Derivation of Cumulated Age Adjusted Tumor Rates for Use in Low Dose Extrapolation

摘要

If crude experimental proportions of animals with tumors from chronic bioassays for carcinogenicity are used for low-dose extrapolation in a risk analysis, different dose-specific patterns of mortality due to competing risks can bias the results. In order to adjust tumor rates for differential mortality across dose groups, Farmer, Kodell and Gaylor (1982) recommended using nonparametric estimates of probability distributions of times to onset of tumors, with competing causes of death removed, when performing a risk analysis. The paper extends the approach of Farmer, et al (1982) by proposing a method for adjusting tumor rates to reflect lifetime or near-lifetime tumor incidences that would be obtained if all dose groups experienced the control mortality rate from causes other the tumor of interest. Thus natural mortality due to competing risks is explicitly included, rather than removed. The proposed standardized tumor rates are calculated as a summation of adjusted age-specific probabilities of dying with a tumor during the course of an animal bioassay for carcinogenicity plus the probability of being alive with a tumor at the terminal sacrifice. In a dose-response bioassay involving two or more treatment groups, comparable standardized tumor rates can be estimated only through the time of the last death in the shortest surviving dose group, which generally will be the time of the terminal sacrifice.