Age-Related Differences in Susceptibility to Carcinogenesis II, Approaches for Application and Uncertainty Analyses for Individual Genetically Acting Carcinogens
An earlier paper (Hattis et al., 2003) developed a quantitative likelihood-based statistical analysis of the differences in apparent sensitivity of rodents to mutagenic carcinogens across three life stages (fetal, birth-weaning, and weaning-60 days) relative to exposures in adult life. This report assesses three types of uncertainties that arise in the application of the earlier results to human quantitative risk projections for full life exposures to a generic individual mutagenic carcinogen. These are
(1) uncertainty in the central estimates of the life-stage-specific sensitivity factors estimated earlier,
(2) uncertainty from chemical-to-chemical differences in life-stage-specific sensitivities for carcinogenesis
(3) uncertainty in the mapping of rodent life stages to human ages/exposure periods
The results of this analysis indicate that the third of these sources of uncertainty is quantitatively the most important. The interspecies time mapping is accomplished by (1) assuming that the developmental ages in mice, rats, and humans are equivalent at the reported times of sexual maturity for each gender, based on literature data, and (2) mapping other times in each species in proportion to the growth in body weight relative to body weights at sexual maturity. As it happens, this approach leads to differences of several fold in central estimates of the duration of the human equivalent of the "birth-weaning" period in rodents?the period of maximum sensitivity for carcinogenesis by the mutagenic agents in the available data base. The potential implications of this are explored with the aid of lognormal distributions for the human equivalent time periods estimated from the rat-mouse differences. The distributions are truncated at the upper end so that the human equivalent of the sum of birth-weaning and weaning-60 day rodent periods is not allowed to exceed 16 years in human males or 15 years in human females?the approximate average ages when vertical growth ceases, based on data from the third National Health And Nutrition Survey.
The combined effect of the three types of uncertainties listed above is estimated with the aid of Monte Carlo analyses. Final results are based on averages of three sets of 5000 Monte Carlo trials each. Overall, the population arithmetic mean risk from lifetime exposures to a generic mutagenic carcinogen is estimated to be about 3.5 fold larger than for exposure only during the "adult" (60+ day equivalent for rodents) period, with 5%-95% confidence limits of 1.7 ?7.4 fold.
A final portion of the paper notes some additional issues that need to be represented in an uncertainty analysis for a model example chemical with an apparent mutagenic mode of action?acrylamide. These are (1) differential exposure of children of various life stages per body weight3/4 relative to adults (2) a multiplicity of animal bioassays available for human risk projections, (3) adjustments for the inclusion of an appreciable portion of the "weaning-60 day" period in the existing acrylamide bioassays, in contrast to the assumption in our analysis that testing starts in full adulthood at about 60 days of age in rodents, (4) integration of likelihood-based uncertainties in estimated dose response slopes from the bioassay data into the overall uncertainty analysis, (5) incorporation of estimates of delivered dose, across species and life stages, preferably with the aid of physiologically-based pharmacokinetic models, along with pharmacodynamic uncertainties in interspecies projections. Incorporation of all of these considerations into an integrated analysis of cancer risks for full lifetime exposure to acrylamide awaits further work.