You are here:
Incorporating Human Dosimetry and Exposure into High-Throughput In Vitro Toxicity Screening
Citation:
ROTROFF, D. M., B. A. WETMORE, D. J. DIX, S. S. FERGUSON, H. J. CLEWELL, K. A. HOUCK, E. L. LECLUYSE, M. E. ANDERSEN, R. JUDSON, C. M. SMITH, M. A. SOCHASKI, R. J. KAVLOCK, F. BOELLMANN, M. T. MARTIN, D. REIF, J. F. WAMBAUGH, AND R. S. THOMAS. Incorporating Human Dosimetry and Exposure into High-Throughput In Vitro Toxicity Screening . TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 117(2):348-58, (2010).
Impact/Purpose:
Importantly, these tools are necessary to move beyond hazard rankings to estimates of possible in vivo responses based on in vitro screens.
Description:
Many chemicals in commerce today have undergone limited or no safety testing. To reduce the number of untested chemicals and prioritize limited testing resources, several governmental programs are using high-throughput in vitro screens for assessing chemical effects across multiple cellular pathways. In this study, metabolic clearance and plasma protein binding were experimentally measured for 35 ToxCast Phase I chemicals. The experimental data were used to parameterize a population-based, in vitro-to-in vivo extrapolation model for estimating the human oral equivalent dose necessary to produce a steady state in vivo concentration equivalent to in vitro AC(50) (concentration at 50% of maximum activity) and LEC (lowest effective concentration) values from the ToxCast data. For 23 of the 35 chemicals, the range of oral equivalent doses for up to 398 ToxCast assays was compared with chronic aggregate human oral exposure estimates in order to assess whether significant in vitro bioactivity occurred within the range of maximum expected human oral exposure. Only two of the 35 chemicals, triclosan and pyrithiobac-sodium, had overlapping oral equivalent doses and estimated human oral exposures. Ranking by the potencies of the AC(50) and LEC values, these two chemicals would not have been at the top of a prioritization list. Integrating both dosimetry and human exposure information with the high-throughput, toxicity screening efforts provides a better basis for making informed decisions on chemical testing priorities and regulatory attention.
