Human red blood cell acetylcholinesterase inhibition as the appropriate and conservative surrogate endpoint for establishing chlorpyrifos reference dose.
Chlorpyrifos (O,O-diethyl O-(3,5, 6-trichloro-2-pyridinyl)- phosphorothioate) is an organophosphorus (OP) insecticide used for controlling insect pests. Currently, the reference dose (RfD) used by the Environmental Protection Agency (EPA) to establish acceptable human exposure tolerances for chlorpyrifos is based upon inhibition of blood butyrylcholinesterase (BuChE), which is not the target enzyme of chlorpyrifos, and does not play any role in cholinergic transmission. Data are presented showing that inhibition of acetylcholinesterase (AChE) associated with red blood cells (RBC), an enzyme similar to or identical with that in the nervous system, is a more appropriate endpoint on which to base the RfD. Basing an acceptable level of human exposure (e.g., RfD) on inhibition of RBC AChE provides a significant margin of safety, since it is 12- to 14-fold more sensitive as an indicator of chlorpyrifos exposure than the AChE in the most sensitive relevant neurological tissues (brain or retina). Inhibition of RBC AChE activity is consistently exhibited at lower dosages of chlorpyrifos than those required to result in clinical symptoms of OP toxicity, or alterations in cognitive functional responses. There is no unique sensitivity of the fetus or neonates to chlorpyrifos when administered by an appropriate oral dose. Thus, inhibition of RBC AChE activity is an appropriate surrogate measurement of chlorpyrifos exposure and provides a conservative endpoint for establishing appropriate margins of safety for both adults and infants.
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W L
WL
Chen
J J
JJ
Sheets
R J
RJ
Nolan
J L
JL
Mattsson
D000328:Adult; D000818:Animals; D004390:Chlorpyrifos / Q000097:blood*; D002800:Cholinesterase Inhibitors / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D007223:Infant; D007306:Insecticides / Q000097:blood*; D008297:Male; D008452:Maximum Allowable Concentration; D011247:Pregnancy; D051381:Rats
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D004390:Chlorpyrifos