Department of Environmental Health, Harvard School of Public Health, 401 Park Drive West, Boston, MA 02215, USA.
Int J Environ Res Public Health. 2012 May;9(5):1971-83. doi: 10.3390/ijerph9051971. Epub 2012 May 22.
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.
累积风险评估已被提议作为一种方法，用于评估同时暴露于多种化学和非化学应激源相关的健康风险。基于生理学的药代动力学/药效学（PBPK/PD）模型可以允许包括和评估多种应激源，包括非化学应激源，但研究尚未利用 PBPK/PD 模型在累积风险背景下共同考虑这些不同的暴露。在这项研究中，我们专注于城市低收入环境中儿童接触有机磷（OP）农药的情况，这些儿童会同时接触其他农药（包括拟除虫菊酯）和可能改变这些暴露影响的非化学应激源（包括饮食）。我们开发了一种方法框架，利用现有的毒死蜱 PBPK/PD 模型来评估化学和非化学应激源对 OP 的影响。我们评估了会影响 OP 剂量或乙酰胆碱酯酶（AChE）抑制的特定人群的应激源，这是相关的 PD 结果。我们通过 PBPK 模型中的代谢和 PD 结果的隔室，将同时接触拟除虫菊酯和饮食因素对 OP 剂量的影响纳入其中，并模拟了多种暴露范围和潜在体重下的应激源组合。我们的分析表明，化学和非化学应激源都会影响 OP 暴露的健康影响，在给定 OP 剂量下，AChE 抑制的变化范围可达 5 倍。我们展示了一种在存在其他特定人群环境应激源的情况下对 OP 风险进行建模的方法，为了解共同暴露和最能影响 OP 健康风险的变异性因素提供了信息，并有助于儿童从农药中累积的健康风险。更一般地说，该框架可以用于通过代谢或 PD 结果来告知任何受化学和非化学应激源影响的化合物的累积风险评估。
