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There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure.

The possible interaction of environmental contaminants with the endocrine system has been an environmental concern since the early 1990s. To examine these interactions test guidelines have been introduced by regulatory agencies to screen for possible endocrine active compounds. One of these guidelines is the EPA's OPPTS 890.1550 [Steroidogenesis (Human Cell Line-H295R)]. This guideline requires the quantification of two major biomarkers (testosterone and estradiol) in various biological test systems. Traditional quantitation methodologies such as Radioimmunoassay (RIA) and Enzyme-linked Immunosorbent Assay (ELISA) have been used to quantify low levels of steroids. However, those methodologies have drawbacks such as the radioactive safety, antibody availability, separate assay for each biomarker, and lack of selectivity. In the current study, a rapid and sensitive liquid chromatography/positive atmospheric pressure photoionization tandem mass spectrometry method (LC/APPI-MS/MS) has been developed and validated for the simultaneous quantitation of testosterone and estradiol in the H295R cell line. Briefly, the media from cultured cells was extracted with dichloromethane (CH(2)Cl(2)) containing internal standards of both testosterone-d(3) and estradiol-(13)C(3); then, the extracted organic layer was concentrated down to dryness. The final residue was derivatized with dansyl chloride solution, and directly analyzed by LC/APPI-MS/MS. The calibration curves, with concentration ranging from 10 to 2500 pg/mL, were linear with coefficient >0.99. The lower limits of quantitation for both testosterone and estradiol were 10 pg/mL. This method was successfully validated to support requirements of the current EPA Steroidogenesis guideline. This type of method may also provide value for rapid and precise measurements of these two hormones in other in vitro or in vivo test systems.

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.

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