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i Linear extrapolation for risk estimation at low level exposure: the asbestos example J Corbett McDonald MD FRCP, Professor National Heart & Lung Institute London University and School of Occupational Health McGill University, Montreal Emeritus 1. Introduction Asbestos exposure can cause two kinds of malignant disease - cancer of the bronchus (lung cancer) and primary tumours of the pleura or peritoneum (mesothelioma). It remains uncertain whether asbestos can cause lung cancer in the absence of tobacco smoke or other co-carcinogen and also whether pure chrysotile or only certain amphibole fibres - crocidolite, amosite and tremolite, in particular - can cause mesothelioma. These doubts lie at the heart of all etiological questions on asbestos and carcinogenecity, and cannot be avoided when considering the validity of extrapolation. Equally unavoidable is the concept of a threshold or so called "safe" level of exposure. Conceptually and biologically both linear and non-linear relationships - sigmoid for example - may or may not have a threshold. Although the four possibilities are probably indistinguishable, threshold and non-threshold models provide quite different estimates of risk at very low N exposure levels. ~ N ~ ~ ~ ~ ~ v!

The measurement of response in terms of morbidity or mortality in response to toxic or carcinogenic agents seldom presents a serious problem but concepts of dose and exposure are far more difficult to deal with. In human populations dose is very seldom known or usable in epidemiological studies. Exposure as a surrogate for dose is inevitably more complex and requires more precise definition, qualitatively and quantitatively, than is ever possible. With asbestos fibres, for example, there are reasons to believe that their biological activity will depend on mineralogical type, fibre dimensions, airborne concentration and pattern of exposure in and over time. Of the dozen or so cohort studies of asbestos workers in which an attempt has been made to assess exposure for each cohort member all were based on dust counts, not fibre concentrations; fibre size distributions were not known and reliable information on fibre type was generally lacking. In every study exposure has been expressed as the product of duration and intensity (cumulative exposure), implying the biologically unlikely assumption that these two variables, one fairly precise and easily measured and the other vague and approximate, are interchangeable. It should thus be evident that the carcinogenic risk associated with the inhalation of asbestos is an extremely complex multifactorial problem requiring the appropriate statistical analysis of individual exposure in terms of fibre type, size, concentration, duration and timing together with comparable information on smoking habit. Small wonder that present views on the subject are essentially speculative; however, although health policies 2

and decisions cannot wait for certainty, note should be taken of the nature, size and implications of possible error_ 2. Exposure response 2.7 The eoidemioloaical data Present opinion is based largely on findings from a relatively small number of cohort studies of lung cancer mortality in workers exposed occupationally. The main studies are summarized in Table 1 (1); as clearly stated, exposure was expressed in them all as the product of duration and intensity, the latter based on dust particle counts. The slopes shown in the last column are for lines fitted to relative risks derived from observed SMRs on the assumption of a linear non-threshold model. In fact, straight lines do not necessarily provide the best fit and, as shown in Figure 1, none of the lines describing the SMRs themselves actually pass through the origin (2). Nor do the slopes listed in Table 1 or shown in Figure 1 take any account of smoking; indeed, only in one was smoking habit known. The simple view is often taken that as the interaction between asbestos and smoking can be assumed to be multiplicative, linearity will not be affected by the contribution of either factor. However, in six studies where it has been possible to study the interaction (3), only one showed the relationship to be multiplicative and that in the cohort of American insulation workers where asbestos exposure was not quantified (see Table 2). If, as seems somewhat more probable, the interaction is generally more than additive but less than multiplicative, the linear hypothesis for asbestos per se is further undermined. 3

Just as the epidemiology of lung cancer is dominated by smoking, that of mesothelioma is strongly affected by fibre type; as a result the quantitative information available on exposure- response for the latter is scanty. Several studies (4) suggest that the risk is related to duration of exposure and that few if any cases occur within less than several months of first exposure for the amphiboles or several years for commercial chrysotile*. Indirect evidence of a systematic relationship for amphiboles is afforded by analyses of lung tissue at autopsy from mesothelioma cases and controls in Canada (5) and Australia (6). The nature of this evidence, the interpretation of which entails several assumptions, is illustrated in Figures 2 and 3. 2_2 Statistical extrapolations Until fairly recently occupational epidemiology was primarily concerned with identifying health hazards at work and with providing a rational basis for setting a 'threshold limit value' or other hygienic control measure sufficient to reduce risks to an acceptable level. More recently, concern has grown about the possibility of risks to the general public at exposure intensities well below those found in the workplace. Underlying this concern is the fear, probably related to experience with ionizing radiation, that there might be no safe threshold for carcinogens. As occupational epidemiology is not.able to the term 'commercial' is used to indicate that the chrysotile is frequently contaminated with fibrous tremolite.

provide a direct answer to this type of question, several valiant attempts have been made to obtain some measure of possible risk by linear extrapolation. The assumptions underlying these efforts are very large and subject to many uncertainties which can be considered under three headings:- a) Exposure-response The nine cohort studies in eight industrial groups summarized in Table 1 show that the difference in gradient between those for textile and friction product workers was about 50 fold. The experience of American insulation workers and of men engaged in the manufacture of amosite insulation products, are not shown in the Table because exposure was not assessed individually. However, with certain assumptions, especially as to linearity, it seems likely that the gradients for these two groups lay somewhere between those for cement workers and textile workers. There are at least two possible explanations for the variation. First, some of the exposure estimates may have been seriously incorrect; if so, the error was systematic or the response relationships would have been lost. Second, neither the original dust particle measurements nor the usual conversion to fibres, countable with the optical microscope, may adequately reflect the biological hazard; experimental work on fibre size and the dynamics of penetration and retention all suggest that this could be an important part of the explanation, perhaps all of it. b) Fibre type Differences between the various types of asbestos fibre can probably be ignored in predicting risks of 5

6 lung cancer and asbestosis, but mesothelioma is another matter. The evidence that virtually all peritoneal and most pleural cases are attributable-to amphibole exposure, rather than to chrysotile, is strong though not conclusive. The uncertainty is compounded by the lack of adequate exposure-response information for mesothelioma. In none of the nine cohorts shown in Table 1 was the relationship of inesothelioma to exposure examined. Despite this, some reports have suggested that an indication of risk can be obtained from a small number of other cohort studies, in which only average group exposure had been roughly estimated. All the cohorts used for these estimates entailed exposure to pure amphiboles or to amphibole-chrysotile mixtures; generally excluded from consideration were those in which the mesothelioma risk was low. c) Conversion All the available exposure-response data from occupational cohorts are based on total respirable dust measurements. Determination of the equivalence of these measurements in terms of fibres (>5 µm long) per millilitre (f/mL) is a difficult and dubious operation. Even in chrysotile mining and milling, the range of conversion ratios is at least 40-fold. A problem of similar magnitude concerns the equivalence in fibre terms of measurements made in the general environment, nearly all of which are gravimetric and usually expressed in nanograms per cubic metre (ng/m3). The conversion factor relating mass to optical fibre concentration had a range of 5 to 150 and probably varied with fibre type (1).

On taking these three types of uncertainties into account, the possible error in any estimate made by extrapolation could range over five orders of magnitude. Even this would not take account of such questions as sampling error in environmental measurement, fibre type, or fibre size distributions. In a paper by Enterline in 1981 (7), estimates of lung cancer deaths, based on extrapolation from linear and curvilinear exposure-response models, were made. Using conversion factors of 3 for f/mL per mpcf and 40 x 103 for f/mL per ng/m3, and linear extrapolation from his own exposure-response data (SMR = 100 + 0.658 mpcf-yr), he estimated that continuous lifetime exposure at 5 ng/m3 (approximately the average outdoor level in urban areas of the US) would result in 4.6 lung cancer deaths per million population. On the other hand, a curvilinear model, for which there was experimental but not epidemiological support, would result essentially in zero deaths. Several other estimates of current and lifetime risk of lung cancer and mesothelioma for the US population have been made purely by extrapolation. A simplified comparison of these estimates is set out in Table 3. To achieve a measure of comparability, some liberties were taken with the published data, and the figures shown are therefore approximate. The differences between the lung cancer estimates are mainly due to the idiosyncratic selection of exposure-response data from industrial cohorts. The NRC committee used three of the nine cohorts included in Table 1 and added six others, in all of 7 ~ .1

a which only group estimates of exposure had been made. Schneiderman used only two of the nine and included three of the six added by the NRC committee. Nicholson used four of the nine cohorts and not the other five. Other estimates of lifetime risk associated with non- occupational chrysotile exposure were made by Doll & Peto (8) who calculated that exposure for 40 hours a week for 20 years would result in 10 excess deaths per million population. Hughes & Weill (9) published similar estimates for school children and asbestos cement production workers (see Table 4). 2.3 Validity of risk estimates Any hope of being able to validate estimates of mortality risk of the magnitude shown in Table 3 and Table 4 by any form of planned epidemiological survey would appear quite impossible. There are so many other known and unknown confounding factors which affect human health to a greater degree than very low level asbestos exposure, the allowance could not be made for these even in the largest conceivable prospective or retrospective study. Nevertheless there are some data which throw light on the problem. On the basic question of the linear-exposure-response model, exploratory analyses of several sets of cohort data (10,11) have now been made by multivariate relative risk methods. These have shown that the pattern of risk in relation to exposure intensity differs substantially from that with cumulative exposure and

might well be sigmoid rather than linear; further work on these lines is in progress. More direct evidence is afforded by observed trends in mesothelioma mortality in Canada, the United States, Australia, Great Britain and Scandinavia. In all these countries, with a combined population approaching 400 million, the incidence in males and females began to separate in about 1950. Since then there has been a steady upward trend of about 10% per annum in men but little evidence of an increase in women. These national trends in mesothelioma mortality were reviewed in detail in the recent comprehensive report by the Health Effects Institute - Asbestos Research (10); their main conclusion, summarized below, expresses the implications of these observations very well:- "The risk assessment mode7...... predicts that the number of background (that is, not asbestos-related) mesothe7iomas iin the United States might be increased by 10, from approximately 400 per year (200 each in men and women) to about 410 per year, if the whole population were exposed for 20 years in buildings to the average level of 0.0002 f/mL....., or for 13 years to the average level of 0.0005 found for schools. This small increase would not be detectable by an analysis of national age-specific trends in mesothelioma incidence nor could such an analysis confirm the risk assessment model........ . The data do, however, indicate that the overall risk to the population for mesothe7ioma in buildings is 1ike7y to be smaller in comparison 9 r

to the ]ifetime background mesothelioma rate, which is about I in 5,000." At considerably higher levels of exposure than those found in public buildings, but below those observed occupationally, other epidemiological findings are relevant (1). For example, cases of mesothelioma have been observed in the vicinity of crocidolite mines, mills and factories, but not near comparable chrysotile operations. It is also clear that occasional cases of inesothelioma and possibly of radiographic abnormality can be attributed to exposure in the household of asbestos workers. The latter facts are reasonably well documented but with little or no information on fibre type or exposure intensity/duration. 5. Conclusion Whether or not the risk of malignant disease is linearly related to airborne asbestos exposure remains open to question and" whether or not there is a threshold below which the excess risk is zero is probably beyond the power of science to determine.. Certainly the risk of any given airborne fibre concentration is considerably greater after amphibole than commercial chrysotile exposure. The practical issue which remains is thus more philosophical and political than scientific. Asbestos cement and friction products are very valuable for building construction, water supplies, drainage and for vehicle brakes, especially in parts of the world where cost is a major consideration. Until such 10

time as less hazardous but equally effective and affordable substitutes can be found, the strictly controlled use of chrysotile need entail no detectable risk. Society must therefore determine whether its resources should be directed at attempts to further reduce risks conceivably associated with the use of asbestos, a difficult and costly task, rather than concentrate on the major threats to life, health and happiness, which are all too abundant. These decisions should be taken by well-informed local people in the light of national priorities; it is unlikely that they will be the same everywhere. 6- References 1. McDonald JC. Health implications of environmental exposure to asbestos. Environ Health Perspect, 1985;42:319-328. 2_ McDonald JC. Cancer risks due to asbestos and man-made fibres. In: Recent Results in Cancer Research, Vol 120, (ed Band P), Springer-Verlag Berlin Heidelberg 1990, pp 122-131. 3. Berry G, Newhouse ML, Antonis P. Combined effects of asbestos exposure and smoking on mortality from lung cancer and mesothelioma in factory workers. Br J Ind Med, 1985;42=12-18.

12 4. Liddell D. Epidemiological observations on mesothelioma and their implications for non-occupational exposure to asbestos_ In: Proceedings of Symposium on Health Effects of Exposure to Asbestos in Buildings, December 14-16, 1988, (eds Spengler JD, bzkaynak H, McCarthy JF, Lee H), Harvard University Energy and Environmental Policy Centre, Cambridge, MA, 1989. 5. McDonald JC, McDonald AD. Epidemiology of mesothelioma. In: Mineral Fibres and Health (eds Liddell FDK, Miller K), CRC Press, Bocca Raton FLA, 1991; pp 143-164. 6. Rogers AJ, Leigh J, Berry G, Fergusson DA, Mulder HB, Ackad M. Relationship between lung cancer fiber type and concentration and relative risk of inesothelioma. Cancer, 1991;67:1912-1920. 7. Enterline PE. Extrapolation from occupational studies: a substitute for environmental epidemiology. Environ Health Perspect, 1981;42:39-44. 8. Doll R, Peto J. Effects on health of exposure to asbestos. London, Health & Safety Commission, Her Majesty's Stationery Office, 1985. ' 9. Hughes JM, Weill H. Asbestos exposure-quantitative N assessment of risk. Amer Rev Resp Dis, 1986;133:5-13. V7 O N i A ~ ~ O1 0)

13 10. Vacek PM, McDonald JC. Effect of intensity in asbestos- cohort exposure-response analyses. In: Occupational Epidemiology (ed Sakurai H, et al), Elsevier Science Publishers, 1990, pp 189-193. 11. Vacek PM, McDonald JC. Risk assessment using exposure intensity: an application to vermiculite mining. Brit J Ind Med, 1991;48:543-547. 12. Health Effects Institute - Asbestos Research. Asbestos in public and commercial buildings, Cambridge MA, HE1.AR, 1991. 13. McDonald JC. An epidemiological view of asbestos in buildings. Toxicol Ind Health, 1991;7:187-193.

TABLES AND FIGURES Source Table 1 Exposure-response for lung cancer in McDonald (1) male cohorts where exposure estimates Table 3 were made for each subject individually Table 2 Lung cancer and smoking in asbestos Berry etal (3) workers Table 8 Table 3 Estimated lifetime risks per million McDonald (1) population from non-occupational Table 4 exposure to asbestos Table 4 Lifetime risk estimates for populations McDonald (13) exposed to chrysotile only Table 4 Figure 1 Standardized mortality ratio (SMR) by exposures to asbestos fibres. Exposure- response relationships from 11 studies Figure 2 Concentrations of chrysotile and amphibole fibres more than 8pm in length in lung tissue at autopsy from mesothelioma cases and controls Figure 3 Relationship of loge (odds ratio) to log,o (fibre concentration in lung) for total uncoated fibres by light microscopic analysis McDonald (2) Figure 2 . McDonald & McDonald.(5) Figure 3 Rogers e al 6) Figure 1

Number Luna can<er Re)etia slapc Stndy _ n Type of /ndustry Study Place Fihcr ttyr in eohon Tou1 death> empected case a per mlxbyr I Mlmnaand Mcl)onild(fll Quclwc Chrysa6lc 1U.939 3.291 1&l OIW 2 mulme Gcnera) Hendersanand U.$. ChryzaWc 1,075 78) 133 a3sa manufactwe En4rGne It5) CroudnOte Anwsite 3 Cement prvducu Weill Iss) New Orlearu Chry.ntJe CrocidoGt< 5,W5 501 49.2 U.658 e Teztilea Dement (ty) S. Carolina C~hysotile 'i60 191 ].5 6.896 Table 1 5 Tutilu MeDovld (W) & Cuoatu Ghrywtile 2,543 857 29.6 5.863 5 Mafnly tutiks M<UonaM (e9) Pennaylvavla CJ.ryaoti)e 4,137 1,392 50.5 5.101 Amoute 7 Frictien produtt. Berry and New. Enelud QocdoGte Chrpetile 9,113 1,610 139.5 'efteeGve)y urv' houx(f0) Crvddolite e Frietion produc4 M<DOrWd Ul) Cannectiat Chry.ntile 3,64) 1,26T e9.1 'e!(ectively ura' 9 Cemena Product-+ FSnaebaein 4)f1 Ontario Chrykot{k 536 138 5.J noe dculatM Gocdnlite Table 2 Pable 3 'able 4 Nommaken Rmaken• sway obv.c.e6 F~peta R fati euk ohserwd Ezyned Re3aiire riek (U rmuption rwkca 0 0.05 0 y 29t i.) New York and Nc.lcncy, 196}T1" (2) Insularora. USA an 4 0.9 5.> 2" 514 5.3 Unada, I%T-T6'a ' (3) !kmorim fattary 5 02 #.0 l5 9.6 4.7 worknn. 1961-T]'• (41 Fa.aory rock<ra I 0.1 5.0 14 19 24 (wamcn4 UK, 1%0-70' (SI Faqory.wkcra. 4 055 ] 3 75 31.02 24 UK,1911-90 A.Wt«capmrrc 16) Minen and mi)leas. Gnadti1951-75 .ntrot dau'• Yes Not Y¢ Not Lunpon¢r .l7 6 IS( 69 Cnmro)s 93 103 3.0 274 l"0 IJ CombinW nnaia Relativc aWntoa 95z eRCt wnRdenec (N55) liml¢ Lung cancer Mesothe5oma Enterline (!2) 2 100' Schneidennan (F5) 3-32 4-24 Nicholson (40) 12-18 6-24 NRC Committ.ee (46) Smokecs, male 64-320 Smokers, female 23-120 Nonsmokers, male 6-29 9-46 Nonsmokers, female 3-15 'This figure should probably have been about 50 (see tezt). N N 0 Wpulaticn(n) Cancertration (llration AttriOutable cases f/ml) (yr) Lug cancer Nesochelinte Total N ~ A AsbeStos ~t 0.5 20 26 5 31 ~ wcrkers(10,000) 40 51 6 57 i ~ Sd,ool chi ldrrn (1 millian) 0.001 6 0,6 0.9 1.5 . - 0.003 1.9 2.6 4.5 BaSed an tUgY¢s an4 Weill (1986)

Figure 1 Figure 2 Figure 3 Lung Cancer SMR 1 .- - - - - - - - - 700 200 Exposure WmIA F-1CC Fibre[)ub r lo rl G~.LGi, Z (~ilip Sw)d 30 )0 io So w )o t0 fs ( 1 1 1 1 1 1 ( fC ( 9.i Relative risk (odds ratio) (loge scale) a 10 54 1 300 [r.l.[i.. Z (ltob.bil(t) s[lle) 20 30 w so w 70 ao p rt 1e I 1 ( 1 ( r 1 1 ( ( • • 4-0 4•5 5•0 515 6•0