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Implications of EPA's New Strategic Plan for Evaluating Toxic Chemicals: Pathway-Based Risk AssessmentOn March 25th, the EPA released a strategic plan to incorporate advances in molecular biology and computational sciences into toxicity testing and risk assessment practices across the Agency. This ambitious plan proposes a landmark transformation in toxicity testing and risk assessment over the next ten years, to rely increasingly on knowledge of toxicity pathways. This rapidly evolving science studies the manner in which genes, proteins, and small molecules interact to form molecular pathways that maintain cell function, and how exposure to environmental agents can perturb these pathways and produce adverse effects. EPA has embraced new technologies and databases as a foundation for advances in safety assessment, as described in their strategic plan. Implications for Testing The goal of this plan is to increasingly rely on in vitro tests, particularly in human cell lines, to replace expensive and time-consuming whole-animal studies for predicting human health effects. The strategy envisions the eventual use of whole-animal tests to focus primarily on mechanisms and metabolism. These new approaches will allow rapid testing of chemicals, exploration of various types of adverse effects under differing exposure scenarios, investigation of sensitive populations, and examination of the toxicity of chemical mixtures. For example, with increased knowledge, it will be possible to predict when interaction with multiple toxicity pathways might be expected to lead to non-additive outcomes. Priorities for research will focus on in vitro assays for the key targets of chemicals in the environment for which limited knowledge is available (e.g., developmental, neurotoxicity, immunotoxicity, and reproductive toxicity). Implications for Risk Assessment New information derived from changing test methods will inform the major components of the risk assessment (i.e., hazard identification, dose response, exposure, and rick characterization). Dr. Elizabeth L. Anderson, Exponent's Group Vice President for Health, who is a co-author of EPA's first risk assessment policies and guidelines, noted: "This shift to toxicity pathway–based risk assessment is a logical progression in the evolving use of better science to inform risk assessment. All of EPA's risk assessment guidance, beginning with the earliest guidelines in 1976, encouraged the use of better science to replace default assumptions. This new strategy, and the reports by the National Academy of Science/National Research Council on toxicity testing, provide a clearer, though ambitious, path forward. Exponent anticipated these changes more than two years ago when the Centers for Epidemiology/Computational Biology and Toxicology/Mechanistic Biology were established. The use of better science informs the risk assessment process and helps to replace default assumptions. The evidence clearly shows that new approaches are having an impact on risk assessment now." Current Applications Risk assessors are currently developing and using computer-based technologies and structure/molecular/bioactivity profiling, together with exposure and dose information, to predict which chemicals will most likely cause effects of concern for humans. EPA has launched ToxCast to develop cost-effective approaches for prioritizing the toxicity testing of large numbers of chemicals in a short period of time. The pharmaceutical and agrichemical industries have relied heavily on High-Throughput Screening (HTS) to support new product development by evaluating large numbers of chemicals per day in terms of molecular, biochemical, or cellular processes. Using these same approaches, ToxCast is forecasting the potential human toxicity of chemicals. These methods are in active development and offer opportunity for participation of entities outside the Agency. These methods should assist in improving Quantitative Structure Activity Relation (QSAR) models, which are in wide use to predict toxicity. For example, QSAR is use to evaluate flavors for foods, chemicals in consumer products, untested substances in the environment, and chemicals that are subject to the European Union Regulations on the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH), which seek to protect public health and to promote alternative test methods. Stakeholder involvement is invited. Exponent is on the forefront of these developments. For more information related to risk-based product evaluations, please contact us. For further assistance, please contact: Elizabeth L. Anderson, Ph.D., FATS
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