Current Assessment of the Effects of Environmental Chemicals on the Mammary Gland in Guideline Rodent Studies by the U.S. Environmental Protection Agency (U.S. EPA), Organisation for Economic Co-Operation and Development (OECD), and National Toxicology Program (NTP)
Makris, Susan L., Environmental Health Perspectives
National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA
BACKGROUND: Evaluation of the structural and/or functional integrity of the mammary gland (MG) across life stages is integral to the assessment of developmental, reproductive, and carcinogenic risk for environmental chemicals.
OBJECTIVES: In this commentary I characterize MG assessment recommended in U.S. Environmental Protection Agency, Organisation for Economic Co-operation and Development, and National Toxicology Program guideline toxicology study protocols and identify any information gaps for the evaluation of MG development, structure, and function.
DISCUSSION: Several data gaps, issues, and challenges were identified. Current guidelines that include a lactation phase do not provide specific recommendations to record observations on maternal or offspring lactation or nursing behavior. In guideline studies, the assessment of MG toxicity often relies upon indirect, nonspecific, or surrogate end points, and information that could be useful in the interpretation of these data (e.g., mode of action or toxicokinetics) is often unavailable. Most guideline studies designed to assess general organ toxicity do not expose test animals during sensitive stages of MG development; histopathological evaluation of the developing MG is not routinely conducted; and evaluation of MG tissue for both sexes is inconsistendy recommended.
CONCLUSIONS: I propose the following general recommendations to enhance MG assessment in guideline toxicology studies: a) inclusion of more specific criteria for the evaluation of MG end points in guideline language, b) inclusion of histopathological evaluation of MG development (using whole-mount techniques) in existing or new guideline protocols that include offspring with perinatal and/or pubertal treatment, c) incorporation of perinatal exposures into rodent subchronic and carcinogenicity assays, and d) expansion of the histopathological evaluation of male MG tissue.
KEY WORDS: carcinogenicity study, endocrine-disrupting chemicals, extended one-generation reproduction study, mammary gland, perinatal exposure, risk assessment, subchronic toxicity study, toxicity testing guidelines, two-generation reproduction study. Environ Health Perspect 119:1047-1052 (2011). doi:10.1289/ehp.l002676 [Online 30 November 2010]
Evaluation of the structural and functional integrity of the mammary gland (MG), an important reproductive tissue/organ, is integral to the assessment of developmental, reproductive, and carcinogenic risk for environmental chemicals [Organisation for Economic Co-operation and Development (OECD) 2008; U.S. Environmental Protection Agency (EPA) 1991, 1996, 2005a, 2005b]. When using a life-stage-oriented approach to risk assessment, it is important to assess early developmental periods (including in utero through puberty), function during reproductive life stages, and continued health in later life stages.
The evidence for alterations in MG development, lactational function, and cancer risk is reviewed by Rudel et al. (2011). Examples of hormonally active agents that are associated with MG alterations include diethylstilbestrol (DES), genistein, atrazine, bisphenol A (BPA), dibutyl phthalate, dioxin, methoxychlor, nonylphenol, polybrominated diphenyl ethers (PBDEs), and perfluorooctanoic acid (PFOA).
Animal studies are traditionally used in predicting potential toxicity and risk to humans. The use of this approach to screen environmental chemicals for MG toxicity is supported by parallels between MG effects induced in animal models and alterations in human MG health. Examples include altered timing of puberty, alterations in lactation (e.g., ability to lactate, quality and quantity of milk), and induction of mammary/breast cancer.
Standardized study designs or protocols (i.e. …