Dose-response relationships for polyhalogenated dioxins and dibenzofurans following subchronic treatment in mice. I. CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin.
The dose-response relationships for induction of liver, lung, and skin ethoxyresorufin-O-deethylase (EROD) activity and liver acetanilide-4-hydroxylase (ACOH) activity following subchronic exposure to either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin, 2,3,7,8-tetrabromodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), or octachlorodibenzofuran (OCDF) were determined in female B6C3F1 mice in order to estimate the relative enzyme inducing potency of these chemicals in three different tissues. The relative potencies were calculated based on tissue concentrations as well as administered dose. A dose-dependent induction of EROD activity in liver, lung, and skin and of ACOH activity in liver was found for all seven chemicals. When based on administered dose, the relative potencies for specific congeners did not vary substantially among tissues. The relative potencies for TCDF and 1-PeCDF, congeners which have much shorter half-lives than TCDD, increased for all enzymes when estimated from tissue concentrations. The relative potency of OCDF, which is poorly absorbed, was greater when estimated from tissue concentrations than when estimated from administered dose. 4-PeCDF is highly sequestered in hepatic tissue and when the relative potency was estimated based on tissue concentration, its potency for skin enzyme induction increased. These data indicate that the relative potency of these chemicals is influenced not only by the relative binding affinity to the Ah receptor, but also by differences in pharmacokinetic properties of these chemicals. In addition, it may be useful to derive two sets of toxic equivalency factor values, one used for estimating intake equivalents and the other for estimating tissue equivalents.
DeVito
M J
MJ
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. devito@epamail.epa.gov
Diliberto
J J
JJ
Ross
D G
DG
Menache
M G
MG
Birnbaum
L S
LS
D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004147:Dioxins / Q000008:administration & dosage / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008954:Models, Biological; D012867:Skin / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
D001572:Benzofurans; D004147:Dioxins; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2