Seth G. McGrew

Project title: New insights from a study of chlorpyrifos toxicology in humans

Degree: MS (Thesis) | Program: Environmental Health (EH) | Project type: Thesis/Dissertation
Completed in: 2018 | Faculty advisor: Lianne Sheppard


Background: Chlorpyrifos is among the most heavily used conventional insecticides in the United States. The public is chronically exposed to low levels of chlorpyrifos in food crop residues and drinking water. In 1971, Dow Chemical Company conducted a study in human subjects to determine a level of chlorpyrifos that can be ingested every day without inhibiting plasma cholinesterase (plasma-ChE) and red blood cell cholinesterase (RBC-ChE), two markers of the acute toxicological effect of organophosphate exposure. The study's only reported significant effect was plasma ChE inhibition in the subjects treated at 100µg/kg/day, the highest dose level tested. Objective: The primary goal of this thesis is to reassess the original safety evaluation to see whether new analysis supports revision of the previously reported effect of treatment on plasma ChE activity. The project also seeks to characterize the recovery trend that follows treatment. A review of regulatory documents intends to clarify past use of Dow's safety evaluation in EPA's regulatory process. Methods: The analysis uses repeated measures ANOVA and linear mixed effects (LMM) regression to examine plasma ChE activity data for treatment effects at each dose level. Trends in recovery of plasma ChE activity are assessed by LMM regression with splines for subjects treated at 30µg/kg/day and 100µg/kg/day. Results: The original analysis by repeated measures ANOVA used a subset of data for the 30µg/kg/day group to make its determination of no treatment effect on plasma ChE activity (p = 0.12). When all measurements are included in the ANOVA, the data indicate a significant effect at that dose level (p = 0.012). An LMM regression model that imposes no pattern of dose dependence estimates significant inhibitory effects on plasma ChE at the 30µg/kg/day and 100µg/kg/day levels (p < 0.0001), and nearly significant inhibition at 14µg/kg/day (p = 0.066). Inhibitory effect estimates are 0.029, -0.070, and 0.349µmoles acetate/min/ml/day for treatment at 14, 30, and 100µg/kg/day, respectively. LMM regression that assumes a linear relationship between dose and treatment effect estimates significant inhibition for treatment at all three dose levels. LMM regression with splines estimates that subjects treated at 30µg/kg/day recovered their plasma ChE activity at 0.047µmoles acetate/min/ml/day, and subjects treated at 100µg/kg/day recovered more than twice as rapidly at 0.101µmoles acetate/min/ml/day. Conclusions: The original analysis failed to detect an effect from treatment at 30µg/kg/day that is well supported by the data. Plasma ChE inhibition by chlorpyrifos has approximately linear dose dependence for repeated daily treatments at 14, 30, and 100µg/kg/day. Acute plasma ChE inhibition may precipitate more rapid recovery than less severe inhibition. Earlier identification of the treatment effect at 30µg/kg/day would have reduced the maximum acceptable oral dose established by the EPA in 1986. URI