ToxSci Advance Access originally published online on June 19, 2008
Toxicological Sciences 2008 105(1):33-43; doi:10.1093/toxsci/kfn118
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Toxicokinetics Of 2,3,7,8-TCDF and 2,3,4,7,8-PeCDF in Mink (Mustela vison) at Ecologically Relevant Exposures
* Aquatic Toxicology Laboratory, National Food Safety and Toxicology Center
Department of Animal Science, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
Summit Toxicology, L.L.P., Falls Church, Virginia 22044
Entrix, Inc., Okemos, Michigan 48864
¶ The Dow Chemical Company, Midland, Michigan 48642
|| Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan S7J 5B3, Canada
1 To whom correspondence should be addressed. E-mail: zwiernik{at}msu.edu. Tel: (517) 749-5243. Fax: (517) 432-2310.
Received September 7, 2008; accepted June 5, 2008
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Abstract |
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Wild mink (Mustela vison) living along the Tittabawassee River in central Michigan exhibit elevated hepatic and dietary polychlorinated dibenzofuran (PCDF) concentrations exceeding mink-specific, literature-reported toxicity reference values (TRVs) on a toxicity equivalents basis. However, no apparent effects on individuals or population are evident, suggesting that available TRVs may overpredict risk for the site-specific mix of congeners. To investigate this discrepancy, a 180-day spiked feed study was conducted to assess: (1) the dosages of key congeners necessary to achieve liver concentrations bracketing those observed in wild mink, (2) time to achieve steady-state concentrations, and (3) effect of coadministration of 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) on the toxicokinetics and distribution of each congener. Adipose and hepatic PCDF concentrations were measured at 0, 90, and 180 days. PCDF concentrations in mink scat were determined at several time points and indicated nearly complete absorption of both TCDF and 4-PeCDF from the diet. Elimination half-times of TCDF were < 15 h and were inversely proportional to dose, while those for 4-PeCDF were approximately 7–9 days with no clear dose dependency in the tested dose range. Coadministration of 4-PeCDF and TCDF accelerated clearance of TCDF compared to administration of TCDF alone. Clearance of 4-PeCDF was not affected by TCDF coadministration. Distribution of 4-PeCDF, but not TCDF, demonstrated increased hepatic sequestration with increasing dose. 4-PeCDF toxicokinetics were described using a previously published two-compartment model. Overall, the toxicokinetic information gathered here illustrates the impact of CYP1A1 induction on bioaccumulation and toxicity potential of TCDF and 4-PeCDF. This information may provide insight into why the current TRVs do not appear to correctly characterize the risk for these two congeners when they are the primary components of an environmental mixture.
Key Words: mink; polychlorinated dibenzodioxins and polychlorinated dibenzofurans (dioxins and furans); toxicokinetics; 2,3,7,8-tetrachlorodibenzofuran; 2,3,4,7,8-pentachlorodibenzofuran.