RATIONALE FOR THE USE OF DIETARY CONTROL IN TOXICITY STUDIES - B6C3F1MOUSE

Significant variability in critical study parameters such as tumor inc idences and survival, increasing tumor incidence and decreasing surviv al in common toxicity test models, and agent-induced changes in body w eight(BW) and BW distribution all generate concern about the reproduci bility, consistency, and equity of chronic toxicity tests used in regu lation. These concerns have led to suggestions to control BW in chroni c tests by the modulation of dietary intake without inducing malnutrit ion [dietary control (DC)] thereby minimizing tumor and survival varia bility both between and within studies. Evaluating the reports of the best controlled set of chronic experiments, the National Toxicology Pr ogram bioassay series, from studies initiated from 1981 to 1990, there is an increase in tumor incidence, especially liver tumors, with a co nsistent increase in BW. The studies are classified as to whether norm al or aberrant BW growth curves occur. When the studies with normal gr owth curves are considered, the variance in the BW at 12 mo on test (B W12) can account for over 50% of the variance in liver tumor incidence . Additional stratification by study type, which alter tumor prevalenc es, as well as appreciation of housing effects [group housing decrease s survival (in male mice) and induces tumors in males and females when compared to individual housing], further increase the strength of the correlations, accounting for up to 90% of the variance seen in tumor incidences. These updated analyses further support the hypothesis that it is the BW variation that is resulting in much of the variability s een in tumor incidences and refine the suggestions for the BW curves u sed as the desired targets for DC.