Document daRvvGjjMVZEZKzzvYbqRJb39

Quantitative rijki of mejothelioma and lung cancer 583 the same range of possible slopes for the chrysolite lung cancer relationship as for the amphiboles, and determine the scaling constant by fixing the predicted exces; mortality at the median exposure for chrysotile cohorts (70 f/ml.yr) to 0.1 % for the best estimate and 0.5% for the cautious estimate. The resulting values are shown in Table 10. The pattern of excess lung cancer--broadly con stant relative excess from 10' to 40 (perhaps more) yean from exposure (see Appendix A) implies that for exposure starts between 20 and 40 yr of age there is very little difference in the predicted risk. There may be some decline for very long follow up, but the rate of decline is unknown. As for mesothelioma we address this possibility approximately by truncating the predicted excess at age. 80. IS THERE A THRESHOLD? Another question with important implications for risk at low levels of exposure is whether, there is a threshold for cancer initiation by asbestos. The HSE's recent Review of fibre toxicology (Meldrum, 1996), presents arguments mainly on a toxicological basis t believing that there may be a threshold for asbesios induced lung cancer. The argument is essentially based- on a view of (he carcinogenic process induced by asbestos as being an extension of the chronic inflammatory processes producing fibrosis. It is widely' agreed - that heavy doses of chrysotile are required to produce lung fibrosis. And some evidence has been deg.Ved from the New Orleans cohort sug gesting a threshold dose of about 30 f/ml.yr for radio logical fibrosis (Weill, 1994). Analysis of necropsy material from the Carolina cohort also shows a dis tinct step increase in fibrosis score for cumulative exposures around 20-30 f/ml.yr (Green et al., 1997). This does not apply to omphibole exposure: radiologi cal fibrosis which progressed after the cessation of exposure has been documented (Sluis-Cremer, 1991), in South African amphibole miners under medical surveillance and with cumulative doses less than 5 f/ml.yr. This suggests that if a threshold applies to the lung cancer effect of amphibole asbestos, it is very low. The adoption of a slightly concave exposure response slope entails a moderately threshold-like behaviour. Several lines of argument also suggest that any threshold for mesochelioma is at a very low level. Some cohorts (Neuberger and Kundi, 1990; Newhouse and Sullivan, 1989; McDonald and McDonald, '978; Thomas et al., 1982: Rossiter and Coles, 1980), re produced mesotheliomas in conditions where no excess lung cancer was seen. Occupational PMRs for British men suggest that (he range of jobs for which mesotheliomu rates ure above background levels is very wide (Hutchings el at., 1995: Hodgson et al., 1997). Also the proportion of mesotheliomu cases in population studies for whom no likely source of asbestos exposure can be identified is often quite high. All these observations suggest that relatively brief exposures may carry a low, but non-zero, risk of causing mesothelioma. Some authors (Ugren and Browne, 1991; Liddell. 1993) have argued for a mesothelioma threshold, or threshold-like behaviour of the dose-response. Such arguments are fraught with statistical and logical dif ficulties. The attempt (Ilgren and Browne, 1991) to deduce a 'threshold' by identifying the lowest esti mated dose received by any observed case is a logical nonsense. Furthermore, the existence of zero cases in a dose category (human or animal) should not be automatically interpeted os zero risk. Direct statistical confirmation of a threshold from human data is vir tually impossible. One would need'accurate'assess ment of very low doses across a large population with long term follow up. Case-control studies with lung content measures of exposure (McDonald et al.. 1989; Rbdelsperger et al., 1999; Rogers el al., 1991) do not suggest any threshold, or downward inflexion of the dose response at the lower end of their exposure scales. Some of the animal data cited by Ilgren and Browne are suggestive of a threshold-- particularly that from intra-pleural and intra-peritoneal injection--but it is not clear how this would translate into a estimated human effect threshold for exposure by inhalation. Taking this evidence together we do not believe there is a good case for assuming any threshold for mesothelioma risk. QUANTIFIED RISK ASSESSMENT Under current conditions, the main interest in the health risks of asbestos relates to exposure circum stances well outside the range for which we have direct observations. The statements we can make about risk therefore incoiporate two kinds of uncer tainty. First there is the usual statistical uncertainty of inferring underlying risk from observations in particular groups. This kind of uncertainty depends essentially on the number of events (in this case can cer deaths) observed. The uncertainty can therefore--given some assumptions--be quantified: the more observed events, (he less the statistical uncertainty. Statistical uncertainty is expressed as a confidence interval (a range of values with--conventionally--a 95% probability of covering the true value). The second kind of uncertainty relates to the ques tion whether the relationship between exposure and outcome seen in the observed range continues to hold outside that range. This kind of uncertainty cannot be quantified statistically. Qualitatively one can reason ably argue that the agreement will be better for exposures close to. the observed range, but with increasing distance from the observed range our con fidence that we know what tu expect decreases. For example, previous assessments of cuncelr risk from asbestos have all ussumed that the effect is linear. i'1 : !.,