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J.Health Sci., 56(5), 566-575, 2010
-Regular Article-
Human Blood Concentrations of Dichlorodiphenyltrichloroethane (DDT) Extrapolated from Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling
Hiroshi Yamazaki,*, a, b Ryohji Takano,a, c
Kana Horiuchi,a Makiko Shimizu,a
Norie Murayama,a Masato Kitajima,c
and Fumiaki Shonod
aLaboratory of Drug Metabolism and Pharmacokinetics and
bHigh Technology Research Center, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida 194-8543, Japan,
cFujitsu Kyusyu Systems, Momochihama, Sawara-ku, Fukuoka 814-8589, Japan and
dJapan Chemical Industry Associations (JCIA), 1-4-1 Shinkawa, Chuo-ku, Tokyo 104-0033, Japan
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for dichlorodiphenyltrichloroethane [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, DDT] in humans based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing liver compartment, and a central compartment for DDT. Evaluation of the rat model was performed by making comparisons between predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after daily oral treatment with DDT (10 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of DDT in vitro were established from data from rat liver microsomes and from pooled human liver microsomes. The ratio of intrinsic clearance values of DDT based on rat in vivo and rat in vitro experiments was used as the scaling factor for estimating in vivo hepatic intrinsic clearance in humans in the final human PBPK model. These results indicate that a simplified PBPK model for DDT is useful for a forward dosimetry approach in rats and/or humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.
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