Academic journal article Environmental Health Perspectives

A Novel Method for the Development of Environmental Public Health Indicators and Benchmark Dose Estimation Using a Health-Based End Point for Chlorpyrifos

Academic journal article Environmental Health Perspectives

A Novel Method for the Development of Environmental Public Health Indicators and Benchmark Dose Estimation Using a Health-Based End Point for Chlorpyrifos

Article excerpt

Introduction

Organophosphorus (OP) insecticides are among the most widely used synthetic chemicals for the control of agricultural and domestic insect pests. Approximately 70% of the insecticides in current use in the United States are OP-based, which amounts to a total of approximately 33 million kilograms of these chemicals applied each year (U.S. EPA 2011). OP insecticides phosphorylate numerous enzymes including a large number of B-esterases whose primary function is to hydrolyze choline-based esters such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (Chambers and Levi 1992). These esterases are present throughout the body, with high abundances in the plasma, hematocrit, and brain. The primary mechanism of action of OP insecticide-induced toxicity is the inhibition of AChE by active oxon metabolites, resulting in the accumulation of acetylcholine neurotransmitter within the cholinergic synapses (Casida 2009), resulting in cholinergic toxicity due to continuous stimulation of cholinergic receptors throughout the central and peripheral nervous system. Symptoms of acute exposure to organophosphates or similar cholinesterase-inhibiting compounds may include headache, dizziness, numbness, tremor, nausea, sweating, blurred vision, respiratory depression, and slow heartbeat (Calvert et al. 2008; Eaton et al. 2008). Very high doses may result in unconsciousness, incontinence, and convulsions or fatality (Eaton et al. 2008).

Currently, the most sensitive biomarker of effect of exposure to a variety of OP insecticides, in both animals and humans, is the inhibition of cholinesterases (Clegg and van Gemert 1999; Nigg and Knaak 2000; Reiss et al. 2012). With cholinergic biochemical changes as the primary end point of toxicity, risk assessments have been conducted to determine benchmark doses corresponding to a given percentage of cholinesterase inhibition. In its most comprehensive OP insecticide cumulative risk assessment update, the U.S. Environmental Protection Agency (EPA) elected to use 10% AChE inhibition in the brain ([BMD.sub.10AChE]) as the point of departure (PoD) response level, stating that "The 10% response level is health protective in that no functional or behavioral effects have been noted below this level in adult or juvenile animals" (U.S. EPA 2006). In addition to the formal 10% brain AChE inhibition guideline set by the U.S. EPA for organophosphorus insecticide exposure, Reiss et al. considered a 20% AChE inhibition in red blood cells (RBC) as a reasonable guideline for protection against OP insecticide toxicity. Following consideration of a number of additional studies (U.S. EPA 2014, 2015, 2016b), the U.S. EPA's 2016 revised human health risk assessment indicated that additional, more sensitive, end points may exist and should be considered in assessing risk associated with exposure to this chemical (U.S. EPA 2016c). In particular, this realization has led to increased efforts to understand the risk associated with CPF exposure during prenatal and postnatal windows of exposure and the potential neurodevelpomental outcomes associated with early exposure and to the consideration of appropriate biomarkers of effect linked to adverse neurodevelopmental outcomes (U.S. EPA 2016b, 2016c). In reviewing the available information and potential risks from CPF exposure, the U.S. EPA's updated assessment stated, "The agency has endeavored to derive PoDs and uncertainty/safety factors for risk assessment that are protective of both AChE inhibition and any adverse effects that could occur at lower doses" (U.S. EPA 2016c).

Although the methodology for developing PoDs for neurodevelopmental end points is still under consideration (U.S. EPA 2016c), the method for determining the PoD benchmark doses in the context of biochemical changes commonly involves developing a cholinesterase inhibition dose-response curve following OP exposure in rats. Specifically, using an appropriate pharmacodynamic relationship between known external dose and resulting cholinesterase inhibition, a benchmark dose, usually defined for oral, dermal, or inhalation exposure in mg/kg/day, is estimated based on the designated biomarker of effect level: for example, 10% AChE inhibition in the brain. …

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