Application of Adverse Outcome Pathways to U.S. EPA’s Endocrine Disruptor Screening Program

Abstract

Background:The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) screens and tests environmental chemicals for potential effects in estrogen, androgen, and thyroid hormone pathways, and it is one of the only regulatory programs designed around chemical mode of action.Objectives:This review describes the EDSP’s use of adverse outcome pathway (AOP) and toxicity pathway frameworks to organize and integrate diverse biological data for evaluating the endocrine activity of chemicals. Using these frameworks helps to establish biologically plausible links between endocrine mechanisms and apical responses when those end points are not measured in the same assay.Results:Pathway frameworks can facilitate a weight of evidence determination of a chemical’s potential endocrine activity, identify data gaps, aid study design, direct assay development, and guide testing strategies. Pathway frameworks also can be used to evaluate the performance of computational approaches as alternatives for low-throughput and animal-based assays and predict downstream key events. In cases where computational methods can be validated based on performance, they may be considered as alternatives to specific assays or end points.Conclusions:A variety of biological systems affect apical end points used in regulatory risk assessments, and without mechanistic data, an endocrine mode of action cannot be determined. Because the EDSP was designed to consider mode of action, toxicity pathway and AOP concepts are a natural fit. Pathway frameworks have diverse applications to endocrine screening and testing. An estrogen pathway example is presented, and similar approaches are being used to evaluate alternative methods and develop predictive models for androgen and thyroid pathways. https://doi.org/10.1289/EHP1304

Fluorescent microarray for multiplexed quantification of environmental contaminants in seawater samples

“…Main concerns for certain pollutants derive from the amounts generated by humans, their extremely negative effects on the environment or because of their accumulation in water, sediments, or biota. Included are endocrine disruptor chemicals (EDCs), a group of substances that may interfere with the endocrine and hormonal system of fishes and other non-vertebrate's organisms [5][6][7]. Some antibiotics, massively used in aquaculture facilities to combat fish infections and infestations, affect not only the ecosystem equilibrium but also human health spreading drug-resistant bacterial strains [8].…”

When Are Adverse Outcome Pathways and Associated Assays “Fit for Purpose” for Regulatory Decision‐Making and Management of Chemicals?

“…The EDSP Tier 1 guideline tests (USEPA ) include several in vivo assays to measure chemical interactions with the thyroid hormone pathway but, to date, do not include any mechanistic assays for thyroid targets, and therefore, it may be difficult to link an apical in vivo response to a thyroid mechanism of action (Browne et al ). In addition, relying exclusively on animal testing to screen chemicals for potential endocrine disruption limits the number of chemicals that can be screened.…”

“…The USEPA (2019a) Endocrine Disruptor Screening Program (EDSP) provides an example of using AOPs to target assay development in order to link a MIE to an AO of regulatory concern with respect to the estrogen, androgen or thyroid signaling pathways. The EDSP Tier 1 guideline tests (USEPA 2019b) include several in vivo assays to measure chemical interactions with the thyroid hormone pathway but, to date, do not include any mechanistic assays for thyroid targets, and therefore, it may be difficult to link an apical in vivo response to a thyroid mechanism of action (Browne et al 2017). In addition, relying exclusively on animal testing to screen chemicals for potential endocrine disruption limits the number of chemicals that can be screened.…”

Reconnaissance of Surface Water Estrogenicity and the Prevalence of Intersex in Smallmouth Bass (Micropterus Dolomieu) Inhabiting New Jersey

“…Although EDs have been documented extensively in natural systems, establishing cause-and-effect relationships with biological observations is typically not possible and the fulfillment of Hill's Criteria or simple weight-of-evidence associations are the most satisfactory observational support [2,11,12]. Given the global ecological health implications of ED exposure, considerable efforts have been endeavored to develop strategies that evaluate and predict the significance of exposures [13][14][15].…”