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New High Throughput Methods to Estimate Chemical Exposure
Citation:
New High Throughput Methods to Estimate Chemical Exposure. U.S. Environmental Protection Agency, Washington, D.C.
Impact/Purpose:
This SAP reviewed the use of EPA's ExpoCast model to rapidly estimate potential chemical exposures for prioritization and screening purposes. The focus was on bounded chemical exposure values for people and the environment for the Endocrine Disruptor Screening Program (EDSP) Universe of Chemicals. In addition to exposure, the SAP reviewed methods to extrapolate an in vivo dose from in vitro dose data. This involved presenting pharmacokinetic (PK) data for chemicals that have been run through a battery of high throughput endocrine screening assays and the methodology to use that PK information to estimate an in vivo dose. This exposure and RTK information along with high throughput in vitro bioactivity data will allow the EPA to assign a risk ranking to chemicals and prioritize them accordingly. ExpoCast is an EPA initiative to develop the necessary approaches and tools for rapidly prioritizing and screening thousands of chemicals based on the potential for human exposure. This focus for ExpoCast is distinct from many existing exposure tools that support regulatory risk assessment. Traditional exposure tools are lower throughput, requiring considerable data to make predictions of sufficient precision for a full risk assessment. ExpoCast efforts have focused on empirically assessing the uncertainty in forecasts made with limited available data, finding that in some cases even highly uncertain forecasts may be useful for prioritization and screening. In order to relate high throughput bioactivity data and rapid exposure predictions, an in vitro-in vivo extrapolation (IVIVE) via PK is needed. This IVIVE relates the in vitro compound concentrations (µM) found to be bioactive to the in vivo doses needed to produce serum concentrations equal to the in vitro concentrations. Without the time and resources necessary to generate in vivo PK data for the thousands of chemicals in the EDSP universe, high throughput pharmacokinetics (HTPK) can serve as a useful surrogate. HTPK methods were developed for pharmaceuticals to estimate therapeutic doses for clinical studies. HTPK technologies have been effective for pharmaceutical compounds and predicted concentrations are typically on the order of the measured in vivo concentrations. For non-therapeutic compounds in humans, PK data is not available and so it is essential to carefully characterize the predictive ability of the HTPK models and define the domain of applicability. High throughput exposure prediction and high throughput PK, when taken together with in vitro bioactivity profiling as a surrogate for hazard, will allow for a risk-based, rapid prioritization and screening of chemicals in the EDSP universe and beyond.
Description:
EPA has made many recent advances in high throughput bioactivity testing. However, concurrent advances in rapid, quantitative prediction of human and ecological exposures have been lacking, despite the clear importance of both measures for a risk-based approach to prioritizing and screening chemicals. A recent report by the National Research Council of the National Academies, Exposure Science in the 21st Century: A Vision and a Strategy (NRC 2012) laid out a number of applications in chemical evaluation of both toxicity and risk in critical need of quantitative exposure predictions, including screening and prioritization of chemicals for targeted toxicity testing, focused exposure assessments or monitoring studies, and quantification of population vulnerability. Despite these significant needs, for the majority of chemicals (e.g. non-pesticide environmental compounds) there are no or limited estimates of exposure. For example, exposure estimates exist for only 7% of the ToxCast Phase II chemical list. In addition, the data required for generating exposure estimates for large numbers of chemicals is severely lacking (Egeghy et al. 2012).
URLs/Downloads:
New High Throughput Methods to Estimate Chemical Exposure (PDF, NA pp, 941 KB, about PDF)072914minutes.pdf