An approach to using mode-of-action (MOA) information across animal species has been developed to support both integrated ecological and human health assessment methods development and cross-species extrapolation for human health assessments. By assessing the effects and MOA data for a given toxic agent, the relationship between MOA and species relatedness (i.e., evolutionary relationships) can be determined. A case study assessing the utility of this approach was performed for bisphenol A (BPA). BPA, a component of polycarbonate plastics, epoxy resins, and polyester resins, was selected 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. Cross-species MOA information for developmental and reproductive effects of BPA, limited to the animal kingdom, was reviewed from the literature, and the relationship between species relatedness and MOA was assessed. 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. 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 tested 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
untested species for toxic agents. Such predictions could be useful for applying MOA information in an integrated ecological and human health risk assessment as well as for 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 Program (EDSP) since the program is concerned with protecting human and wildlife health. This report was developed in support of EPA's Office of Research and Development's Multi-Year Plan for Endocrine Disruptors (2003).