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A quantitative approach for integrating mechanistic data across human health and ecological endpoints to inform risk assessment using Aggregate Exposure Pathway and Adverse Outcome Pathway networks
Citation:
Hines, D., R. Conolly, AND A. Jarabek. A quantitative approach for integrating mechanistic data across human health and ecological endpoints to inform risk assessment using Aggregate Exposure Pathway and Adverse Outcome Pathway networks. Society of Toxicology, Baltimore, Maryland, March 10 - 14, 2019.
Impact/Purpose:
This project develops approaches for integrating exposure, toxicokinetic, and toxicodynamic data across human health and ecological endpoints to inform cumulative risk assessment (CRA). It applies the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks, along with Physiologically Base Pharmacokinetic (PBPK) models, to a case study of a chemical at a hypothetical contaminated site to demonstrate how an AEP-PBPK-AOP construct can inform quantitative source-to-outcome analyses. The results of this case study provide an example of how our approach can facilitate the identification of primary exposure pathways, the quantification of the relative source contribution of contaminants to individual species, and the evaluation of risk for multiple outcomes. Additionally, this work demonstrates how our approach can highlight knowledge gaps and uncertainties, and can help to quantify which gaps are the most valuable to research.
Description:
Environmental stressors and contaminants can lead to Adverse Outcomes (AOs) in both human health and ecological receptors. Evaluating risk of AOs across multiple organisms in a community is crucial to characterize the cumulative impacts of stressors and contaminants; but is challenging due to species-specific differences in exposure pathways, behavior, physiology, and toxicity mechanisms. This work addresses some of these challenges by developing a quantitative source-to-outcome approach using the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks. We demonstrate this approach using a case study of a hypothetical wetland site contaminated by the perchlorate anion, a molecule that affects established AOPs by competitively inhibiting iodide uptake into the thyroid at the sodium-iodide symporter (NIS). External exposure pathways were quantified in a hypothetical AEP network for humans, fish, and small herbivorous mammals under mild, moderate, and high contamination scenarios. Ecological Network Analysis was applied to describe the relative source contribution (RSC) of exposure to each species. Exposures were linked to an AOP network for NIS inhibition using published physiologically based pharmacokinetic models, then combined with available mechanistic dose-response data to calculate a hazard index (HI) for each potential AO in each species. Surface water contamination provided the largest RSC for exposure in fish, while groundwater contamination was the largest RSC in humans and small herbivorous mammals. HI results predicted that small herbivorous mammals would have the highest risk of AOs in all scenarios, while the relative risk of AOs between humans and fish differed by exposure pathway. We demonstrate how the AEP-AOP construct can link transport and transformation, exposure, toxicokinetics, and toxicodynamics; as well as inform cumulative risk assessment, by 1) organizing existing mechanistic data, 2) identifying data gaps, 3) quantifying uncertainties, and 4) facilitating simultaneous evaluation of risk in human health and ecological endpoints. The views expressed in this poster are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.