title: Acetylcholinesterase inhibition dose-response modeling for chlorpyrifos and chlorpyrifos-oxon.
abstract: This paper evaluates new data for cholinesterase inhibition with chlorpyrifos (CPF). Marty et al. (2012) recently conducted a CPF cholinesterase inhibition study in rats that included testing of males and females, dosing by gavage or diet, administration in corn oil or milk, and with pups and adults. Additionally, the study included cholinesterase inhibition testing for CPF-oxon, the active moiety that inhibits cholinesterase. The study included 5-6 dose groups with eight animals/sex/group for most of the tests. This paper provides a benchmark dose (BMD) analysis of the data from Marty et al. (2012), including a BMD meta-analysis that includes CPF cholinesterase inhibition data from different assays within the Marty et al. (2012) study and, in one case, from another study. From the meta-analysis, the recommended BMD(10)s, based on brain acetylcholinesterase inhibition, are 1.7 mg/kg/day (BMDL₁₀ = 1.3mg/kg/day) for acute doses to children and adults, and 0.67 mg/kg/day (BMDL₁₀ = 0.53 mg/kg/day) for repeat doses to children and adults. At the dose levels considered in this analysis, there was no evidence of a difference in responses between males and females, corn oil versus milk administration, or pups versus adults. The data on pups versus adults show that an extra safety factor to protect the young is not needed for CPF. CPF data from the literature suggest that brain cholinesterase inhibition is the most appropriate metric for cholinesterase inhibition risk assessment.
authors.affiliation: Exponent, 1800 Diagonal Road, Suite 500, Alexandria, VA 22314, USA. rreiss@exponent.com
authors.forename: Richard
authors.initials: R
authors.lastname: Reiss
authors.forename: Barbara
authors.initials: B
authors.lastname: Neal
authors.forename: James C
authors.initials: JC
authors.lastname: Lamb
authors.forename: Daland R
authors.initials: DR
authors.lastname: Juberg
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002648:Child; D004390:Chlorpyrifos / Q000031:analogs & derivatives* / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D051381:Rats; D018570:Risk Assessment
chemical_list: D002800:Cholinesterase Inhibitors; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D000110:Acetylcholinesterase; D004390:Chlorpyrifos