Quantitative and statistical analysis of differences in sensitivity between Long–Evans and Han/Wistar rats following long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

• Published in: Regulatory toxicology and pharmacology Vol. 57; no. 2-3; pp. 136 - 145
• Main Authors: Sand, Salomon, Fletcher, Nicholas, Rosen, Dietrich von, Kalantari, Fereshteh, Viluksela, Matti, Tuomisto, Jouni T., Tuomisto, Jouko, Falk-Filipsson, Agneta, Håkansson, Helen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2010
• Subjects: Animals; Benchmark dose; Benchmarking; BMD; Body Weight - drug effects; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1A2; Cytochromes - metabolism; Dose-response; Dose-Response Relationship, Drug; Farmakologi och toxikologi; Female; Liver - drug effects; Liver - enzymology; Liver - metabolism; Liver - pathology; Medicin och hälsovetenskap; Organ Size - drug effects; Organ Specificity; Pharmacology and Toxicology; Polychlorinated Dibenzodioxins - toxicity; Rats; Rats, Long-Evans; Rats, Wistar; Species Specificity; Strain sensitivity; Strain variation; TCDD; Time Factors; Toxicity Tests, Chronic - methods; Toxicity Tests, Chronic - statistics & numerical data; Vitamin A - blood; BMD; TCDD; Dose-response; Strain variation; Strain sensitivity; Benchmark dose
• ISSN: 0273-2300; 1096-0295; 1096-0295
• DOI: 10.1016/j.yrtph.2010.01.006

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.