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Liddoll FDK. Exposute-reapotue- asbestos and mrsotbefinma. Eur Rupir Rev 1993; 3: 11, 98-99. (1991.12.18; with addendum 1993.03.11) Exposure-Retponse: Asbestos and Mesothelioma - F D K LIDDELL Depanmenr of Epidemiafngy and Biosrmirria, McCiB Uaiwer.riry, Moarreal, Canada Abstract In each cohort in which it can be examined satisfactorily, the relationship between duration of asbestos exposure and the risk of ineso0teiioma is direct, and several are quite strong. It is thus dear thete are very powerful exposuto-.esponse relationships. There is good evidence that these relationships ate sub-linear at very short durations of exposure and probably again at rnther long duntions of exposure. The likelihood is that the underlying relationship is sigmoid, regudless of fibre type. In their report to the Health and Safety Commission in 1985, Doll and Peto' stated that, although the predicted risk of inesotbelioma increased in approximate propoetion to duration of asbestos exposure for exposures of up to about 10 yeaes, there was very little difference between the predicted effects of stopping or continuing exposure after 20 years. However. t(ose examination of their data suggests a much mote positive conclusion. Table ) displays three models of risk: Not surprisingly, the over-simplified Model 1 is quite inadequate. The fit by Model 2, tvhich has been used by Peto and eowamkas; appears somewhat betAer, but the goodness-of-fit 3? statistic (Sdf) is 46.s, associated with a P value of 0.000(Y7. Model 3, asen'bed to Peto and endorsed by Doll and Peto,t yields a corresponding statistic of 7.2, suggesting a vety good fit: the great impmvetnmtt over Model 2 amse from the incorporation of the term for duration of exposure - see the last line of Table 1. A formal test of the degree of improvement was carried out by fittingexponential models including I) lapse and 2) lapse and duration; the second term decreased the Likelihood Ratio statistic by 9.8 (using I extra degree of fteedom), an improvement of enormous statistical significance. While it is true thee was no death fmm msot&ulioma among those with 30 or more years of service, the expected number of deaths even on Model 3 was so low the shortfall was quite insigaificant; fuNwr. for mw with 20-29 years of scheduled serviee. the.e were nearly twice as many cases as expected. Thus it seetns sasonabte to claim that the risk of ine,sotheliosu incieased in approximate proportion to the duration of exposure up to at least 30 years. Table 1. - Three models of inesothelioma risk in terms of subject-years, lapse, and_d~t,ion of exposure. - Model I risk - subject-years Model 2 risk - (lapse)33 x subject-yaars Model 3 risk - ((lapse)4 -(lapse - duration)4) x subject-years which, except for rather long durations, can be taken as: risk a(duration) x(lapse)3 x subjeet-years or effectively Model 2 modified by a 'linear' term for duration - N ~ O N ~ .P O N O -1-

the findings in man are for such low 'doses' that the risk might have been thought to increase moroor-less exponentially - but this is certainly not the epidesniological finding. Finally, the evidence of Browne and Smither" must be mentianed. At first sight, it runs counter to the findings discussed here. However these authors' results cannot be evaluated because no 'denominatons• are available; it is entirely possible that the distribution, by duration of employment, of all Cape Asbestos employees over the years were so highly skewed that them is no real contradiction with the present findings. Two further factors must be borne in mind: the Cape Asbestos experience dates back many decades when intensities of exposure were unthinkably high; and a substantial proportion of 'short-service cases' may in fact have atisea from neighbourhood exposu.e, which was known to have been far from negligible near the Barking plant in which the great majority of the cases had worked. Addendum - 1993.03.11 It has recently been reported'= that, among 10.926 Quebec asbestos workers born 1891-1920 and followed to the end of 1988, thece have been 33 suspec[ed nv+Dtteliomas in all; of these, eight and 20 were in miners and millers from Asbestos and itom the Tbetford Mines region, respectively, and five were among men employed in a small asbestos products factory in Asbestos. 1Lete were no cases of inesothelioma among the 4438 men employed for less than two years, eight cases among those 2448 employed for 2-10 years, and 25 mesotheliomas among the 4040 men with at least 10 years employment. This information supersedes that in the last line of Table 2, so that there have now been twelve cohorts with a'tumour-fine' duration, and the numbers expected in these periods now total 7.3. Again excluding the findings from referoncrs 5. and 6., the legitimate test becomes of nro observed, where 4.9 were expected, and yields P= 0.007. I3eferettce.s 1. Doll R, Peto J. Efeus on Health ofEcposun to Asbestos. Health and Safety Commission. London: HMSO, pp 33-40. 2. Peto J, Seidman H, Selikoff U. Mesothelioma monality in asbestos workers: implications for models of caeinogenesis and risk assessment. Br J Cancer 1982; 45: 124-135. 3. De Klerk NH, Armstrong BK. Musk AW, Hobbs MST. Cancer mortality in relation to measures of occupational exposure to crocidolite at Wittenoom Gorge. Br J Ind Med 1989; 46: 529-536. 4. Sluis-Cremer GK, Liddell FDK, Logan WPR, Bezuidenhout BN. The mortality of amphibole miners in South Africa, 1946-80. Br J Ind Med 1992; 49 : 566-575. 5. Jones JSP, Pooley FD. Sawle GW, Smith PG, Berry G. Wignall BK, Aggarwal A. The consequences of exposure to asbestos dust in a wariime gas mask factory. In: Wagner JC (Ed). Biological Effear of Mineral Fibres. IARC Scientific Publications 30. Lyon: International Agency for Research on Cancer, 1980, pp 637-653. 6. Seidman H, Selikoff IJ, Gelb SK. Mortality experience of amosite factory workers: dose-response relationships 5 to 40 years after onset of short-tetm work exposure. Am J Ind Med 1986; 10: 479. 7. Newhouse ML, Berry G, Wagner JC. Mortality of factory workers in east London 1933-80. Br J Ind Med 1985; 42: 4-11. 8. Hughes JM, Weill H. Hammad YY. Mortality of workers employed in two asbestos cement manufacturing plants. Br! Ind Med 1987; 44: 161-174. 9. Liddell D. Epidemiological observations on mesothelioma and their implications for non-occupational expastiro to asbrstos. In: Spengler JD, Ozitaynak H. McCarthy JF, Lee H (Eds). Symposium on Health Effects ofEsposurc to Asbestos in Buildings, December I4-16, 1988. Cambridge MA: Harvard University Energy and Environmental Policy Center 1989, pp 47-69. 10. McDonald JC, McDonald AD. Epidemiology of Mesothelioma. Jn: Liddell D, Miller K (Eds). Mineral F'ibets and Health. Boca Ratat, Florida: CRC Press 1991, pp 147-168. 11. Browna K, Smither WJ. Asbestos-related mesothelioma: factors discriminating between pleural and peritoneal sites. Br J Ind Med 1983; 40: 145-152. 12. McDonald AD, Liddell FDK. McDonald JC. Malignant mesothelioma in Quebec chrysotile miners and millers: a preliminary report. In: Proceedings of the 9th International Symposium on Epideniology in Ocarpatioiwl Health, Cineinrw[i, Ohio, September. 1992. In press. -3-