Nonlinear model analyses of urinary metabolite levels of organophosphate pesticides corresponding to cholinesterase activity inhibition in rats

摘要

Background and aim Urinary dialkylphosphates (DAPs) are generally used for the exposure assessment of organophosphate pesticides (OPs) whereas they are common metabolites of OPs and not specific indices for each agent. This study aimed to clarify the relationship between cholinesterase (ChE) activity inhibition as the neurotoxicological endpoint of OPs and the amount of DAP excreted into urine in rats exposed to dichlorvos (DDVP) and fenitrothion (FNT), of which the magnitudes of acute toxicity are different. Methods A total of 40 male Wistar rats (11-week-old) was divided into four groups for each OP and orally administered 0 (control), 0.2 (low), 1.0 (middle) or 5.0 (high) mg/kg/day of the respective OP for 10 days with a 2-day interruption after the first 5 days. The urine was collected 6, 12 and 24 hours after the final administration, and then the blood and brain were taken. The ChE activities of the brain, red blood cell (RBC) and plasma were analyzed by Ellman method. DAPs were measured by using gas chromatography-mass spectrometry. Statistical analyses and nonlinear model estimation were conducted with drc R package. A lower confidence limit of excretion corresponding to 20% inhibition of each ChE activity (ELL20) was estimated. Results & Discussion The ELL20 (nmol/24-hour urine) of DDVP and FNT were 1156 and 261 for the brain, 481 and 262 for RBC, and 735 and 315 for plasma, respectively. The ratio of DAPs excreted in 24-hour urine for DDVP and FNT was 99% and 52% for low, 63% and 29% for middle, and 40% and 16% for high group, respectively. The differences in ELL20 between two OPs were considered to be attributable to a possibly slower metabolism of FNT than DDVP, and/or to the production of other metabolites than DAPs.