EPA Science Inventory

In vitro metabolism and bioavailability tests for endocrine active substances: What is needed next for regulatory purposes?

Citation:

Jacobs, M., S. Laws, K. Willett, P. Schmieder, J. Odum, AND T. Bovee. In vitro metabolism and bioavailability tests for endocrine active substances: What is needed next for regulatory purposes? ALTEX. Society ALTEX Edition, Kuesnacht, Switzerland, 30:331-351, (2013).

Description:

Legistation and prospective legislative proposals internationally (may) require that chemicals be tested for their ability to disrupt the hormonal systems of mammals. Chemicals found to test positive in vitro are considered to be endocrine active substances (EAS) and may be putative endocrine disruptors (EDs) in vivo. While there is a growing body of international in vitro test guidelines addressing EAS mechanisms and modes of action, to date there are still few 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 test to in vivo adverse outcome pathways, and a previous OECD review paper indicated how this could be done. This paper revisits 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. The complexity of in vivo metabolism presents major challenges for the development of predictive models suitable for the extrapolation of data from in silico-vitro approaches to models that can occur in vivo. Therefore, the long-term recommendations are intended to foster an international harmonization 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

Purpose/Objective:

Legistation and prospective legislative proposals internationally (may) require that chemicals be tested for their ability to disrupt the hormonal systems of mammals. Chemicals found to test positive in vitro are considered to be endocrine active substances (EAS) and may be putative endocrine disruptors (EDs) in vivo. While there is a growing body of international in vitro test guidelines addressing EAS mechanisms and modes of action, to date there are still few 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 test to in vivo adverse outcome pathways, and a previous OECD review paper indicated how this could be done. This paper revisits 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. The complexity of in vivo metabolism presents major challenges for the development of predictive models suitable for the extrapolation of data from in silico-vitro approaches to models that can occur in vivo. Therefore, the long-term recommendations are intended to foster an international harmonization 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

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Completion Date: 06/10/2014
Record Last Revised: 06/10/2014
Record Created: 06/10/2014
Record Released: 06/10/2014
OMB Category: Other
Record ID: 278121

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

MID-CONTINENT ECOLOGY DIVISION