ToxSci Advance Access originally published online on February 17, 2009
Toxicological Sciences 2009 108(2):258-272; doi:10.1093/toxsci/kfp034
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The Effect of Plasma Lipids on the Pharmacokinetics of Chlorpyrifos and the Impact on Interpretation of Blood Biomonitoring Data
* Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674
Battelle, Pacific Northwest Division, MS P7-59, Richland, Washington 99352
1 To whom correspondence should be addressed at Toxicology & Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674. Fax: (989) 638-9863. E-mail: mjbartels{at}dow.com.
Received November 25, 2008; accepted February 4, 2009
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Abstract |
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Lipophilic molecules, like chlorpyrifos (CPF), present a special problem for interpretation of biomonitoring data because both the environmental dose of CPF and the physiological (pregnancy, diet, etc.) or pathological levels of blood lipids will affect the concentrations of CPF measured in blood. The objective of this study was to investigate the distribution of CPF between plasma and tissues when lipid levels are altered in late pregnancy. CPF was sequestered more in the low-density lipid fraction of the blood during the late stages of gestation in the rat and returned to nonpregnant patterns in the dam after birth. Plasma partitioning of CPF increased with increases in plasma lipid levels and the increased partitioning of CPF into plasma lipids resulted in less CPF in other tissue compartments. Gavage dosing with corn oil also increased plasma lipids that led to a moderate increase of CPF partitioning into the plasma. To mechanistically investigate the potential pharmacokinetic effects of blood lipid changes, an existing CPF physiologically based pharmacokinetic/pharmacodynamic model for rats and humans was modified to account for altered lipid-tissue partition coefficients and for major physiological and biochemical changes of pregnancy. The model indicated that plasma CPF levels are expected to be proportional to the well-known changes in plasma lipids during gestation. There is a rapidly growing literature on the relationship of lipid profiles with different disease conditions and on birth outcomes. Increased blood concentrations of lipophilic chemicals like CPF may point to altered lipid status, as well as possibly higher levels of exposure. Thus, proper interpretation of blood biomonitoring data of lipophilic chemicals requires a careful consideration of blood lipids.