggested that this had become only a slightly increased risk. In the late 1980s, a marked increase in the number of cases of TB admitted to US hospitals resulted in the unsuspected transmission of M. tuberculosis to hospital workers. The high background prevalence of positive tuberculin skin test (TST) in certain socio-economic or immigrant groups from which many hospital workers came, and the poor association of TST conversion with work-related exposures to TB, made it difficult to quantify the risk of TB occupational transmission to workers. In 1993 in the United States, an estimated 3.2% of reported persons with TB were health care workers. Despite problems in defining risk, work-related infection should be considered when hospital workers develop TB or convert their TST.

M. tuberculosis is spread almost exclusively person to person on infectious particles with a diameter of 1 to 5 µm that result from coughing, talking or sneezing. The risk of infection is directly related to the intensity of exposure to infectious aerosols-small shared spaces, increased density of infectious particles, poor clearance of infectious particles, recirculation of air containing infectious particles, and prolonged contact time. In health care settings, procedures such as bronchoscopy, endotracheal intubation and nebulized aerosol treatment increase the density of infectious aerosols. Approximately 30% of close contacts-persons who share a common space with an infectious person-become infected and undergo skin-test conversion. After infection, 3 to 10% of persons will develop TB within 12 months (i.e., primary disease) and an additional 5 to 10% will develop TB in their lifetime (i.e., reactivation disease). These higher rates occur in developing nations and situations when malnutrition is more prevalent. HIV-infected persons reactivate TB at higher rates, approximately 3 to 8% per year. CFR varies; in developed nations, it is between 5 and 10%, but in developing nations, these rates range from 15 to 40%.

Clinical presentation

Prior to the HIV epidemic, 85 to 90% of persons with TB had pulmonary involvement. Chronic cough, sputum production, fever and weight loss remain the most frequently reported symptoms of pulmonary TB. Except for rare amphoric breathing or post-tussive crackles over the upper lobes, physical examination is not helpful. An abnormal chest x ray is found in nearly all cases and is usually the first finding to suggest TB. In primary TB, a lower- or middle-lobe infiltrate with ipsilateral hilar lymphadenopathy with atelectasis is common. Reactivation TB usually results in an infiltrate and cavitation in the upper lobes of the lungs. Although sensitive, chest x rays lack specificity and will not give a definitive diagnosis of TB.


Definitive diagnosis of pulmonary TB can be made only by isolating M. tuberculosis from sputum or lung tissue, although a presumptive diagnosis is possible if acid-fast bacilli (AFB) are found in sputum from persons with compatible clinical presentations. The diagnosis of TB should be considered on the basis of clinical signs and symptoms; isolation and treatment of persons with compatible illnesses should not be delayed for the result of a TST. In developing nations where TST reagents and chest x rays are not available, WHO suggests evaluating persons with any respiratory symptom of three weeks' duration, haemoptysis of any duration or significant weight loss for TB. These persons should have a microscopic examination of their sputum for AFB.

Other affected occupations

Worker-to-worker and client-to-worker airborne transmission of M. tuberculosis has been documented among hospital workers, airline flight crews, miners, correctional facility workers, animal caretakers, shipyard workers, school employees and plywood factory workers. Special consideration must be given to certain occupations such as farmworkers, animal caretakers, manual labourers, housekeepers, janitors and food preparation workers, although most of the risk may be due to the socio-economic or immigration status of the workers.

Special consideration should be given to pulmonary TB among miners and other groups with silica exposure. In addition to an increased risk of primary infection from fellow miners, persons with silicosis are more likely to progress to TB and have a greater TB-specific mortality compared to non-silicotic workers. As in most persons, TB reactivates among silicotic persons from longstanding M. tuberculosis infections that predate silica exposure. In experimental systems, silica exposure has been shown to worsen the course of infection in a dose-dependent fashion, but it is unclear if silica-exposed, non-silicotic workers are at greater risk for developing TB. Silica-exposed foundry workers without radiographic silicosis are at a three-times greater risk of TB-specific mortality compared to similar workers without silica exposure. No other occupational dust exposures have been associated with enhanced progression of TB.

Migrant farmworkers are more likely to develop reactivation TB than the general population. Estimates of positive TSTs in migrant farmworkers range from approximately 45% in 15 to 34 year-old persons to nearly 70% in workers more than 34 years old.

Clinical laboratory workers are at increased risk for occupationally acquired TB through airborne transmission. In a recent ten-year survey of selected hospitals in Japan, 0.8% of laboratory workers developed TB. No community sources were identified, and work-related exposures were identified in only 20% of the cases. Most cases occurred among the workers in the pathology and bacteriology laboratories and autopsy theatres.


Several treatment regimens have been shown to be effective in different outpatient settings. Among compliant patients in developed nations, daily doses of four drugs (including isoniazid and rifampin) for two months followed by daily doses of isoniazid and rifampin for the next four months has become a standard treatment regimen. Directly observed, twice weekly administration of the same drugs is an effective alternative in less compliant patients. In developing nations and in situations where anti-tuberculous medications are not readily available, 9 to 12 months of daily dosing with isoniazid and rifampin has been used. A treatment regimen should be consistent with the national policy and take into consideration the organism's susceptibility to standard, available anti-tuberculous medications and duration of therapy. Because of limited resources to control TB in developing nations, efforts may focus on the primary sources of infection-patients with sputum smears that demonstrate AFB.

In health care settings, work restrictions are indicated for infectious workers with pulmonary TB. In other settings, infectious workers may simply be isolated from other workers. In general, persons are considered non-infective after two weeks of appropriate antituberculous medications if there is symptomatic improvement and decreasing density of AFB in the sputum smear.

Public health controls

The main public health control of occupationally or community-acquired TB transmission remains identification, isolation and treatment of persons with pulmonary TB. Ventilation to dilute infectious aerosols; filtration and ultraviolet lights to decontaminate the air containing the aerosol; or personal respiratory protection may be used where the risk of transmission is known to be exceptionally high, but the efficacy of these methods is still unknown. The utility of BCG in worker protection remains controversial.

Miscellaneous bacterial infections in the health care environment

Common bacterial infections of the lung may be acquired from patients or within the community. Work-related airborne transmission of bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenza, Neisseria meningitidis, Mycoplasma pneumoniae and Legionella spp (table 10.26) occurs and the resulting illnesses are included in many hospital surveillance programmes. Occupational bacterial respiratory tract infections are also not restricted to health care workers. Infections with Streptococcus spp are, for example, a well-established cause of disease outbreaks among military recruits. However, for a specific worker, the prevalence of these disorders outside the workplace complicates the distinction between occupational and community-acquired infections. The clinical presentation, diagnostic tests, epidemiology and treatment of these disorders are described in standard medical textbooks.

Infections in the immunosuppressed worker

Immunosuppressed workers are at increased risk from many OAPs. In addition, a number of organisms which do not cause disease in normal individuals will produce disease in the immunosuppressed. The type of immunosuppression will also affect disease susceptibility. For example, invasive pulmonary aspergillosis is a more frequent complication of chemotherapy than of acquired immunodeficiency syndrome (AIDS).

Invasive pulmonary aspergillosis is usually seen in the immunosuppressed, particularly individuals with neutropenia. However, invasive pulmonary aspergillosis is occasionally reported in individuals without an apparent predisposition to disease. Invasive pulmonary aspergillosis normally presents as a severe, necrotizing pneumonia with or without systemic involvement in a neutropenic patient. While invasive aspergillosis is most frequently seen as a nosocomial infection in chemotherapy patients, this is a highly fatal disease in any neutropenic worker. Techniques which reduce nosocomial aspergillosis-for example, the control of dusts from construction projects-may also protect susceptible workers.

A variety of animal pathogens become potential zoonoses only in the immunosuppressed patient. The zoonoses transmitted by aerosol exposure seen only in the immunosuppressed include encephalitozoonosis (due to Encephalitozoon cuniculi), avian tuberculosis (due to Mycobacterium avium) and Rhodococcus equi infections. Such diseases are of particular concern in agriculture. Methods for the protection of immunosuppressed workers are incompletely investigated.

In the immunosuppressed worker, many potential pathogens cause invasive and severe disease not seen in normal patients. For example, severe infections with Candida albicans and Pneumocystis carinii are classical manifestations of AIDS. The spectrum of occupational pathogens in the immunosuppressed worker, therefore, potentially involves disorders not present in immunologically normal workers. The diseases of immunosuppressed individuals have been thoroughly reviewed elsewhere and will not be further discussed in this review.

Public Health Controls: Overview

OAPs predominantly occur in five groups of workers: hospital workers, agricultural workers, meat production workers, military personnel and biomedical laboratory workers (table 10.26). Avoidance of infectious aerosols is the most effective way of reducing infection in most situations but often is difficult. For example, Coxiella burnetii, the aetiological agent for Q fever, may be present in any environment previously contaminated with the biological fluids of infected animals, but avoidance of all potentially infected aerosols would be impractical in many low-risk situations such as sheep herding or rodeos. Control of concomitant diseases may also reduce the risk of OAPs. Silicosis, for example, increases the risk for reactivation of TB, and reducing silica exposure may reduce the risk of TB in miners. For OAPs that have significant mortality and morbidity in the general population, immunization may be the most important public health intervention. Education of workers about their risk of OAPs assists in worker compliance with occupational disease control programmes and also aids in the early diagnosis of these disorders.

Among hospital workers and military personnel, human-to-human transmission is usually the main route of infection. Worker immunization may prevent disease and may be useful in the control of pathogens of high morbidity and/or mortality. Because there is a risk for persons who may not have been adequately immunized; identifying, isolating and treating ill persons remains a part of disease control. When immunization and respiratory isolation fail or the associated morbidity and mortality is intolerable, personal protection or engineering controls to reduce the density or infectiousness of aerosols may be considered.

For agricultural, meat production and biomedical laboratory workers, animal-to-human transmission is a common transmission pattern. In addition to immunization of susceptible persons when possible, other disease control strategies may include immunization of the animals, veterinarian-controlled antibiotic prophylaxis of well-appearing animals, quarantine of newly arrived animals, isolation and treatment of ill animals, and purchase of pathogen-free animals. When these strategies have failed or there is high morbidity and mortality, strategies such as personal protection or engineering controls may be considered.

Environment-to-human transmission of infectious agents is common among agricultural workers, including many labourers. Worker immunization is possible when a vaccine is available, but for many of these pathogens, disease incidence in the general population is low and vaccines are rarely feasible. In agricultural settings, the sources of infection are widespread. As a result, engineering controls to reduce the density or infectiousness of aerosols are rarely feasible. In these settings, wetting agents or other methods to reduce dust, decontaminating agents and personal respiratory protection may be considered. Because control of OAP in agricultural workers is often difficult and these diseases are rarely seen by medical personnel, education of workers and communication between workers and medical personnel is essential.


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