Basic Exploratory Research versus Guideline-Compliant Studies Used for Hazard Evaluation and Risk Assessment: Bisphenol A as a Case Study

By Tyl, Rochelle W. | Environmental Health Perspectives, November 2009 | Go to article overview

Basic Exploratory Research versus Guideline-Compliant Studies Used for Hazard Evaluation and Risk Assessment: Bisphenol A as a Case Study


Tyl, Rochelle W., Environmental Health Perspectives


BACKGROUND: Myers et al. [Environ Health Perspect 117:309-315 (2009)] argued that Good Laboratory Practices (GLPs) cannot be used as a criterion for selecting data for risk assessment, using bisphenol A (BPA) as a case study. They did not discuss the role(s) of guideline-compliant studies versus basic/exploratory research studies, and they criticized both GLPs and guideline-compliant studies and their roles in formal hazard evaluation and risk assessment. They also specifically criticized our published guideline-compliant dietary studies on BPA in rats and mice and 17[beta]-estradiol ([E.sub.2]) in mice.

OBJECTIVES: As the study director/first author of the criticized [E.sub.2] and BPA studies, I discuss the uses of basic research versus guideline-compliant studies, how testing guidelines are developed and revised, how new end points are validated, and the role of GLPs. I also provide an overview of the BPA guideline-compliant and exploratory research animal studies and describe BPA pharmacokinetics in rats and humans. I present responses to specific criticisms by Myers et al.

DISCUSSION AND CONCLUSIONS: Weight-of-evidence evaluations have consistently concluded that low-level BPA oral exposures do not adversely affect human developmental or reproductive health, and I encourage increased validation efforts for "new" end points for inclusion in guideline studies, as well as performance of robust long-term studies to follow early effects (observed in small exploratory studies) to any adverse consequences.

KEY WORDS: basic/exploratory studies, bisphenol A, end points, 17[beta]-estradiol, guideline-compliant studies, routes of administration. Environ Health Perspect 117:1644-1651 (2009). doi:10.1289/ehp.0900893 available via http://dx.doi.org/ [Online 29 June 2009]

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Differences in perspective on basic research studies versus large-scale, guideline-compliant studies evaluating the potential developmental/reproductive effects of bisphenol A (BPA) reported by Myers et al. (2009) reflect disagreement in and ignorance of the roles and strengths and weaknesses of these study types. This controversy affects BPA safety assessment, which has become a major public policy issue. In this article I review characteristics and uses of basic/exploratory research versus regulatory guideline-compliant studies, using BPA as a case study.

Background

Basic/exploratory research in toxicology is conducted to identify unknown potential hazards, elucidate the mode/mechanism of action for known toxicants, or explore novel end points for possible subsequent formal validation. These studies commonly employ routes of administration and/or doses that are not relevant for humans; include few dose groups and few animals per group, and/or nonvalidated end points; are not tracked to adverse outcomes; and are typically creative, short term, relatively inexpensive, and funded by universities, government grants, and nongovernmental organizations (NGOs). These basic research studies play significant roles but are limited in assessing potential risks to human health. To assess risks, governmental agencies rely on guideline-compliant studies using appropriate exposures (routes, doses, durations), validated end points linked to adverse outcomes, and appropriate group sizes and numbers. Exploratory research and risk assessment studies are interactive and iterative (National Research Council 2000).

Risk-relevant studies are performed under regulatory testing guideline (TG) protocols and Good Laboratory Practices (GLPs). The Food and Drug Administration (FDA 1978) established standards for design, conduct, and reporting of nonclinical laboratory studies in support of applications for FDA marketing permits. The U.S. Environmental Protection Agency (EPA) prescribed GLP standards for studies on health and environmental effects and chemical fate testing under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA; U. …

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