Quantitative and statistical analysis of differences in sensitivity between Long-Evans and Han/Wistar rats following...

In this study, differences in sensitivity between Long-Evans (L-E; dioxin sensitive) and Han/Wistar (H/W; dioxin resistant) rats following long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were statistically and quantitatively investigated. Sensitivity differences were analyzed by comparing benchmark doses (BMDs) for the two strains considering a number of toxicological endpoints including data on body and organ weights, hepatic foci, hepatic CYP1A1 induction, as well as tissue retinoid levels. Dose-response relationships for L-E and H/W rats, described by the Hill function, were assumed to be parallel, which was supported according to statistical analysis. It was concluded that L-E and H/W rats differed statistically in their response to TCDD treatment for most of the parameters investigated. Differences between the strains were most pronounced for hepatic foci; L-E rats were approximately 20-40 times more sensitive than H/W rats. For body and organ weight parameters, L-E rats were approximately 10-20 times more sensitive than H/W rats. For retinoid parameters and hepatic CYP1A1 induction, estimated differences between the strains were generally about 5-fold, and associated with a low uncertainty. In conclusion, the present study employs a dose-response modeling approach suitable for statistical evaluation of strain and species differences in sensitivity to chemical exposure. The study demonstrates quantitatively the differences in sensitivity between the L-E and H/W rat strains following long-term TCDD exposure.