Dose–Response Relationships for Disposition and Hepatic Sequestration of Polyhalogenated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls Following Subchronic Treatment in Mice,, ,

Abstract

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.

Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife

“…These subchronic studies also showed that octaCDD is extremely poorly absorbed and absorption from the gastro-intestinal tract decreased with increasing dose (143 (88,131,(144)(145)(146)(147)(148). In this respect, it should be noted that the structure-activity relationship for binding to the Ah receptor and to CYP1A2 are not identical (149). As the level of CYP1A2 is increased, dioxinlike compounds redistribute from the adipose tissue back to the liver.…”

Differential Regulation of Expression of Hepatic and Pulmonary Cytochrome P4501A Enzymes by 3-Methylcholanthrene in Mice Lacking theCYP1A2Gene

“…Recent studies have demonstrated a role for CYP1A2 as a hepatic binding protein (DeVito et al, 1998;Diliberto et al, 1999). Using CYP1A2 (Ϫ/Ϫ) mice, it has been shown that CYP1A2 protein mediates the sequestration of TCDD and polychlorinated dibenzofurans (PCDFs) in liver (DeVito et al, 1998;Diliberto et al, 1999).…”

“…Using CYP1A2 (Ϫ/Ϫ) mice, it has been shown that CYP1A2 protein mediates the sequestration of TCDD and polychlorinated dibenzofurans (PCDFs) in liver (DeVito et al, 1998;Diliberto et al, 1999). CYP1A2, however, has no effect on the pharmacokinetic behavior of nondioxin-like compounds such as PCB 153 (DeVito et al, 1998).…”

“…Using CYP1A2 (Ϫ/Ϫ) mice, it has been shown that CYP1A2 protein mediates the sequestration of TCDD and polychlorinated dibenzofurans (PCDFs) in liver (DeVito et al, 1998;Diliberto et al, 1999). CYP1A2, however, has no effect on the pharmacokinetic behavior of nondioxin-like compounds such as PCB 153 (DeVito et al, 1998). CYP1A2, through its role in the oxidation of uroporphyrinogen to uroporphyrin (Sinclair et al, 1998(Sinclair et al, , 2000, contributes to the development of uroporphyria in mice by TCDD (Smith et al, 2001).…”

My Winding Road: From Microbiology to Toxicology and Environmental Health

“…Mixtures were also a major topic for my research group focusing on dioxins. I hired Mike DeVito as a postdoc, and we focused on the relative potency of a variety of dioxin-like compounds, including some dioxins, furans, and PCBs, as well as some brominated dioxins and furans (68)(69)(70)(71)(72). We examined the ability of a suite of these chemicals to induce CYP1A1 and CYP1A2 in mouse liver, lung, and skin.…”