Development of a Screening Approach to Interpret Human Biomonitoring Data on Volatile Organic Compounds: Reverse Dosimetry on Biomonitoring Data for Trichloroethylene

Abstract

A screening approach is developed for volatile organic compounds (VOCs) to estimate exposures that correspond to levels measured in fluids and/or tissues in human biomonitoring studies. The approach makes use of a generic physiologically-based pharmacokinetic (PBPK) model coupled with exposure pattern characterization, Monte Carlo analysis, and quantitative structure property relationships (QSPRs). QSPRs are used for VOCs with minimal data to develop chemical-specific parameters needed for the PBPK model. The PBPK model is capable of simulating VOC kinetics following multiple routes of exposure, such as oral exposure via water ingestion and inhalation exposure during shower events. Using published human biomonitoring data of trichloroethylene (TCE), the generic model is evaluated to determine how well it estimates TCE concentrations in blood based on the known drinking water concentrations. In addition, Monte Carlo analysis is conducted to characterize the impact of the following factors: (1) uncertainties in the QSPR-estimated chemical-specific parameters; (2) variability in physiological parameters; and (3) variability in exposure patterns. The results indicate that uncertainty in chemical-specific parameters makes only a minor contribution to the overall variability and uncertainty in the predicted TCE concentrations in blood. The model is used in a reverse dosimetry approach to derive estimates of TCE concentrations in drinking water based on given measurements of TCE in blood, for comparison to the U.S. EPA's Maximum Contaminant Level in drinking water. This example demonstrates how a reverse dosimetry approach can be used to facilitate interpretation of human biomonitoring data in a health risk context by deriving external exposures that are consistent with a biomonitoring data set, thereby permitting comparison with health-based exposure guidelines.

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

“…In this way, compounds with similar properties can be grouped, and data for similar compounds can be used to fill gaps in the knowledge of a particular compound. For example, a recent study evaluated the possibility of predicting the in vivo kinetics of volatile organic compounds (VOCs) using PBBK models derived solely on the basis of physiological data and QSPR modeling (Liao et al, 2007). The authors concluded that acceptable predictions could be made for inhalation of lipophilic VOCs, such as trichloroethylene, but that the necessary QSPR algorithms were not available for water-soluble VOCs such as acetone.…”

Using Biomonitoring Equivalents to interpret human biomonitoring data in a public health risk context

“…Other approaches to interpretation of biomonitoring data in the context of current risk assessments include the application of 'reverse dosimetry' modeling in order to identify a possible distribution of external exposure levels that led to an observed distribution of measured biomarker concentrations in a population (Clewell et al, 2008;Georgopolous et al, 2009;Liao et al, 2007;Tan et al, 2007). As noted by numerous authors, the reverse dosimetry approach is computationally intensive, is data-set specific (a new reverse dosimetry modeling exercise is required for every set of biomonioring data) and is an attempt to address probabilistically what is an infinite-solution problem (Rigas et al, 2001;Georgopolous et al, 2009).…”

Advancing human health risk assessment: Integrating recent advisory committee recommendations

“…To meet this need for methods, both forward dosimetry (Hays et al, 2007) and reverse dosimetry (Liao et al, 2007) approaches were developed that use pharmacokinetic tools to convert an applied dose for humans into an internal concentration (and vice versa ). By applying pharmacokinetic tools to existing chemical risk assessments, external safe doses, such as reference doses or tolerable daily intakes, or other dose response values, can be converted to corresponding biomarker concentrations in blood or urine, and with such a conversion, a comparison can then be made to the actual concentration measured by a human biomonitoring study.…”