[Uncertainty analysis of quantitative risk assessment in temporally variable exposures: model observations based on...

Unit risks used for quantitative cancer risk assessment are defined for constant lifetime exposures. The condition of temporal stability, however, usually is not fulfilled in environmental health applications. In practice, cancer risks for time-dependent exposures are often estimated by calculating lifetime average exposure, assuming a mean life expectancy of 70 years. In the present paper we discuss the question whether this is an appropriate procedure considering various variants of multi stage and epidemiological relative risk models. For this purpose, lifetime risks for time dependent exposures as calculated according to the respective model assumptions, were compared with lifetime risks estimated by the lifetime average exposure approach. As typical exposure histories in environmental health applications we studied exposures either limited to the first 5 years of life (children scenario) or limited to duration of employment (30th to 65th year of age; occupational scenario). The consideration of multistage models (Armitage-Doll- and Moolgavkar-Venzon-Knudson model) in general would not induce serious bias in risk estimation when exposures are limited to middle ages (occupational scenario). On the other hand, when exposures occur only in very young ages or only in very old ages the risk estimated by using lifetime average exposure is not comparable with the predictions of multistage models. Whereas the degree of possible underestimation is bounded by factors well below 10, the amount of possible overestimation is unbounded and may become arbitrarily high, when exposures concentrate in extreme ages. In a second part of the study we investigated different relative risk models, taking lung cancer as an example. The models differed with respect to assumptions on latent periods and moderating effects of age at exposure and age at risk. The simulations showed that the unit risk concept is appropriate for the occupational scenario. For the children scenario results strongly depend on the assumptions made. Whereas the degree of possible underestimation is acceptable, in some models the degree of possible overestimation may become arbitrarily high. Both parts of the study showed that bias induced by using lifetime average exposure is acceptable when exposures are limited to middle ages. On the other hand, the unit risk concept should not uncritically be applied to exposures limited to early childhood (e.g., in kindergartens or due to mouthing activities). Depending on the assumptions made, lifetime risk may either be moderately underestimated or grossly overestimated. Without additional knowledge on mechanisms or latency period risk estimations are of questionable value. With respect to exposures in childhood regulation should concentrate on initiating substances or substances known to have long latent periods, respectively. With respect to cancers which occur relatively frequent already in childhood specific considerations are recommended.