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.
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.
Sand
Salomon
S
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Salomon.Sand@slv.se
Fletcher
Nicholas
N
von Rosen
Dietrich
D
Kalantari
Fereshteh
F
Viluksela
Matti
M
Tuomisto
Jouni T
JT
Tuomisto
Jouko
J
Falk-Filipsson
Agneta
A
Håkansson
Helen
H
D000818:Animals; D019985:Benchmarking; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D013045:Species Specificity; D013997:Time Factors; D036401:Toxicity Tests, Chronic / Q000379:methods / Q000706:statistics & numerical data; D014801:Vitamin A / Q000097:blood
D003580:Cytochromes; D000072317:Polychlorinated Dibenzodioxins; D014801:Vitamin A; C017170:Cyp1a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2