Document p2M3yyzkRQGrgkNK0aGG5OQ4B

JAN-11-20Q1 THU 05:02 PN Scand J Work Environ Health 1997,23:93--103 Fax NO. P. \r .1 Asbestos, asbestosis, pleural plaques and lung cancer by Gunnar Hillerdat, MD,1 Douglas W Henderson, MRC Path2 KHierdal S, Handeraon QW, Asbestos, asbestosis, pleural plaques and lung cancer. Scand J Work Environ Health 1S97.23I2):9S--103. Inhalation of asbestos fibers increases the risk of bronchial carcinoma. It Etas been claimed that asbestosis is a necessary prerequisite for the malignancy, but epidemiologic sorties usually do not have enough statistical strength to prove that asbestos-exposed patients without asbestosis are without risk. Several recent studies do actually indicate that there is a risk for such patients. In addition, case-referem studies of'patients with lung cancer show an attribu tab) e risk for asbestos of 6% to 23%, which is muds higher than the actual occurrence of asbestosis among these patients. Thus there is an Increasing body of evidence that, at low exposure levels, asbestos produce* a slight increase in the relative risk of lung cancer even in the absence of asbestosis. Consequently, all exposure to asbestos must be minimized, Kpy farms asbestos, lung cancer, lung fibrosis, pleural plaques. The main cause of lung cancer is smoking. However, brosis is an obligatory precursor to asbestos-related lung inhalation of asbestos fibers can increase the risk for this cancer or not. tumor considerably. The first reports of lung cancer in The purpose of this review is to examine some Of the connection with exposure to asbestos all concerned pa statements made by the two factions and the findings -- tients with asbestosis fie, pulmonary fibrosis caused by often statistically weak -- that tie behind these claims. asbestos) (1--4). The German physician Nordmann was, Pirn, some basic facts must be remembered. _ in 1938, one of the first to suggest that lung cancer in asbestosis was an occupational disease, and he assumed that the tumor resulted from the proliferating alveolar and epithelial cells in the fibrotic lung (2). Thus, from Latency time the outset, it was assumed that the cancer was caused by tie fibrosis, not the asbestos fiber in itself ("the asbesto- The risk of carcinoma fir very low or undeteetably low sa-omcer hypothesis'*). In 1943 the German government for the first 10 years after exposure to asbestos, but it declared lung cancer associated with asbestosis to be an gradually increases and is highest after more than 30 occupational disease. It took another 20 years to reach years(17,34,4l-~43). According to some studies, expo the same conclusion in the United States (5). sure to low doses will not only produce fewer cancers, Over the years, many researchers have remained in favor of "the asbesrosis-cancer hypothesis" (6--13). but also possibly longer latency times than high doses (44). Consequently, long-time follow-up is necessary, or Gradually, however, several papers have appeared which a number of cancers can be missed and risk evaluation have shown that an increased risk for lung cancer occurs also in asbestos workers without obvious asbestosis. This will be flawed (3b). finding has led to the proposition that it is the asbestos fibers, not the asbestosis, that are responsible for the jtnor ("the asbestos-cancer hypothesis"). As a conse- Type of asbestos 9tience, a linear dose-response relationship was assumed l I The main types of asbestos are those consisting of ^mween asbestos and lung cancer (14--40). However, ho consensus has yet been reached on whether lung fi f straight fibers (amphihoies), of which the most important , Department of Lung Medicine, Karolinska Hospital, Stockholm, Sweden. * Department ofHissopathoiogy, Flinders Medical Centre, Bedford Pair., Adelaide, South Australia, *pnm requests to; Dr Gunnar Hillcrdal, Department of Lung Medicine Karolinska Hospital, S-17176 Stockholm, Sweden. V 93 JAN*11-2001 THU 05i02 PH FAX NO. I .Vi** Asbestos, asbestosis. pleural plaques and lung censer are crociddiie, amosite, tremoiite and anthophyllite, and those with curly fibers, of which there is only one impor tant type, namely, chrysolite. These fibers all differ in their diameters and lengths and also in their ability to resist breakdown in biological tissues. Chrysotiie is by far the most widely used. It also has die fastest clearance from (he body, probably due to its higher solubility. As a consequence. In workers' lungs at autopsy, when the exposure occurred some decades earlier, the most com monly found fibers are amphiboies, even if the exposure had been predominantly chrysotiie asbestos. Possibly for this reason, amphiboies seem to carry a greater risk for mesothelioma than does chrysotiie (7,27, 45), As for lung cancer, however, a recent review has concluded that there is little evidence to Indicate lower lung cancer risk (46). To confuse matters even more, there are differences between diameters and lengths of the same type of asbestos, the result being different risks for die various diseases. For example, very long chrys olite. as was used in the textile industry, results in a considerably higher risk for cancer than does the "nor mal" short-fibered chrysolite (27). The "threshold value" The existence of a threshold value below which no ex cess lung cancer occurs has been suggested (9,11). On the other ha^d, there are claims that even low doses of asbestos ctin increase the risk (20, 30, 31, 34, 44, 47--31), la several studies, it has been shown that expo sure to a low dose of pure' chrysolite (less than 20 fiber- years) causes no measurable increase in lung cancer (25, 52--55). . . However, it should be remembered that the effects of exposure to low doses of carcinogens are very difficult to measure and even more problematic to prove statistical ly, because very large cohorts are needed (40,56,57), Failure to prove statistically an excess of any disease with a low risk does not prove that such an excess does not exist, epidemiologic studies are simply not sensitive enough (58). This basic epidemiologic truth is too often forgotten. Ofcourse, if one subscribes to "the asbestosis-cancer hypothesis", a threshold is automatically implicated (since a fairly high exposure is necessary for asbestosis to develop)! on the other hand, "the asbestos-cancer hy pothesis" is compatible both with a threshold and with out a threshold. .. Smoking habits Smoking and exposure to asbestos have synergistic ef fects on lung cancer risk, It seems that a multiplicative 94 Scand J Work Environ Health 1997. voi S3. no 2 yJMT model fits the data best (21, 31, 34,43,59,60). ConigJ) quefltly, correctioivfor smoking habits must be made ; all comparisons concerning risks of lung cancer, Howev- s er, in the real world, the differences in smoking habju f' between various occupational groups iri the same society ; are not very great, and a relative risk in excess of 1.4 a unlikely to be due to such differences (61). .. ;.- Increased risk of lung cancer in ether types of lung fibrosis in man Proponents of "the asbestosis-cancer hypothesis" have drawn attention to the fact that other types of fibrosis in humans (eg, idiopathic, other pneumoconioses, and those that occur in collagen diseases) also have an Increased incidence of lung cancer. In fact, it is mainly in systemic sclerosis (62) and cryptogenic fibrosing alveolitis (63, 64) that any larger number of lung cancers are found. The risk of lung cancer in silicosis is also moderately increased (relative redo 3.4 for smokers with silicosis and 1,7 for nonsmokers) {65--67), Whether this in creased risk is due to the silicosis or to the silica particle itself is another problem. The typical cancers in systemic sclerosis are periph eral adenocarcinomas or bronchioalveoiar cell carcino mas (62), but those in idiopathic fibrosis are similar to the bronchial carcinomas found to smokers {63,64,68). Of special interest is the review by MmtshJaa & Kobayashi (68). They collected J54 patients with lung cancer In idiopathic pulmonary fibrosis from the literature. They found that the following factors were typical for these cancers; there was a predominance among men, almost all occurred in smokers, the tumors were of the same type as among patients Without pulmonary fibrosis (ex cept for a higher incidence of small-ceD carcinoma), and the tumors were peripheral and mainly situated in die lower lobes. Ini other words, die tumors were similar to those reported for patients with asbestosis. It should be remembered, however, that "idiopathic" fibrosis is more than twice as common in perrons with some type of occupational exposure to solvents or parti cles (69). At least some of the substances which presum ably caused the fibrosis might in themselves be carcino genic also. Indeed, asbestosis can be difficult to differen tiate histologically from "idiopathic" interstitial fibrosis (apart from the presence of asbestos bodies) unless the exposure history is known. In lungs with interstitial fibrosis, squamous-cell meta plasia and atypical cell proliferation can be seen far into the small bronchi (63,70). Thus there are data indicating that the risk of lung cancer is increased in at least some types of diffuse fibrosis other than that causad by asbes tos, and thus there is a plausible pathological mechanism JAM-11-2001 THU 05-03 PM . ... FAX NO, Hillerdal & Henderson to support this conclusion. These observations can be interpreted as supportive of the "asbestosis-cancer hy pothesis". Correlation batwaen fibrosis and lung cancer In animal studies In asbestos-exposed rats, the incidence of malignant tu mors is related to die degree of fibrosis. However, as has been pointed out, the lung cancers in rats are histologi cally different from those in humans. The only conclu sion one can draw from animal experiments is that both the ftbrogeme and the carcinogenic effects are doserelated, Mutagenicity of asbestos Though the opposite has been claimed, asbestos is in fact a complete carcinogen <59,71, 72). This is evident for humans from the occurrence of mesotheliomas, for which asbestos seems to be the single causative agent. Epidemiologic studies in humans and excess lung earner in asbestos exposure with and without asbestesls Them ts no doubt that patients with clinical and radiolog ical asbestosis have a high risk of dying from lung cancer (table 1). At the highest exposure levels such as occurred in the early years of the industry, there may have been a lower cancer risk because the patients died from asbes tosis before there was enough time to develop cancer (41,82). Several reports have indicated that the incidence of lung cancer is increased also for asbestos-exposed work ers who lack radiological evidence of asbestosis. Some of these reports are listed in table 2. Radiological diagnosis ofasbestosis The radiological diagnosis of asbestosis is not easy. The system developed by the International Labour Organisa tion (ELG) for evaluating pneumoconiosis, which has a 12-grade scale for parenchymal opacities, is used. As a Stmeral consensus, according to ihe ILO system, a de ft* of I/O m a worker exposed to asbestos is accepted as manifest asbestosis, while 0/3 is not. Unfortunately, the agreement between readers (or even the same reader at 2 different times) at this level is often not very good. The specificity and the sensitivity when compared with autopsy findings is also poor, and false negative and false positive results are very common (87--89), A con founding factor is smoking, which can cause a signifi cantly higher incidence of small irregular opacities in chest roentgenograms (90, 91). Since smoking is the main cause of lung cancer, there can be bias in (hat the risk for patients with radiological "asbestosis" might he overestimated, - Dose-response for asbestosis Even if the correlation between exposure to asbestos and the occurrence of asbestosis is generally good, the lungs of some patients may be heavily burdened by asbestos without developing asbestosis (92). Correlation between lung cancer and asbestosis according to autopsy findings In many studies, the exposure to asbestos has been so large Am most workers have some degree of asbestosis at autopsy. As proof of the "asbestosis-cancer hypothe sis" some studies have been cited in which all patients with lung cancer also had asbestosis to some degree at autopsy. For instance, Kipen et ai (1987) published 138 cases of lung cancer among asbestos insulation Workers who all had asbestosis at autopsy; 18% of the asbestosis cases were not diagnosed from X-ray appearances (87), in 1989 Sluis-Crenter reported autopsy findings from 339 amphibole asbestos miners (both crocidolite and amosite). Lung cancer correlated with heavy smoking, age, and asbestosis. The standardized mortality ratio for lung cancer did not show any excess for 302 exposed men without asbestosis, hut It became progressively high er for those with asbestosis (93). The authors concluded that, in Ae absence ofasbestosis at necropsy, a bronchial carcinoma in a man exposed to asbestos is unlikely to be due to asbestos. Since this study is one of the mast cited in support of the "asbestosis-cancer hypothesis", it has to be realized that the study has some flaws. It is not an epidemiologic study. It was retrospective and based on the reports of different pathologists. We know nothing of the selection since only a portion of the workers came to Table 1. Lung cancer in patients with asbestosis. (SMR - stan dardized mortality ratio, PS - risk ratio) Author N Lung cancer 06* Ex- SMR per earn served peeled or HR at deaths Coats st al, 1987(73) 1SS 39 7.1 Berry, 1981 (74) 283 33 Hutskonea. 1378 (75) McMillan St *1,1978(76) 202 32 31.2 - 9.0 Buchanan. 1965 (77) 285 30.9 Slgls-Crsmer, *3911781 Hughes & Writ, 1991 (12) 37 77 43 5.2 a.3 9 2.1 4.3 Wilkinson 8 af, 1985(75) Hlllsrdal. 1954 (SO) 211 166 2.3 9 3.9 2.3 Scand J Work Smiron Haalth 1997, vat 23. no 2 95 Asbestos, asbastosis, pieurai plaques and lung cancer Tail* t. Relative risk ot lung cancer lrt asbestos-exposed cohorts without asbestosis (observad/expected values). (N * number of work- ars, 0 * observed number of cases, * expected number ot cases, Rfi a risk ratio) 1V Author Cohort No asbestosis Plaques only N O 6 RR N0 2 SS ` Siuls-Cremar, 1991 r?s> Ease. 1976 132) Fleteher, 1972 183) Loomis U, 1989 m SMs-Cremer. 199t (79) USetle McDonald, 1960 W flwfitti994 (80) SandiniJSmholm, 1997 (35) Hush 4 Yfeill.1991 \m wottefs loomfctal,19&8 W Amphibolr miners Snipyard workers Shipyard workers Normal population Normal population Ciwywtlle miners IN = 4559) Plaque earners Shipyard workers Asbestos cement PUque carmre 494 7 5.61 1.2 739 1,56' r, ,, 1095 8 4.3 ,, 10 8.1 1.2 '* v. 302 11 12,4 ,, 235 13 5,4--* 2.4 408 18 59 - 8.7*** 24 3,0 288* 3.7* 190' 2.8* 1430 41 25.2* 1.4 926 3 2,8 62 2 1.5 1.3 83* 11 3.3 3,3 * Unsaidfled. talcuieisd from article and miqftr contain some with asbestos** (not dear from article), * Calcifies, calculated from antcfe and might contain soma wire asbestosis (not clear from article), 4 Only workers with i 20 years of latency from ttr exposure, * Istlmxted value Item text 4 A few ot these patients pwbaWr tad wtosris, n eieat fro* t*xt ' P 9,05; *' p < Ml;' * P < 0.005;"** P < MtH. autopsy, and there was also bias, because the patholo gists know/it an early stage whether the patient had catKerornotl . . ......... . However, most autopsy findings do support the `'as- hcstosts-cancer" theory. There are exceptions however, For instance, there is 1 study in which more than half the patients exposed to asbestos had lung cancer hut bo as bestosis at autopsy (88). , ;i- v Correlation between lung cancer and asbestosis according to radiological findings ' Some epidemiologic studies have been made concerning radiological findings and subsequent development of lung cancer. The study of Hughes & Weill (12) is of special interest since it has been cited by many reviewers ami by die authors themselves as support for the "asbestssis-cancer hypothesis" and "proof that cancer is no mofe common than expected in asbestos-exposed per sons without asbestosis. As seen from table 2, she rela tive risk for lung cancer in men without asbestosis in this group is in fact 1.2 (ie, a 20% increase), and. though this is of course not statistically significant, it is statistical speciousness to claim that a lack of excess tumors has been proved in this study. In addition, the authors col lected data from 2 factories. In 1 of the 2 crocjdollte was used to some extent, and this factor was the only I ofthe 2 factories in which there was an excess of lung cancer @6 Scant! J Work Environ Haaitb 1697, vol 23, no 2 (94). Thus crocidoJite seems to be the main risk factor rather than the occurrence of asbestosis. - Some studies on asbestos-related' Sung cancer have, also been published in which some of the patterns did not have any fibrosis (76,95--97). Thus, io many instances, the risk of asbestosis docs not parallel the risk of lung cancer (25). Asbestos fibers or bodies and tong cancer In several studies, the occurrence of asbestos fibers of v| bodies or both in the lungs of lung cancer patients -- .) either in rejected lung tissue or at autopsy -- have bees j compared with findings from referents. Some such stud- , ; ies are summarized in table 3. The fiber levels are ip* creased in patients with lung cancer even if there is m? /; asbestosis present. For example, in the Karjalaoen study - : (98). only 2 of the 113 cancers had radiological asbesio- sis. and another 7 had slight histological fibrosis. Pleural plagues and risk ot lung cancer .. in most investigations, pleural plaques are the most cotsmen radiological finding in persons exposed to asbestos* JAN-11-2001 THU 05:04 PH Fax NO. Hlllerdal <S Henderson Table 3, Asbsstos fibers and bodies and lung cancer. Author Karlaiainsn si it, 19R (9i) Material Operated Casts (N) Asbastosis 113 9 Msrtischnig, 1977 (47) Smith. 196S (93) Ktehlmoto, 1SS2 fit! Hirsute st al, 1990(101) Autopsy Autopsy Autopsy Autopsy Operated 30 107 92 337 139 -- -- 10 Resuiii OR 2,8 a s x 10^5 par pram GR1-5&1 je1S*& per pram Slpfsflcsnt higher Ms Of ferruginous bodies in patienu with lung ranw . More asbestos bodies in patients with lung cancer More asbestos bodies In patients with lung eatWer (P < 0.01) More asbestos bodies In patients with lung cancer: high counts P < 0.01: . iawecuiftsP<aS5 I They are in themselves harmless and can be regarded as persons with plaques will have values that are little or no an objective sign ofprevious asbestos inhalation. If there different from those ofthegerteral population (111,114). is a linear dose-response relationship between lung can Ten percent of the persons with nonmalignant asbes cer and asbestos, the logical consequence would be that tos-related pleural lesions without signs of parenchymal persons with plaques should have an increased incidence of bronchial carcinoma. On the other hand, if the "asbes- fibrosis will develop radiological and clinical evidence of it ins 10-yeor period (76,80, 121). Slightly restrictive tosis-cancer hypothesis'' is correct, there should be no lung function has been reported for groups with asbes increased risk unless the plaques we combined with as tos-induced pleural lesions; the principal determinant of hestosis. this restrictive lung function is probably parenchymal inflammation or fibrosis (122), In careful pathological Radiological diagnosis ofplaques The ELG system for diagnosing plaques has a low specifierty and sensitivity. At autopsy less than half of the plaques seen radiclogically actually exist, but despite this fact more than twice as many remain undiagnosed (102--J 05), Thus, to reach an acceptable level of specif icity. strict criteria are necessary (102, 106). Unfortu investigations, small lesions in the bronchioles and sur rounding parenchyma can be found in most patients with pleural plaques (123, 124). Thus the followers of the "asbestesis-caacer hypothesis" might accept the fact that persons with plaques do have an increased risjr of cancer -- and attribute this fo subradiological asbestosis, which may be present in some these patients. " nately, dre sensitivity will then be low -- and the majori ty ofdie genuine plaques will never be diagnosed (102-- 105). It is difficult to evaluate any study using unspeci fied or JLO criteria. Plaques and risk of cancer Whether patients with plaques have an increased risk, of bronchial carcinoma or not has been hotly debated. A strong opinion argues that there is no excess cancer for Degree of exposure and plaques camera of ample plaques compared with those without (13, 125, 126) or that, if there is such an excess, it is In the general population in a society in which there are explicable by more prevalent smoking among patients no "endemic plaques", SO--90% of strictly defined pleu with plaques (127). However, in some studies, the inci ral plaques discovered in chest roentgenograms are due dence of bronchia] carcinoma has been reported to be to occupational exposure to asbestos (80), A good corre increased for those with plaques (table 3). lation between pleural plaques and asbestos fibers or Many studies indicate that plaques are more than bodies in the lung has been shown by many researchers twice as common in chest X rays of lung cancer patients (22, 99,107-- 115). Asbestos bodies in sputum are also as in X ray* of the general population (128--132), The correlated with pleural and parenchyma) changes (116). same holds true for plaques at autopsy or determined There is also a fair correlation between the number of during operation (table 4), but these studies could be shestos fibers in the lung parenchyma and the size of biased by the investigator's knowledge of a tumor. the plaques (113,115,117).This correlation supports the ! There are also reports in which no access has been finding that the average or cumulative dust exposure is a | found in patients with plaques. Harper et al compared 13 significant determinant for the progression of pleural j patients with bronchia} carcinoma from 1500 workers abnormalities (! 18--120). Since definite criteria would ! exposed to asbestos and found no trend toward an asso single out those with the largest plaques, they would tend j ciation of pleural plaques with subsequent malignancy to select those with the heaviest exposure. ! (133). __ However, even If the mean of asbestos fibers or bod- j It seems that even low levels of exposure to asbestos fe* in persons with plaques is higher than in the normal (such as the environmental plaques in Finland) can result population, there is a fairly large variation, and some i in plaques. These plaques do not seem to indicate a Sc&ndJ Work Srmmrt Health 1S97> vd23, no 2 97 Asbestos, aabestosh. pleural plaques and lung cancer TabM,Pleural plaques and carreer# autopsy or operation. (RR = risk ratio) Author Material TVue ol referents Ob Ex fiR served pected Warn, et at 1384 (103) Smith. 1%8 (39) Mollo, et at 1385 (117) Toty.eta! 1376 (132) 409 autopsies the group 109 autopsies 1019 autopsies trie group 125 operated cancer Compared within Agrigender matched Compared within Operated without 4 3,4 1.2 27 IS 17 U 3d 10.4 2,9 measurably increased risk of cancer {134), This study also showed that there w3 no increased risk in persons with fibrosis only -- but fibrosis in combination with plaques gave a relative risk of 2,8! In a later Finnish study, a rough estimate of the relative lung cancer risk for patients with these mainly environmental plaques In comparison with that of the general population gave the figure of 1,1 (J36) -- which is such a small risk that unrealistically large population studies would be neces sary to prove it statistically (137), Lobardistribution and histological typo of lung earner in patients w/Ut asbestos exposure Generally, lung tumors are more common in the upper lobes than in the lower.ones. In asbestos workers the reverse is true (31,81,95,138). This reversal is seen also is asbestos-exposed cohorts without pulmonary fibrosis (50, $3,139). In 1 of these studies, in patients with more than 2 million fibers/g of dry weight of lung tissue, 59% of the cancers were situated In the lower lobes, while, in' those with less, only 29% had this distribution (138). '. Adenocarcinomas are reported to be relatively more common among persons exposed to asbestos than among unexposed persons (95, 75, 128, 139--141). There is, however, no consensus on this report (137), and the incidence of all (he main types of bronchial carcinoma i* In fact increased (96, 138, 141, 143--146). There are indications that with heavier exposure, and thus in pa tients with asbestosis, relatively more adenocarcinoma* are seen 122, 31, 139, 142, 145). At lower exposure levels, squamous-cell carcinomas seem to be more com mon (47, 80, 143, 146). This phenomenon might reffca the relative importance of smoking versus asbestos; at a lower exposure level to asbestos, the "tobacco effect'' predominates, creating mainly squamous carcinomas. Relative anduattributable" rise of asbestos in lung cancerpatients Various reports have tried to outline the importance of asbestos as a cocarcinogen in lung cancer. Case-referent or similar studies of patients with lung cancer repotted an attributable risk of 6% to 23% for asbestos (table 5). Occupations with exposure to asbestos are overrepre sented among clinical cases of lurtg cancer 029,136, 151), The actual occurrence of asbestosis among clinical 'cases of lung cancer is much lower than the 6% to 23%, when asbestos played a role according to the epWemioio* gists. Of special interest is the study by Wilkinson et al (79), in which lung cancer cases were compared with referents, not only regarding occupational exposure and Table 5. Percentage of "attributable risk" of asbestos in lung cancan (SR risk ratio) Author Cohort O a Vos i Irvin* et #1933(146) ... XatjafetaHiHU, 1934(115) imhefSBi et # 1935(145) .. Kmtlk.efal, 1366 (143) . Vera rial, 1305 (142) Man In west Sooted Surgery Workers (gas, electricity) Surgery Patients Cases W 65 310 176 1002 Asbastosis 5(1+4) ? Staleri|,1396(46( Wilkinson et #, 1995 (79) itetri31,1978(147) Jlrvfiolffl rial, 1993 (148) Surgery patients General population . fifltaborg 201 271 535 147 -- 7 7 Baveraf at# 1932 (149) 1 if 5* <20 years. * Exposed > 20 ytarc. * P<0,85;**P<0.01: *'*P<0,0tli. Trieste 756 7 83 ScsndJ Wait Environ Health 1997, vol 20, m 2 Referents _ 297 1240 176 1119 201 STS 59 111 109 756 RR Attributable risk (%} -- 1.4 3.0 1.7* 2.3*'* 2.35**' 1,7* 1,6" ` i.6--i a s 13 23 S1 18 20 20 JAN-11-2001 THU 05:05 PM 4^* smoking habits, but also regarding the occurrence of 'i: parenchymal small lesions according to ILQ. As seen from the tables, the relative risk for lung cancer for patients with changes compatible with osbestosis (I/O or more) was 2,03, and for those without asbestosis i; was 1.56. All the studies died here and seen in the table agree ; fairly well. One must therefore conclude that lung cancer .. risk is increased also in patients without asbestosis. mctianfsm of asbestos-related lung cancer It has been claimed that fibrosis in the lung parenchyma j$ unlikely to cause cancer in the large bronchi, where a ; large part of asbestos-related cancers are seen (58,152, . 153). In tracheal organ cultures, necrosis and desquama tion of surface cells accompanied by basal cell hyperpla sia can be seen after I week (154), and this occurrence is presumably independent of any accompanying paren chymal changes. These changes presumably cause an increase in the susceptibility of epithelial ceils of the bronchi to be transformed by environmental carcinogens (31). fibrosis of the luags and cancer of the bronchi can thus be seen as end points of 2 unknown mechanisms , that may work independently (153), I "riuOt Concluding remarks There is aa increasing body of evidence which indicates fjjF that asbestos at low exposure levels produces a slight i; increase in the relative risk of lung cancer. The relative risk of cancer in asbestosis patients is higher, but it is Unclear whether this higher risk is attributable entirely to' higher fiber burden within Jang tissue (a dose-response , effect) or whether there is also an adjuvant effect of .. fibrosis by way of cytokine production, over and above the dose effect This conclusion is not a purely academic question but has important practical consequen ces in 2 different areas. One is in the legal world and the other is in the world of mdustrial hygienists. The legal consequences have an important bearing for many persons. Accepting a no.threshold hypothesis for lung cancer would open the field for a large number of patients with low-grade expo*t*re to claim compensation for lung cancers caused by exposure, even when the principal cause of the . tumor is smoking. However, science should try io find the facts independent of how the law might be affected . . *7 these findings. Fn other words, law should follow ..^teace, not the other way around. The legal world has to ' . eorae to terms with whether -- and if so, how much -- a FAX NO. Hitlerdal & Henderson small increased risk, such as an increased risk of 10% or 20%, should be compensated. Proposals have been made (33). The more important fact is that even if an increased risk of 10% or 20% is not very important for a person, it will result in a large number ofbronchial carcinomas in the general population where smoking, unfortunately, is far from eliminated. Given this fact, society cannot con clude from the present data that lung cancer risk is in creased only when exposure is heavy enough to cause asbestosis. Anyone claiming such an unproved hypothe sis shoulders a heavy responsibility. All exposure to as bestos roust be minimized, and if asbestos is to be used, stringent precautions must be taken, References 1. Gtoyne SR. Two cases of squamous carcinoma of the lung occurring in asbestosis. Tubercle 1935|I7:3--10- 2. Honteann M. Dcr Bewfskrcbs der Asbwtarbeiter. Z Krebs* forscb 1938;47:28S~302. 3. Lynch KM, Cannon WM. Asbestosis; analysis of forty ae&opsfed cares. Dis Chest 1948;14;874--aS>4. MI R, Mortality from lung cancer in asbestos workers. 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