Asbestos related disorders

An updated summary of current understanding of asbestos 
related disorders is presented, along with a review of the 
history of the disorders, and the mineralogy, biological 
tissue burden, pathogenesis, pathology and clinical aspects 
of the asbestos related disorders, with particular emphasis 
on important information for the clinician.

F ROM THE BEGINNING OF THE 20TH CENTURY, SEVERAL diseases have been associated with asbestos exposure.Some have a definite association whereas others initially considered to be associated with asbestos exposure were afterwards proven not to be.The fo llowing are unequivocally recognized as asbestos related diseases.Asbestosis -an interstitial fibrosis of the lung parenchyma; Benign asbestos pleurisy -also called benign pleural effusion, an exudative and transient inflammation of the pleura; Pleural plaques -accumulations of collagen fibres forming hyalin masses that are avascular, acellular and circumscribed, usually limited to the parietal pleura; Pachypleuritis -accumulations of collagen fibres forming hyalin masses that are avascular, acellular and diffuse, affecting the parietal and visceral pleura, occasionally invading the interlobular spaces of the lung parenchyma, which has been called 'crow's feet' and is not to be confused with asbestosis; Maladies de l'amiante RESUME : Les auteurs presentent une mise-a-jour des connaissances actuelles des affections rellees al' exposition a l'amiante, revisant l'histoire de ces affections, la minerolgie, la metrologie, la pathogenese, la pathologie et Jes aspects clinques de ces affections reliees a l'amiante, en insistant sur les informations Jes plus interessantes pour le clinicien.
Rounded atelectasis -an effect of asbestos-induced pleural disease that is caused by the scarring of the pleura and adjacent lung tissue, with retraction of the scar tissue and partial collapse of adjacent lung tissue; Bronchogenic carcinoma -a malignant bronchopulmonary tumour similar to that associated with cigarette smoking and other lung carcinogen exposures; Malignant mesothelioma -a malignant tumour of the mesothelium of the pleura, that is usually fatal within 12 to 24 months after clinical diagnosis.
Benign nodules in the lung parenchyma are occasionally seen in asbestos workers.They can be benign lymphoid nodules, scars of localized fibrosis or more strikingly rounded atelectasis.
Diseases not accepted unequivocally as related to asbestos exposure will not be discussed here; readers are referred to an exhaustive review ( 1 ).

HISTORICAL ASPECTS
Asbestos, from the Greek a0~£01:0s, meaning ' inextinguishable', has been known since antiquity.It was initially used for the wicks of torches in temples, and from 2500 BC in pottery.In the time of the pharaoes, Herod noticed that asbestos linens were used for the incineration of corpses.Charlemagne stunned his guests by throwing his asbestos table cloth on the fire to clean it.Asbestos was the Salamander wool of alchemists (2).
Asbestos use remained on a small scale, related to crafts, until the discoveries of the vast deposits of Quebec and Russia at the end of the 19th century.In Quebec, exploration of a mine started in 1878 at Asbestos, a small township named by its product and where chrysotile, the white asbestos, has been produced ever since.In Russia, commercial production of chrysotile started in 1885.In South Africa crocidolite blue asbestos was initially produced in 1880, and amosite and anthophyllite became commercially available in the First World War.
The world production of asbestos increased slowly at the beginning of the 20th century to reach a total amount of 5x I 0 9 kg by 1930.Rapid acceleration of production in the following years resulted in a yearly production of 5xl0 9 kg, responding to the demand for its use in some 3000 applications.Twenty years after the industrial use of asbestos began in Europe, Auribeault (3) in 1906 described 50 cases of pulmonary fibrosis in an asbestos textile factory in Normandy, France, while in England, Murray (4) described the first case of asbestosis in a 30-year-old asbestos worker, the last survivor of a group of 10 employed in the same workshop.Also in 1906, Marchand (5) first described asbestos bodies.After 1926, it became accepted that asbestos was toxic for the pleura, lung and airways.
The huge problem posed by the industrial use of asbestos on public health and hygiene became clear in the 1950s.In 1955, Jacob and Bohling (6) reported on calcified pleural plaques; in 1960, Wagner et al (7) described 33 cases of malignant mesothelioma, of whom 28 were exposed to crocidolite asbestos from South Africa.In the following years, animal experimentation confirmed the fibrosing and carcinogenic potential of all types of asbestos fibres.
In the 1960s and '70s, large epidemiological studies by several American and European teams were presented at international conferences in New York in 1964 (8), 1979 (9) and 1990 (10); at the International Agency for Research on Cancer (IARC) in 1972 and 1979 (11); in Montreal in 1980 (12); in Cardiff, Wales in 1986 on the biological effects of chrysotile (13); and in Paris in 1991 on malignant mesothelioma (14).
In the 1980s, studies on the biological mechanisms of asbestos related diseases were initiated in several laboratories around the world (15)(16)(17), which have increased our understanding of the pathogenesis of the disease processes.

MINERALOGY
The term asbestos refers to a family of naturally occurring, flexible, fibrous hydrous silicate mineral s that are relatively indestructible and heat resistant.For the mineralogist, the term asbestos is part of the morphological terminology to describe a property known as 'crystal habit' , used to describe the fibrous aspect in which some minerals crystallize.The characteristics of this 'crystal habit' are the high ratios of length to breadth (aspect ratio), flexibility , similarity to organic fibres , the small diameter of elementary units (elementary fibrils) that can be associated longitudinally to form bundles of fibres or, in less oriented aggregates, due to variations in mineral content and different forms of the component crystals.
Although more than 30 minerals show asbestiform crystallization, only six minerals are of industrial use: chrysotile, crocidolite, amosite, anthrophyllite, tremolite and actinolite (Table 1).Asbestos related diseases have been reported in association with exposure to all types of asbestos fibres; the incidence of various diseases and the intensity of the pathological processes vary with the different types of fibres .Chrysotile: Chrysotile fibres result from a peculiar hydrothermic transformation (serpentinization) of ultrabasic rocks, a group that also includes lizardite and antigorite.The crystalline structure of serpentines is complex but their chemistry is simple, being hydrated magnesium silicates with some iron as a substitution element.Chrysotile fibres are relatively translucent with a silky sparkle.Depending on the mine of origin, they have more or less flexibility.The elementary fibrils have an average diameter of 0.03 µm and are grouped to form an open core cylinder with layers of intertwined fibrils forming an onion-peel structure around the core.Each tube is about 20 nm in diameter; the tubes are grouped in slivers 0.1 mm 2 which contain 20x!0 6 tubular fibrils, in a relatively parallel orientation.
Chrysotile is of commercial interest because of its mechanical properties of resistance to heat and traction, and its flexibility, adsorbancy, chemical resistance to alkalines, and the ease with which it may be spun for textile products.It has a weak resistance to acid, but resists other chemicals and heat over 100°C, and loses its structure above 575°C.Amphiboles: The amphibole asbestos group contains several minerals, similar in structure but distinct in chemical composition.The asbestiform structure of the five amphiboles differs slightly from that of chrysotile, as it is more rigid, does not form a cylindrical structure but runs in chains of silicate tetrahedra.This chain-like structure is stacked lightly, which permits good cleavage.Because of their rigidity, amphiboles form fewer aggregates than chrysotile, fibres are more read-ily seen in aerosols, generate more fibre dust and are more resistant to acid and heat.
Crocidolite is a sodium iron silicate formed in thermally metamorphosed banded ironstones.It is often referred to as blue asbestos, and has been mined in South Africa, Australia and Bolivia.It is not as harsh as amosite and has been used in spinning and insulation.Jt is reputed to be the most dangerous due to its strong association with mesothelioma.
Amosite, mined only in the Transvaal area of South Africa, is an iron magnesium silicate.Brownish in colour, amosite has the longest fibres but its harshness renders it unsuitable for spinning; it has been used mainly for heat insulation.
Anthophyllite is a white amphibole, a magnesium silicate containing various quantities of iron.It occurs in fibrous masses with short fibre bundles.It was mined and used in Finland until 1970.
Tremolite is a white amphibole, a green yellow calcium and magnesium si licate that is mined in relatively pure form in Italy and Japan and is a common contaminant in most chrysotile mines.
Specialized references can be consulted for further details (18,19) .

ASBESTOS PRODUCTION AND USES
The world production of asbestos increased until l 975 to 1980 when production reached some five million tons of the material per year.It has now stabilized at about four million tons per year.
The development of an asbestos mine usually starts with an open pit operation where mechanical shovels and bulldozers work to break down the rock for transportation of the raw material to a processing mill.As opposed to the traditional underground mining process, open pit operations account for 70% of the total production of asbestos.
The raw material is further processed by fragmentation , sorting and screening operations to concentrate the desired asbestos material and eliminate the undesired ores.The milling process further concentrates the fibre , eliminates undesired minerals, removes grit and dusts, dries and finally separates the fibres into various commercial grades.
At the present time, chrysotile represents 95% of the world production, and the main market is the production of asbestos-cement.Chrysotile is produced mainly in Russia, Canada, Swaziland and Zimbabwe; minor production plants exist in California, Australia, Cyprus, Italy, Brazil and China.Arnosite was produced only in South Africa.Crocidolite is produced in South Africa, Australia (now ceased) and Bolivia.Anthophyllite was produced only in Finland.
Asbestos is used in over 3000 applications, of which the major ones are: asbestos cement products, including pipes, shingles, clapboards, flat sheets, corrugated sheets, moulded sheets for the building construction industry; vinyl asbestos floor tile; paper for insulation and fi ltering products; brake linings and clutch facings; textile products such as yarn, tape, felt, tubing and rope; and spray products for sound, heat and fire insulation.
The major end users in the past have been the building Can Respir J Vol 1 No 3 Fall 1994

Asbestos related disorders
construction industry, shipbuilding and the automobile and railroad equipment industries, where much of the insulation and friction materials are now made of nonasbestos fibre materials.
The longest asbestos fibres are used mainly in the textile and insulation industries; the intermedi ate fibres are used in asbestos cement production, and friction and filter production; and the shortest fibres are used in the vinyl-asbestos tile industry and in paints.The mill tailings of the mining process can be used in road construction and for the extraction of magnesium.

ASBESTOS FIBRES IN ENVIRONMENT AND IN
HUMAN TISSUES In industrial settings, the control of asbestos dust has proven to be the most effective mode of disease prevention, through legislation limiting asbestos dust exposure in the work place below I fibre/cm 3 of air.The current American standard is 0.2 fibres/cm 3 of air.In the past, asbestos exposure in the workplace may have been over 100 fibres/cm 3 for 3 some cases and was commonly between 5 and 20 fibres/cm .
To enforce legislation, methods for airborne dust sampling were developed; particles are sampled on a membrane filter and counted under a light microscope at a magnification of 500 times, screening fo r fibres having a length greater than 5 µm and length to width ratio greater than 3.It remains the method of reference but many chrysotile fibres will not be seen.
Transmission electron microscopy (TEM) can magnify up to 100,000 times but preparation of the specimen is more time consuming and expensive.The method has been a tool of significant impact in environmental air pollution in the neighbourhood of asbestos mills, plants and factories.
For clinical diagnosis, worker's compensation and medicolegal purposes, the search for asbestos fibres in biological samples is increasingly used to document past exposure to asbestos.In that context, analyses of human tissues supplement clinical methods of diagnosis of the asbestos related diseases.Laboratory methods in optical and electron microscopy are available in specialized laboratories (20)(21)(22), where samples are first separated by fi ltration.
Optical microscopy is used to count ferruginous bodies and fibres longer than 5 µm and larger than 0.25 µm in diameter.This method is widely used by pathologists for routine lung pathology, sputum cytology and lung lavage cytology to provide a set of fundamental indices of asbestos exposure.The limitations of optical microscopy are the same as for air sample analyses.
Asbestos fibres and other fibrous particles can be coated by macrophages with an iron-protein coat with formation of bead-like structures on the fibres .They are rarely found on fibres shorter than IO µm long, and are more associated with amphiboles than chrysoti le, possibly because of the greater dissolution and breakdown of chrysoti le.These ferruginous or asbestos bodies (AB) can be found in virtually anyone in the population if appropriate methods are used .In cases of asbestos related diseases, they can usually be found in the lung parenchyma.However, they are often not seen in asbestosis due to chrysotile exposure alone, unless phase contrast microscopy is used after tissue digestion (20)(21)(22).

Asbestos bodies in lung tissue
On sputum cytology samples, the control population has no AB, and any AB seen constitutes an index of significant exposure.On Jung lavage samples, nonexposed subjects have less than 1 AB/mL of lavage effluent; more than 1 AB/mL suggests lung tissue AB greater than 1/mg dry lung which corresponds to a nontrivial exposure.On lung tissue samples: nonexposed white collar workers have less than 0.1 AB/mg; nonexposed blue collar workers have less than 0.5 AB/mg; blue collar workers with minimal exposure have more than 0.5 AB/mg and less than 2 AB/mg; patients with pleural plaques have in the order of l .7 AB/mg; patients with mesothelioma have AB within the range of nonexposed to the range of patients with asbestosis; long term asbestos workers with grade O asbestosis have up to 1300 AB/mg; long term asbestos workers with grade l asbestosis have about 8000 AB/mg; long term asbestos workers with grade 2 asbestosis have about 73,000 AB/mg.

Asbestos fibres by optical microscopy in lung ti ssue
The general population has less than 250 fibres/mg tissue; exposed persons with grade O asbestosis have 2400 fibres/ mg ; persons with grade l asbestosis have 8000 to 19,000 fibres/mg ; and persons with grade 2 asbestosis have 14,000 to 200,000 fibres/mg

Asbestos fibres by TEM in lung tissue
The general population has less than 1000 fibres/mg (average 2 to 300 fibres/mg), 90% of which are less than 5 µm in length, and fewer than 100 fibres more than 5 µm long, 70% of which are chrysotile and none are amphibole, amosite or crocidolite; residents of a mining town such as Thetford Mines, Quebec may have 10 times the level found in the general population; patients with pleural plaques have 100 to 5000 fibres/mg; patients with mesothelioma have fibres from within the range of normals to the range of patients with asbestosis; asbestos workers with grade O asbestosis have about 2000 to 19,000 fibres/mg ; workers with grade 1 asbestosis have about 135,000 fibres/mg ; workers with grade 2 asbestosis have about 1,370,000 fibres/mg.Finally, uncoated fibres always outnumber the coated fibres, particularly for chrysotile fibres and in the general population.

Deposition and clearance of asbestos
For the nonfibrous minerals, it is well recognized that particles greater than 10 µmin diameter rarely reach the lung beyond the upper airways and that most particles deposited in the alveoli are less than 5 µm in diameter.However, these considerations do not apply to the fibrous minerals such as asbestos.Fibre deposition in the lung is largely ruled by the fibre diameter, the fibre length having a relatively less impor-tant effect.Thus fibres 200 to 300 µm in length with a diameter less than 3 µm can be found in the lung.Typical fibre length in asbestos bodies is 20 to 50 µm and many fibres less than 5 µm long can also be found (22).
In animal experiments, it has been clearly shown that the fibres are primarly deposited in the bifurcations of conducting airways and in the alveolar parenchyma (16).The deposition of inhaled fibres is diffuse and extends to the subpleural lung tissue, where the concentration may be markedly elevated.
Clearance of asbestos fibres from the lung occurs by a variety of pathways, including the mucociliary escalator system, translocation into the interstitium and into the lymphatic system and dissolution, degradation, defibrillation and breakdown of the fibre materials originally inhaled.The short fibres are cleared more readily from the lung so that over time the overall mean length of fibres appears to increase.Thus, chrysotile fibres are cleared more rapidly than the amphiboles (22,23).These considerations are of interest in relation to the effects of fibre type, size and length:width ratio in the pathogenesis of asbestos related diseases.

ASBESTOSIS Pathogenesis
The fundamental problem with asbestos fibres in biological tissues (15)(16)(17) is related to their toxicity in inducing fibrosis and cancers of the lung and pleural space.In the fibrosing processes, the disease starts as an inflammatory reaction which evolves in a fibrosing repair process, leaving permanent scars.In the cancer processes (24 ), the disease starts as a multistep process in which the DNA of the target cells suffers increasing amounts of damage -genetic mutations -through a variety of molecular injuries, resulting eventually in tumour cells proliferating over time to a clinically detectable disease.Several experimental studies in animals and studies in vitro of cell cultures have documented that all types of asbestos fibres can produce all asbestos related diseases, asbestosis, bronchogenic carcinoma and mesothelioma.
In vitro experiments have shown that asbestos fibres (Figure 1) can cause cell membrane damage which, if severe enough, will cause cell death, gene mutation, chromosomal aberration and cell transformation.Asbestos fibres are also capable of inducing macrophages in the lung to produce various growth factors for fibroblasts and other cells participating in the pathogenesis of asbestos related diseases.The mechanisms of pathogenesis are incompletely understood but the general outlines are already developed (21,24).Specificities of asbestos fi bres: type, dimension, durability and chemical functionalities: The dose, fibre type, dimension and durability of the fibre with surface chemical reactions will influence toxicity, carcinogenicity and fibrogenicity to variable degrees.The dose-response is well documented epidemiologically and experimentally for the majority of asbestos related diseases.Studies in vitro and in animal experiments have shown that toxicity is related to the fibrous nature of the mineral, as demonstrated by the absence of toxicity of pulverized asbestos or nonfibrous analogues of asbestos.The diameter of the asbestos fibres is important because fibres greater than 3 µm in diameter do not penetrate into the lower lung but those less than 3 µm will penetrate cell membranes and be translocated into the interstitium of the lung and pleural space to cause disease.The length of fibres is also important; the shortest fibres (less than 3 µm) are phagocytosed or translocated to the lymphatics to be drained to the pleural space, whereas fibres longer than 5 µm are incompletely phagocytosed and stay longer in the tissues.
The amphiboles are generally recognized to be 10 times more carcinogenic than chrysotile for the mesothelium; this fact is particularly well documented for crocidolite.Amphiboles are also more prone to induce pleural fibrosis .Lung fibrosis, however, is equally affected by both types of asbestos fibres (23).
The composition of asbestos fibres can influence their toxicity.The relative solubility of chrysotile will attenuate its toxicity whereas its 'splittability' (multiplication effect) will enhance toxicity.Surface properties as well as electrical charges will also influence toxicity.Breakdown of the bonds between atoms on the surface leads to unstable atoms with residual charges which constitute active sites.The adsorption of carcinogens such as polycyclic aromatic hydrocarbons enhance the carcinogenicity of asbestos; similarly, the catalysis of chrysotile can liberate free radicals, which are toxic to cells.
The initial lung injury occurs almost immediately after exposure at the alveolar duct bifurcations, where the terminal bronchioles divide into individual alveolar spaces.In animal experiments, after only I h of exposure to asbestos there is active uptake of fibres by the type I epithelial cells, and within 48 h increased numbers of alveolar macrophages accumulate.Although one exposure may not cause asbestosis in all cases, it may be expected that chronic exposure will cause this lesion to progress, forming first a localized peribronchiolar fibrosing alveolitis, followed by diffuse fibrotic scarring.Any increase in asbestos dose exposure amplifies the cellular responses.The initial injury starts a cascade of events in which macrophages flood the site of injury and stimulate the proliferation of fibroblasts.Macrophage derived cytokines regulate the disease process: Fibronectin is a glycoprotein produced by the macrophage capable of recruiting fibroblasts to the site of injury and initiating their prol iferation.In lavage fluid, fibronectin is increased significantly only in asbestos-exposed individuals (25), and procollagen 3 (indicating new production of collagen or scar tissue) increases significantly when a fibrotic process is in the early phase and evolves to grade 1 asbestosis.In asbestos workers without clinically evident disease, levels of fibronectin and procollagen 3 in lavage are comparable to controls, but these levels are significantly elevated in those with asbestos associated alveolitis (subclinical asbestosis), or clinical asbestosis.
In addition to fibronectin, alveolar macrophages recovered from patients with asbestosis release exaggerated quantities of cytokines, including platelet-derived growth factor  (PDGF), insulin-like growth factor (IGF-1), and fibroblast growth factor (FGF) (15)(16)(17).PDGF, IGF-1 and FGF attract fibroblasts to sites of injury and up-regulate their proliferative activity, leading to the formation of scar tissue.Activated macrophages produce tissue damaging molecules: Damage to the initially injured area is aggravated by macrophages releasing free oxygen radicals, through direct cytotoxicity and peroxidation of cell membranes, to sustain further the inflammatory process (26,27).An additional source of tissue destructive substances comes from the release by the macrophage of plasminogen activator (28), which converts plasminogen to plasmin, a protease which can degrade the interstitial matrix glycoproteins, thus increasing tissue destruction.Progression and latency of asbestosis: The chronic and progressive nature of asbestosis has been documented from the initial subclinical lesion to clinical asbestosis (15)(16)(17)25,29) by means of lung lavage, thin section analyses under electron microscopy, thin section computed tomography (CT scan), and 67 gallium lung uptake.Such studies have shown that the inflammation and injury produced by exposure to asbestos fibres is continuous from the time of expo-Figure 2) Asbestosis grade J seen in a sheep as peribronchiolar inflammation and fibrosis lim ited to the surroundings of some of the peripheral airways.Hematoxylin-eosin xl9. 6 ure, through the latent or subclinical phase, to the development of clinical disease identifiable by the classic methods of chest x-ray changes and pulmonary function impairment.
Lung lavage studies have shown the changes that take place at the time of subcli nical disease, while CT has shown significant abnormalities in the presence of normal radiography in 20 to 35% of long term asbestos workers without clinical asbestosis.Similarly , 67 gallium scans are abnormal in many asbestos workers without clinical asbestosis. 67Gallium uptake is a useful indicator of early (subclinical) lung injury long before it is recognized in chest radi~raphs.Fully 75% of subjects who initially had a positive 6 gallium scan without clinical asbestosis went on to 'full blown' clinical asbestosis over a four-year period (25).
After clinical recognition of asbestosis it is generally accepted that this is often a chronic and progressive disease.Viallat et al (30) studied a population of asbestos workers in a Corsican township when almost 80% of the workers had no radiographic evidence of disease; despite no further exposure, more than half later developed radiographic evidence of disease.Other studies have also documented disease progression after cessation of exposure in animals and in humans.The progression rate at present appears to be closer to 20%, due to decreases in the intensity of exposure associated with improved industrial hygiene and methods of recognition .Susceptibility to asbestosis: It is recognized that when exposure to a toxic substance is well in excess of the tolerance level, the disease will appear in all exposed subjects, as was the case in the British workshop where Murray (4) described his first cases of asbestosis.Such a situation can be easily reproduced experimentally, but in recent years is rarely seen.More often a fraction of the workforce develops disease even when apparently not exposed to higher levels than other workers in similar situations (25,29,(31)(32)(33).This phenomenon of individual susceptibility has been studied in terms of immunology, of pulmonary structure and of clearance capacity.Human immunohistocompatibility studies, including our own (34), have been unable to find an immunological marker of the human leukocyte group A system which can be asso-ciated with susceptibility.However, some characteristics of the upper airways have been linked to susceptibil ity (3 3) by influencing alveolar clearance of asbestos dust from the lung.
In humans it is not possible to measure directly the lung clearance of inhaled asbestos dust and to relate that to the development of asbestosis, but several independent observations suggest that clearance is linked to the risk of disease (35 ).First, lung tissue fibre burden has been found to be higher in asbestos workers than in the general population; second, asbestos workers with disease limited to the airways have twice the lung fibre burden of workers without airway disease; third, patients with asbestosis have twice the fibre burden of patients with disease limited to the airways; finally, analyses of lung lavage fibre content of workers wi th asbestosis are higher than in exposed workers without asbestosis.Studies in the sheep model have been particularly useful in showing a higher level of fibre retention in animals with asbestosis than in those not developing the disease after comparable exposure (35).The longer fibres were particularly associated with this effect.Thus, the individual clearance capaci ty appears to play a critical role in the susceptibility to develop disease.The relative risk of developing asbestosis for an asbestos worker decreases in proportion to the asbestos fibre dust level in the workplace.Recent reports suggested a I% risk after a cumulative dose of 10 fibres-year/m 3 of air.This finding contributed to a lowering of the current threshold limit value (level of exposure) to less than l fibre/m 3 of air, given the normal 30 to 40 years of work for most asbestos workers .

Pathology
The sheep model of asbestosis has been repeatedly documented to parallel human asbestosis and has been particularly useful in correlating cellular and clinical events (15).Figure 2 shows scarring in and around a bronchiole from a sheep exposed to a single dose of asbestos and sacrificed eight months after exposure.Because of the relative lack of sensitivity of clinical tools, this lesion cannot usually be recognized by routine pulmonary function tests or chest radiography.It is our understanding that only when these lesions cover some 25 to 50% of the airways will there be a measurable change in pulmonary function .Similarly, it is only when the peribronchiolar process becomes sufficiently diffuse (Figure 3, grade 2 or more pathological asbestosis) that it becomes detectable by radiographic methods.Such early lesions have been reported in asbestos-exposed individuals with minimal functional impairment, as j udged by standard clinical diagnostic tools.Similarly, studies in subjects suspected of interstitial lung diseases also demonstrated these early lesions.Mildly symptomatic subjects complaining of shortness of breath with normal chest x-rays had pathological evidence of fibrosis.Such lesions are not visible in the chest radiograph because they are not sufficiently widespread.
Exposure of the lung to asbestos dust can initiate one of the following reactions (15).occasionally or to very low doses of fibres, who may never develop asbestosis.This is also seen in a large proportion of long term asbestos workers who have no detectable changes related to their asbestos exposure.Experimentally, this type of transient tissue reaction occurring without histopathological lesions has been reproduced in animals (36).
A low retention reaction.Asbestos exposed subjects who possess effective clearance mechanisms may have a biological reaction limited to the site of deposition of fibres at the bifurcation of peripheral bronchioles.The fi bres initiate macrophage attraction to the site, and an inflammatory reaction which evolves to scar formation limited to the distal airways.This type of lesion has been seen in humans and in animal models.
A high retention reaction.This reaction is seen in the most susceptible subjects, who retain the most fibres.The tissue reaction is the most intense and causes a dense accumulation of inflammatory cells, activated macrophages and neutrophils, and fibrosing alveolitis results (Figure 3).The macrophages and neutrophils initiate a cascade of biological events at the site of fibre deposition, sustained by weak clearance of the longest fibres.This high retention reaction is known to initiate asbestosis in humans and in animal models.Pathologically, asbestosis is a fibrosis of the lung associated with retention of asbestos bodies recognized at optic microscopy, or of asbestos fibres seen by TEM.The definition of asbestosis, upgraded by a committee of the College of American Pathologists, now recognizes both the severity and the extension of the fi brotic process (21,37).
Macroscopically, the lung gross features vary with the severity of the disease process.Early, the visceral pleura loses its transparency and the parenchyma has grey streaks of fibrous tissues in the interlobar and interlobular septa with invasion of lung tissue.In a later phase of disease, the pleural surface has a nodular aspect, quite similar to liver cirrhosis, and the lung parenchyma is characterized by loss of volume, scars and cyst formation, usually prominent in the lower zones.
The College of American Pathologists has defined four grades of severity of asbestosis, now commonly used (37).
Grade 1 -Fibrosis involving the wall of at least one respiratory bronchiole with or without extension into the septa of the immediately adjacent layer of alveoli; there is no fibrosis in more distant alveoli.This is the asbestos airway disease of Churg (21 ).
Grade 2 -Fibrosis as in grade I, plus involvement of alveolar ducts or two or more layers of adjacent alveoli; there still must be a zone of nonfibrotic alveolar septa between adjacent bronchioles (Figure 3).
Grade 3 -Fibrosis as in grade 2, but with coalescence of fibrotic change such that all alveoli between at least two adjacent bronchi have thickened, fibrotic septa; some alveoli may be obliterated completely.
Grade 4 -Fibrosis as in grade 3, but with formation of new spaces of a size larger than alveoli, ranging up to I cm; this lesion has been termed honeycombing.Spaces may or may not be lined by epithelium.
The pathological description also includes three extension grades based on the proportion of respiratory bronchioles involved by the disease process.Three grades of extension are defined: Grade A -only occasional bronchioles are involved, most showing no lesion; Grade B -more than occasional involvement is seen, but less than half of all bronchioles are involved; Grade C -more than half of all bronchioles are involved.
This approach to the pathological description of the disease process is complete, precise and has been useful in correlation studies of other parameters of disease severity such as radiographs and lung function tests.

Clinical findings
The symptoms and physical signs of asbestosis are quite similar to those of other interstitial lung fibroses, ie, dyspnea, dry cough and nonspecific malaise.Dyspnea on exertion is the usual presenting symptom, which worsens as the disease progresses with associated loss of lung function .Nonproduc- Fine crisp nonmobile crepitations are the most important physical findings in asbestosis.They can be heard early in the lower lateral lung fields in the late inspiratory phase, and as disease progresses, they are audible in the lower posterior lung fields and in mid and late inspiratory phases; in severe disease, they are audible throughout inspiration and in all auscultatory fields .Rales are a good physical sign for early detection of disease, often preceding changes in lung volumes and airflow .In most cases, however, rales appear with changes in lung function and chest radiography.Other adventitious sounds are usually absent.
Finger clubbing may be present, but does not necessarily relate to the severity of asbestosis.Cyanosis and reduced chest expansion are late manifestations.
Lung function tests reveal usually a restrictive change associated with mild end expiratory airflow limitation.The restrictive pattern progresses as disease worsens but the airflow obstruction does not worsen as the rigidity of the lungs enhances airflow in the peripheral airways .

Radiology
The radiological tools used in the diagnosis of asbestos related disorders are the posteroanterior (PA) and lateral chest radiograph, oblique chest films and CT scans of the chest in conventional and high resolution (HRCT) modes (Table 2).The plain standard high kilovoltage PA and lateral chest radiographs are adequate for basic radiological information .Oblique films facilitate recognition of pleural changes and pleural based abnormalities.
The International Labour Organization is an organization that has facilitated the development of an International Classification of Radiographs of Pneumoconioses (38).The goal of the classification is to code abnormalities in a simple and Figure 4) Computed tomography scan of an asbestos worker with asbestosis and bilateral diffuse pleural thickening.In this window of the lower lung.field,parenchymal nondependent subpleural densities may be seen reproducible manner.The organization provides standard reference chest radiographs which are used in the classification.
The CT scan is not justified in the periodical examination of asbestos-exposed workers, but has a place in clinical investigation, in defining pleural changes and in early detection of interstitial Jung fibrosis .In lung cancer or mesothelioma, CT scan allows a better definition of the extent of disease, for orientation of diagnostic or therapeutic interventions, and to follow disease progression.
The HRCT can detect discrete abnormalities of the lung interstitium often adjacent to pleural plaques or thickenings.Furthermore, HRCT permits a better appreciation of emphysematous changes and helps to differentiate the contribution of these changes and those of early asbestosis in borderline cases (17,39,40).
The HRCT changes are not pathognomonic but relatively characteristic when the following changes are seen bilaterally on HRCT: thickening of the interlobar and interlobular septa in the periphery of the lung (Figure 4); parenchymal bands extending from the pleural surface in the parenchyma (Figures 4, 5); honeycombing, small cystic zones of lung destruction with thick walls, mostly located in posterior areas and in nondependent areas of the lung (Figure 6); curvilinear lines in nondependent areas, parallel to the pleural surface but located l cm from the latter (Figure 7), which correspond either to lung fibrosis that precedes honeycombing or to areas of atelectasis due to local changes close to the pleura or to infl ammation ; nondependent subpleural densities which are a nonspecific indicator of interstitial lung disease (Figures 4,  5, 6, 7).
Although HRCT can recognize subtle changes of early interstitial lung disease often not visible on chest radiograph, The diffuse interstitial abnormalities are more prominent there is currently no technique of imaging that is as sensitive as histopathological examination of the lung, which can detect the disease process within hours after asbestos fibre deposition (16).Pathological changes can be recognized experimentally within days after asbestos exposure, but in human work conditions it takes at least 10 years before changes can be seen on the chest radiograph.Obviously, the pulmonary abnormalities seen on chest radiograph or HRCT cannot be attributed to asbestosis in the absence of pleural plaques and a history of significant asbestos exposure.
On standard chest radiographs, asbestosis is usually manifested as diffuse reticulonodular infiltrates at the lung bases (2,32).Early in the disease process, the abnormalities of the lung parenchyma are seen in the lower two-thirds of the lung fields as fine thickenings in the vascular markings (Figure 8); later the infiltrations become more clearly reticular, better defined in the peripheral lung and extending more diffusely into other lung fields (Figure 9).The changes do not have the clarity of silicotic nodules and can mimic chronic congestion of the lung secondary to left heart failure.In the advanced stage of asbestosis, the radiographic images have the appearance of honeycombing, with coarse infiltrations associated with severe tissue destruction and distortion.All the infiltrates of asbestosis are nonspecific and can be seen in other lung diseases.When the lung changes are accompanied by pleural manifestations of asbestos exposure, the diagnosis of asbestosis is more likely (Figure I 0).However, several cases of asbestosis documented pathologically had no pleural changes on chest radiograph and HRCT.
Small nodular opacities, septa!lines, linear coarse or fine linear opacities, a ground glass appearance and honeycombing are all seen in asbestosis.Lung volume may be normal or reduced.Progressive massive fibrosis with confluent masses of fibrotic tissues seen in other pneumoconioses is possible, Computed tomography scan of an asbestos worker with asbestosis and bilateral minimal pleural thickening.The honeycombing is prominent in both lung fields and parenchymal changes of a reticular nature are well marked but less frequently seen; a focal mass should be fully investigated for possible tumour.

Early detection
Pulmonary fibrosis secondary to asbestos dust inhalation is the end-stage of a long inflammatory process.Early in the tissue reaction, one finds macrophage accumulation and activation in the lung periphery, leading to organization of a fibrosing peribronchiolar alveolitis, the fundamental lesion of asbestosis.Later, the process extends into adjacent inter-Figure 7) Computed tomography scan of an asbestos worker with asbestosis, showing cun,ifinear lines in nondependent areas, parallel to the pleural surface but located about I cm from the subpleural lines

Figure 8) Chest radiograph ofan asbestos worker showing abnormalities of the lung parenchyma in the lower two-thirds of the lung field as fine increases and thickeninis in the vascular markinis.
There is also a peripheral reticulation of the lung fields, and minimal bilateral pleural thickening.In older patients with rardiomegaly, as in this case, the condition is often confounded with congestive heartfaihtre, at the time of the initial physician visit stitium and progresses to a diffuse fibrosing alveolitis, the lesion recognizable on a standard chest radiograph.To use the various clinical tools appropriately, the clinician must know the sensitivity and specificity of each.
Crackling rates: For the occupational medicine physician, the finding of end inspiratory rales in axillary lung fields in Figure 9) Top Chest radiograph of an asbestos worker showing more advanced abnormalities of the lung parenchyma.The coarse reticulation is d(ffuse, of higher densi(y and the cardiac silhouette is beginning to be ill-defined.Bottom In an enlarged image of the lower left lung field, the coarse reticulation is better appreciated an asbestos worker constitutes an early indicator of asbestosis, and correlates well with radiographic findings and lung function changes.In asbestos workers recognized as having asbestosis, rales are usually present.However, in exposed workers not yet recognized as having asbestosis, rales constitute the only abnormality in fewer than 5% of cases (25).Recording rales for further analyses using sophisticated acoustic methods has been of interest but is of limited practical application.
Chest radiograph: The standard PA chest radiograph is the main tool in the detection of pneumoconioses.However, it is well documented that in at least I 0% of symptomatic subjects Can Respir J Vol 1 No 3 Fall 1994 with biopsy-proven interstitial lung disease, the chest radiograph is normal; in asbestos workers, similar observations have been reported.Furthermore, it is not uncommon to find pathological changes of asbestosis in workers not previously recognized on clinical grounds.CT scan of the thorax: Investigation of asbestos workers with conventional IO mm slice CT scans does not reveal more abnormalities than the standard chest radiograph, but permits a better appreciation of pleural changes.With the newer generation of CT scans and thin 2 mm slices, the clarity and precision have improved significantly and have permitted increased sensitivity.The CT scan with thin slices has now been documented as detecting early interstitial lung disease in 10 to 20% of symptomatic asbestos workers with normal radiographs (39,40). 67Gallium lung scan: The 67 gallium lung scan has been used for over 20 years to detect occult tumours and infections and more recently to quantify lung inflammation.In the latter conditions, the degree of lung uptake has been correlated with pathological changes.ln asbestosis, 67 gallium lung scan detects inflammatory activity as seen pathologically and progresses to radiographically recognized asbestosis in 75% of cases (25,29).It is not a first line method of disease detection but it recognizes the inflammatory activity of early asbestosis, which does not necessarily require withdrawal of the subject from work.The interest in the 67 gallium lung scan has decreased in recent years, largely due to improvement in CT scans.Bronchoalveolar lavage (BAL): In the investigation of diffuse interstitial lung diseases, BAL provides new information on the effective cells and biochemical molecules regulating the disease process.In the investigation of workers at risk of asbestosis, BAL is of interest to: eliminate other causes such as silicosis, sarcoidosis, tuberculosis, etc; document the specific mineral dust exposure; support other clinical data suggestive of an alveolitis; and study the biological mechanisms of the disease.
This procedure has shown that some asbestos workers develop a macrophagic and neutrophilic fibrosing alveolitis which precedes the radiographic recognition of asbestosis (16,25).Pulmonary function tests: The abnormalities in the traditional Jung function tests such as volumes and diffusion capacity will appear at about the same time as changes in the chest radiograph (25,29,32,41 ).However, measurement of the lung pressure-volume curve as an early indicator of asbestosis is correlated with changes in the 67 gallium lung scan, BAL and lung biopsies (25,29), demonstrating that these early alterations are associated with peribronchiolar fibrosing alveolitis.Attempts to detect this lesion with the flow-volume forced maximal expiration curve have not been supported by studies in lifetime nonsmokers (29).

Diagnosis
The criteria for diagnosis of asbestosis have been the object of several task force reports such as that of the American Thoracic Society (42), the Canadian Thoracic Society (43) and other individuals (44).Briefly.most agree that Can Respir J Vol 1 No 3 Fall 1994 Asbestos related disorders

Figure 10) Chest radio graph ()fan asbestos worker showing typical changes of asbestosis, with bilateral interstitial reticular infiltrates and bilateral pleural thickening. This image is almost diagnostic of asbestosis
histopathological material is the most sensitive and specific method, when the pathological examination is coupled with mineralogical assessment.In the absence of pathological material, which is often the clinical situation, the diagnosis of asbestosis is a matter of judgement, based on: first, a reliable and significant history of exposure; second, an appropriate time interval between exposure and detection; third, radiographic evidence of diffuse lung fibrosis, on chest radiograph or CT scan; fourth, a restrictive pattern of lung function impairment; fifth, bilateral inspiratory crackling rales; and sixth, clubbing of fingers and/or toes.
In general, it is suggested that criteria I and 3 are essential and the others confirmatory.The extent of the radiological changes needed for the diagnosis of asbestosis is debated, some requiring an International Labour Organ ization grade of 1/1 and others accepting a grade of 1/0.We are of the opinion that an abnormal chest radiograph or CT scan suggestive of a diffuse interstitial lung disease, in association with a significant history of asbestos exposure, should be sufficient to establish a diagnosis of clinical asbestosis.

Evolution and complications
The outcome of patients with asbestosis is currently much better than the first cases of Murray ( 4), who all died before age 30.Although life expectancy after diagnosis of asbestosis

Compensation
Once the diagnosis of asbestosis is established , th e wurkcr should not be further exposed to asbestos dust, and compensation for occupational disease should be provided.The modes of compensation vary from one country to another, anu in Canada from one province to another.
Whereas for recognition of asbestosis th e rad iog raph has a promine nt role, functional impairment is more impo rta nt in setting of the le vel of compe nsation.Asbestosis is progressi ve and follow -up is required.

Medical interventions
Medical interve ntion in cases of as bes tosis is important: at the time of initial diagnosis and in the assessme nt or impairment; to follow prog ress; in the trea tment of int e ruirre nt resp iratory infections: c1n d in the treatment of hypoxcmia and ri g h t heart failu re, the late co mplications of a prog ress ive restriction of lung function.O ther mod alities nf support arc preve ntion of complications anu the relief of rnugh .There is no evide nce of hcncfit fro m the use of steroids or i111mu11osupprcssor therapy in asbestosis, a nd the !alter form of treatment has e ven been shown to worse n experimental asbestosis.

BENIGN PLEURISY Pathogenesis and pathology
T he pathogenesis of benign asbestos pleurisy is largely un known ( 47 ,48).T he clearance o f inhaled asbestos fi bres is in part through the lung lymphatics, to the intc rstitiurn .the pleural cavities and the lymph nodes (49).Direct contact of asbestos fibres with the pleu ra appears to he the initial L'.vcnt.Recently, an animal model has been developed and the role o f che motac tic fa ctors for ne utrophils and othe r inll anunatory ce lls has bee n stressed (48).The no nspec ific inll ammatory reactio n of be ni gn ple urisy is charac tc ri zccl by an inll am matory reaction with fi brin de position, accompanied by reaction of mesothelial cells, giving the impression of pseudo-organization (21 ).T hi s pleurisy is ofte n tra nsient but can leave scars as pleural thickenings in the costophrenic angles, and occasio nall y result in adhesive !'ihrothorax.

Clinical findings
Beni gn pleurisy is defi ned by fou r crite ria (50): fi rst, asbestos exposure; second, rad iog raphic or thoracoecntcsis con fi rmat ion of pleural e ffus ion ; th ird, absence of other causes of effusio n; and fo urth , absence of tumour in a fo llowup of at least th ree years.This de fi nition is somewhat arbi trary but nonetheless prac tical.Many workers with be ni gn asbestos pleuri sy arc asymptomatic and are fo und at periodic radiography as in the case in Figure l l.Some have shortness of brea th and chest pain.The pleura l fl uid is usual ly an e xudate wit h or witho ut blood staining.The benig n pleurisy of asbestos ex posure is asympto matic in 66% or ca es and rec urre nt in 28 % of cases .It is associated w ith ac ute chest pain in 17% of cases, with u1 w ithout fever, a11d may occ ur with or without assoe iatccl asbestosis.According to Epler (50), bcnign pleu risy is the most freq uen t abno rmality seen in asbestos workers with less than 20 years of exposure.T he incide nce in the e xposed populatio11 is in the order of 3% .wi th a pos itive dose-re-,ponse rel ation.It may be seen in white collar workers in the as hcstos industries.
Most cases of ben ign asbestos pleurisy have less than 500 mL of effu sion.On phys ical exami nation, the rindings are those of pleural effusion , with du llness or percuss ion and plcuriti c rnb on auscultation.Function meas urements show a restrictin: pattern proporti onal to the severity of the effusion and ,Moc iated pain .The effusion can be transient or recurrent, a,ymptomatic or sy mptomatic, uni-or bilateral.The latency period is usually less than 20 years and it is often the first man ifestation of asbestos related di seases, but it is not a precurw of other diseases.Usually there is complete re olution of the effusion, but with residual pleural plaques or pachypleuritis.

Radiology
Pleural effusio ns are often the first manifestation of mal ignant pleural or pulmonary ncopl as ia , and subjects with as bcsws exposure and a pleura l effusion should be considered as ha, ing a tumou r until proved otherw ise.However, Epler et al (50 ) have documented that benign pleural effusion is the most freq ue nt di sorder seen in the first 20 years follo wing initial a,hestos exposure, and usually is the only one to be seen in thl' first IO years.
Radiographically. the effu sion presents as blunting of costophren ic ang les.The fluid is usually of mini mal volume, can bl' mobili zed on lateral decubitus films and is transient as opposed to that of malignant tumours.Benign pleurisy can often lead to chronic pleural changes and HRCT can he of help in excl uding an early mcsnthelioma.

Early detection
This condition is most often asym ptomatic and early detl'ction has little interest as prognosis is usually favo urable.

Diagnosis
The four cri teria for the diagnosis of benign asbestos pleurisy noted above are somewhat arbitrary but nonetheless practica l.

Evolution and complications
The outcome of benign pleuri sy is either toward a .',pontancouspain less or pain ful regression with minimal or no pkural scar, one or many rec urrences of the effusion and. in a kw cases.evolution to diffuse pac hy pleuri tis or rounded atdcctasis.It is not a precursor of mesothcl iom a.

Compensation
Benign pleurisy is often the cause of te mporary work ,toppagc which shoul d be covered by an insura nce plan.PL'rmanent compensation is ra rely needed as most cases have only mini mal scars.and there is apparently no relat ionship to olhcr future asbestos di seases.

Medical interventions
Thoracoccntes is and pleural biopsy may he neeLkd Ill c\l'lude other causes of pleural effusion.Treatml'nt is to relieve ,yrnptom,.but follow-up for at least two years is impnati vc.
Can Resp ir J Vol 1 No 3 Fa ll 1994

PLEURAL PLAQUES Pathogenesis and pathology
The pathogenesis of pleural plaques has been reviewed (47).Two pathogen ic theories are suggested: a direct effect llf fibres reachi ng the pleural space and an indirect effect.The latter theory is in part su pported hy the assoc iation of smoki ng and as bes tos pl eural plaqu es .The direct contact theory is more plausible; it recognizes plaques a a local reaction to fibres reaching the pleural space, a preferential way by which short fib res are cleared ( 49).This latter study has shown that short and th in fibres may be found in thl' pl eural space after inhala tio n.The thin and poi ntl'd nature of the fibres found in the pleura l spacl' faci litate penetration into the ti ss ues, with inju ry and an inflammatory and hemorrhagiL' reaction organizing to prod uce pleural pl aque.' ,.The latter mec hanical theory is pa rtly based (lll the observatio ns of Epler ct al (50) in 44 subjects who developed pl eura l plaques follow ing transient pl eural e ffu sions .Churg (2 1) has dcscrihed the occasional transfo rmation of a chronic inflammatory and cl'llu la r pleural reaction into an acellular plaque.
Pleural plaq ues arc les ions of hyaline rihrosi s mainl y located in the sub mcsothcli al layers of the parietal pleura at the level of the costal margins, diaphragm and paraspinal areas.They can be found in the pericardium and less often elSC•• where in the mediasti nal pleura.Visceral pleural pl aq ue arc less frequently seen but can ex tend into the interlobar fissures.Microscopically, pl aques are composed of layers or virtually acellul ar collagen.the surface being covered with a thin layer of mesothel ial cells.Calcification or dystrophic type is often found in plaques.Although they arl.! typical of ashestos ex posure, generally, there are no asbestos bodies or fib res in the plaques.

Clinical findings
Pleural pl aques are asymptomatic in the absence of obliterat ion of the costophrenic angles or associated asbestosis, and have a latency period between initial exposure and r:1diographic recognition of some 20 years.They have no clinical manifestations, are usually bilateral and often in the retrocardi ac area where they are not easily seen on chest radiograph.They have limited progression and art' often round in the absence of asbestosis.

Radiology
Pleural plaq ues arc seen as focal irregular thickeni ngs or the parietal pl eura in the sub mcsothclial port ion and. in reality, arc extraplcural (2,32).They can al so be seen adjacent to vi scera l pleura, uncom monly in the intcrlobar fi ssures.
Pleural plaques are the mos t frl'qucn t manifestation of asbestos exposure, and a,hestos exposure is the most freq uent cause of pleura l plaques.Usually, they are considered a good indicatur of asbestos exposure, and appear to be related to amphihnle exposure; chrysotilc has only a limited tendency to produce plaques.Latency time for the production of plaques is on average 30 years with a range of three to 57 years.

GG 83
Figure Calc ification is not necessarily see n on standard radiographs hut affects mainly parictal plaques which are characterist ically located alon g the diaphrag m and posterolateral chest wall.They also can be fo und in paravertehrnl areas, which are rarely seen on a PA film .
Early.pl aqucs arl' thin.linear with sharp margi ns ; early detection depends on the thickness of the plaques and optimal radiog raphic techniq ue.They appear as rounded discrete opaci ties arising l"rom the parietal pleura, and can have a smooth or uneven surface .O blique films inc rease the radiographic visibility of plaques by 50% over the standard PA and late ral chest fil ms .With ti1nc, the margin s or pl aq ues become more ro unckd and better defined.Plaques rarely occupy morL' .than l"nur intercosta l spaces.
The CT scan can show pla4ues much earl ier and at a less well defined stage than the c hest radiogra ph (fi gure 12 ).The paravc rteb ral and pe ri carcliac plaques particu larly arc better seen.The dia phragm pl aq ues, which were not always well ide ntified with CT. arc correctly evaluated with mul tip le thin slice HRCT.The CT scan can clearly J ifferentiate pl aques from cxt raplcural f"at pads.which may be di ffi cult on the plain c hest radiograph.Furthermore, in the presence of extensive and calcified pleura l plaques.CT scan permits a cleare r appreciation of the lung parenchyma than the plain radingraph.

Early detection
Recognition of pleura l plaques in as bestos workers is mainly of interest as a marker of exposure , as in the majority of cases the pleura l plaques do not affect lung funct ion.Nonetheless.everal recent studies have shown t.hat the CT scan can permit a belier appreciation of pleural changes tha n the chest rad iograph.Pleural plaques u •ua lly do not take up 67 11• ga 1um.

Diagnosis
Histop,itho logieal material is the most sensitive and specil"ic source of diagnostic evidence o f pleural plaq ul's which otherw ise can be recogn ized on chest radiograph or CT sc,111.

Evolution and complications
Pleural plaques have a tendency to enlarge and c1lcil"y with time.and may also become con llue nt.It has been suggested that mesothelioma may develop at the edge or such plaques.

Compensation and medical interventions
Loca li zed pleural plaq ues arc indicators of asbestos exposure and do not affect lung function significantly.T hus, they are usually not compensated fo r, nor arc they an indicati on for work cessation.However.when multiple pleural plaq ues produce a restrictive syndrome.compensation and work re-,triction should apply as f"nr ashcstosis.Med ical interventio ns arc limited to the recognition or the nature and cause o f plaques.

PACHYPLEURITIS Pathogenesis and pathology
Whereas plaques m ainly occur in pari etal ple ura. the d if-fL1se pleu ral thickening of pachyplc uritis is a disease or the 1isceral ple ura.The pathogenic mechanisms different iat ing pachypleuritis fro m circu mscribed pleural plaques arc not Jdined, but the fundamental irritat ive mechanism remai ns likely.In the case o f pachyplcuritis.fibres deposited in the rarcnchymal subplcural a reas may lead to d iffuse pleural fibrosis with associated interstitial lung fi brosis (48 ).The mechanisms which cause pleural fibros is to e xtend into the interlobular space., o f the lung a rc unknown.but coul d result from three phenomena : first, the con n ue nce o f large pleural plaques in IO to 20% of cases; second, the extension of ,uhrleural fibrosis to the visceral ple ura.resul ting in a d iffuse pleu ral th ic ke ning in IO to 30% o f cases: and third.the scar lll° an cxudat ive benig n ple urisy prod ucing a d iffuse ple ural thic kening.T he latter is the m ost freque nt and o fte n cause~ ,ignific:mt restriction o f lung expansion, eve n in the abse nce llf inter titial lu ng fibrosis (48 ).

Clinical findings
The diffuse nature of the pachypleuritis is respo nsi ble for the symptom of dyspnea o n exertion which is often present .mJrelates to significant loss o f lung function.Dry cough may also be an accompanying symptom.T hese d iffuse rihrotic thickenings of visceral pleura are not speci fic to asbesto, exposure and can be assoc iated with old in n ammato ry r-:actions to tuberculosis, thoracic surgery.he morrhagic chest trauma or drug reaction.T he development o r pachyplc uritis, rnntrary to pleural plaques, often fo llows pleural effusions and is like ly init iated by the accumulation of fib res in the ,ubpleural zones of the lu ng (49) .Because of the relati ve thinness of the fibrosis or the pleura, it cannot be de tected easily on physical e xaminati on.Diffuse pac hypleuritis may he limited to one side or invo lve both sides a nd can rest rict lung expansion but rarely produces respirato ry insufficiency.~lost often, asbestos related pachypleuritis is associated with diffuse interstitial fibrosis.In over 30 % of cases, there is :1 pa,t history of asbestos benign plcuritis.Other causes include n1nll uence of pleural plaq ues in 25% of cases, malignan t pleu ral effusion, chest trauma, pleural infection a lone or in cnmbination with one o r more of the above (33 % ), and fi na ll y the extension of parcnchymal fibrosis to the visceral and parietal pleur:1 ( I()<;; ).

Radiology
On the chest radiog raph.paehyplcuritis is manifested as dillu, e pleural thickening wi th a smooth surface extending 111w more than 25% or the pleural surface and usuall y into the costodiaphragmatic ang le.Ex tensio n of pachyplcuritis in two or more fields bilaterally constitutes the best indication that asbestos is the cause.
Can Respir J Vol 1 No 3 Fall 1994

Asbestos related disorders
With a CT scan.p,1,•hypleuriti, is defined as a pleural thi ckening more than 5 cm wide, more than 8 cm long and more tha n 3 m m th ick, affecting mainly visceral pleura (Figure 13) in posterior and posterolateral areas o r the lower w nes .Because o f this location, CT scan can provide a better guide to the e xtent of ple ural thic keni ng.compared with chest rad iographs.Extension of the fi brosis in the interlohar and interlobular fi ssures forms a •crow's foot • appearance l>r a rou nded atc lectasis (pseudut umo ur, with a ple ural basis ).CT scan is particularly useful in di fferen ti ati ng pleuritis t'rom pleural fat deposits.

Early detection
Pachyp leuritis is nnt spec ific fo r asbestos exposure, and early recognition is o r inte rest mainly because it can alter lung fu nct ion .

Diagnosis
Pachy ple uritis can be recognized histopatho logicall y and in most cases on th,• chest radiograph and CT scan.

Evolution and complications
Asbestos pachypleuritis can restrict lung func tion extensively if bilateral and severe, and rarel y may cause respiratory insufficiency.

Medical interventions
As pachypkuritis is o ft e n due to causes other than asbestos exposure, elimi nation of the o ther causes is pa11 o f the initial medical assessmen t, as is the evaluatio n of functio nal impairment, which may le ad to consideratio n u r compensation for loss of lung funct ion.

ROUNDED ATE LE CT ASIS Pathogenesis and pathology
This effect or asbestos-ind uced pleural d isease is caused hy scarring of the pleura and adjacent lung tissue, with retraction of the scar tissue and partial col lapse o f adjacent lung tissue.It is relatively uncom mon and the speci fi c mechanisms causing this pleuropul monary prncess arc nut knmvn beyond those causi ng the pleural disease, but it is mllre often recognized w ith the advent of the CT scan.

Clinical findings
Rounded :1tdcctasis, also called pseudotumour (F igure 13 ). is usually asymptomatic and is detected on chest radiograph as a pleural based op:t,•ity suspected to be tumo ur in most cases.Occasionally chest pain in the area may be the pre senting sympto m.In the past, pscuclotu mours were oltcn resccted.but with the CT scan, the true nature o f the rounded atelectasis ,•an he r,•cogn iz.cd without surgery .

Radiology
Extcnsiun or the visceral pleura l fibrosis into the intcrlobar and interlobular fiss ures is ofte n a late event, seen many years a fte r exposure cessa tion.It can progress, thro ugh retractio n or scar tissue .to cause torsion of the adjacent lung tissue.gi ving rise lo the rounJed all'IL'Clasis lesiPII.i'Pllkd lung or Bleskovsky' s syndrome (Fi gure I JL also ca lled ;t pscudotumour.mim icking a carcinoma or confluence or pncumoco niosis.A characteristic feature is a comet's tai l risi ng from the middle of the mass.and m:1y be belier apprL'ciatccl on the oblique chest rndi ograph or CT scan: it is due lo tractiun of lhL' hrnnchn vasc ular markings towards the centre of the mass from the hilum. The diagnosis or rounded atclcctasis can be made on thL• radiological images and usually has the foll ow ing characteri stics: first.ro und les ion of 2 to 7 cm diameter: second .pleural -based loL•ation : third.curvil inear shadows extending toward s the hilum (conwt 's tail): fourt h.int rap ulmo na ry locatiun (acute angle between pleura and lesi on) with pleural thidening adjaL'l'nt to the lesion: fifth.thicke ning of intnlobar fi ss ur~: sixth.separa tion of dia phragm from lung tissue: and seventh .sluw progression (as opposed to lUlllOUrs).

Diagnosis
The diagnosis of rounded atelectas is used to de pend un histopatholog ica l ev idence but the scan has pro vitkd image\ that arc quite speci fic for the condition.

Evolution and complications
The rolded lung is a late ma nifestation or complicated diffuse pleural thi cken ing.It is slowly progn.:ssivcand may cont ribu te lo rest ric tion in lung func tion.

Compensation
Diffuse pleu ral thickening may cause sign iric:1111 loss <11 lung function .The c riteria for compensation and work 1cstric tio11 should he the same as for asbestos is.

Medical interventions
Recognition may pose a clin ical probl em that necessitates thL' usc or CT scan , bro nchoscopy and transthoracic needle aspi ration biopsy lo climinalc a lurnour as the cause of lhc radiographic opacity.

LUNG CARCINOMA Pathogenesis and pathology
The pathogenesis of asbestos related cancers 1., 111rn111plctl'ly understood and the subject of controversy t 1 ).Some in\'CSligators consider asbestos as a tumour promote r as opposed to an initiator, on the basis of weak activity in standard lcsts for carcinogenic substances (mutagenicity and production of chromosomal abnormalities); the fibres would then have the e ffect of increas ing the susceptibility or the lung to other carcinogens.Othe rs consider the experi111en1:.ilevi-<ll'ncc of an excess of lung cancers in animals not exposed to t:arcinogens o ther than asbestos, and the excess of lung tumour in lifetime nonsmokers, as being in favour of a tumour initiator.An additional point of debate is the participation of fibrosis in !he genesis of lung carcinoma, a position supported by several large epidemiological studies that have fou nd an excess of lung cancers only in lhe most heavily exposed 11orkers, who also have the highest incide nce of radiographic changes suggest ive of asbe stosis.Ho wever, bronchogenic carcinoma is fo und in lifetime nonsmoking asbestos workers, and these lesions can be produced in animals in the absence tif fibrosis.
The existence of asbestos related lung c ancers in the absence of asbestosis is further complicated by the smoking risk factor.T he l 0-fold excess risk of lung ca ncer in smoke rs appears to he potentiated to 50-fold in smoke rs who work \1 ilh asbestos.The fibre type does not seem to be important, although it has been sugge sted that crociJolite fibre e xposure may represent a hig h risk.The risk.estimate is largely a function or the amount of tobacco smoked and the amount or a,bcstos exposure.Other risk factors in the workplace.such as contaminant metals, ionizing radial ion and other clwmit:als such as benzopyrene and polycyclic aromatic hydrocarbons, may also nmtrihute to the added risk in the initiation and promotion of lung cancer in asbestos workers.
The pathology of asbestos related cancers is not distinct in type, nature or location within the lung from that associated wilh cigarette smoking.The cell type distribution is about 35~ epidermoid, 25% small (oat) cell, 30 % adenocarcinoma and 10% large cell can:inoma.This distribution is not distinct from that of populations 1101 exposed to asbestos.

Clinical findings
The clinical presentation of a sbestos related lung tumours is indistinguishable from th.ti of lung tumours caused hy Dlher carcinogens, except for the possible association or symptoms of asbestosis.

Compensation
In presenn• of asbestosis, it is uni versall y accepted that lung cancers should be comJK'nsated.In the abse nce of asbestosis, compe nsation is debatable.some a uthorities refusing compensation for all cases in the absence of asbestosis, others favouring compe nsation for cases of long exposure (ahnut in excess or 20 year.,), in spite of the absence of asbestosis.A detailed d isc ussion of this point is beyond the scope of this rL'vicw and the interested reader is referred to C hurg (21 ).

MALIGNANT MESOTHELIOMA Pathogenesis and pathology
With an incidence of one to two cases per million people per year in the general population or North America, malignant mesothelioma is considered rclativl'ly rare.The clear association of asbestos with mesothclioma was established initially by Wagner and associates (7.I 3 ).After the gathering or careful occup:.ilional and environmental exposure history and mineralogical analysis of lu ng tissues, it is overwhelmingly clear that the majority of cases of mcsothelioma are found in subjects e xposed to asbestos fibres (51)(52)(53).Asbestos acts as an ini tiator and a promoter and thus is considered a complete carc inogen, al least in the induction of mesothelioma in anima ls.Even in women, in whom the inc idence is two lo l O times less common than in men, tissue a nalysis for m ineral fibres revealed that 9 8% of 117 cases in the United Kingdom had amphibole counts in the lungs greater than controls (54).In general, the amphihoks are considered.i11 part due to their re lative durability, to be the cause of most cases but pure chrysolilc cases have also been seen, although to a lesser degree.In some c ases, the nearly equal numbe r of the two types of fib res in the lung tissue makes it impossi ble to establish a causal rela tionship for eithe r of the fibre types, a nd all asbestos fibre types have produced meso thelioma.
In anima l studies (55) the process starts a fter fibre injection in the pleura by the formatio n of a g ranulomatous lesion w ith subsequent deposition of aecllular dense collagen, which coa lesces and is surrounded by a layer of mescnchy-111,tl cells and a surface of normal mesolhe lium.Later.neoplastic transformation with extensive surface growth occurs, showing a variety of diffe re ntiation into mescnchymal to e pithelial cells.
The rationale for a greater propensity uf amphibolc to induce mcsothelioma in humans has been related to its geometric prope11ies (greater diameter, rig idity), favouring deeper pe netration, and its resistance to degrndation, favouring its persistence in lung tissues.It is universally accepted tJiat mcsot.hcliomahas no association with cigarette smoke exposure.Gross pathology: In the early stage s, the mcsothclioma appears as multiple small greyish nodules on the visceral and parie tal pleura which coalesce and form larger masses of tumour.They are often accompanied by pleural effusion.Tumo ur will develop by direct extension, forming large masses which invade the adjacent struc tures, including the chest wall, intcrlobar fi ssure, lung parenchyma, mcdiasti num, perica rdium, diaphragm, esophagus, large vessels of !he mediastinu m , contralateral pleura and the peritoneal cavity.Death is usually caused by restriction of one or more vital struc tures.Malignant mesothelioma may be or peritoneal origin in fewer than 25% of cases, usually in association with am phi bole expo ure.The gross appearance of the tumour is  Histopathology: Malignant mesothclioma has a variety of histolog ical presentatio ns da ~si ri cd as epithelia l in some :i0'7o o r cases , sareomatoid in 16 % or cases and mixed in 34% or cases .The epithe lial type exp resses one or more growth patterns such as tubular.papillar.micrucystic and soliJ.which arc onen mixed within the tumour with some variation from :.irca to area.The sarco matoid ty pe has sp indl e-shaped dongatL:d cells; nul"iear picomorphism and mi tosi s are common.In the mixed rorm .epithelial and sarcomatous fo rms are present in variable proportions.
T he carci noembri ogenic a ntigen is negative in 9Wk o r cases or malignant mcsot hcl ioma (and whe n posi tive on ly very weakly) but positi ve in 90'/c cases of' adenocarcinorna.
C ytokeratin immunochc mical stain ing is usually pos iti ve and the pat tern or staining is dist inct from that or aclenoearcinoma.being more d iffuse in the mcsothel ioma and exh ib iti ng a pre dom inant ly periphe ral location in the adenoc arei no ma.Vimcntin is usually negat ive in both type of tumo urs, bu t may be pos it ive in 20 1 1c, or mesothclioma cases.T he patho logical diagnosi s o f malignant mes(lt he lioma C;111 be very d ifficu lt and the ex pertise or an intl•restcJ patho log ist is of"le n necessary for a final diagno..,is .

Clinical findings
T he inc idence o r malignant mesothcl ioma is in the orciL'r of o ne per m illion adul ts. in the absence of asbestos ex posure.and increases to its hig hest levels in crocidolite-e xposecl wo rk ers.For the general North American pop ulation.tlw incidence rate is l'stimatcd at between 2.5 to 13 cases per mil lion ad ult males per year.In the asbes tos exposed popu la-tiu ns .the ra tes L'all be live-lo 20-folc.lhigher.with a grad ie nt or 10 to I fur crucidulitL' tu chrysot ilc exposures (56).
The chid complaint is usuall y chest pai n. dull and achi ng in nature anc.lOL'casion,il ly L'liciled by in spiration.which is pers istent and requires progressi vel y hi ghe r doses or ana lgc-,ics.Cough and dyspnea are al,qi frt'que nt, !he latter be ing ma inly due to pl e ural effusio n.Weight loss.fe ver and general ma laise arc often present.Symptoms of osteoarthropathy arc ve ry un usual.S hort ness of breath is usu,ill y pro gressive as the tumour cxll'nds within lhc chcsl tu cncisL' the lung and in filtratL' 1hc mediastinal structu res.
The sites or prcscn t,niun ul mcsot he lioma can be in the pleural, pcric,irdi ,1! or abdominal ca\'i tics, the latte r be ing more o ft en sl'cn in casL•s wi th high amphibole exposure .The reason for these prel'crenccs arc unh.nown.
One or the peculiarities of mesothelioma is the apparent 20 10 50 years of dormanc y ur latL•ncy or the process in hu mans, which is unexp lained but no t unique , as othe r can-~e rs also have a si mi lar dormancy peri od at'ler exposure: the raJialiun cancers are an example of this phenomenon.
As the di sease progresses, there may be involvement of the lu ng parenchyma, reduction in the si ze o f the involved hem ithora x, mcd iast inal and hilar invasion , pericardia I thickening and effusion.abdominal e xtension and chest wall in vas ion.
Most of these changes can be appreciated on pLiin ches t radiograph but the CT scan acids precision and cLiri ty to the• obsc rvat ions.

Early detection
There is no method or ea rly recog niti on or rnesothel ioma at the present ti me .The majority of patients with mcsothcli oma have chest pain as the earliest reason for consultation.

Diagnosis
Open thoraco tom y biopsy is usu ally needed to establi sh ;L i"irrn di agnosis or malignant mcsuthl'ii oma.The combined use uf micruscop) and imm uno histuchcmi stry is usually diagnostic.

Evolution and complications
Diffuse pleural thickening o ft en restricts lung function and m,Ly bL' c1s limi ting as asbestosis.

Compensation
All mali gnant mesot hel iomas that ,ire associated with .L significant ashestos exposure al work slwuld k l"ully l'\llll • pcnsated as !he di sease 1s nearl y always fatal within 24 mon ths or diagnosis.

Medical interventions
The various thera peut ic modalities for m,il ignant mcsothel ioma incl ude surgery , radiothera py, che motherap y and recently immunothcrapy llf cytoh.inctherapy; al l have been L'LJUally unsucL:ess ful in curin g the di sease.At best, an extension or a kw months of survival after initi al di ag nosis may be de monstrated objectively in selected studi es ( 14 ).Medic.ti intervention s remain supportive• in nature hy proviclmg sy,npto matic relie f.Prevention C urren t practice in public heal th regarding the protcctiun of worke rs aga inst !he risk associated with the ir j\ib is legis -latL•d in each counlry.The laws in eac h Canadi,1n provi nce est abl ish stc1ndard., or permi ss ible expos ure levels and health surveillance of workers by periodical medical examinati ons.Interested readers , Ill' referred lo a detailed lnternatiomd I .abourO rgani zation publicaliun (. '17)

INDUSTRIAL HYGIENE
Indu strial hyg ie ne is based on the trad iti onal tec hniq ues o r reduction in dust ex posure by enclosure of the sources or dust.adequate venti la tion .coat ing ancl scali ng or products.the use or spcci,t!i 1.L •d tools and frequent cleani ng o r the workp lace.In some particularl y dusty cirrnmslance, , individ ual pro tection is recom me nded.Hygien ists use the threshold limit values rm specific dus ts as standa rds to regul ate the indu strial hygiene conditions.T he thresho ld limit va lue for asbestos is I ribrl'!cm 3 of air for chrysotilc and 0.2 fihrc/c m 3 for amphibnles in mos! indu st riali1ed coun tries .

Can Respir J Vol 1
No 3 Fall 1994 Asbestos related disorders..

Figure 1 )
Figure 1) Cytospin of a lung lavage in an asbestos worker showing several fibres, many o.f length greater than the average macrophage diameter (8 µm ).Wright-Giemsa stain X740

Figure 3 )
Figure 3) Left Asbestosis in a more inflammatory stage with cellular infiltration and asbestos ferruginous bodies.Hematoxylin-eosin x80.Right Asbestosis in a morefibrotic stage with.fibrosisaround the peripheral airways and extension of the.fibrosis into the inTerstitium between ainrnrs.Hematoxylin-eosin x20

Figure 5 )
Figure5) Chest radio graph (left) and computed tomography scan (right) of an asbestos worker with asbestosis, seen as subpleural densities.
tive cough and chest pain are usually present only in some cases, late in the evolution of disease.When cough is productive, it should be considered to be due to a complication such as bronchitis or pneumonia.The chest tightness and pain of patients with asbestosis are attributed to muscle pain, appearing only when dyspnea becomes severe.Hemoptysis is not a usual complaint in asbestosis and should be investigated.The symptoms of asbestosis may occur during the working years or follow ing exposure cessation, as disease may become clinically apparent only after retirement.