Albumin binding as a potential biomarker of exposure to moderately low levels of organophosphorus pesticides.

We have evaluated the potential of plasma albumin to provide a sensitive biomarker of exposure to commonly used organophosphorus pesticides in order to complement the widely used measure of acetylcholinesterase (AChE) inhibition. Rat or human plasma albumin binding by tritiated-diisopropylfluorophosphate ((3)H-DFP) was quantified by retention of albumin on glass microfibre filters. Preincubation with unlabelled pesticide in vitro or dosing of F344 rats with pesticide in vivo resulted in a reduction in subsequent albumin radiolabelling with (3)H-DFP, the decrease in which was used to quantify pesticide binding. At pesticide exposures producing approximately 30% inhibition of AChE, rat plasma albumin binding in vitro by azamethiphos (oxon), chlorfenvinphos (oxon), chlorpyrifos-oxon, diazinon-oxon and malaoxon was reduced from controls by 9+/-1%, 67+/-2%, 56+/-2%, 54+/-2% and 8+/-1%, respectively. After 1 h of incubation with 19 microM (3)H-DFP alone, the level of binding to rat or human plasma albumins reached 0.011 or 0.039 moles of DFP per mole of albumin, respectively. This level of binding could be further increased by raising the concentration of (3)H-DFP, increasing the (3)H-DFP incubation time, or by substitution of commercial albumins for native albumin. Pesticide binding to albumin was presumed covalent since it survived 24 h dialysis. After dosing rats with pirimiphos-methyl (dimethoxy) or chlorfenvinphos (oxon) (diethoxy) pesticides, the resultant albumin binding were still significant 7 days after dosing. As in vitro, dosing of rats with malathion did not result in significant albumin binding in vivo. Our results suggest albumin may be a useful additional biomonitor for moderately low-level exposures to several widely used pesticides, and that this binding differs markedly between pesticides.

Pretreatment of rats with an organophosphorus insecticide, chlorfenvinphos, protects against subsequent challenge with the same compound.

A single oral pretreatment of rats with chlorfenvinphos (CVP) reduced toxicity of the same compound subsequently administered. This protection occurred 8 hr and became maximal 24 hr after the oral pretreatment at a dose of 15 mg/kg (about half of its LD50). The 24-hr pretreatment with CVP increased the LD50 of CVP threefold, but did not change the type of toxic signs and time to death caused by CVP. The CVP pretreatment did not appreciably change the toxicities of the cholinergic agonists, carbachol and oxotremorine, but significantly increased the toxicity of another organophosphate, dichlorvos. Oral treatment of rats with CVP (15 mg/kg) inhibited brain acetylcholinesterase (AChE) activity. This inhibition became maximal at 4 hr (about 20% of control) and lasted more than 24 hr after the administration. Twenty-four hours after oral administration of CVP (15 mg/kg), the second dose (CVP 30 mg/kg, po) was less effective in inhibiting cholinesterase activities of the brain, erythrocyte, and plasma compared with naive rats treated with the same dose. The difference in brain AChE activity between control and CVP pretreatment groups was greater in magnitude than that measured in erythrocytes. CVP concentration in plasma after the oral administration of CVP (30 mg/kg) was decreased by the CVP pretreatment. Area under the concentration vs time curve (AUC) in the CVP-pretreated group was about one-fourth of AUC in the control group. This decrease in the AUC was comparable to the decrease in the toxicity of CVP. Thus, the protection against subsequent CVP challenge may be due to the reduction in the inhibition of brain AChE activity caused by the decrease in plasma CVP concentration.