Non-monotonic dose responses in EDSP Tier 1 guideline assays

Abstract

In the fields of endocrinology and toxicology, there are ongoing debates about whether endocrine disrupting chemicals (EDCs) produce non-monotonic dose responses. This type of response is typically characterized by a U- or inverted U-shaped relationship between dose and effect. In a recent report, a US EPA panel concluded that non-monotonicity is observed for EDCs, but that these responses are not expected in vivo, and are not typically observed in apical endpoints, i.e. endpoints that are indicators of adverse effects. Here, we have analyzed the shapes of the dose response curves in an EPA report analyzing the effectiveness of the Endocrine Disruptor Screening Program (EDSP) Tier 1 assays. This report included the results of 11 guideline assays for each of 4 chemicals. We found indications of non-monotonic dose response curves (iNMDRCs) for 3 of the 4 coded chemicals. In total, 27% of assays with dose response data included at least one iNMDRC. When the endpoints from the 4 test chemicals with dose response data were considered together, 9% were consistent with non-monotonicity. Collectively, these results indicate that non-monotonic responses occur in guideline endpoints including the kinds of adverse outcomes that regulatory agencies use in chemical safety assessments such as circulating hormone concentrations and organ weights. These results should inform discussions about whether NMDRCs are ‘real’ and occur frequently enough to be important. Because risk assessments typically involve high dose testing, limited dose groups (often only 3) and extrapolation to lower doses that are not expected to have adverse effects, the presence of NMDRCs challenges this status quo.