Document Rj68DBxLNrN7xd4vyOykwYbpv

PLAINTIFFS EXHIBIT ..DQW-353 v. 11 T/l j** l(T? THI BRITISH JOURNAL OP CLINICAL PRACTICE Asbestos Exposure - Its Related Disorders KIMON CONSTANTINIDIS, MD, Medical Research Council, Pneumoconiosis Unit, Penarth, Glamorgan. SUMMARY - UaOn m--t otter kkM fettt, asbcstot cm prodocc at (coat three Mid dbaaaaai aibnteiit, lna| caacar aad acaotteBoaa eftte piaara aad pcritoocom. Wcriim vftk ubcciate an at fraatar tiik of datatepte# laag caacar tkaa dialr teakhy contemporaries aad Maa ftadks have loggcstcd that aibcuoa aipeaan ofcfco*t astestotb laarcaaaa tba risk of kwg aaaaas. MaaoUaSoou af ika piaara aad paritoaaam Is a ran tanoar bat k has baaa foaad 1M1 cvcr-iacrcaslag frcqacacy la parsaaa azpoaad la relatively tnafl amoaats sf atbastos; iha lataat pariod between eipoaure to asbastos dost aad davalopmaat of iha lamour asaafly sacaada 2# years. GENERAL AND HISTORICAL ASPECTS Asbestos is the generic name given to cer tain varieties of fibrous mineral silicates which vary considerably in physical proper ties and chemical composition. Although asbestos has been known since antiquity, in recent years there has been an increased in terest in the biological effects of exposure to asbestos dust The commercially important types of asbestos are the serpentine chrysotile, which is the most widely used, and the hornblende (amphibole) group of minerals, crocidoiite, amosite and anthophyllite. Around 3,000 BC anthophyllite was being used in Finland to strengthen earthenware pots, the first asbestos composite; the Chinese and Egyp tians used cloth and .mats of woven asbestos. The ancient historian Plutarch first used the name asbesta, a Greek word meaning inex tinguishable or inconsumable, and it was then in use in lamp wicks as in the perpetual lamps of the Vestal Virgins. The Romans in ancient times found several uses in spinning and weaving for asbestos mined in Italy and Cyprus and Pliny referred to the use of respirators to avoid the inhalation of asbestos dust snd made mention of asbestos shrouds used in cremations for the Roman Hite to permit easy collection of the ashes for burial. In 1230 Marco Polo recorded that in the Tartar Empire he was shown textiles which resisted tne might of fire. The modern asbestos industry dates from the 1880s, when large-scale development of huge deposits in Canada and Russia began. CHEMICAL AND PHYSICAL DATA The chemical composition of different types of asbestos from various localities has been reported, by several authors (Sinclair, 1939; Timbrell, 1970; Morgan and Cralley, 1973). Chrysotile (white asbestos) is a hydrated magnesium silicate which usually occurs in seams close to the earth's surface (Mg,Si]Oj(OH)4). The fibres may be long and flexible because of unique structure of tubular microfibrils. It is heat-resistant and some fibres may be heated to 3,000F without be ing visibly affected. Chrysotile does not resist sea water, acids and alkalis. Hie mean value of the fibril diameters are generally in the range of 30 - 40 nm (Atkinson, Gettms and Richards, 1971). The fibril morphology is so unique that the mineral species can be iden tified on this basis alone with the use of a transmission electron microscope (Langer, Rubin and SelikofT, 1972). The largest com mercial deposits are in the Ural Mountains and in Quebec Province. It is also mined in China, Cyprus, Italy, British Columbia, Southern Africa and the USA. Crocidoiite or blue asbestos is a hydrated sodium ferroso - ferric silicate (NaFe (SiO^, FeSiOj)- It is also known as Cape blue, because formerly it was mined only in Cape Province, South Africa. Its commercial value is mainly determined by its chemical proper ties. It is highly resistant to acids and alkali solutions, and is remarkably strong. The fibres may.be soft or harsh but they always possess a high degree of elasticity. Amosite, (MgFe)0.Si0j, which occurs only in South Africa, is named after the initial letters of Asbestos Mine of South Africa, the name of the mine where it was first worked. The fibres possess superior heat resistance. It is unaffected by immersion in acids and it is fairly resistant to alkalis and salt water. Anthophyllite (7Mg0. 8Si0}. HjO) is mainly produced in Finland and it is the least com- FST0005S50 DOW 07052 *0 THI BRITISH JOURNAL OR CLINICAL SRACT1CS mercially useful of the amphiboles. The fibres ate brittle and short, sometimes soft and flexi ble. It is infusible, and resistant to adds and alkalis. USES OF ASBESTOS The uses of asbestos are multiple and more than 1,000 different uses in industry have been reported (Hendry, 1965). Asbestos is used in heat insulation (boiler and pipe pack ing. insulation blocks and boards, pot holders, gloves lining, ironing board covers, fire fighting suits, sheets and ropes, firemen's helmets), in friction materials (dutch plates, brake lining, bearing packings), in the building industry (pipes for water and sewage, floor riles, pipes for gas, ceiling board, artificial wood, cements, paint, roof coating), in electrical installations (insulating cables, electrical wires, switch boxes, tapes, condensers, spark plugs) and miscellaneous uses (automobile undercoating, life-jackets, da> for pottery and sculpture, cigarette filters, artificial snow, fire hose, mail bags, air plane wings, etc). From 1900, croddolite wag m demand in the shipbuilding industry because chrysorile was not a good insulating material when exposed to sea water, but it has now been replaced by amosite. OCCUPATIONAL AND ENVIRONMENTAL EXPOSURE Until recently large amounts of asbestos fibre escaped into the air from the mines and mills so that not only the workers but the whole population of the nearby towns and countryside have been exposed. Obviously the greatest exposure to airborne asbestos dust is likely to occur in the industry: mining, crushing, carding, spinning and formulation, all offer opportunities for heavy exposure. Asbestos is obtained from both deep and sur face mines and most of it is bound into the parent rock in clumps and this, together with the use of dust suppression, has minimized the danger of asoestos exposure for the miners. The raw asbestos is crushed in mills to release the fibres suitable for spinning. Bagging of fibres used to be a very dusty process until the recent introduction or pressure-packing methods and leak-proof bags. Asbestos cement spraying has often been documented as a significant source of environmental exposure and the process has been stopped in some places. Asbestos is vir tually indestructible and, therefore, it even tually has to be removed from ships, buildings, etc, when it is often very dry and the proportion of respirable fibres in the dust high; removing old lagging material usually takes place in confined spaces, increasing the risks of exposure to asbestos. Workmen not directly involved in asbestos applications may receive massive dust ex posure; fitters, joiners and general labourers are not classified as 'asbestos workers* and they are unaware of the dangers of dust in halations and do not use protective overalls and respirators. The risks attached to children living and playing near to asbestos processing factories has been well demonstrated by Wagner (1965), and housewives have developed mesothelioma as a result of undusting asbes tos-contaminated overalls of their husbands (Newhouse and Thompson, 1965). PHYSICAL AND CHEMICAL FACTORS AS AETIOLOGICAL MECHANISMS OF ASBESTOS DISEASES Physical factors play a major role in the aetiology of asbestos diseases since they govern the respirability of the fibres and the efficiency of penetration of the different types of asbestos to various parts of the lungs. The first study on the aerodynamic properties of the fibres was carried out by Timbrell (1965) and subsequent inoculation experiments (Burger ana Engelbrecht, 1970) have re emphasised the importance of fibre length in relation to fibrosis; recent studies (Wagner et al, 1970} have indicated a relationship be tween fibre size and the development of mesotheliomas. Timbrell'i hypothesis (Tim brel!, 1973) explains why there is: 1) a higher risk of mesothelioma in mining and milling croddolite than amphiboles; 2) a high asbestosis and lung carcinoma risk in mining anthophyllite but no mesothelioma; and 3) a low mesothelioma and low bronchial car cinoma risk In chrysorile mining and a high er mesothelioma and bronchial carcinoma risk in insulation workers exposed to a mixture of fibres (Gilson, 1973). So it has been found that the most important factor in fluencing the entry of the fibres into the lungs is the tailing speed of the particle. It is a future of a cylindrically shaped partide that the falling speed is related to the square of the diameter but not closely to the length. Fibres more than 3 pm in diameter mostly fall and imj ren this pen alv font tie ` are tic ar at siA* ar al nr at. th J* ar hi i re. fri ki Pr. Tr.. am me. cro Trt mes pre. vaa. avc- and * and less eft). OO TI. -4>en dfari: cle rk cfnay i (jpacror cfinalogi cjybestc _eonjunc cardno matter CAR In ini lungs w. ed to ch of S6 m{ TKI SaiTISH JOURNAL OP CLINICAL PRACTICE 91 impact in the upper respiratory net and an removed with the sputum. Fibres thinner than this, though they may be lonfer, can penetrate to the respiratory bronchioles and alveoli where they will be retained. Fibres longer than 200 pm tend to be thick and set* de out quickly and an not inhaled. In Fig. 1 are shown the different sizes and shapes of the asbestos fibres. Chrysolite ana the amphibole fibres will exhibit different aerodynamic behaviour if they an long but similar behaviour if they are snort. Anthophyllite has the largest diameter of aQ and; therefore, less of it will penetrate into the alveoli and pleura; because of its size it can* not enter into the cells (except phagocytes) and produce mesothelioma. Crocidolite has the smallest diameter and has more chance of penetrating the alveoli and pleura than the amphiboles. Chrysotile has a small diameter but it is curly and, therefore, much less will reach the alveoli than would be anticipated from its diameter. In South Africa the North Western Cape Province produces crocidolite and the Transvaal produces both crocidolite and amosite. The paradox is that in the NW Cape more than 100 mesotheliomas due to crocidolite have been seen, whereas in the Transvaal only one possible case of mesothelioma was shown in the 10 years preceeding 1969 (Wagner era/, 1971). Trans* vaai fibres, both crocidolite and amosite, are on average 27 times the volume of Cape fibres and therefore have a higher fibre settling rate and shorter time available for inhalation and less efficient penetration into the deeper parts of the bronchial tree. The modes of action of asbestos as a chemical carcinogen have been analysed by Harington (1973), who considered two possi ble mechanisms: 1) asbestos in the pure state may act as a carcinogen, possibly as a macromolecular iron or metal complex in an analogous way to iron-dextran; and 2) asbestos fibres In the impure state may act in conjunction with trace metals known to be carcinogenic, with oils and other organic matter or with a combination of both. CARCINOGENICITY STUDIES IN ANIMALS In inhalation experiments carcinoma of the lungs was observed in rats repeatedly expos ed to chrysotile dust at a mean concentration of 86 mg/m1 for 30 hours per week (Gross el aA 1967). Within 16 months 20 out of 72 rats developed adenocarcinoma and 4 squamous cell carcinoma, while no tumours occurred in 39 controls. In another experiment (Wagner, 1972), 4IS rate were exposed to aO types or asbestos dust at different lengths of exposure, 233 rats for 7 hours for only one day and 182 rats for 5 hours a day for 90 days, at a con centration of 12 mg/ra1. At the end of the 90day period of exposure, the amount of dust fas the lungs of the animals exposed to chrysolite was approximately one-sixth of that found in the animals exposed to amphibole samples. One squamous carcinoma of the lung was seen in the long exposure to croddolite group and mesotheliomas were observed in three 'rats, one in the group with long exposure to crocidolite and two in the shorter period group, one with amosite and one with croddolite. Intratracheal injection in rats (Pyter and Shabad, 1973) has shown that chrysolite promotes the carcinogenicity of benz (a) pyrene. Intrapleural administration of asbestos in rats (Wagner and Berry, 1973) has produc ed mesotheliomas in varying numbers: crocidolite 61%, amosite 36%, anthophyllite 34%, Canadian chrysotile 30% and Rhode sian chrysotile 19%. The authors concluded that it seemed unlikely that the presence of oils and waxes played a significant part in the development of mesothelioma. Intraperitoneal injection of crocidolite and chrysotile (Reeves tt al, 1971) can produce mesothelioma white injection of amosite failed to do so. Mesothelioma in pleura and peritoneum has also been produced by other workers in rats and rabbits (Gross tt al, 1967) and hamsters (Smith el al, 1963) MEDICAL MANIFESTATIONS OF ASBESTOS DISEASES Exposure to asbestos dust can produce pulmonary fibrosis, bronchial carcinoma, mesothelioma and pleural plaques. Laryngeal carcinomas have also been reported (Newhouse and Berry, 1973) and benign pleural effusions (Gaenslcr and Kaplan, 1971). PULMONARY FIBROSIS (ASBESTOSIS) The frequency with which asbestosis oc curs in the exposed population depends on the length and degree of exposure and probably on the size and type of fibre. The n THI 1R1TISH JOURNAL Of CLINICAL PRACTICI CROCIDOLITE AMOSITE 10pm Fig. 1. Electron micrograph* of crocidofft*. amoaita. enthophyllt* and chrysotile at th* tarn* magnification lx 1,7000). Charactaristic feature* are the curved flexible chryaotila fibre* in eontraat to the rectilinear shape of tha amphibol* fibres and the small ala* of the diameter of the crocidoUt* fibres. (Courtesy of (ARC and V. Timbrell.) t i I -1 C/ cn 09 cn co haze reco 20th ptibr that (Met reco pre\ tithe eflec torie etch In take occu I97C grea (fenauto Unit are c dust: of a num large A e;tswu of th gene remc evide stage arres at dc from repo, S7 . CLI Th henc diagi tion, finge bing assot occu muct spun and tighti occa vane (redu the f * V' 7 THE ERITISH JOURNAL OF CLINICAL PRACTICE 1 htzards due to exposure to tsbestos were first recognised in Europe at the beginning of the 20th Century. The first recorded case of pulmonary asbestosis in Great Britain was that reported by Murray (1907) and in 1930 (Merewether and Price) asbestosis was recognised as an industrial disease and preventive measures were taken. But although improvements in dust control were effective in most of the asbestos textile fac tories, the new cases of asbestosis reported each year are steadily increasing (Gilson, 1966). On the other hand, in a study under taken in New York City in a nonoccupational setting (SelikofT and Hammond, 1970), the authors failed to demonstrate a greater frequency of the finding of asbestos (ferruginous) bodies in the lungs of routine autopsies between 1934 and 1967. In the United States approximately 40,000 workers are exposed to asbestos in the insulation in dustry and about 30,000 in the manufacture of asbestos products (Seaton, 1973). The numbers exposed to demolition work are large but unknown. Asbestosis can occur after quite short ex posure but in recent years the average length between exposure and development of signs of the disease has been 10 years or longer. In general the disease is progressive even after removal from contact, but there is some evidence that if exposure ceases at an early stage progression may be slow or even arrested (Newhouse, 1967). The average age at death from asbestosis has gradually risen, from around 30 at the time of the original report of the disease to 41 in the 1930s and 37 in 1963 (Gilson, 1963). In general both the symptoms and physical signs of asbestosis are those of a diffuse in terstitial fibrosis and have no pathognomonic features. Asbestosis may be associated with an in creased incidence of abdominal tumours, par ticularly ovarian neoplasms (Real, 1960X peritoneal tumours (Br med J, 1964), gas trointestinal tumours (SelikofT et at, 1964) and with bronchial carcinoma (Dull, 1933). Some of the ovarian carcinomas were subse quently shown to be peritoneal mesotheliomas (Hourihane, 1964). The accepted evidence is that the broncmal car cinoma occurs in cases of definite asbestosis and that excessive exposure to all major types of asbestos used commercially are implicated (Wagner, 1975). RADIOLOGY The early changes appear mainly at both bases and spread upwards into the middle and upper zones (Fig 2). Accentuation of the normal vessel markings and a horizontal linear pattern resembling Kerley-B lines might appear (Fletcher and Edge, 1970). A . "honeycomb" appearance may be seen in ad vanced stages or the disease. The area of both lung fields decreases due to contraction of the lungs and elevation of the diaphragm. Rheumatoid Caplan's nodules in asbestosis CLINICAL FEATURES OF ASBESTOSIS The onset of the disease is gradual and hence difficult to define. The main criteria for diagnosis include cough, dyspnoea on exer tion, basal crepitations and clubbing of fingers and toes. Rapid development of club bing may herald the development of an associated bronchial carcinoma. Cyanosis occurs in advanced stages. The sputum is mucoid. Asbestos or ferruginous bodies in the sputum indicate exposure to asbestos dust and not necessarily asbestosis. Chest tightness, inability to breathe in deeply and, occasionally, to yawn are common in ad vanced disease, due to increased stiffness (reduced compliance) of the lungs caused by the fibrosis (Parkes, 1973). Fig. 2. Chest radiograph of a patient with asbestosis. There is evidence of pleurisy at the left base, plaques and irregular opacities spreading upwards. r ST0005654 I 07056 *4 THI SSITISH JOURNAL OF CLINICAL PRACTICI have been reported (Richards and Barrett, 1958; Tellesson, 1961; Morgan, 1964; Matt son, 1971). Pleural plaques, calcified or noncalcified, may be present but are evidence only of asbestos exposure (Meurman, 1968). The 1LO U/C International Classification of Radiographs of Pneumoconiosis (1971) provides a means of systematically recording the radiographic changes in the chest provok ed by the inhalation of various dusts in cluding ssbestos and takes into consideration the different sizes, shapes, profusion of opacities and the number of zones affected. PHYSIOLOGY In the diagnosis of asbestosis lung function tests are of particular value as the radiological findings are not specific. Characteristic functional abnormalities in clude progressive reduction in vital capacity and total Tung capacity and reduction ut dif fusing capacity for carbon monoxide. In creased static recoil pressure and a decrease in lung compliance are usually found. Exer cise tests show hyperventilation and arterial desaturation. Airways obstruction was not considered a feature of asbestosis (Williams and Hugh Jones, 1960; Thomson ei al, 1965), though recent reports (FournierMassey tt al. 1971; Muldoon and Warwick, 1972; Becklake, 1973) express the view that an obstructive function profile is not uncom mon in the presence of asbestosis. A short clinical description and comments on lung function tests on a patient with asbestosis (the patient in Fig. 2) as a typical example are given below:- A 32-year-old insulation engineer presented with in creasing breathlessness on exertion and symptoms of chronic bronchitis with frequent chest illnesses during the winters of the preceeang six years. Because or these he had spontaneously reduced his ciiarettss from 20 to 10 per day and avoided industrial fumes where possible: On examination he was short of breath, exhibited clubbing of the Angers, and bilateral wheeze and crepitations at the bases were present The bronchogram was normal. Lung function tests were:- Commeat] The low FEV, and increased residual volume are evidence of airways obstruction which is the main cause for the patient s breathlessness, which in turn is aigrivattd by exercise hyperventilation. The low transfer factor and increased alveoio-tncrial oxygen tension during exercise indicate impaired pulmonary gas transfer which, in the absence of textures of emphysema, is due to interstitial fibrosis, the high resting FCO, end physiological dead space suggest that the disturbance to gas exchange aggravated by hypoventilation which may bt a con sequence of the airways obstruction. Observed Expected Forced Expiratory Volume (t) 0 9 3-1 Forced Vital Capacity 111 22 41 FEV, X 100 - FVC% 41 72 Total Lung Capacity (11 6-2 6 2 Residual Volume 39 20 RVX 100-TLCK 63 36 Transfer factor (ml/mln/torr) 11 27 Exercise ventilation air/0, (1/min) (Y29 23 Arterial blood Pea, rental (torn 71/70 90 Arterial blood Pto, 49/39 40 A - *00. rental Itorri 19/35 20 VdXIOO'VtresVex 67/S 5 35/29 These tests art sometimes difficult to interpret when applied to individuals with early disease because of the wide range of predicted normal values and the smok ing habits and the polluted atmospheres where most asbestos workers live. Nevertheless, sequential studies, even using the simple ventilatory parameters of FEV and FVC at yearly intervals, will reveal deviation from normal and add precision to the diagnosis (EJmea, PATHOLOGY AND IMMUNOLOGY The distribution of the fibrosis in cases of asbestosis is predominantly in the lower part of the lungs, which is helpful in the differen tial diagnosis; in sarcoidosis, tuberculosis and allergic alveolitis it is predominantly in the upper zones end in fibrosing alveolitis it is more generalised. In mixed cases of asbestosis and silicosis, fibrosis may occur in the upper zones. Associated pleural thicken ing may help in the differentiation. Microscopically in the early cases the lesions are confined to the respiratory bronchioles of scattered acini. Their walls are thickened by an increase in reticulin fibres. Asbestos bodies and fibres can be seen in the bronchioles and lumina (Fig. 3) lying free and ingested by phagocytes which may be multinucleate. Asbestos bodies consist of asbestos fibres which have been coated by iron and protein. Demonstration of asbestos bodies in die sputum will provide confirmation of previous exposure. In experimental animals and probably in man they are found within a few weeks of exposure. In the established cases they are extraordinarily persistent and may be found 20 years or longer after exposure has ceased (Hinson, 1965). A whole-lung sec tion with marked asbestosis is shown in Figure 4. ' ST000565S i DOW 07057 the iritisr journal of clinical fractici M studies would probably show asbestos bodies t aggregated in areas of fibrosis. Lung biopsy is rarely indicated in the diagnosis of asbestosis (Scon and Hunt, 1975). Non-organ-specific autoantibodies, especially antinuclear autoan tibodies, are found with increased frequency in asbestos workers and this appears to be related to the development of asbestosis and not to exposure to asbestos dust alone (Warwick. 1973). Fig. 3. Electron micrograph (x 3.000) showing asbestos (ferruginous) bodies and fibres in lung tissue. (Courtesy of V. TimbrtUJ Fig. 4. Whole lung section with merited asbestosia. In the late stages of asbestosis the fibrosis spreads out into distal alveoli and eventually a widespread fibrosis occurs more marked at the bases with dilation of the uninvolved small airways (Webster, 1970). Histological CARCINOMA OP THE LUNGS Carcinoma of the lungs was first reported in cases of asbestosis in 1935 (Lyncn and Smith). The incidence of this tumour has in creased rapidly and by 1964 60% of those workers in the United Kingdom diagnosed as having asbestosis to a degree wananting compensation developed carcinoma (Wagner, 1975). The excess of lung cancer varied con siderably between surveys. In some of the surveys the workers were exposed to a mix ture of fibres (Elmes and Simpson, 197IX or to chrysotile (Manusco and El-Attar, 1967) or amosite (Selikoff et o4 1972). The in cidence of bronchial carcinoma was relatively low in a population of chrysotile miners in Quebec (McDonald et al, 1971) and particu larly high among insulation workers exposed to amosite (SelikofT et al, 1972) The fact that cigarette smoking and asbestosis have a multiplicative carcinogenic effect has been es tablished (Berry et at, 1972). The increased risk of developing carcinoma of the lungs appears to be related to the dose of asbestos dust inhaled (Newhouse, 1961). The com monest type of lung cancer appears to be adenocarcinoma (WhitweO et at, 1974) The primary site of origin of carcinoma in asbestosis was investigated in the United States of America (Issclbacher et al, 1953) and it was shown that about four-fifths arose in the lower lobes, whereas in the normal population more than 50% arise in the upper lobes. Some authors (Selikoff et al, 1964; Manusco and Coulter, 1965) suggested that an excess mortality from bronchial carcinoma may occur in workers exposed to asbestos who do not have clinical ly detectable asbestosis. MESOTHELIOMA OF THE PLEURA AND PERITONEUM The relationship between malignant mesothelioma and exposure to asbestos was first suggested by Wagner and his colleagues rST0005656 DOW 07058 H TMK BRITISH JOURNAL OP CLINICAL PRACTICI (Wtgner et al, I960), who reported 33 cues from workers exposed to North West Ctpe of South Africs' crocidolite asbestos. Mesothelioma wu not found in the chrysotite or amosite mining areu of South Africa nor in the crocidolite area adjacent to the amosite deposits. An interesting finding wu the long latent period, a mean of approximately 40 years between initial exposure and subse quent development of the tumour. The development of the malignancy wu not related to the amount of asbestos dust inhal ed. Since then reports from various countries have described several mesotheliomu in rela tion to ubestos exposure (SelikoflT et al, 1965; Elmes et al, 1963; Thompson, 1970; Dels et al, 1971). Malignant mesotheliomu in childhood have also been reported*, (Kauff man and Stout, 1964; Lieben and Pistawka, 1967; McDonald et al, 1970; Whitwell and RawclifTe. 1971). In a review of 42,597 death certificates for children who died of cancer in the United States between 1960 and 1968,31 had a diagnosis of mesothelioma and, of these. 13 were confirmed by data from hospital records. The illness presented with acute pleural effusion and encasement of the lung by tumour, with survival usually of less than six months (Grundy and Hiller, 1972). The case histories gave no information on en vironmental exposures. Some of the patients may give a history of continuous exposure to asbestos over many years though a significant proportion gave a history of only transient exposure sometimes amounting to a few weeks only, several years previously. In a small proportion there is no history of exposure to ubestos dust Unlike carcinoma there is no correlation between cigarette smoking and mesothelioma of the pleura and peritoneum. Mesothelioma is not associated with exposure to anthophyllite asbestos mined in Finland. Clinical Features In the majority of cases of pleural mesothelioma the patients appear in good general health when first seen at the hospital (Elmes and Simpson, 1976). Their usual presenting complaints are of chut pain and dyspnoea. Cough and haemoptysis ve oc casionally present The pain may be localis ed or of a diffused generalised or pleuritic type. The shortnus of breath is progressive and is related to lung compression and restriction of the chest wall by the tumour itself and usociated pleural effusion and atelectasis. When the pleural effusion is small the fluid is usually non-haemorrhagic; however, during the course of the illneu the patients develop at some time a haemorrhagic effusion, thickenina first of the parietal and then of the visceral pleura, gross clubbing of fingers and toes, a raised sedimentation rate and a polymorph leukocytosis (Elmes, 1973). At the late stages the pleura becomes thicken ed, adherent and contracted. The contraction leads to a kyphosis towards the affected side, with a drooping shoulder and overlapping of the ribs (Stumphius, 1971). Clinical evidence of metastasis to other organs is rarely pre sent, though local spread may occur to in volve lymph nodes, ribs, mediastinum and pericardium with resulting enlarged supraclavicular lymph nodes, rib tumours or rib fractures, superior vena caval obstruction and cardiac tamponade. Local spread may lead to pleural effusion on the opposite side. Attempts to aspirate the effusion result in rapid re-accumulation and occasionally in subcutaneous lumps. Extension through the diaphragm is often followed by free spread throughout the peritoneal cavity with ascites and at autopsy it may be difficult to define which was the primary site. Hypertrophic pulmonary osteoarthropathy is not en countered frequently. Paraplegia may develop due to the impairment of the blood supply to the spinal cord. Peritoneal tumours are more likely to oc cur in men with heavy exposure (Elmes and Simpson. 1976). A full but not distended ab domen with equivocal signs of ascites are commonly seen. Diffuse abdominal pain. Ion of weight and symptoms of intestinal obstruc tion may occur. There is no clinical characteristic which distinguishes mesothelioma from other tumours with dif fuse peritoneal spread, except evidence of past exposure to asbestos (Elmes, 1973). Symptoms and signs of a co-existent asbestosis may be detected. The average sur vival period in pleural or peritoneal tumour does not usually exceed the one year. Radiology Pleural mesothelioma presents as a pleural effusion or an irregular pleural thickening or more usually with a combination of both, where the irregular pleural thickening may be seen above the fluid level. The diaphragm may be raised and some shift of the F ffe i me us at. sic *P P* CO t --I I CD cn i. o> i * <-n \ n* DOW 07059 v d .* h.5 r a 8,8'B' Sl**? $ <LzL^ ? 3 8,1*8 >*S a,iL'K '*rij' 68. also spread through the diaphragm to both pleural cavities. Hydropneumothorax may occur either spontaneously or as a result of aspiration (Fig. 6). Pleural calcification may by visible, as may the pulmonary lesions or asbestosis. Pathology Macroscopically the mesothelioma appears as a thick grey or white mass encasing the lung (Fig. 7). The tumour may vary in size from a very small mass to one that may oc cupy the entire hemithorax. The small ones tend to project freely into the pleural cavity, whereas many of the large ones develop adhesions to neighbouring tissue. There may be foci of degeneration, necrosis, haemorrage or calcification (Shabannah and Sayegn, 1971). Fig. 5. Malignant mssothslioms of the lung in a patiant axpoaad to asbaatoa dust mediastinal structure to the affected side usually occurs, suggesting the existence of an atelectasis (Fig. S). In the early stages the le sion is unilateral but in the late stages it may spread across the mediastinum to the op posite side. A peritoneal mesothelioma may 8S9SG001Si 5 7 SP2.V.U f ? 8 3 Fig. 7. Section of lung showing mesothelioma. (Courtesy of J. C Wagner.) Fig. . Hydropneumothorax In a caaa of pleural maaothalioma. Mesothelial tumours are characteristically pleomorphic in that they appear to be derived from both epithelial and connective tissue cells. Because of the resemblance of the histological appearances of malignant mesothelioma to the other malignant types it is very difficult to diagnose it with certainty by biopsy and to distinguish it from adenocarcinoma or fibrosarcoma. The presence of different elements in the tumour is strongly in favour of a diagnosis of y a ffle . N THB BRITISH JOURNAL Of CLINICAL fRACTICI mesothelioma (Parkes, 1973). Hyaluronic acid in the fluid may help in the diagnosis (Wagner el al. 1962), though this is not always present and it may occasionally be round in pleural effusions associated with other tumours. Tumour cells in the lung and the hilar lymph nodes may contain dust par* tides, a phenomenon rarely appearing in car cinoma ceils (McCaughey, 1979). Asbestos bodies and Abres are present in die lungs in the majority of cases. than expected incidence of bronchogenic car cinoma when plaques are present has beat reported (Fletcher, 1972). Management In an analysis of 300 cases of pleural and peritoneal mesotheliomas. Elmes (1976) concluded that conventional treatment by surgery, cytotoxic drugs and radiation is in effective at relieving symptoms and may encourage the spread of the tumour: conser vative treatment offers the best quality of life. Intrapleural administration or ribonucleic acid in cases of pleural mesothelioma with Pig. I. Chest radiograph with bilateral extensive good results has been reported (Forbes and pleural plaquaa in a patient exposed to asbestos ( Mackaness, 1963). PLEURAL PLAQUES duet DISCUSSION , Pleural plaques associated with asbestos Asbestos exposure is now widespread and exposure are found predominantly on the asbestos fibres have been found in the lungs parietal and diaphragmatic pleura. They are of people without industrial asbestos ex bilateral, most prominent in the lower halves of the pleurae, well circumscribed, irregular in shape, distributed beneath the surface of the posure (Um Chang, 1971). Evidence of haematogenous spread of asbestos fibres was provided by several authors who -T oO ribs, sometimes spreading over the intercostal reported this finding of asbestos fibres in spaces (Fig. 8). They are not associated with adhesions (Meurman, 1966) and are better seen on anterior oblique views taken at 43. Asbestos fibres may be seen but not asbestos bodies. Plaque formation does not appear to occur in the peritoneum. Microscopically the the urine (Wyss. 1953) and spleen (Keal I960) and asbestos bodies in the thyroid (Keal I960) in cases of asbestos exposure, though these are chance findings without any pathological significance. There is no doubt that all the major commercial types of cn c~. cr plaques consist mainly of avascular, aceuular asbestos are able to cause carcinoma and the fibrohyaline connective tissue made up essen tially of thick bundles of collagen fibres. Calcification of the pleural plaques occurs commonly and they should be distinguished from tuberculous pleurisy, calcified production of lung carcinomas in certain animals by all types of asbestos supports this conclusion. The epidemiological evidence in man, however, shows that there are clear differences in risk with the type of fibre and haematoma, silicosis, talc pneumoconiosis nature of exposure. There a also evidence and old pneumothorax. A strong correlation that all commercial types of asbestos except exists between plaque formation and ex anthophyllite may cause mesothelioma. Toe posure to asbestos dust of all types, but an risk is greatest with croddolite, less with immediate cause-and-effect relationship has amosite and apparently less with chrysotile. not been established. A latent interval of 20 Population studies have shown that a propor years between first exposure and evidence of tion of cases of mesothelioma have no known plaque formation is usual Those environmen association with exposure to asbestos. The tally exposed from birth develop plaques at an earlier age than those occupationally ex posed, (Jones and Sheers, 1973). A higher successful management of the asbestos problem depends on the prevention of exposure of the workers to asbestos dust DOW 07061 TtU BRITISH JOURNAL OR CLINICAL NtACTiCl In the United States of America (NIOSH, 1972) and United Kingdom (DEP. 1970) have been laid down various standards for working with asbestos in industry. Measure* ment of asbestos dust concentrations in the atmosphere can be made by using the Royco Electronic Counter which has the advantage of eliminating human error in counting or by the gravimetric method using for example the Hexlet sampler or with the use of a microscope by counting the number of dust panicles or asbestos fibres deposited from a measured sample of air. So far there has been no evidence of an in* creased incidence of mesotheliomas in the general public as a result of asbestos air pollution and studies of the geographical dis tribution of cases of mesotheUoma in the United Kingdom over a 10-year period (Gilson. 1970) indicate that the new cases are nearly all from areas where there has been a recognised occupational exposure to asbestos in the past There is no evidence either that exposure of the general population to asbestos from beverages, drinking water, food or pharmaceutical preparations increase the risk of asbestos-induced diseases. Acknowledgement This review was mainly based on research work and surveys of my colleagues in the Research Pneumoconiosis Unit, J. C. Gilson, former Director of the Unit, P. C. Elmes. Director cf the Unit, J. C. Wagner and J. E. COTES. The description cf the physical properties and characteristics of asbestos fibres was based on research work cf Or V. Timbrell. I wish to thank Mrs i. Henley for her secretarial assistance and Mr R. Harris for the prims cfthe chest x-rays. REFERENCES Atkinson. A W_ Getttes. A E. Richer*. A L. <1971): Morphology of chrysolite, pmaenud at the second Intsr- nationai Conference on the Physics sad Chemistry cf Asbestos minerals. Louvain. BccXIakc. M. (1973): Lens function, lo: ttahekat effectsf Aibntes. F. Bogouski. J. C. Gilson, V. Timbrel, J. C. Wijncr. Eds. Lyon: IARC, Jl. . "--Taerfyfe*cGt o- fNnaaewswbnhewosutaosssee.eMx**p.oLwsun.reT`uetrnaomdk., M-. 1t1972): Combat* smokins on monthly from tune cancer in rectory workers. Loom. 2. 476. 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Gilson. V. TfanbmB. J. C. Wagner. Lyon: IARC. 247. Elmca. F. C. (1974): Management of mesotheSoma. Raport of Meeting. Mr J CIS Cant. 74, 47. Elmca. P. C. McCaughcy. W. T. E. Wade. O. L. (194S): DilTuse mesothelioma of the pleura and asbestos, tr med y. i. iso. Elmes. P. C- Simpson. M. J. C. (1971): Insulation workers in Belfast J. Mortality 1940-44. dry bid Med. 2S, 224. Elmca. P. C- Simpson. M. J. C. (1974): The clinical aspects of mesothelioma. Q J Med. XLV, 179, 427. Fletcher. D. E (19772): A mortality study of shipyard workers with pleural plaques, fr J fad Med. 29, 142. Fletcher. D. E- Edge. J. A (1970): The early radiological changes in pulmonary and pleural ttbr-cowv CU AaeOeL 21, 3SS. Forbes. I. J- Mackancsa. O. B. (1943): Mkoate in macrophages. Lanai. 2, 1203. Foumier-Maiiey. G. G. Becklaka. M. A. Roadtw. C. E. Gibbs. G- McDonald. J. C. (1971): Lung function patterns in relation to questionnaire, dual exposure and radiologic changes in Quebec aabeRos workers. Ficacmad at the Annual Meeting of the Canadian Thoracic Society, Toronto. Gaenster. E. A- Kaplan, A1. (1971): Asbestos pleural dfclion. Ann Intern Mad. 14, 17E Gilson. J. C. (1945): Problems end perspective*, the chang ing hazards of exposure to asbestos. Ann NY 4cod So. IJ2. 694. Gison. J. C. (1944): Wycn memorial tectum. 1943. Hcahh hazards of ubestos. Recent studies on ks biological effects. Tranunion! Societyfor Occupational ktaiktM. 14, 62. Gilson. J. C. (1970): Asbestos health hazards, meant obcer vations in the United Kingdom. In Pneumoconiosis. Free Int Conf. H. A. Shapiro. Ed Hohanncsburg. Capo Town: Oxford Univ Press. pl73. Gilson. J. C. (1973): Asbestos cancer, peat end lUtura hazards. Free nor Soc Mad. 44, 395. Gross. P,, Oe-TmidDa. A T. P- ToUer. F. 1, Kaachak. M. BabyaX. M. A (1947): Experimental tshestoaa. the development of lung esneer in rau dth pubnonanr deposits of chrysolite asbestos duet. Arab enter HUM. 11. 343. Grundy. G. W- MDIer. A W. (1972): Mafignant mesothelioma in childhood. Concur. 24, 1214. Harington. J. 1 (1973): Chemical factors (Mudteg trace demean) a* edehMical machanisma. In Haioeknt effects ef Album. f. BogouakL J. C. GOaon. V. tins, brett. J.C. Waanw. Lyon: IARC. p304. Hendry, N. W. (1963): The geology, occurrences and major uses of ubestos. Ana NYAcaiScL 113, 12. Hinson. A F. W. (1943): Cancer ofthe lungs and other dto- .tascs after exposure to asbestos dusL SrUJ DU Chest, 39, 111 PST0005660 OOU 07062 THK BRITISH JOURNAL OP CLINICAL PRACTICE ICI /torn.). c,a ______ . EpidttnMecy of ssboxoo corn Br mod Butt. It, 71. Weiner. J. C-. Monday, O. E. Herrington. J. S. (1962): Hiitochcmical dcmonunaoe of hyohmk eode ia ptcunl nwioctwtomoA J Fttk. Baa, M, 73. Weiner. J. C, Skggs. C. A, Merehend. P. (I960): Diffuse picuril mesothcfaome end eebestee txsoom in the North* wi Cmo Province. Br J tad Mad, 17, 2C0. Wtmck. T7 M. (1973); Immunology end eebeetoeie. la Sio/ofire/ Ifftcu tfAibauot. P. Bofoutki. J. C. Gilson, V. Timbres oad J. C. Wegmr. Lyon: IARC, 131. WtORcr. 111970): The pothOfCMao of esbeetoeia. la H. A. Shapiro. Pneumoconiosis, frocssdfngs qf a Intor- national Conference, /olaaaobary. Capo Tow (MM Univ Proot, p92. WhitotU, F, Newhouee. M. U Bennett. D. R. (1974): A study of tbo histologicel ooO types of loaf nnem ip workon suffering from isbettoeh ta tbo Uaaod Yingdnm. Br J ind MtdTii in ^_ WhitwdL P, Reudtt. R. M. (1971): Diflfam iMlmoia pbo- rsl mesothefiome oad oobootoo onooon. Thorn* Id, A WiOiofno. IL, Huah-Jonaa, P. (I960): Tbo fri/Wonci of tuna functiea chongae ia isbestows. Thorax. IS, 109. Wyio, V. (1933): Pwoonia A i|l> A aatioato aoSc wine A o|troi topoM A riscbio tebwrorirn Mau Modtndtm. U, Contributions to this Journal Clinical articles, reports of clinical trials and contributions to the Skin Clinic and Spot Diagnosis are welcomed by the Editors. When accepted, this is on the understanding dial they are not submitted to another journal. 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