A Cross-Species Mode of Action (MOA) Information Assessment: A Case Study of Bisphenol A (BPA)

EPA has released a report entitled, A Cross-Species Mode of Action Information Assessment: A Case Study of Bisphenol A [EPA/600/R-50/044F] (PDF, 98pp, 2 MB, About PDF). This report describes an approach to predict chemical effects and mode of action (MOA) for animal species without data from MOA information for species with data, and a case study to demonstrate the approach. In this report, bisphenol A (BPA) is used as an example to demonstrate the cross-species MOA approach; this is not a health assessment nor an integrated risk assessment of BPA. This report was developed in support of EPA's Office of Research and Development's Multi-Year Plan for Endocrine Disruptors (2003).


The cross-species approach assessed the effects and MOA data for a given toxic agent and determined the relationship between MOA and species relatedness (i.e., evolutionary relationships). MOA was defined as the key step in the toxic response after chemical interaction at the target site that is responsible for the physiological outcome or pathology. This case study considers whether species that are more closely related in terms of phylogeny also exhibit a more similar mode of action for reproductive and developmental effects after BPA exposure. And further, this case study considers whether the MOA of related species without data can be predicted. BPA, a component of polycarbonate plastics, epoxy resins, and polyester resins, was selected for the case study because it is a high production volume chemical; data have been identified for both vertebrate and invertebrate species; and the estrogen agonist MOA (i.e., binding and activating the estrogen receptor to transcribe estrogen-responsive genes) has been well described for a number of vertebrate species.

Using only published information on MOA for animal species, reproductive and/or developmental in vivo effects data for BPA were identified for 16 species representing seven animal classes (gastropods, crustaceans, insects, amphibians, fish, birds, and mammals) in three phyla (mollusks, arthopods, and chordates). For the invertebrate species, the data were insufficient to determine the MOA among mollusks and arthropods. For the tested vertebrate species, the data support a relationship between species relatedness and the estrogen agonist MOA. However, while the data strongly support the estrogen agonist MOA for fish and mammals, the data set was less robust for birds and amphibians. Thus, the cross-species MOA approach holds promise for predicting the MOA among species without data, for toxic agents with data for a number of related species.

This approach, in turn, could be applied to make MOA and effects predictions for species without data in an integrated ecological and human health risk assessment, interspecies extrapolation in human health assessments, and chemical screening and toxicity testing prioritization of chemicals. For example, cross-species MOA data may provide useful information for chemical prioritization in the Office of Prevention, Pesticides and Toxic Substances' (OPPTS) Endocrine Disruptor Screening and Testing Program (EDSTP) since the program is concerned with protecting human and wildlife health. Future efforts for 1) developing methods for integrated risk assessment; and 2) using MOA information in human health assessments,can build upon the results of this case study.

  • 2002: Draft document was sent to internal/agency peer review.
  • 2003: External review draft document was sent to external peer review.
  • 2004: EPA revised the report in response to comments.
  • 2005: EPA released the final report.
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U.S. EPA. A Cross-Species Mode of Action (MOA) Information Assessment: A Case Study of Bisphenol A (BPA). U.S. Environmental Protection Agency, Washington, D.C., EPA/600/R-50/044F, 2005.

This download(s) is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy.