Differences in acute toxicity syndromes of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin in rats.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent congener of polychlorinated dibenzo-p-dioxins. The potency of 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD) is only 10% of that of TCDD for typical aryl hydrocarbon receptor (AHR)-mediated effects. Acute lethality, macroscopic effects, and liver toxicity of TCDD and HxCDD were compared in male rats of the strain Han/Wistar (Kuopio; H/W), and of the lines A and B. The latter two rat lines originate from crossbreeding of H/W and Long-Evans (Turku/AB) rats. H/W and line A rats are highly resistant to acute toxicity of TCDD due to an altered AHR, while line B rats are moderately resistant due to H/W-type alleles of another, yet unidentified gene contributing to TCDD resistance ("gene B"). The rats received 200-10,000 microg/kg of either TCDD or HxCDD intragastrically and were monitored for 46 days. In all rats, the highest dose of HxCDD (10,000 microg/kg) reduced body weight more effectively than an identical dose of TCDD. Only HxCDD (10,000 microg/kg) caused gastrointestinal hemorrhage, pale (fatty) livers and death by day 15 in H/W and line A rats. In line B rats, HxCDD caused pronounced hepatic fatty degeneration, whereas TCDD induced hepatic accumulation of biliverdin and its derivatives. Both congeners induced sinusoidal distension in liver. In H/W and line A rats, the estimated LD(50) values were >10,000 microg/kg and 2000-10,000 microg/kg for TCDD and HxCDD, respectively; for line B rats they were 480 microg/kg and 1000-2000 microg/kg, respectively. Thus, HxCDD was more potent than TCDD in inducing acute mortality in H/W and line A rats, contrary to what is predicted by toxic equivalency factor (TEF) values. In line B, the expected rank order of potencies prevailed. These findings suggest that in addition to the canonical AHR-mediated toxic pathways, HxCDD possesses an AHR-independent mechanism of toxicity, whose main manifestations are rapid body weight loss, mortality, fatty liver and gastrointestinal hemorrhage.
Niittynen
Marjo
M
Department of Environmental Health, National Public Health Institute, PO Box 95, FI-70701 Kuopio, Finland. marjo.niittynen@ktl.fi
Simanainen
Ulla
U
Syrjälä
Paula
P
Pohjanvirta
Raimo
R
Viluksela
Matti
M
Tuomisto
Jouko
J
Tuomisto
Jouni T
JT
D000818:Animals; D001664:Biliverdine / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D005234:Fatty Liver / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006824:Hybridization, Genetic; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D002274:Carcinogens, Environmental; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C078219:1,2,3,4,7,8-hexachlorodibenzodioxin; D001664:Biliverdine