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In vitro metabolism and bioavailability tests for the predictive toxicology of endocrine active substances
Jacobs, M., S. Laws, C. Willett, P. Schmieder, J. Odum, AND T. Bovee. In vitro metabolism and bioavailability tests for the predictive toxicology of endocrine active substances. Presented at Society of Toxicology, FutureTox II, Chapel Hill, NC, January 16 - 17, 2014.
Legislation and prospective legislative proposals internationally (may) require that chemicals are tested for their ability to disrupt the hormonal systems of animals. Chemicals found to test positive in vitro are considered to be endocrine active substances (EAS) and may be putative endocrine disruptors (EDs) in viva. Whilst there is a growing body of international in vitro test guidelines addressing EAS mechanisms and modes of action, to date there are still little or no standardized methods to incorporate metabolic and toxicokinetic aspects into these in vitro tests for EAS. In vitro assays for EAS should incorporate metabolic enzyme systems to better address the relevance of EAS tests to in vivo adverse outcome pathways, and a previous Organisation for Economic Co-operation and Development (OECD) review paper indicated how this could be done. Here, we revisit those recommendations, addressing where research and funding efforts are needed to expedite the development of suitable in vitro metabolism systems to improve the accuracy of in vitro assays for identifying EAS and EDs. Recommendations are made for projects to support short, medium and long-term goals. In addition, an international OECD expert group has now initiated a first necessary step with respect to the critical evaluation and creation of a reference chemical list for the (pre) validation of the incorporation of metabolism into the existing regulatory in vitro assays. The complexity of in viva metabolism presents major challenges for the development of predictive models suitable for the extrapolation of data from in silica/in vitro approaches to that which (can) occur in viva. Therefore, the long term recommendations are intended to foster an international harmonisation of databases, delineation of metabolic pathways, and development of predictive tools that will provide a fundamental understanding of the processes by which metabolism occurs, increasing the predictive accuracy of in silico/in vitro methods.
Review of potential short, medium and long-term goals that could facilitate the development of in vitro metabolism systems to improve the accuracy of in vitro assays for indentifying endocrine active substances.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION
ENDOCRINE TOXICOLOGY BRANCH