Dose-response relationships for disposition and hepatic sequestration of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls following subchronic treatment in mice.
Humans are exposed to mixtures of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls mainly through the diet. Many of these chemicals are dioxin-like and their relative toxicity is related to their ability to bind and activate the Ah receptor. The present study examines the structure-activity relationship for disposition of these chemicals in female B6C3F1 mice following subchronic exposures. Mice were treated 5 days/week for 13 weeks by oral gavage with different doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD),2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), octachlorodibenzofuran (OCDF), 3,3',4,4',5-pentachlorobiphenyl (126), 3,3',4,4',5,5'-hexachlorobiphenyl (169), 2,3,3',4,4'-pentachlorobiphenyl (105), 2,3',4,4',5-pentachlorobiphenyl (118), and 2,3,3',4,4',5-hexachlorobiphenyl (156). All of the chemicals examined exhibited dose-dependent increases in the liver/fat concentrations except PCBs 105, 118, and 156. While TCDD is the most potent toxicant in this class of chemicals, 4-PeCDF, PeCDD, OCDF, TCDF, and PCB126 were sequestered in hepatic tissue to a greater extent than was TCDD. The high affinity for hepatic tissue supports the presence of an inducible hepatic binding protein for some dixin-like chemicals. The differences in disposition between these chemicals suggests that pharmacokinetic differences between congeners is important in the relative potency of these chemicals.
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
M J
MJ
DeVito
D G
DG
Ross
A E
AE
Dupuy
J
J
Ferrario
D
D
McDaniel
L S
LS
Birnbaum
D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D001822:Body Burden; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology; D004147:Dioxins / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D013997:Time Factors
D001572:Benzofurans; D001713:Biphenyl Compounds; D004147:Dioxins; D019388:Cytochrome P-450 CYP1A2