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Daland R. Juberg, Dow AgroSciences Paul Price, The Dow Chemical Company May 4, 2011

Regulatory Sciences and Government Affairs. Quantitative Assessment of Sensitivity and Variability in Humans: Modeling the Effects of Low Dose Exposure to Dietary Residues of Chlorpyrifos. Daland R. Juberg, Dow AgroSciences Paul Price, The Dow Chemical Company May 4, 2011. Background.

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Daland R. Juberg, Dow AgroSciences Paul Price, The Dow Chemical Company May 4, 2011

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  1. Regulatory Sciences and Government Affairs Quantitative Assessment of Sensitivity and Variability in Humans: Modeling the Effects of Low Dose Exposure to Dietary Residues of Chlorpyrifos Daland R. Juberg, Dow AgroSciences Paul Price, The Dow Chemical Company May 4, 2011

  2. Background • ACC/LRI request for proposals to use science to advance risk assessment (2007) • Goal: replace safety factors with quantitative predictions of adverse effects • Leverage extensive knowledge on chlorpyrifos • Project expanded in 2010 to address new data on variation in human metabolism • Basis for EPA SAP (2011)

  3. Chlorpyrifos • Widely used active ingredient in insect control products for agriculture (registered in 1965; 100 countries globally) • Extensive toxicological database including: • Full toxicological database for global registrations • Occupational exposure and health monitoring data • Epidemiology studies • Toxicological mechanism and endpoint upon which human exposure limits are based is cholinesterase inhibition

  4. What was Done? • Source-to-outcome model that evaluates the relationship between dietary residues in food and impact on cholinesterase inhibition (ChEI) in exposed populations. Based on combined models: • Dietary model estimates daily dose from dietary residues • PBPK/PD model measures changes in ChEI from oral exposure • The effort is an example of the upstream ‘obligatory perturbation’ concept described in the NAS Toxicity in the 21st Century

  5. Advancements in Risk Assessment • Assessed variability in both exposure (variation of residue levels across foods and variation in individual’s dietary consumptions) and response (variation in physiology and metabolism) • Evaluated response to the range of actual human exposures • Assessed human sensitivity in multiple age groups (infants, children, adults) • Background rates of the apical effects did not prevent the determination of a population threshold for the key event (AChEI) and all subsequent effects of chlorpyrifos

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