SAP Reports on Integrated Endocrine Bioactivity and Exposure-Based Prioritization and Screening
EPA’s Science Advisory Panel was charged with advising EPA on the following three topic areas associated with integrating bioactivity and exposure: 1) estrogen bioactivity, 2) androgen bioactivity, and 3) Integrated Bioactivity Exposure Ranking (IBER). The SAP has published its report on this review. The report contains the following summary:
“In general, the Panel agreed the ER Model for assessing estrogen bioactivity had several strengths. For example, they believed that the ER AUC approach was a computationally, timeresourceful, and insightful approach to determine the estrogenic bioactivity of a chemical. They also noted the AUC ranking had a strong utility for ranking chemicals in association with potential estrogen bioactivity. The Panel concurred that the ER AUC model demonstrated outstanding performance in the characterization of reference chemicals, and in concordance with the selected chemicals for in vivo uterotrophic responses. Although the Panel highlighted several strengths of the ER Model, they also pointed out several limitations and/or weaknesses of the model. For instance, they noted that the models did not incorporate uncertainty or sensitivity analyses. They recommended that the Agency explore the inclusion of such analyses. The Panel also noted that the Agency provide more transparency in describing details about the underpinnings of the model. In regard to the Agency’s efforts to assess androgen bioactivity, the Panel noted that current knowledge suggests that chemicals which impact androgen bioactivity act as relatively weak antagonists rather than agonists. Based upon these largely antagonistic activities of chemicals, they advised that it is critical that the HTS AR bioactivity assay battery include careful assessments and attention to the potential cytotoxic effects of chemicals that may otherwise appear as false positives due to assay interference. This applies to effects generated by the test chemical as well as solvents used in the formulation of chemical doses. The range of chemical structures tested in the assay battery should be expanded to maximize the screening potential. Furthermore, the AR bioactivity battery should include methods to assess the potential effects of chemicals, as well as their metabolites formed by enzymatic conversion in biological systems. The AR bioactivity battery specifically addresses the classical AR nuclear receptor/genomic actions of chemicals, but does not consider other potential non-classical/non-genomic mechanisms that mimic or inhibit androgen bioactivity. Concerning the Agency’s proposed Integrated Bioactivity Exposure Ranking (IBER) approach, the Panel noted that it was rationally developed and laid a foundation for a theoretical basis with the potential to prioritize further EDSP screening of compounds with estrogenic activity. The Panel especially highlighted the practicality of the statistical modeling of the IBER approach. Although the Panel positively remarked about the IBER approach, they cautioned that the approach needed further refinement before it is employed by the Agency’s Endocrine Disruption Screening Program. Suggested areas of exploration to further refine the IBER approach included gaining a better understanding of how monitoring data would be to strengthen the approach. The Panel also expressed concern about the limited amount of NHANES exposure data integrated into the IBER model.”
Click here for the SAP’s report.