Dose-response trend tests for tumorigenesis, adjusted for body weight.
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.
Gaylor
D W
DW
National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA. dgaylor@nctr.fda.gov
Kodell
R L
RL
D000367:Age Factors; D000840:Anisoles / Q000633:toxicity; D001835:Body Weight; D015197:Carcinogenicity Tests; D004305:Dose-Response Relationship, Drug; D004319:Doxylamine / Q000031:analogs & derivatives / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced*; D009579:Nitrobenzoates / Q000633:toxicity; D013223:Statistics as Topic; D013997:Time Factors
D000840:Anisoles; D009579:Nitrobenzoates; D004319:Doxylamine; C008629:4-nitrobenzoic acid; C035385:doxylamine succinate; C005328:2-nitroanisole