Structure-activity relationships and dose responses of polychlorinated dibenzo-p-dioxins for short-term effects in 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant and -sensitive rat strains.
Dose responses of the characteristic short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD), and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) were compared in the resistant Han/Wistar (Kuopio) (H/W) rats and the sensitive Long-Evans (Turku/AB) (L-E) rats. The resistance of H/W rats is linked to the altered H/W-type aryl hydrocarbon receptor (AHR). Exceptionally, in terms of acute lethality, the most potent congener for H/W rats is HxCDD, followed by HpCDD, PeCDD, and TCDD. The study objectives were to find out if this exceptional sensitivity of H/W rats also holds for nonlethal toxic endpoints and to compare potency and efficacy (magnitude of effect) of PCDDs between L-E and H/W rats. Dose responses for several endpoints were determined, modeled, and used for ED50 and relative potency (REP) calculations. For all endpoints measured, TCDD was the most potent congener, followed by PeCDD, HxCDD, and HpCDD in both strains, and the REP estimates were consistent with the current toxic equivalency factors (TEFs). For most endpoints, H/W rats showed smaller responses to all congeners than L-E rats, and this difference was due to lower efficacy rather than lower potency. H/W rats showed lower efficacy to body weight loss, serum aspartate aminotransferase activity, and serum concentrations of total bilirubin, free fatty acids, and thyroxine. In contrast, effects on cytochrome P4501A1 induction, thymus atrophy, and dental defects were similar in both strains. In conclusion, the results are in agreement with the current WHO-TEFs and imply that relative potency values derived from mortality are not necessarily valid for other endpoints. The results support our previous observations about two different types of AHR-mediated mechanisms. Type I effects are similar in both strains, and type II effects show decreased efficacy of toxic response in relation with the altered H/W-type AHR.
Simanainen
Ulla
U
Department of Environmental Health, National Public Health Institute, Kuopio, Finland.
Tuomisto
Jouni T
JT
Tuomisto
Jouko
J
Viluksela
Matti
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology
D000072317:Polychlorinated Dibenzodioxins; C051452:1,2,3,7,8-pentachlorodibenzo-p-dioxin; C046838:1,2,3,6,7,8-hexachlorodibenzodioxin; D019363:Cytochrome P-450 CYP1A1; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin