Dose-response trend tests for tumorigenesis, adjusted for body weight

• Published in: Toxicological sciences 1999-06, Vol.49 (2), p.318-323
• Main Authors: GAYLOR, D. W, KODELL, R. L
• Format: Article
• Language: English
• Subjects: Age Factors; Anisoles - toxicity; Biological and medical sciences; Body Weight; Carcinogenesis, carcinogens and anticarcinogens; Carcinogenicity Tests; Chemical agents; Dose-Response Relationship, Drug; Doxylamine - analogs & derivatives; Doxylamine - toxicity; Medical sciences; Neoplasms - chemically induced; Nitrobenzoates - toxicity; Statistics as Topic; Time Factors; Tumors
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/49.2.318

Several studies have demonstrated a relationship between rodent body weight and tumor incidence for some tissue/organ sites. It is not uncommon for a chemical tested for carcinogenicity to also affect body weight. In such cases, comparisons of tumor incidence may be biased by body-weight differences across dose groups. A simple procedure was investigated for reducing this bias. This procedure divides the animals into a few groups based on 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 body weight strata and pooled to obtain an overall dose-response trend test. This procedure is analogous to that currently used, of stratifying animals, based on their age at the time of removal from a study. Age stratification is used to account for differences in animal age across dose groups, which can affect comparisons of tumor incidence. Several examples were investigated where the high-dose group had reduced body weights and associated reductions in tumor incidence. When the data were analyzed by body-weight strata, some positive dose-response trends for tumor incidence were demonstrated. In one case, the weight-adjusted analysis indicated that a negative dose-response trend in tumor incidence was a real 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 below, that were caused by chemicals in 2-year bioassays for carcinogenesis. The simple procedure of analyzing tumor incidence within body-weight strata can reduce the bias introduced by weight differences across dose groups.