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Integration of Dosimetry, Exposure and High-Throughput Screening Data in Chemical Toxicity Assessment
Citation:
WETMORE, B. A., J. F. WAMBAUGH, S. S. FERGUSON, M. A. SOCHASKI, D. M. ROTROFF, K. FREEMAN, H. J. CLEWELL III, D. J. DIX, M. E. ANDERSEN, K. A. HOUCK, B. ALLEN, R. S. JUDSON, R. SINGH, R. J. KAVLOCK, A. M. RICHARD, AND R. S. THOMAS. Integration of Dosimetry, Exposure and High-Throughput Screening Data in Chemical Toxicity Assessment. TOXICOLOGICAL SCIENCES. Oxford University Press, Cary, NC, 125(1):157-174, (2012).
Impact/Purpose:
The transition to a new toxicity testing paradigm that relies heavily on in vitro HTS assays will require a parallel investment in characterizing the pharmacokinetics and exposure levels of these chemicals. This parallel effort will add valuable information on parameters critical to interpreting biologically relevant exposure scenarios that should yield more informative prioritization models. The results and approach outlined in this study are part of that parallel effort and provide an important bridge between the nominal in vitro assay concentrations and the human oral equivalent doses required to achieve those concentrations in the blood. The subsequent comparison of the oral equivalent doses with human exposure estimates provides a better basis for informed decisions on chemical testing priorities and regulatory attention (Blaauboer 2010; Cohen Hubal et al. 2010). Continued refinement of the in vitro assays to better reflect in vivo adverse effects and improvement in the suite of in vitro pharmacokinetic assays and IVIVE modeling will eventually allow us to move beyond hazard-based prioritization to risk assessment (Bhattacharya 2011; Judson et al. 2011).
Description:
High-throughput in vitro toxicity screening can provide an efficient way to identify potential biological targets for chemicals. However, relying on nominal assay concentrations may misrepresent potential in vivo effects of these chemicals due to differences in bioavailability, clearance, and exposure. Hepatic metabolic clearance and plasma protein binding were experimentally measured for 239 ToxCast Phase I chemicals. The experimental data were used in a population-based, in vitro-to-in vivo extrapolation model to estimate the daily human oral dose, called the oral equivalent dose, necessary to produce steady-state in vivo blood concentrations equivalent to in vitro AC50 (concentration at 50% of maximum activity) or LEC (lowest effective concentration) values across more than 500 in vitro assays. The estimated steady state oral equivalent doses associated with the in vitro assays were compared to chronic aggregate human oral exposure estimates to assess whether in vitro bioactivity would be expected at the dose-equivalent level of human exposure. A total of 18 (9.9%) chemicals for which human oral exposure estimates were available had oral equivalent doses at levels equal to or less than the highest estimated U.S. population exposures. Ranking the chemicals by nominal assay concentrations would have resulted in different chemicals being prioritized. The in vitro assay endpoints with oral equivalent doses lower than the human exposure estimates included cell growth kinetics, cytokine and cytochrome P450 expression, and cytochrome P450 inhibition. The incorporation of dosimetry and exposure provide necessary context for interpretation of in vitro toxicity screening data and are important considerations in determining chemical testing priorities.
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Integration of Dosimetry, Exposure and High-Throughput Screening Data in Chemical Toxicity Assessment