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PubMedDate not supplied

Determination of chlorpyrifos, chlorpyrifos oxon, and 3,5,6-trichloro-2-pyridinol in rat and human blood.

Analytical methods to quantitate chlorpyrifos and two potential metabolites, chlorpyrifos oxon (oxon) and 3,5,6-trichloro-2-pyridinol (TCP), in human and rat blood are described. Chlorpyrifos and the oxon were extracted simultaneously with a methanol/hexane mixture from 0.5 mL blood that was deactivated with an acidic salt solution. The extract was then concentrated and analyzed by negative-ion chemical ionization gas chromatography-mass spectrometry (NCI-GC-MS). TCP was extracted from a separate 0.1-mL aliquot of blood, also deactivated by the addition of acid. The t-butyldimethylsilyl derivative of TCP was formed using MTBSTFA, and the analysis was performed by NCI-GC-MS. Stable isotope analogues of chlorpyrifos (-13C2-15N), oxon (-13C2-15N), and TCP (-13C2) were used as internal standards. Oxon was observed to partially degrade to TCP during the sample analysis. Accurate oxon and TCP measurements were obtained with the use of oxon-13C2-15N, TCP-13C2, and TCP-13C2-15N internal standards, which compensated for both the degradation of oxon and the formation of artifactual TCP during analysis. The limits of quantitation were 1 ng/mL blood for both chlorpyrifos and oxon and 10 ng/mL for TCP. Calibration curves were linear over the concentration range of 2.5-2500 ng/mL solvent for chlorpyrifos and oxon and between 5 and 1060 ng/mL solvent for TCP. Taking concentration factors and extraction efficiencies into account, these linear ranges represent blood concentrations of approximately 0.3-300 ng/mL blood for chlorpyrifos and the oxon and 6-1300 ng/mL blood for TCP. The lowest spike level for chlorpyrifos and the oxon was 1 ng/mL blood, and the lowest spike level for TCP was 10 ng/mL blood. Recoveries from rat blood were as follows: 106-119% for chlorpyrifos, 94-104% for oxon, and 85-102% for TCP. In addition, chlorpyrifos and oxon were incubated with rat and human blood for various time intervals before deactivation to determine precautions that needed to be taken when collecting and handling specimens. No change in chlorpyrifos concentration was observed in rat blood up to 180 min at 37 degrees C. In contrast, the oxon was rapidly hydrolyzed to TCP in both rat (t 1/2 approximately 10 s) and human (t 1/2 approximately 55 s) blood held at 37 degrees C. The hydrolysis rate for the oxon was independent of whether a rat had been administered chlorpyrifos previously, the initial oxon concentration, the presence of chlorpyrifos, and the age or gender of the human volunteers. These results suggest rapid sample preparation is critical for accurate determinations of the oxon metabolite of chlorpyrifos. These methods provide excellent tools for use in chlorpyrifos pharmacokinetic modeling studies.

Adult↗
PubMed2006

Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility.

Diisopropylfluorophosphate, originally developed as a chemical warfare agent, is structurally similar to nerve agents, and chlorpyrifos has extensive worldwide use as an agricultural pesticide. While inhibition of cholinesterases underlies the acute toxicity of these organophosphates, we previously reported impaired axonal transport in the sciatic nerves from rats treated chronically with subthreshold doses of chlorpyrifos. Those data indicate that chlorpyrifos (and/or its active metabolite, chlorpyrifos-oxon) might directly affect the function of kinesin and/or microtubules--the principal proteins that mediate anterograde axonal transport. The current report describes in vitro assays to assess the concentration-dependent effects of chlorpyrifos (0-10 microM), chlorpyrifos-oxon (0-10 microM), and diisopropylfluorophosphate (0-0.59 nM) on kinesin-dependent microtubule motility. Preincubating bovine brain microtubules with the organophosphates did not alter kinesin-mediated microtubule motility. In contrast, preincubation of bovine brain kinesin with diisopropylfluorophosphate, chlorpyrifos, or chlorpyrifos-oxon produced a concentration-dependent increase in the number of locomoting microtubules that detached from the kinesin-coated glass cover slip. Our data suggest that the organophosphates-chlorpyrifos-oxon, chlorpyrifos, and diisopropylfluorophosphate-directly affect kinesin, thereby disrupting kinesin-dependent transport on microtubules. Kinesin-dependent movement of vesicles, organelles, and other cellular components along microtubules is fundamental to the organization of all eukaryotic cells, especially in neurons where organelles and proteins synthesized in the cell body must move down long axons to pre-synaptic sites in nerve terminals. We postulate that disruption of kinesin-dependent intracellular transport could account for some of the long-term effects of organophosphates on the peripheral and central nervous system.

Animals↗
PubMed2003

Effects of soil pH on the biodegradation of chlorpyrifos and isolation of a chlorpyrifos-degrading bacterium.

We examined the role of microorganisms in the degradation of the organophosphate insecticide chlorpyrifos in soils from the United Kingdom and Australia. The kinetics of degradation in five United Kingdom soils varying in pH from 4.7 to 8.4 suggested that dissipation of chlorpyrifos was mediated by the cometabolic activities of the soil microorganisms. Repeated application of chlorpyrifos to these soils did not result in the development of a microbial population with an enhanced ability to degrade the pesticide. A robust bacterial population that utilized chlorpyrifos as a source of carbon was detected in an Australian soil. The enhanced ability to degrade chlorpyrifos in the Australian soil was successfully transferred to the five United Kingdom soils. Only soils with a pH of >/=6.7 were able to maintain this degrading ability 90 days after inoculation. Transfer and proliferation of degrading microorganisms from the Australian soil to the United Kingdom soils was monitored by molecular fingerprinting of bacterial 16S rRNA genes by PCR-denaturing gradient gel electrophoresis (DGGE). Two bands were found to be associated with enhanced degradation of chlorpyrifos. Band 1 had sequence similarity to enterics and their relatives, while band 2 had sequence similarity to strains of Pseudomonas. Liquid enrichment culture using the Australian soil as the source of the inoculum led to the isolation of a chlorpyrifos-degrading bacterium. This strain had a 16S rRNA gene with a sequence identical to that of band 1 in the DGGE profile of the Australian soil. DNA probing indicated that genes similar to known organophosphate-degrading (opd) genes were present in the United Kingdom soils. However, no DNA hybridization signal was detected for the Australian soil or the isolated degrader. This indicates that unrelated genes were present in both the Australian soil and the chlorpyrifos-degrading isolate. These results are consistent with our observations that degradation of chlorpyrifos in these systems was unusual, as it was growth linked and involved complete mineralization. As the 16S rRNA gene of the isolate matched a visible DGGE band from the Australian soil, the isolate is likely to be both prominent and involved in the degradation of chlorpyrifos in this soil.

Australia↗
PubMed2003

Abiotic transformation of chlorpyrifos to chlorpyrifos oxon in chlorinated water.

In vivo transformation of chlorpyrifos to chlorpyrifos oxon is believed to be a prerequisite for this insecticide to display acute toxicity to organisms. We discovered that active chlorine dispersed in water causes the rapid abiotic transformation of chlorpyrifos to chlorpyrifos oxon. The proposed mechanism for the transformation is an electrophilic attack by hypochlorous acid (HOCl) on the thion (P=S) double bond of chlorpyrifos followed by desulfuration of chlorpyrifos to its oxon analog. The pH of a Cl-aqueous solution controls the speciation of HOCl and hypochlorite (OCl-) in water and thereby influences the transformation process. Chlorpyrifos oxon is a potent anticholinesterase that is about 1,000 times more toxic than chlorpyrifos. Because chlorination is commonly used for treatment of domestic water supplies, the findings raise a new concern about the safety of domestic use of chlorpyrifos products.

Chlorine↗
PubMed2004

The effect of cooking on chlorpyrifos and 3,5,6-trichloro-2-pyridinol levels in chlorpyrifos-fortified produce for use in refining dietary exposure.

Various types of produce were fortified with chlorpyrifos and then boiled, baked, canned, or concentrated as appropriate for the type of produce. Both uncooked and cooked samples were analyzed for chlorpyrifos and 3,5,6-trichloro-2-pyridinol, and then, chlorpyrifos cooking factors were calculated by comparing the postcooked concentration to the uncooked concentration. The cooking factors were dependent upon the commodity and cooking procedure: 0.320-1.19 for boiled samples, 0.022-1.18 for baked pulp, and 0.119-0.661 for canned samples. Concentrating chlorpyrifos-fortified orange juice 4-fold resulted in a concentration factor of only 2.6, indicating a loss of chlorpyrifos. Green bean and green pepper plants treated in the greenhouse yielded higher chlorpyrifos concentrations but similar cooking factors to lab-fortified samples. The cooking factors can be used with food consumption databases and modeling tools to refine the dietary exposure according to current product label uses.

Chlorpyrifos↗
PubMed1997

Automated sample clean-up and fractionation of chlorpyrifos, chlorpyrifos-methyl and metabolites in mussels using normal-phase liquid chromatography.

An automated method based on normal-phase LC has been developed for the sample clean-up of mussel extracts prior to gas chromatographic analysis of residues of chlorpyrifos, chlorpyrifos-methyl and their metabolites chlorpyrifos-methyl-oxon and 3,5,6-trichloro-2-pyridinol. Pesticides were extracted by means of a high speed blender using acetonitrile-acetone (90:10, v/v). The extract obtained was filtered and concentrated using rotavapor and the residue was dissolved in hexane. One ml of the hexanoic extract was injected on the silica-gel column, using hexane as mobile phase. Pesticides and metabolites were eluted in fat-free fractions with different mixtures of hexane-ethyl acetate. Diode array detection allowed monitoring on-line the elution of lipids. Purified extracts were analyzed by GC using nitrogen-phosphorus detection for quantitation and MS for confirmatory purposes. The method is fully automated from the injection of the extract to the collection of fractions, which are directly injected into the GC system. In this way, neither further clean-up nor solvent exchange were necessary prior to GC analysis. Recoveries obtained from fortified mussel samples at two concentration levels-100 and 20 ng g-1 for parent pesticides and 200 and 40 ng g-1 for metabolites-were higher than 90%. Limits of detection of the whole procedure of analysis were lower than 1 ng g-1 for parent pesticides and than 10 ng g-1 for metabolites. This method has been successfully applied to bioconcentration studies with mussels exposed to chlorpyrifos. Chlorpyrifos and its metabolic derivative 3,5,6-trichloro-2-pyridinol were detected and confirmed by MS in analyzed samples.

Animals↗
PubMed2001

Biological monitoring of exposure of the general population to the organophosphorus pesticides chlorpyrifos and chlorpyrifos-methyl by determination of their specific metabolite 3,5,6-trichloro-2-pyridinol.

In this study we determined the concentrations of 3,5,6-trichloro-2-pyridinol (TCPyr) in urine samples from the general population. TCPyr is a specific metabolite of the organophosphorus pesticides chlorpyrifos and chlorpyrifos-methyl. By the introduction of a new sensitive analytical method a limit of quantification (LOQ) of 0.1 microgram per litre urine could be achieved, a tenfold improvement of recent methods. Extraction of TCPyr from the urine and the clean up process were carried out by automatic steam distillation. Separation and quantitative analysis were performed using capillary gas chromatography and mass selective detection in selected ion monitoring mode. The excretion of TCPyr was studied by analysing spontaneous urine samples from 5 women and 45 men between the ages of 22 and 57 (median: 40 years) living in Mecklenburg-Vorpommern (Germany) who were not occupationally exposed to organophosporus pesticides. TCPyr was detected in all specimens and the concentrations were quantified. The median excretion was 1.4 micrograms/l (range: 0.12 to 124.8 micrograms/l), the 95th percentile 11.3 micrograms/l. Under the worst case assumption that all TCPyr measured in urine originated from the intake of intact pesticides and not (less toxic) breakdown products, a TCPyr concentration of 1.4 micrograms/l urine corresponds to a daily intake of approximately 2.5 micrograms chlorpyrifos/chlorpyrifos-methyl. The intake at the 95th percentile would be about 23 micrograms chlorpyrifos/chlorpyrifos-methyl per day. According to FAO/WHO the acceptable daily intake (ADI) is 10 micrograms per kg bodyweight and day for both chlorpyrifos and chlorpyrifos-methyl.

Adult↗
PubMed2005

Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism.

OBJECTIVES: The Q192R polymorphism of paraoxonase (PON1) has been shown to affect hydrolysis of organophosphorus compounds. The Q192 and R192 alloforms exhibit equivalent catalytic efficiencies of hydrolysis for diazoxon, the oxon form of the pesticide (DZ). However, the R192 alloform has a higher catalytic efficiency of hydrolysis than does the Q192 alloform for chlorpyrifos oxon (CPO), the oxon form of the pesticide chlorpyrifos (CPS). The current study examined the relevance of these observations for in-vivo exposures to chlorpyrifos and chlorpyrifos oxon. METHODS: Using a transgenic mouse model we examined the relevance of the Q192R polymorphism for exposure to CPS and CPO in vivo. Transgenic mice were generated that expressed either human PON1Q192 or PON1R192 at equivalent levels, in the absence of endogenous mouse PON1. Dose-response and time course experiments were performed on adult mice exposed dermally to CPS or CPO. Morbidity and acetylcholinesterase (AChE) activity in the brain and diaphragm were determined in the first 24 h following exposure. RESULTS: Mice expressing PON1Q192 were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1R192. The time course of inhibition following exposure to 1.2 mg/kg CPO revealed maximum inhibition of brain AChE at 6-12 h, with PON1R192, PON1Q192, and PON1 mice exhibiting 40, 70 and 85% inhibition, respectively, relative to control mice. The effect of PON1 removal on the dose-response curve for CPS exposure was remarkably consistent with a PBPK/PD model of CPS exposure. CONCLUSION: These results indicate that individuals expressing only the PON1Q192 allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1Q192.

Acetylcholinesterase↗
PubMed1996

Maturational differences in chlorpyrifos-oxonase activity may contribute to age-related sensitivity to chlorpyrifos.

Chlorpyrifos (CPF), a commonly used cholinesterase-inhibiting insecticide, is lethal at much lower doses to young animals than adults. To explain this higher sensitivity in younger animals, we hypothesized that young rats have less chlorpyrifos-oxonase (CPFOase) activity than adults. To test this hypothesis, CPFOase activity was measured in the brain, plasma, and liver of male, postnatal day 4 (PND4) and adult (PND90) Long-Evans rats. CPFOase is biochemically defined as a Ca(2+)-dependent A-esterase that hydrolyzes chlorpyrifos-oxon (CPFO), the active metabolite of CPE. No brain CPFOase activity was detected at either age. Plasma and liver CPFOase activities were markedly lower at PND4 compared to adult: PND4 plasma and liver CPFOase activities were 1/11 and 1/2 the adult plasma and liver activities, respectively. Because the Km of CPFOase activity was high (i.e., 210-380 microM), it was important to determine if this CPFOase activity could hydrolyze physiologically relevant concentrations (i.e., nM to low microM) of CPFO. This was accomplished by comparing the shifts in the tissue acetylcholinesterase (AChE) IC50 for CPFO in the presence or absence of CPFOase activity. One would expect an increase in the "apparent" IC50 if CPFOase hydrolyzes substantial amounts of CPFO during the 30 minutes the tissue is preincubated with the CPFO. In the adult, both plasma and liver AChE apparent IC50 values were higher in the presence of CPFOase activity, suggesting that the CPFOase in those tissues was capable of hydrolyzing physiologically relevant concentrations of CPFO within 30 minutes. In young animals, however, there was less of a shift in the IC50 curves compared to the adult, confirming that the young animal has less capacity than the adult to detoxify physiologically relevant concentrations of CPFO via CPFOase.

Acetylcholinesterase↗
PubMed2003

Relative inhibitory potencies of chlorpyrifos oxon, chlorpyrifos methyl oxon, and mipafox for acetylcholinesterase versus neuropathy target esterase.

The relative inhibitory potency (RIP) of an organophosphorus (OP) inhibitor against acetylcholinesterase (AChE) versus neuropathy target esterase (NTE) may be defined as the ratio [k(i)(AChE)/k(i)(NTE)], where k(i) is the bimolecular rate constant of inhibition for a given inhibitor against each enzyme. RIPs greater than 1 correlate with the inability of ageable OP inhibitors or their parent compounds to produce OP compound-induced delayed neurotoxicity (OPIDN) at doses below the LD50. The RIP for chlorpyrifos oxon (CPO) is >>1 for enzymes from hen brain homogenate, and the parent compound, chlorpyrifos (CPS), cannot produce OPIDN in hens at sublethal doses. This study was carried out to test the hypothesis that the RIP for the methyl homologue of CPO, chlorpyrifos methyl oxon (CPMO), is >>1 and greater than the RIP for CPO. Mipafox (MIP), an OP compound known to produce OPIDN, was included for comparison. Hen brain microsomes were used as the enzyme source, and k(i) values (mean +/- SE, microM(-1) min(-1)) were determined for AChE and NTE (n = 3 and 4 separate experiments, respectively). The k(i) values for CPO, CPMO, and MIP against AChE were 17.8 +/- 0.3, 10.9 +/- 0.1, and 0.00429 +/- 0.00001, respectively, and for NTE were 0.0993 +/- 0.0049, 0.0582 +/- 0.0013, and 0.00498 +/- 0.00006, respectively. Corresponding RIPs for CPO, CPMO, and MIP were 179 +/- 9, 187 +/- 4, and 0.861 +/- 0.011, respectively. The results demonstrate that RIPs for CPO and CPMO are comparable, markedly different from that for MIP, and >>1, indicating that CPS methyl, like CPS, could not cause OPIDN at sublethal doses.

Animals↗
PubMed2006

Metabolism of chlorpyrifos and chlorpyrifos oxon by human hepatocytes.

The metabolism of chlorpyrifos (CPS) and chlorpyrifos oxon (CPO) by human hepatocytes and human liver S9 fractions was investigated using LC-MS/MS. Cytochrome P450 (CYP)-dependent and phase II-related products were determined following incubation with CPS and CPO. CYP-related products, 3,5,6-trichloro-2-pyridinol (TCP), diethyl thiophosphate, and dealkylated CPS, were found following CPS treatment and dealkylated CPO following CPO treatment. Diethyl phosphate was not identified because of its high polarity and lack of retention with the chromatographic conditions employed. Phase II-related conjugates, including O- and S-glucuronides as well as 11 GSH-derived metabolites, were identified in CPS-treated human hepatocytes, although the O-sulfate of TCP conjugate was found only when human liver S9 fractions were used as the enzyme source. O-Glucuronide of TCP was also identified in CPO-treated hepatocytes. CPS and CPO were identified using HPLC-UV after CPS metabolism by the human liver S9 fraction. However, CPO was not found following treatment of human hepatocytes with either CPS or CPO. These results suggest that human liver plays an important role in detoxification, rather than activation, of CPS.

Adult↗
PubMed1989

Oxidative desulfuration of chlorpyrifos, chlorpyrifos-methyl, and leptophos by rat brain and liver.

The oxidative desulfuration of the three phosphorothionate insecticides--chlorpyrifos, chlorpyrifos-methyl, and leptophos--was studied in rat brain and liver. Hepatic microsomes demonstrated activities of 4-28 nmol/g/min, with male activity 2- to 4-fold higher than female activity. Very low desulfuration activity of all three compounds was observed in both microsomal and crude mitochondrial fractions from brain (3-27 pmol/g/min). There were no sex differences in the brain. Although the liver displayed 140- to 2100-fold greater activity than brain on a wet-weight basis, the brain desulfuration activities of these three compounds as well as those of some previously reported phosphorothionates generally correlate well with the toxicity and may be important in determining the overall acute toxicity levels of phosphorothionate insecticides.

Animals↗
PubMed2005

Children's residential exposure to chlorpyrifos: application of CPPAES field measurements of chlorpyrifos and TCPy within MENTOR/SHEDS-Pesticides model.

The comprehensive individual field-measurements on non-dietary exposure collected in the Children's-Post-Pesticide-Application-Exposure-Study (CPPAES) were used within MENTOR/SHEDS-Pesticides, a physically based stochastic human exposure and dose model. In this application, however, the model was run deterministically. The MENTOR/SHEDS-Pesticides employed the CPPAES as input variables to simulate the exposure and the dose profiles for seven children over a 2-week post-application period following a routine residential and professional indoor crack-and-crevice chlorpyrifos application. The input variables were obtained from a personal activity diary, microenvironmental measurements and personal biomonitoring data obtained from CPPAES samples collected from the individual children and in their homes. Simulation results were compared with CPPAES field measured values obtained from the children's homes to assess the utility of the different microenvironmental data collected in CPPAES, i.e. indicator toys and wipe samplers to estimate aggregate exposures that can be result from one or more exposure pathways and routes. The final analyses of the database involved comparisons of the actual data obtained from the individual biomarker samples of a urinary metabolite of chlorpyrifos (TCPy) and the values predicted by MENTOR/SHEDS-Pesticides using the CPPAES-derived variables. Because duplicate diet samples were not part of the CPPAES study design, SHEDs-Pesticides simulated dose profiles did not account for the dietary route. The research provided more confidence in the types of data that can be used in the inhalation and dermal contact modules of MENTOR/SHEDS-Pesticides to predict the pesticide dose received by a child. It was determined that we still need additional understanding about: (1) the types of activities and durations of activities that result in non-dietary ingestion of pesticides and (2) the influence of dietary exposures on the levels of TCPy found in the urine.

Air Pollutants↗
PubMed2003

The effect of chlorpyrifos and chlorpyrifos-oxon on brain cholinesterase, muscarinic receptor binding, and neurotrophin levels in rats following early postnatal exposure.

Chlorpyrifos (CPS) is a widely used diethyl organophosphorus insecticide in agricultural settings. Household and urinary residue analysis has suggested that children in agricultural communities are at risk of exposure to diethyl organophosphorus insecticides. The effects of repeated postnatal exposure to CPS and its metabolite chlorpyrifos-oxon (CPO) on total muscarinic acetylcholine receptor (mAChR) binding, nerve growth factor (NGF) levels, and brain derived neurotrophic factor (BDNF) levels in the forebrain of neonatal rats were investigated. Peak inhibition of brain cholinesterase (ChE) for CPS and CPO was determined after acute exposure to dosages of each compound (a low and a high for each), which produced similar degrees of initial ChE inhibition. Pups were administered CPS (1.5 or 3.0 mg/kg), CPO (0.25 or 0.35 mg/kg), or the corn oil vehicle by daily gavage from postnatal day 1 (PND 1) through PND 6. This exposure paradigm resulted in persistent ChE inhibition by CPS but only transient inhibition by CPO, suggesting that, even though the initial ChE inhibition is similar between compounds, the effects of repeated exposure differ significantly. Forebrain mAChR density, as measured by the binding of 3H-QNB, and NGF levels were significantly reduced on PND 4 and 7 after CPS but not on PND 12. No effects on mAChR density or NGF levels were observed with CPO. No effects on BDNF levels were observed with either compound. The data suggest that the persistent ChE inhibition and decreased mAChR binding may play a role in the decreased NGF levels following CPS exposure.

Administration, Oral↗
PubMed1986

Suspected chlorpyrifos toxicosis in a llama, and plasma pseudocholinesterase activity in llamas given chlorpyrifos.

Five days after treatment with chlorpyrifos, a 1.5-year-old male llama was unable to stand, had saliva flowing from its mouth, and had constricted pupils, hyperglycemia, a metabolic acidosis, and a plasma pseudocholinesterase activity of 111 IU/L. Mean (+/- 1 SD) plasma pseudocholinesterase activity of 29 healthy llamas was 233.76 +/- 51.55 IU/L. Five to 8 days after topical application of chlorpyrifos (25 mg/kg of body weight) to 3 healthy llamas, the pseudocholinesterase activity decreased to 38% to 62% of pretreatment (base-line) activity and returned to within 90% of base-line activity by the 36th to 48th day after treatment.

Animals↗
PubMed1993

Inhibition of hen brain acetylcholinesterase and neurotoxic esterase by chlorpyrifos in vivo and kinetics of inhibition by chlorpyrifos oxon in vitro: application to assessment of neuropathic risk.

Chlorpyrifos (CPS; O,O-diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate; Dursban) is a widely used broad-spectrum organophosphorus (OP) insecticide. Because some OP compounds can cause a sensory-motor distal axonopathy called OP compound-induced delayed neurotoxicity (OPIDN), CPS has been evaluated for this paralytic effect. Early studies of the neurotoxicity of CPS in young and adult hens reported reversible leg weakness but failed to detect OPIDN. More recently, a human case of mild OPIDN was reported to result from ingestion of a massive dose (about 300 mg/kg) in a suicide attempt. Subsequent experiments in adult hens (the currently accepted animal model of choice for studies of OPIDN) showed that doses of CPS in excess of the LD50 in atropine-treated animals inhibited brain neurotoxic esterase (NTE) and produced mild to moderate ataxia. Considering the extensive use of CPS and its demonstrated potential for causing OPIDN at supralethal doses, additional data are needed to enable quantitative estimates to be made of the neuropathic risk of this compound. Previous work has shown that the ability of OP insecticides to cause acute cholinergic toxicity versus OPIDN can be predicted from their relative tendency to inhibit the intended target, acetylcholinesterase (AChE), versus the putative neuropathic target, NTE, in brain tissue. The present study was designed to clarify the magnitude of neuropathic risk associated with CPS exposures by measuring hen brain AChE and NTE inhibition following dosing in vivo and determining the bimolecular rate constant of inhibition (ki) for each enzyme by the active metabolite, CPS oxon (CPO), in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗