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Toxicol Sci. 2018 Jul 1;164(1):218-228. doi: 10.1093/toxsci/kfy078.

The Influence of Obesity on the Pharmacokinetics of Dioxin in Mice: An Assessment Using Classical and PBPK Modeling.

Author information

1
BioSimulation Consulting Inc., Newark, DE, USA, 19713.
2
Department of Environmental and Occupational Health, University of Montreal, Quebec, Canada H3N 1X9.
3
National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, NC, USA.
4
National Health and Environmental Effects Research Laboratory, U.S. Environmental protection Agency, Research Triangle Park, NC, USA, 27711.
5
National Cancer Institute, Research Triangle Park, NC, USA, 27709.

Abstract

The effects of body fat mass on the elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in mice. When male C57BL/6J mice are fed a high-fat, simple carbohydrate diet (HFD) for 13 weeks, they develop an obese phenotype. In contrast, A/J mice fed an HFD do not become obese. After 13 weeks on a normal diet (ND) or HFD, male C57BL/6J and A/J mice received a single dose by gavage of 0.1 or 5.0 µg of 2,3,7,8-tetrachloro[1,6-3H] dibenzo-p-dioxin per kg body weight. Using classical pharmacokinetics, the blood elimination half-life of TCDD was approximately 10 and 2 times longer in the C57BL/6J on the HFD compared with the mice on the ND at 0.1 and 5.0 μg/kg doses, respectively. The diet did not increase the blood half-life of TCDD in the A/J mice, which did not get obese. Using a physiologically based pharmacokinetic model for TCDD that incorporated experimentally derived percent body fat mass and tissue partition coefficients, as well as data on hepatic sequestration, did not provide accurate predictions to the data and could not explain the increase in half-life of TCDD in the HFD groups. This work demonstrates that obesity influences the half-life of TCDD, but other undetermined factors are involved in its elimination because the increase in body fat mass, decreases in cytochrome P4501A2, and altered partition coefficients could not completely explain the prolonged half-life.

PMID:
29596651
PMCID:
PMC6016688
DOI:
10.1093/toxsci/kfy078
[Indexed for MEDLINE]
Free PMC Article

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