Abstract
Cumulative risk assessment has been proposed as an approach to evaluate the health risks associated with simultaneous exposure to multiple chemical and non-chemical stressors. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can allow for the inclusion and evaluation of multiple stressors, including non-chemical stressors, but studies have not leveraged PBPK/PD models to jointly consider these disparate exposures in a cumulative risk context. In this study, we focused on exposures to organophosphate (OP) pesticides for children in urban low-income environments, where these children would be simultaneously exposed to other pesticides (including pyrethroids) and non-chemical stressors that may modify the effects of these exposures (including diet). We developed a methodological framework to evaluate chemical and non-chemical stressor impacts on OPs, utilizing an existing PBPK/PD model for chlorpyrifos. We evaluated population-specific stressors that would influence OP doses or acetylcholinesterase (AChE) inhibition, the relevant PD outcome. We incorporated the impact of simultaneous exposure to pyrethroids and dietary factors on OP dose through the compartments of metabolism and PD outcome within the PBPK model, and simulated combinations of stressors across multiple exposure ranges and potential body weights. Our analyses demonstrated that both chemical and non-chemical stressors can influence the health implications of OP exposures, with up to 5-fold variability in AChE inhibition across combinations of stressor values for a given OP dose. We demonstrate an approach for modeling OP risks in the presence of other population-specific environmental stressors, providing insight about co-exposures and variability factors that most impact OP health risks and contribute to children’s cumulative health risk from pesticides. More generally, this framework can be used to inform cumulative risk assessment for any compound impacted by chemical and non-chemical stressors through metabolism or PD outcomes.
Highlights
Cumulative risk assessment has recently emerged as an area of interest among regulators as well as stakeholders concerned about environmental justice [1,2,3]
We have developed and applied a framework for using Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD)
Even given the limited information available to estimate effects within a PBPK/PD framework, our approach allowed for characterization of relative impacts of multiple stressors on OP doses and factors that contribute most to increased risk of AChE inhibition amongst this simulated population
Summary
Cumulative risk assessment has recently emerged as an area of interest among regulators as well as stakeholders concerned about environmental justice [1,2,3]. The EPA considers cumulative risk assessment to include both chemical and non-chemical stressors, the latter of which may potentially include (but not be limited to) low income, low community property values, limited access to health care, psychosocial stress, and other stressors not commonly within the purview of EPA decision-making. Despite the inclusion of non-chemical stressors in the definition of cumulative risk, cumulative risk assessments to date have typically ignored those stressors [5]. This is largely because toxicological studies do not have the capacity to consider most non-chemical stressors, as well as because of the limited availability of epidemiological evidence. A recent report evaluating risk assessment methods [6] reinforced the priority that needs to be placed on evaluating risks from multiple stressors simultaneously, with a particular emphasis on identifying how multiple chemical and non-chemical stressors impact individual and population health
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