Dose-response relationships for disposition and hepatic sequestration of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls following subchronic treatment in mice

• Published in: Toxicological sciences Vol. 46; no. 2; pp. 223 - 234
• Main Authors: DEVITO, M. J, ROSS, D. G, DUPUY, A. E, FERRARIO, J, MCDANIEL, D, BIRNBAUM, L. S
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01.12.1998
• Subjects: Animals; Benzofurans - pharmacokinetics; Biological and medical sciences; Biphenyl Compounds - pharmacokinetics; Body Burden; Chemical and industrial products toxicology. Toxic occupational diseases; Cytochrome P-450 CYP1A2 - physiology; Dioxins - pharmacokinetics; Dose-Response Relationship, Drug; Female; Lipid Metabolism; Liver - drug effects; Liver - metabolism; Medical sciences; Mice; Time Factors; Toxicology; Various organic compounds; Subchronic; Toxicity; Liver; Rodentia; Polychlorobiphenyl; Ingestion; Dose activity relation; Toxicokinetics; Pollutant; Tissue; Vertebrata; Mammalia; Mouse; Animal; Chlorine Organic compounds; Chlorocarbon; Distribution; Bromine Organic compounds; Kinetics
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1006/toxs.1998.2530

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.