A comprehensive review of regulatory test methods for endocrine adverse health effects

Abstract

Development of new endocrine disruption-relevant test methods has been the subject of intensive research efforts for the past several decades, prompted in part by mandates in the 1996 Food Quality Protection Act (FQPA). While scientific understanding and test methods have advanced, questions remain on whether current scientific methods are capable of adequately addressing the complexities of the endocrine system for regulatory health and ecological risk assessments. The specific objective of this article is to perform a comprehensive, detailed evaluation of the adequacy of current test methods to inform regulatory risk assessments of whether a substance has the potential to perturb endocrine-related pathways resulting in human adverse effects. To that end, approximately 42 existing test guidelines (TGs) were considered in the evaluation of coverage for endocrine-related adverse effects. In addition to evaluations of whether test methods are adequate to capture endocrine-related effects, considerations of further enhancements to current test methods, along with the need to develop novel test methods to address existing test method gaps are described. From this specific evaluation, up to 35 test methods are capable of informing whether a chemical substance perturbs known endocrine related biological pathways. Based on these findings, it can be concluded that current validated test methods are adequate to discern substances that may perturb the endocrine system, resulting in an adverse health effect. Together, these test methods predominantly form the core data requirements of a typical food-use pesticide registration submission. It is recognized, however, that the current state of science is rapidly advancing and there is a need to update current test methods to include added enhancements to ensure continued coverage and public health and environmental protection.

Summary of the development the US Environmental Protection Agency's Medaka Extended One Generation Reproduction Test (MEOGRT) using data from 9 multigenerational medaka tests

“…The US Environmental Protection Agency (USEPA) formed its Endocrine Disruptor Screening Program (EDSP), following the passage of several Congressional acts, including the Food Quality Protection Act, which amended both the Federal Food Drug and Cosmetic Act and the Federal Insecticide, Fungicide, and Rodenticide Act, and again in separate amendments to the Safe Drinking Water Act. The EDSP has developed the requirements for the prioritization, screening, and testing of pesticides, commercial chemicals, and environmental contaminants for their potential to impact the endocrine system, specifically in relation to estrogen, androgen, and thyroid hormones (for a summary, see Manibusan and Touart ). To achieve this, the EDSP implemented a 2‐tiered testing strategy.…”

“…Endocrine‐active substances are known to disrupt endocrine‐regulated organizational as well as activational processes in an organism . Effects on organizational processes are reflected in changes to the development of the gonad or accessory tissues such that reproduction is adversely affected.…”

Assessment of occupational exposure to pesticide mixtures with endocrine-disrupting activity

“…The dose thresholds/guidance values for "Specific Target Organ Toxicity Repeated Exposure" were used to determine whether the hazardous property of endocrine disruption should be identified for regulatory purposes in accordance with the CLP Regulation (Ewence et al 2015). Nevertheless, the OECD framework is inadequate for the identification of all aspects of endocrine disrupting effects, because it mainly focuses on estrogenicity, anti-androgenicity, and thyroid disruption (Manibusan and Touart 2017).…”

Optimization of a Deep-Learning Method Based on the Classification of Images Generated by Parameterized Deep Snap a Novel Molecular-Image-Input Technique for Quantitative Structure–Activity Relationship (QSAR) Analysis

“…The traditional human-safety assessment of chemical compounds involves repetitive-dosage subacute toxicity testing in vivo using animal models. However, the risk remains that such compounds could pose major public health concerns to humans by potentially disrupting normal endocrine functions with various hormone receptors upon long-term exposure (Genuis and Kyrillos, 2017; Heindel et al, 2017; Manibusan and Touart, 2017; Sifakis et al, 2017; Tapia-Orozco et al, 2017; Heindel, 2018; Marty et al, 2018). However, since some molecular mechanisms differ between species and depend on environmental factors, it is often difficult to apply the outcomes of animal testing to predict the effects on human health (Brockmeier et al, 2017; Leist et al, 2017; Fay et al, 2018).…”