You are here:
Bridging the Gap: Integrating Systematic Review Strategies and New Approach Methodologies for the Cross-Species Extrapolation of Endocrine Targets
Citation:
Vliet, S., S. Lynn, K. Markey, AND C. LaLone. Bridging the Gap: Integrating Systematic Review Strategies and New Approach Methodologies for the Cross-Species Extrapolation of Endocrine Targets. SETAC North America 42nd Annual meeting, Portland, OR, November 14 - 18, 2021. https://doi.org/10.23645/epacomptox.17102588
Impact/Purpose:
Presentation to the SETAC North America 42nd Annual meeting November 2021. Scientific research suggests that environmental contaminants can disrupt the endocrine system by mimicking naturally produced hormones and binding to receptors in the body. This can lead to negative health outcomes in both humans and wildlife. Identifying chemicals that act of endocrine targets is essential to determine the risk of these chemicals to human health and the environment. Although it’s clear that some chemicals cause endocrine-disrupting effects, very few chemicals have been tested because of the many resources and animals needed to test each chemical. New testing methods focused on the molecular biology of a relatively few model species can quickly test chemicals and prioritize them for further testing. Although these methods are useful, it’s unclear if results represent potential health effects in different groups of organisms. Instead of doing more testing, carrying out large, controlled searches of existing data can help answer this question. The first goal of this research is to understand how similar and different endocrine targets, such as the androgen receptor, are across groups of organisms and how these differences influence the toxicity of chemicals. The second goal of this research is to use computer-based tools and data searching methods to carry out large reviews of available toxicity data that will help determine whether new, molecular-based testing methods can predict endocrine activity in different groups of organisms. Results of this research demonstrate that molecular-based screening methods can predict the conservation of endocrine pathways across species, and that combining them with available toxicity data can help connect to health effects across organisms.
Description:
The US Environmental Protection Agency’s Endocrine Disruptor Screening Program (EDSP) is tasked with assessing chemicals for their potential to perturb endocrine pathways. Traditionally, chemical screening for endocrine activity is performed using a tiered toxicity testing strategy that includes animal and resource intensive in vivo studies. In a shift towards more efficient testing, the EDSP has been exploring the use of new approach methods (NAMs) to prioritize chemicals rapidly. However, most NAMs rely on a few model species which may not be sufficient to evaluate the broad diversity of species potentially impacted by chemical exposures. A NAM that can be used to predict biological pathway conservation across taxa and therefore extrapolate from model species to untested species, is the US EPA Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool. The SeqAPASS tool rapidly evaluates protein target sequence and structural similarity to understand conservation of biological targets. As with many NAMs, SeqAPASS is designed to help evaluate chemical-biological interactions at the molecular level. Science-based approaches for endocrine hazard and risk characterization, require the linking of molecular mechanisms to adverse apical responses. To link molecular endpoints captured through NAMs and traditional apical outcomes, tools and techniques are emerging that focus on the systematic identification, review, and evaluation of existing data. The integration of systematic review methods has maximized the use of existing toxicity data, reduced testing resources, and has strengthened transparency and confidence in risk assessments. In this study, SeqAPASS was used to assess the conservation of endocrine targets and generate molecular-level predictions of cross-species chemical susceptibility. Further, the latest tools in data curation science for systematic review practices were applied to anchor SeqAPASS-derived molecular-based predictions of species susceptibility with existing in vitro and in vivo data providing weight of evidence (WoE) for the extrapolation of endocrine responses across species. Overall, this presentation describes a framework for understanding pathway conservation for endocrine targets across species and highlights both the need, and a strategy to bridge the gap between existing NAMs and current systematic review practices. The contents of this abstract neither constitute nor necessarily reflect US EPA policy.
URLs/Downloads:
DOI: Bridging the Gap: Integrating Systematic Review Strategies and New Approach Methodologies for the Cross-Species Extrapolation of Endocrine Targets
SVLIET_SETAC NA_2021_PRESENTATION.PDF (PDF, NA pp, 3890.416 KB, about PDF)