Comparative pharmacokinetics of the organophosphorus insecticide chlorpyrifos and its major metabolites diethylphosphate, diethylthiophosphate and 3,5,6-trichloro-2-pyridinol in the rat.
Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of metabolism and of environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. However, because these same chemicals can result from metabolism or by biodegradation, monitoring total urinary metabolite levels may be reflective of not only an individual's contact with the parent pesticide, but also exposure with the metabolites, which are present in the environment. The objective of the current study was to compare the pharmacokinetics of orally administered DEP, DETP and TCPy with their kinetics following oral dosing with the parent insecticide CPF in the rat. Groups of rats were orally administered CPF, DEP, TCPy or DETP at doses of 140mumol/kg body weight, and the time-courses of the metabolites were evaluated in blood and urine. Following oral administration, all three metabolites were well absorbed with peak blood concentrations being attained between 1 and 3h post-dosing. In the case of DEP and TCPy virtually all the administered dose was recovered in the urine by 72h post-dosing, suggesting negligible, if any, metabolism; whereas with DETP, approximately 50% of the orally administered dose was recovered in the urine. The CPF oral dose was likewise rapidly absorbed and metabolized to DEP, TCPy and DETP, with the distribution of metabolites in the urine followed the order: TCPy (22+/-3mumol)>DETP (14+/-2mumol)>DEP (1.4+/-0.7mumol). Based upon the total amount of TCPy detected in the urine a minimum of 63% of the oral CPF dose was absorbed. These studies support the hypotheses that DEP, DETP and TCPy present in the environment can be readily absorbed and eliminated in the urine of rats and potentially humans.
Timchalk
Charles
C
Pacific Northwest National Laboratory, 902 Battelle Blvd, PO Box 999, Richland, WA 99352, USA. Electronic address: charles.timchalk@pnl.gov.
Busby
Andrea
A
Pacific Northwest National Laboratory, 902 Battelle Blvd, PO Box 999, Richland, WA 99352, USA.
Campbell
James A
JA
Pacific Northwest National Laboratory, 902 Battelle Blvd, PO Box 999, Richland, WA 99352, USA.
Needham
Larry L
LL
National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, Atlanta, GA 30341-3724, USA.
Barr
Dana B
DB
National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, Atlanta, GA 30341-3724, USA.
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D004390:Chlorpyrifos / Q000493:pharmacokinetics*; D008401:Gas Chromatography-Mass Spectrometry; D007306:Insecticides / Q000493:pharmacokinetics*; D008297:Male; D010755:Organophosphates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D010710:Phosphates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D011728:Pyridones / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
D007306:Insecticides; D010755:Organophosphates; D010710:Phosphates; D011728:Pyridones; C034789:diethyl phosphate; C012587:3,5,6-trichloro-2-pyridinol; D004390:Chlorpyrifos; C035638:thiophosphoric acid