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Liddell D. Health effects of historical exposures to asbesto.c. In: Gibbs GW, Dunnigan J. Kido M. Higashi T. (Eds) Heabh Riskr from Exposure to Mineral Fibres: an Interaatioeal Pcrspecrive. North York. Ontario: C.ptus University Press 1993: 49-65. (1992.01_I0; with minor typographic.l corrections 1993.03.09) Health Effects of Historical Exposures to Asbestos Doaglas lJddell Department of Epidemiology and Biostatistics, McGill Univeraity, 1020 Pine Avenue West, Montntil, CGnada H3A 1A2 ABSrRACC .1/!er the 1977 New York:toudemy ofScienaer sympaciam on Health Hatards ofAsbestos Ezposare, It was aornrnonly belie.rd, porticularly in the United Stater, rhat asbestos, in all its forms, war sadr a hazardous mieeral that 'onee fibre could kill'. Three sets of faas had been ignored. Frrat, the undoubted exaerses until then of morraltlry. from pubmonary frbrnsis (arbeuosis). lung ovn-, and mesothelioera, had been due to erposare 20-60 years previoutly, and for most of this period the a..ernge' concentration ofasbertor frbrv in the ocarpational environment had been greater than 100 frbtrt/mi11i1itre (f/ml). Leuels wee being brought down, to around Sf/m1 in 7975, and nearer I f/nd by 1980, so that the risk ofasbartos-related disearemust also haws beenfalling tnpidly. Secondly, o.v 90 % 4f ownmerdally available arbestos always has been ohrysotile. 77rltdly, the only major andy of drqaoaile xavrkers showed that aosr lung rntrcrr war sirtually amfinei to those wlro had been esposed to more than 1Q00 QSbrer/ml) x yearr (e.g. ovn 20 years at SO f/m1J. 7bls paper rnviews all the historical eudencr to date, and thefollowing ovndasionr an drawn. 7he riskoftnaotheliama aJ1er exposare to dtrysotile is oneotder oftnagaitttdelars thanfiian amarire, and two orders lers than from ancidolite. Dre rist of eiaers lung avncer as a rrsttlt of aposrme to chrysottle (exnpt fn tesriles) is less, by more than one order of rnagnitade, than that frnm oroddolke erpottrrx On rralistle asnmrptions, the risk of Irreg cttntwfrom !nlraling one chrysotilefrbre isQbout one br a Fradnad,thousand-b1U1on; the risks ofmaQorhdioma orarbestasis are enen boroer. The highest estbnate of lang oonoer rirkfrom a singlefibre - of crocidol&e - is len than one in a thoarand-billJon. Tlu beliefi that allforrns ofarbertos are equally haurrdous and that one arbertosffbre can kill are seen to be myths - untrue and completely withoutfoundation. IN'iRODUCTION It is fully established tlnt severe expo.wre to respirable asbestos fi6tes bas led to respiratory fibrosis, now called aslestods, exoess lung cancer, and mesothelioma of the pleura, and sometimes of the peritonenm. Unfortuoately, the word 'cevere' in the preoeding sentence is often overlooked, and in some countries there is widespread 'fibrephobia', psopagatad by a number of myths' including those in Table 1. The most important lessons to be leunt from history ue l6ose concerning ~posu+ereaponu relationships, and this paper emphasises the lmowledge we have gained about the sttwgth, strape and gradieot of the relationships between asbestos exposure and the risks of inesothelioma and of lung cancer. IILSfORICAL BACKGROUND Asbestos production The modern asbestos industry started in 1979, when about 50 tons of chrysotile were produced in Qrebec. By 1977, when world production was.t its pe.k, about 5.5 million short tons of chryeotile were produced, 24% in Quebec, 47 % in the USSR, and 29% elsewbete, and in addition about one-quarter of a million tons of the other - amphibole - forrns of as)>euas, maioly anwaite and crocidolite. It is of great importance that ttvoughout- from 1878 to nowadays -chrysotile has always been by f.r the predominant frlm. -1-

It is, therefore, difficult in the extreme to see any relevance of these findings to any of the problems faced today. Nevertheless, these findings have been the basis of what may he called the 'Conventional Wisdom'. Chrysotile erpnsure Meanwhile, the impact on Conventional Wisdom of the results from Quebec was negligible. Over 10,000 male chrysotile production workers (miners and millers) in Quebec, born 1891 through 1920, have been followed; the first report on their mortality was in 19711 the latest in the 1980s .'0 This cohort is especially important for several reasons: a) its size - there were almost 4,500 deaths by 1975, already reported;' and nearly 3,000 more by 1988, recently tnced;" b) the exposure of the great majority of the cohort was to chrysotile alone; c) quantitative estimates have boea made of dust concentrations; and d) it includes workers with very mild exposure as well as those severely exposed. From the start, excess lung cancer mortality has been clearly related to total dust exposure. Such relationships have now been shown in sevenl other cohorts of asbestos workers; however, the slopes of the relationships vary greatly with fibre type and process. Because the slope for Quebec miners and millers was so shallow, the Conventional Wisdom has been'= that them were major methodological shortcomings and that the comparatively low reported health risks from exposure to chrysotile were anomalous. More receatly, there have been several investigations in workforoes exposed to cluysotile alone, and, except in the textile industry, these confirm the low health risks from chrysotile. In 1980, McDonald and colleagues' wrote of the Quebec oohoct: •If the only subjects studied had been the 1904 with at least 20 years' employment in the lower dust concentrations, averaging 6.6 million particles per cubic foot [mpcf), i.e. about 20 flml, ezcess mortality would not have been considered statistically significant, except for pneumoconiosis.' For the complete cohort, there had been about 6% more deaths (all causes) than expected on the basis of mortality in the Province of Quebec, despite exposure averaging roughly 700 (fibres/ml) X years. This 6% excess is in complete contrast to that of 37 % among the 17,800 insulation vrorkers referred to earlier. Cl.early, the consistent findings in humans exposed to chrysotile, by far the most common form of asbestos, provide a much more realistic basis from which to evaluate health effects than do any unique and extraordinary results among amphibole asbestos workers. Experimenral frndings Meanwhile, experimental studies were suggesting that chrysotile was at least as dangerous as amphiboles. A heuristic explanation of the reasons for differential effects in aninuds and humans, based on the argument of Elmes,ts follows. Massive doses of chrysotile fibres, once retained in the lung of a rat, split up into finer and finer bundles, and eventually into fibrils (the basic erystal units, which are less than 0.1 pm in diameter), and so provided a much increased surfiee area for biological reaction. Within the aoimil's life-tpan, clearance from the lung was not great, and doses were so enormous that substantial proportions of animals developed tumours. However, the same dose of amphibole fibres was retained virtually unchanged, with minimal clearance. Thus the effective dose of chrysotile was much greater than that of amphibole. In nun, the retained doses per gtam of lung vrere very much smaller, even after the most severe of historical exposures. The initial build-up of surface area was much greater, exposuee for exposure, with chrysotile than with amphibole, but the chrysotile was largely cleared from the lung before tumouts could develop, whereas amphibole was retained indefinitely. The effective dose of chrysotile in the human lung was thus very mueh less than of amphibole. It is a tenet of scientific method that an experiment should be designed to test a specific theory. Progress is made when experinxntd fnxlings ate not explained by the theory, which has to be discarded in its specific formt another theory is then developed, to be tested in its tutn by a new experiment. Progfessis also made when epidemiologic findings are in conflict with those from experiment the theory apparently supported by the experiment has to be discarded and replaced. It is contrary to the principles of scientific method to maintain the theory in the face of disproof, whether that disproof is demonstrated by experimtmt or by epidemiology. 'ilteeefote, when the theory that chrysotile was at least as dangerous as amphiboles was disproved in man, although supported in animd studies, it was essential on scientific grounds that the human evidence should prevail aver that from animals, and hence over theory. However, the unprincipled approach of ignoring the human evidence was incorporated into Conventional Wisdom, thus perpetuating the first of the asbestos myths of Table 1. . - , Latency One of Merewether's fmdinge was that: 'with continued exposure to high concentrations of dust, the fibrosis mfy be fully developed in from 7 to 9 years, and may muse death after about 13 years of exposure ...' This implied inverse association between severity of exposure and 'latency', i.e. the interval between first expasun: and manifestation of disease, was in conformity with genetal toxicological IrnowleYlge. It is, however, important that this was probably the la.st study in humans to show such an association. In the one study of -3-

of sub-linearity of response to short expacures. Secondly, Browne and Smither,19 reporting 144 cases of confirmed mesothelioma among former employees of Cape Industries Ltd, noted nine ca.ses (six, pleural, three peritoneal) with no more than three months occupational exposure. Because this was a case series, no 'denominators' ace available, and so these results cannot be evaluated: it is by no means impossible that the distribution, by duration of employment, of all Cspe Asbestos employees over the years were so highly skewed that there is no real contradiction with the present findings. Two further factors must be botne in mind: the Cape Asbestos experience dates back many decades when intensities of exposure were unthinkably high; and a substantial pmportion of 'short-service cases' may in fact have arisen from neighbourhood exposure, which was known to have been far from negligible near the Barking plant in which the great majority of the cases had worked. It must also be borne in mind that the whole of this paragraph concerns employees exposed to Australian crocidolite alone or to 'mixtures' compar.tively rich in Cape ctocidolita. Theta have been very few mesotheliomas in the three cohorts exposed to ehrysotile alone or with only a small admixture of amphibole, and there is no evidence to contradict in any way the conclusion that the risk of inesothelioma after only a few months exposure, at least to chrysotile, is vanishingly low. Lung cunaer It has long been accepted that the risk of lung cancer is closely related to accumulated asbestos exposure. Ia 1985, Liddell and Hanley9 showed that, in those cohorts for which adequate data were available, the relationship between SMR and exposute, x, measured as (mpet) x years, could be modelled by a straight line of the form SMR - a + 6.x. However, they recognized that the choice of a linear model was a matter of convenience, and pointed out that it was not biologically plausible. More recently. Vaeek and McDonald have investigated the shape of the relationships in five cohorts of asbestos workers?' For the Quebec study, they defined six levels of the intensity of exposure as follows: (1) <1 mpcf; (2) 1, <3 mpcf; (3) 3, <10 mpcf; (4) 10, <25 mpc$ (5) 25, <50 mpcf; and (6) 50 mpcf or mote. Then for each worker in the cohort they counted the number of years of exposure at each of these six levels. Conditional logistic regression analyses were carried out on the 230 cases of lung cancer occurring after 1950, and at least 20 years after first employment, and their referents, comprising all male workers born in the nme year as the case, employed in the same mining atea, and alive at the end of the year in which the case died. In the full analysis, the "independent' variables were: (1-6) years spent at each intensity level; (7) total duwtion of gaps in employment; (8) years since first employment; and (9) smoking habit. 1he regression coefficients for variables (5), (6), (8), and (9) were all of extremely high statistical significance, but those for variables (1), (2), (3), (4), and (7) were quite small relative to their standard errots. When these last five variables were excluded, the goodness-of-fit statistic was reduced by a quite insignificant amount. Similar pattenss were found in the three other cohorts which had yielded apparently linear exposure•rraponse relationships for eumulative asbestos exposure. (in the fifth, there was little evidence of excess risk by any method of analysis.) . In a later .eport'a on one of these other cohorts, the same authors pointed out that their results were consistent with a relationship in which risk of lung cancerr a) was absent at [telatively] low eoncenttations; b) increased rapidly as concentrations increased; and c) levelled off at high concentrations. Comments a) and b) could also be made about their results on the other three cohorts, and cotnmeat c) for the Quebec miners and tniBers, the only other cohort in which a substantial proportion of members had been exposed to intensities over. 10 mpcf (i•G over approximately 35 f/ml). These authors also stated however that, when risk was modelled as a function of cumulative exposvre, the fit was almost as good as just described. Although them is ittsufficient evidence to postulate a threshold level of intensity below which there is ao risk of lung cancer, the exposure-response relationship does appear sub-linear at levels of inteosity up to at least 3 mpcf (roughly 10 f/ml) for textile worken: and vermiculite miners, or up to 10 mpcf (or ca. 35 f/ml) for chrysotile miners and millers. Summmy In the light of all the evidence, it is clear that there are very strong exposure-response relationships for asbestos and both tnesothelioma and lung cancer. The risk of vtesotheliotna after only a few months exposure, at least to chrysotile, is vanishingly low. The risk after long exposure to asbestos seems less than linearity would predict, and therefore much less than exponential. Thus the relationships appear neither linear nor exponential, but probably sigmoid. Yhe risk of lung cancer is closely related to cumulative exposure to asbestos, but probably not in linear fashion. The risk seems to be even mote closely related to the duration of exposure to high concentrations; it appears very slight at concentrations up to 10 flml or motn, increasing with severity up to around 75 f/ml, and then levelling off. The relation with cumulative exposure would appear to be signwid, i.e. sub-linear at low and at high concentrations, but relatively steep in between. N t11 O N ~ A ~ N ~ t0 -5-

of calculating SMR and excess risk. The risk estimates afe sem to depend not only on the level of exposure but also on the background life-time risk of lung cancer; two examples are given in detail. The approximate nature of these estimates must be emphasised; also that the slope of 0.05 used for chrysotile is an upper bound. Further, all estimates are on the basis of proportionality, i.e_ are considerably higher than would be given by the sub-linear exposure-response relationships that appear to hold at exposure intensities below about t0 fibresJml. From basic considerations, a person exposed occupationally to I fibre/ml inhales:- 20 X 10 t fibtes a minute, assuming minute volume of 20 litres/min, which is 120 x 10' fibres an hour, i.e. 30 X 10 ` fibres in a 5-day week of S hours a day; which, in a 48-week working year, amounts to 14 x 10 a fibres a year. Thus, exposure at this intensity for 20 years implies the inhalation of 28 x 10' fibres. According to Table 6, such exposure to crocidolite entails an exoess lung cancer risk of 20 % of the background. Therefore, it takes inhalation of 28 X 10' crocidolite fibres to produce a risk of lung cancer of 0.02 (on a 10 % backgtound). So the inhalation of a single etocidolite fibre is associated - on these bases - with a lung cancer risk of less than (0.02)/(28 x 10') - 7.1 X 10 'tt - 1l(1.4 x 10'=), i.e. much less than one in a thousand-billion. With slope 0.05 but otherwise on the same bases, the risk from inhaling one ehrysotile fibre would be 20 times lower. On more realistic ass<tmptions and a 5% background, the risk would be down to about one in a hundred- thousand-billion. Envoi That one asbestos fibre can kill is seen to be a myth; this commonly-held belief is completely without foundation. CONCLUSION The ill effects of very severe occupational exposure to asbestos have included respiratory fibrosis (asbestosis), lung cancer and mesothelioma. Until the 1930s. when there was little if any environmental control, asbestosis was a common oufeome, often manifest within ten years of first employment, and frequently fatal. However, as BecklakO remarks, with the, implementation of progressively stringent environmental controls, this disease appears to clinicians and pathologists to be less frequent, less severe, and Izss likely to cause impairment. Thus, in 1989, when a group of experts met in Oxford under the auspices of the World Health Organisation to recommend an occupational safety limit based on health grounds, they considered that controls to reduce the risk of asbestos-related cancer to 'acaptable' limits would effectively eradicate asbestosis. The interval between first exposure to asbestos and the manifestation of telated cancers is long - very seldom less than 20 years, and about 40 years on average - and is not related to degree of exposure. Thus, today's asbestos-telated onces were undoubtedly initiated by exposures 1935 - 1965, when the concentrations of respirable fibres in the occupational environment were about two orders of magnitude higher than in the 1980s. Disease nused by today's exposures will be much less - probably by at Ieast two orders of magnitude - when it does develop, but that will not be until well into-the 21st-Century. The risks of cancer depend greatly not only un the degree of exposure but also on fibee type and industrial process. Although chrysotile is and hs been the predominant asbestos fibre, with amphiboles always accounting for only 5-10% utilisation, the majority of disease has been caused by aocidolite and to a lesser extent amosite. The WHO experts in 1989 recommatded that amosite and crocidolite should not be used if at all possible. As asbestos textile manufaciure has been associated with a high risk of lung canoer, whatever the fibre type, and as it is not yet known with cettainty how to manufacture textiles from chrysotile with adequate safety, this use should be proscribed, along with any use of amosite or crocidolite. Exposttto-tapoau relationships are very strong, and are probably sub-linearr for mesothelioma, in relation to durations of less than, say, six months; for lung cancer, in relation to accumulated exposures up to, say, 10 (fibres/ml) x years. Estimates of risks made an the basis of proportionality, as almost all are, are therefore gtosa overestimates. Chrysotile except in textile manufactum has mused very little disease except when exposures were astronomically high. When controlled to an intensity of I fibre/ml, the risk of excess lung cancer after 10 years employment is only 0.5 % of background, assuming proportionality with a slope of 0.05 (see Table 8). But both these assumptions are liberal; the true risk is very much lower. The risk of inesothelioma as a result of controlled exposure to chrysotile also appears very low indeed. s N tJ1 O N i ~ -7- ql N co c

19. Browne K, Stnither WJ. Asbestos-related me,wthelioma: factors discriminating between pleural and peritoneal sites. Br J Ind Med 1983; 40: 145-152. 20. Liddell FDK, Hanley JA. Relations between asbestos exposure and lung canccr SMRs in occupational cohort studies. Br J Ind Med 1985; 42• 389-396. 21. Vacek PM, McDonald JC. Effect of intensity in asbestos cohort exposure-response analyses. In: Sakurai H, et a1. Eds. Occupational Epidemiology. Elsevier Science Publications 1990: 189-193. 22. Vacek PM, McDonald JC. Risk assessment using exposure intensity: an application to vermiculite mining. Br J Ind Med 1991; 48: 543-547. 23. Sluis-Cremer. G.K., L3ddell, F.D.K., Logan, W.P.D., Bemideohout, B.N. 1992. Tbe mortality of amphibole miners in South Africa, 1946-80. Dr. !. Jnd Med. 49: 566-575. 24. Hughes JM. Epidemiology of lung onoer in relation to asbestos exposure. In: Liddell D, Miller K. Eds. Mineral Fibers and Health. CRC Press ino, Boa Raton FL 1991: 135-145. 25. Becklake MR. The epidemiology of asbestosis. In: Liddell D, Miller K. Eds. Mineral Fibers and Health. CRC Press Inc, Boca Raton FL 1991: 103-119.

Table 3. Proporti.onaZ mortality from mesotheZioma in the major cohorts of male asbestos-exposed workers Fibr® type (and process) No. of cohorts Total deaths Deaths from mesotheli.oma proportiona2 mortaZtty (%) ::hrysotile 5 5,062 11 0.2 -hrysotile with small proportion of amphibole - manufacture 6 3,925 25 0.6 - textiles 2 1,622 26 1.6 vosite 3 871 25 2.9 t !tixed - shipyard work 2 1,077 31 2.9 :rocidolite 3 653 43 6.6 * fiixed - insulation 5 3,055 235 7.7 ~hrysotile with larger proportion of amphibole 2 926 77 8.3 * * Marked heterogeneity s - 11 -

Table 5. Long cancer risks In 32 cohorts of asbestos workers (Standardized XortaZ3ty Ratios [SXRa) with confidence intervaZs [CIS)) ibre type and process No. of Deaths Iroa SXR cohorts Zung cancer (eS In brackets) hrSaotile (solely or predominantly) manufacture, cement 4 62 1.02 (0.78-1.31)' mining/milling, gasmask filters, friction products 5 406 1.23 (1.12-1.36) irisotile and amphibole cement 7 351 1.56 (1.40-1.73)6' manufacture (retirees) 1 77 2.71 (2.14-3.39) aosite mining/milling 1 26 1.38 (1.08-2.14) sosite and crocidolita mining/millinq 1 10 2.22 (1.06-4.09) rocidolite gas mask aesembly 3 33 2.09 (1.44-2.93) mining/milling 2 118 2.47 (2.04-2.96) •xtiles chrysotile 1 59 1.99 (1.51-2.57) chrysotile and amphibole 4 377 1.75(1.58-1.94)• ¢sulation chrysotile and amphibole 1 397 4.24 (3.83-4.67) amphibole 2 84 4.80 (3.83-5.94) a Except where heterogeneity is indicated, the degree of confidence In 95%. b Because of heterogeneity, the true 95 % CI is rather wider. - 13 - N Lt O N ~ A M N OD W