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      Evaluation and Optimization of Pharmacokinetic Models for in Vitro to in Vivo Extrapolation of Estrogenic Activity for Environmental Chemicals

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          Abstract

          Background:

          To effectively incorporate in vitro data into regulatory use, confidence must be established in the quantitative extrapolation of in vitro activity to relevant end points in animals or humans.

          Objective:

          Our goal was to evaluate and optimize in vitro to in vivo extrapolation (IVIVE) approaches using in vitro estrogen receptor (ER) activity to predict estrogenic effects measured in rodent uterotrophic studies.

          Methods:

          We evaluated three pharmacokinetic (PK) models with varying complexities to extrapolate in vitro to in vivo dosimetry for a group of 29 ER agonists, using data from validated in vitro [U.S. Environmental Protection Agency (U.S. EPA) ToxCast™ ER model] and in vivo (uterotrophic) methods. In vitro activity values were adjusted using mass-balance equations to estimate intracellular exposure via an enrichment factor (EF), and steady-state model calculations were adjusted using fraction of unbound chemical in the plasma ( f u ) to approximate bioavailability. Accuracy of each model-adjustment combination was assessed by comparing model predictions with lowest effect levels (LELs) from guideline uterotrophic studies.

          Results:

          We found little difference in model predictive performance based on complexity or route-specific modifications. Simple adjustments, applied to account for in vitro intracellular exposure (EF) or chemical bioavailability ( f u ), resulted in significant improvements in the predictive performance of all models.

          Conclusion:

          Computational IVIVE approaches accurately estimate chemical exposure levels that elicit positive responses in the rodent uterotrophic bioassay. The simplest model had the best overall performance for predicting both oral (PPK_EF) and injection (PPK_ f u ) LELs from guideline uterotrophic studies, is freely available, and can be parameterized entirely using freely available in silico tools. https://doi.org/10.1289/EHP1655

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          Most cited references40

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          In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project

          Background Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency’s ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. Methods We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Results Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. Conclusions This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.
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            Update on EPA's ToxCast program: providing high throughput decision support tools for chemical risk management.

            The field of toxicology is on the cusp of a major transformation in how the safety and hazard of chemicals are evaluated for potential effects on human health and the environment. Brought on by the recognition of the limitations of the current paradigm in terms of cost, time, and throughput, combined with the ever increasing power of modern biological tools to probe mechanisms of chemical-biological interactions at finer and finer resolutions, 21st century toxicology is rapidly taking shape. A key element of the new approach is a focus on the molecular and cellular pathways that are the targets of chemical interactions. By understanding toxicity in this manner, we begin to learn how chemicals cause toxicity, as opposed to merely what diseases or health effects they might cause. This deeper understanding leads to increasing confidence in identifying which populations might be at risk, significant susceptibility factors, and key influences on the shape of the dose-response curve. The U. S. Environmental Protection Agency (EPA) initiated the ToxCast, or "toxicity forecaster", program 5 years ago to gain understanding of the strengths and limitations of the new approach by starting to test relatively large numbers (hundreds) of chemicals against an equally large number of biological assays. Using computational approaches, the EPA is building decision support tools based on ToxCast in vitro screening results to help prioritize chemicals for further investigation, as well as developing predictive models for a number of health outcomes. This perspective provides a summary of the initial, proof of concept, Phase I of ToxCast that has laid the groundwork for the next phases and future directions of the program.
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              Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment.

              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 AC(50) (concentration at 50% of maximum activity) or 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 with 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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                Author and article information

                Journal
                Environ Health Perspect
                Environ. Health Perspect
                EHP
                Environmental Health Perspectives
                Environmental Health Perspectives
                0091-6765
                1552-9924
                7 September 2018
                September 2018
                : 126
                : 9
                : 097001
                Affiliations
                [ 1 ]National Toxicology Program Division, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, North Carolina, USA
                [ 2 ]Integrated Laboratory Systems , Inc., Morrisville, North Carolina, USA
                [ 3 ]ScitoVation, Research Triangle Park, North Carolina, USA
                [ 4 ]Kelly Government Solutions , Research Triangle Park, North Carolina, USA
                Author notes
                Address correspondence to Nicole Kleinstreuer, NICEATM, NIEHS, P.O. Box 12233, MD K2-05, Research Triangle Park, NC, 27709, USA. Telephone: 984-287-3150. Email: nicole.kleinstreuer@ 123456nih.gov
                Article
                EHP1655
                10.1289/EHP1655
                6375436
                30192161
                31173267-974e-41fe-b6aa-e7e29fdb3d23

                EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted.

                History
                : 20 January 2017
                : 12 June 2018
                : 12 July 2018
                Categories
                Research

                Public health
                Public health

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