Dose-response trend tests for tumorigenesis adjusted for differences in survival and body weight across doses

A relationship between rodent body weight and tumor incidence for some tiss ue/organ sites has been demonstrated in many studies. It is not uncommon fo r a chemical tested for carcinogenicity to also affect body weight due to t oxicity and/or food consumption. In such cases, comparisons of tumor incide nce may be biased by body weight differences across dose groups. A simple p rocedure was investigated for reducing this bias. This procedure divides th e animals into a few groups on the basis of body weight. Body weight at 12 months was used, before the appearance of a tumor was likely to affect body weight. Statistics for dose-response trend tests are calculated within bod y weight strata and pooled to obtain an overall dose-response trend test. T his procedure is analogous to stratifying animals on the basis of age at th e time of removal from a study to account for differences in ages of animal s across dose groups that can affect comparisons of tumor incidence. In thi s paper, differences in survival times of animals were adjusted by the Poly -3 technique used by the National Toxicology Program. This technique does n ot require the assignment of cause of death. Several examples from rodent c hronic bioassays were investigated, where the high dose group had reduced b ody weights and associated reductions in tumor incidence. When we analyzed the data by body weight strata, some positive dose-response trends for tumo r incidence were demonstrated. In one case, the body weight adjusted analys is indicated that a negative dose-response trend in tumor incidence was a r eal effect in addition to a body weight reduction. These examples indicate that it is important to consider the effects of body weight changes as low as 10%, and perhaps less, as possibly being caused by chemicals in 2-year b ioassays for carcinogenesis. The simple procedure of analyzing tumor incide nce within body weight strata can reduce the bias introduced by body weight differences across dose groups.