Weak inhibitors protect cholinesterases from stronger inhibitors (dichlorvos): in vitro effect of tiapride

Metoclopramide is a benzamide dopamine receptor antagonist and serotonine receptor agonist widely used as an antiemetic and gastric prokinetic drug. In addition, metoclopramide is a weak and reversible inhibitor of cholinesterases. The authors have previously shown that metoclopramide has a cholinesterase protective effect against inhibition by organophosphates (OPs). The putative mode of protective action of metoclopramide is, when administered in excess, competion for the active site of the enzyme with the more potent OP. In the present paper the authors present their results using another benzamide with weak cholinesterase inhibitory properties, tiapride (TIA). The purpose of the study was to quantify in vitro the extent of TIA-conferred protection, using dichlorvos (dichlorovinyl dimethyl phosphate; DDVP) as an inhibitor. DDVP is a moderately toxic (LD50 in rats in the milligram range), non-neuropathic OP. The substance is responsible for a large number of accidental or suicidal exposures. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood and butyrylcholinesterase (BChE) activities in human plasma were measured photometrically in the presence of different DDVP and TIA concentrations and IC50 was calculated. Determinations were repeated in the presence of increasing TIA concentrations. The IC50 of DDVP increases with the TIA concentration in a linear manner. The protective effect of TIA on cholinesterase could be of practical relevance in the treatment of OP poisoning. The authors conclude that in vivo testing of TIA as an OP protective agent is warranted.     

Oxidative stress and cholinesterase inhibition in plasma,erythrocyte and brain of rats’ pups following lactational exposure to malathion

The organophosphorus (OP) pesticide malathion is a highly neurotoxic compound. Some studies have reported neurotoxicity signs after in utero exposure to OP pesticides. However there is no evidence of the exclusive contribution of the lactational exposure to malathion as a possible cause of neurotoxicity in rats’ pups. In this respect, we investigated the exclusive contribution of malathion (200 mg/kg, b.w.) exposure through maternal milk in rat pups during lactation. We evaluated the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as on biochemical parameters related to the oxidative stress such lipoperoxidation and antioxidant enzyme activities as superoxide dismutase (SOD) and catalase (CAT) in the brain, plasma and erythrocytes of rats’ pups at 21st postnatal day (Pnd). These parameters were also evaluated in the same tissues but at 51 Pnd. Our results showed that the malathion exposure during lactation induced a high inhibitory effect of the brain, plasma and erythrocyte AChE and BChE activities in rat pups. Many changes were observed in the biochemical parameters related to the oxidative stress for pups brain, plasma and erythrocyte. The present study shows, for the first time, that the exposure of postnatal pups to malathion via lactation inhibits the activity of brain, plasma and erythrocytes cholinesterase in the pups. These findings suggest that malathion exposure during lactation induced a cerebral alterations and oxidative stress in rat pups.     

Changes of Cholinesterase Activities in the Rat Blood and Brain After Sarin Intoxication Pretreated with Butyrylcholinesterase

After sarin inhalation exposure of rats pretreated with equine serum butyrylcholinesterase (EqBuChE), cholinesterase activities of the whole blood, acetylcholinesterase (AChE) in erythrocytes, pontomedullar area, frontal cortex, and striatum of the brain, and plasma butyrylcholinesterase (BuChE) were determined. Using different doses of EqBuChE as a pretreatment (intraperitoneal injection), dose-dependent increases in plasma BuChE activity and no changes in the erythrocyte and brain AChE activities were demonstrated. Decreases in plasma BuChE activity and red blood cells (RBC) and brain AChE activities were observed in control rats after sarin inhalation exposure without EqBuChE pretreatment. In rats pretreated with EqBuChE, this inhibition was lower compared with control animals not only in the blood but also in the brain structures studied. These results demonstrate protective effects of EqBuChE pretreatment in rats intoxicated with sublethal concentrations of sarin by inhalation.     

Rates of spontaneous reactivation and aging of acetylcholinesterase in human erythrocytes after inhibition by organophosphorus pesticides

The in vitro rates of spontaneous reactivation and aging in human erythrocyte acetylcholinesterase were studied after inhibition by a dimethoxy (R1R2) and diethoxy substituted (R1R2) organophosphate pesticide (OP) of general structure R1R2P(O)X. These have been compared with data for human plasma cholinesterase previously reported using a similar methodology. A significantly slower rate of aging for erythrocyte acetylcholinesterase was found compared to plasma cholinesterase, whether inhibited by dimethoxy or diethoxy substituted OPs. For diethoxy OPs the rate of spontaneous reactivation of the inhibited plasma enzyme was significantly slower than for the inhibited red cell enzyme. This acetylcholinesterase, and previously published plasma cholinesterase, data suggest that in practise a blood sample taken 30-40 h after significant acute OP exposure will still show inhibition in either plasma or erythrocyte cholinesterase when analysed, but that any inhibited plasma enzyme is more likely to be in the aged form. In contrast a substantial proportion of the erythrocyte acetylcholinesterase is found unaged and therefore sensitive to reactivation by oximes. Samples from an occupational exposure where depressions in plasma or erythrocyte cholinesterase activity from baseline measurements were reactivated ex vivo using the oxime 2-PAM support this hypothesis. These data also confirm that the plasma enzyme is a more sensitive than erythrocyte acetylcholinesterase as an indicator of OP exposure and thus the potential value of ex vivo oxime reactivation of erythrocyte acetylcholinesterase in a blood sample to indicate subclinical OP exposure may be limited. However, this study is too small to draw conclusions on the sensitivity of ex vivo oxime reactivation of acetylcholinesterase as a novel biomarker of excessive OP absorption. Given that there is a better relationship between anticholinergic symptoms and red cell acetylcholinesterase inhibition, and that the slower resynthesis rate of any aged or inhibited red cell enzyme may be interpretatively useful when venepuncture is delayed, it is suggested that red cell acetylcholinesterase activity does have a place in monitoring potential OP exposure.     

Changes of cholinesterase activities in the rat blood and brain after sarin intoxication pretreated with butyrylcholinesterase

After sarin inhalation exposure of rats pretreated with equine serum butyrylcholinesterase (EqBuChE), cholinesterase activities of the whole blood, acetylcholinesterase (AChE) in erythrocytes, pontomedullar area, frontal cortex, and striatum of the brain, and plasma butyrylcholinesterase (BuChE) were determined. Using different doses of EqBuChE as a pretreatment (intraperitoneal injection), dose-dependent increases in plasma BuChE activity and no changes in the erythrocyte and brain AChE activities were demonstrated. Decreases in plasma BuChE activity and red blood cells (RBC) and brain AChE activities were observed in control rats after sarin inhalation exposure without EqBuChE pretreatment. In rats pretreated with EqBuChE, this inhibition was lower compared with control animals not only in the blood but also in the brain structures studied. These results demonstrate protective effects of EqBuChE pretreatment in rats intoxicated with sublethal concentrations of sarin by inhalation.     

Dose-related inhibition of brain and plasma cholinesterase in neonatal and adult rats following sublethal organophosphate exposures.

Developing mammals are markedly more sensitive to acute toxicity from exposure to a variety of organophosphorus (OP) pesticides. The present study examined dose-related inhibition of both brain and plasma cholinesterase activity in neonatal and adult rats exposed to sublethal doses of one of three common OP pesticides, methyl parathion, parathion and chlorpyrifos. Effective dose 50 (i.e., ED50 or dose which would inhibit 50% of the cholinesterase activity) values were determined and then correlated with an indicator of acute toxicity, the maximal tolerated dose (MTD). It was found that ED50 estimates for both brain and plasma cholinesterase correlated highly (r = 0.932-0.992) with previously derived MTD values. In no case was there a significant difference between in vivo brain and plasma cholinesterase inhibition across doses in neonatal rats was high (r = 0.962-0.975) but lower in adults (r = 0.700-0.943). The results suggest that in vivo inhibitory potency of the three OPs towards either brain or plasma ChE activity is highly correlated with sensitivity to acute toxicity in both neonatal and adult rats. Additionally, under defined experimental conditions, plasma ChE inhibition may be a useful quantitative index for the degree of brain cholinesterase inhibition following OP exposures.     

Cold exposure decreases the effectiveness of atropine-oxime treatment in organophosphate intoxication in rats and mice

1. The effect of cold environment on the acute toxicity of organophosphates (OP), without and with atropine-oxime treatment, was studied in rats and mice by exposing them to +5 and -5 degrees C temperature. The tested OPs and oximes (given intraperitoneally) were diisopropylfluorophosphate (DFP), isopropyl methylphosphonofluoridate (sarin) and dichlorovinyl phosphate (DDVP), pralidoxime (PAM) and obidoxime. 2. An exposure to low environmental temperature decreased the effectiveness of atropine-oxime therapy in OP poisoned rats and mice, evaluated by means of acute LD50 values. 3. The lowering of environmental temperature did not influence the ability of PAM to reactivate tissue cholinesterase in rats intoxicated by 0.5 x LD50 doses of DFP. 4. The acute toxicity of atropine and oximes was not affected by cold environment in rats, but in mice it was increased by 1.1-2.1 times. 5. The decrease in the effectiveness of atropine-oxime therapy at cold environment may be explained by the observation that the cold temperature sensitizes the animals to the inhibition of brain acetylcholinesterase by OP.     

Interindividual variations in enzymes controlling organophosphate toxicity in man.

1 Interindividual variations in an unexposed population have been defined for five enzymes involved in organophosphate (OP) toxicity. The enzymes measured were: red blood cell acetylcholinesterase (AChE), lymphocyte neuropathy target esterase (NTE), serum cholinesterase (ChE), serum paraoxonase and serum arylesterase. 2 AChE and arylesterase were normally distributed in the population whilst the distribution of NTE, ChE and paraoxonase deviated significantly from normal. 3 Assay precision and intra-individual variability were measured for each of the enzymes; the effect on interindividual variation was assessed. 4 Variations in enzyme activities between individuals could have profound effects on susceptibility to OP toxicity. Prior determination of these enzymes may be predictive of susceptibility. 5 Lymphocyte NTE has some limitations as an indicator of exposure to neurotoxic OPs.     

Serum creatine phosphokinase: a probable marker of severity in organophosphorus poisoning

Organophosphorus (OP), the commonest agent for poisoning in India due to its easy availability, acts by inhibiting acetylcholinesterase at muscarinic and nicotinic receptors. Erythrocyte cholinesterase (EchE) and plasma cholinesterase (PchE) are reduced in OP poisoning, but their estimation is costly and not regularly performed. There are emerging options for new cheaper biochemical markers in relation to OP poisoning. Serum level of creatine phosphokinase (CPK) is often found to be elevated in OP poisoning. This study was conducted to see if CPK may be used as an alternative of cholinesterase levels in blood to assess the severity of OP poisoning. This was a prospective and observational study. Sixty-three patients of OP poisoning without any prior treatment, presenting within 6 hours, were selected and their clinical severity was categorized according to Peradeniya organophosphorus poisoning (POP) scale. Level of serum CPK, blood EchE and pH were measured following admission, and total dose of atropine (mg) until the final clinical outcome (complete recovery or death) was calculated. Student's t-test and Pearson's correlation coefficient was used for the assessment of statistical significance. According to POP scale, clinical severity was mild (score 0-3) in 17 (27%), moderate (score 4-7) in 32 (50.8%) and severe (score 8-11) in 14 (22.2%) patients. Serum CPK, EchE level, blood pH and total atropine dose strongly correlated with clinical severity. Our study recommends serum CPK as an alternative marker.     

Relevance of developmental testing of exposure to methamidophos during gestation to its toxicology evaluation

The organophosphate insecticide (OP) are known to be able to promote cholinergic toxicity related to neurobehavioral findings. The measures of cholinesterase activity are the most common index of its action. The influence was evaluated, of the OP methamidophos (1.0 mg/kg), by oral exposure during gestational organogenesis of rats, on maturational and behavioral aspects of offspring development. This dose did not promote evidence of maternal toxicity. The pesticide did not affect body weight gain of the dams and offspring, but interfered with the offspring's physical and maturational development landmarks according to age. The behavioral performance of the offspring with or without a pharmacological challenge was tested at different postnatal days (pnd 14, 21 and 40) in an open-field apparatus. The results showed a large standard deviation that prejudiced the conclusions. There were no observed alterations in the swimming behavior tested also at pnd 7, 14 and 21. As long as the obtained results showed some subtle effects on rat development, the data, as possible additional effect biomarkers for risk analysis, will aid further studies of the embryo-feto-toxic potential of OP exposure.     

Neurologic and immunologic effects of exposure to corticosterone, chlorpyrifos, and multiple doses of tri-ortho-tolyl phosphate over a 28-day period in rats

An animal (rat) model of chronic stress (corticosterone in the drinking water) was used to study the interaction of stress and the organophosphorus (OP) neurotoxicants chlorpyrifos (60 mg/kg subcutaneously in a single dose) and tri-ortho-tolyl phosphate (TOTP, at 75, 150, or 300 mg/kg given 7 times orally in a 2-wk period). Adult male Long-Evans rats were provided with corticosterone in drinking water (400 microg/ml, w/v) for a total of 28 d, which led to significantly decreased weight and decreased cellularity of the thymus and spleen. Seven days after initiation of corticosterone treatment, half of the rats were given chlorpyrifos, and an additional 7 d later the 2-wk, 7-dose treatment of TOTP was initiated. During the 28-d test period, behavior of rats was evaluated using a functional observational battery (FOB), motor activity, and passive avoidance. Reductions in body weight, grip strength, and ambulatory movements occurred as a result of corticosterone treatment. Decreased body weight and grip strength were also elicited by TOTP, and the interactions of corticosterone and TOTP enhanced the effects on body weight and grip strength. Blood cholinesterase levels were obtained during the 28-d study period and found useful for monitoring OP exposure. At the end of the 28-d testing period, rats were sacrificed and activities of cholinesterase, neurotoxic esterase (neuropathy target esterase), and/or carboxylesterase were evaluated in blood, liver, and/or brain regions (basal forebrain, caudate putamen, cerebral cortex, hippocampus). All these esterases in brain were inhibited in a dose-related manner by TOTP, with some enhancement in rats drinking corticosterone-containing water. In addition, choline acetyltransferase, glial acidic fibrillary protein (GFAP), glutathione peroxidase, and superoxide dismutase were evaluated in one or more of the brain regions already identified. Choline acetyltransferase, glutathione peroxidase, and superoxide dismutase activities were unaffected by treatments. However, GFAP was elevated above control levels in the cerebral cortex of rats by all treatments (corticosterone, chlorpyrifos, TOTP). Neuropathological examination revealed early stages of dose-related increased distal myelinated fiber axonal degeneration seen in the medullary fasciculus gracilis at only the highest dose of TOTP (300 mg/kg).     

Histopathologic effects of maternal 4-<Emphasis Type="Italic">tert</Emphasis>-octylphenol exposure on liver,kidney and spleen of rats at adulthood

The present study was performed to investigate the potential toxic effects of prenatal exposure to 4-tert-octylphenol (OP) on liver, kidney, spleen, and hematologic parameters of male and female rats in adult life. The rats were treated with OP subcutaneously in utero at doses of control (vehicle, corn oil), 100 or 250 mg/kg per day. After birth, the rats were allowed to grow until adulthood and then liver, kidney and spleen were investigated histopathologically. Also the blood collected from rats were analyzed for any hematologic changes. The red blood cells of male and female rats were decreased in 250 mg/kg per day OP-treated group compared with the control group. μ-RBC of male rats in high dose treatment groups were increased significantly compared with the controls and 100 mg/kg per day treatment groups. μ-RBC of female rats in treatment groups were increased in a dose-dependent manner compared with the controls. In liver, kidney and spleen of male and female rats treated with OP, degeneration of hepatic parenchyma, tubular degeneration and hemorrhage were observed in histopathologic examination. The hemosiderin deposition in spleen of the high-dose group was increased in both male and female rats. In conclusion, findings of this study demonstrate that maternal administration of high doses of OP causes adverse effects on spleen and liver tissues of male and female offsprings at adulthood. Specifically, OP caused decreases in the number of red blood cells indicated by increased destruction in the spleen.     

Protective effect of polyurethane immobilized human butyrylcholinesterase against parathion inhalation in rat

Organophosphates (OP) are used in large quantities around the world as agricultural insecticides. Exposure to these toxic chemicals is a serious global health problem. Human plasma butyrylcholinesterase is known to be a good scavenger of organophosphorus pesticides and chemical warfare agents. In this study, purified human plasma butyrylcholinesterase (HuBChE) from pooled outdated human plasma, was immobilized onto the polyurethane foam. The immobilized enzyme showed greater stability at and above room temperature (up to 55 °C), compared to the enzyme in solution. Scavenger properties of immobilized enzyme were tested in vitro with parathion and its active metabolite paraoxon. In, in vitro experiments polyurethane foam with immobilized active enzyme removed 40% of parathion and 50% of paraoxon inhibitory effect (based on cholinesterase inhibition). In, in vivo experiments groups of rats inhaled parathion through filters with immobilized active enzyme (Group I), immobilized inactivated enzyme (Group II), and control group (Group III) inhaled solvent only without any parathion or filter. In the Group II animals, activity of plasma and red blood cells cholinesterase was significantly decreased (30 and 28%, respectively) compared to Groups I and III animals. In other tissues such as brain, skeletal muscle and lung, activity of the acetylcholinesterase (AChE) in the Group II animals, was decreased significantly (29, 28, and 22%, respectively). There was no significant differences between Groups I and III animals enzyme activities. In conclusion, immobilized butyrylcholinesterase (BChE) may be useful in scavenging and detoxifying organophosphate compounds both for medical protection and decontamination procedures.     

Cholinesterase activities determination in frozen blood samples: an improvement to the occupational monitoring in developing countries

1. Studies were carried out on rural workers in Brazil to determine the decrease in the activity of plasma butyrylcholinesterase (BChE), erythrocyte cholinesterase (AChE) associated with exposure to organophosphorus pesticides (OP). The goal of this work is to help prevent injury to these workers. 2. In developing countries the distance between area of pesticide use and reference laboratories is a drawback for analytical techniques, since cholinesterase activity determinations require fresh blood samples. Field methodologies can be a useful alternative to laboratory tests, however they are not as sensitive as those found in laboratories. 3. The modification of Ellman's Method presented in this paper allows blood samples to be frozen and maintain enzymatic stability: 7 days for AChE and 3 days for BChE. The proposed method is also more sensitive than Ellman's Method Modified by Magnotti (EMMM). 4. The results suggest that the Ellman Method Modified by Oliveira-Silva (EMMOS) is valid for monitoring procedures. This method represents an important contribution to the process of monitoring OP exposures, since the evaluations no longer have to be conducted near the site of OP use.     

Paraoxonase and acetylcholinesterase activities in humans exposed to organophosphorous compounds

Different kinds of organophosphorous compounds (OP) are used as pesticides in Turkish agriculture. Suicidal, accidental, or occupational exposure may occur in developing countries. OP inhibit acetylcholinesterase (AChE) activities; on the other hand, serum paraoxonase (PON1) hydrolyzes the toxic metabolites of a variety of OP. In recent years, some studies have shown that PON1 activity is an important marker in individuals who are exposed to OP. Both serum cholinesterase and PON1 activities were measured spectrophotometrically from 18 male agricultural workers who were chronically exposed to azinphos methyl, chlorpyriphos, or malathion and other pesticides during cereal spraying, transportation, and storage. The individuals were classified according to PON1 phenotypes using the antimode 60% stimulation method to determine the dividing point between non-salt-stimulated, A type (homozygotes for the low-activity allele), and salt-stimulated AB (heterozygotes) and B types (homozygotes for the high-activity allele). A positive correlation was found between AChE activities and percent of PON1 stimulation. The individuals with phenotype A had the lowest enzyme activities. This study suggests that individuals with phenotype A might be more sensitive to OP-induced toxicity.     

PARAOXONASE AND ACETYLCHOLINESTERASE ACTIVITIES IN HUMANS EXPOSED TO ORGANOPHOSPHOROUS COMPOUNDS

Different kinds of organophosphorous compounds (OP) are used as pesticides in Turkish agriculture. Suicidal, accidental, or occupational exposure may occur in developing countries. OP inhibit acetylcholinesterase (AChE) activities; on the other hand, serum paraoxonase (PON1) hydrolyzes the toxic metabolites of a variety of OP. In recent years, some studies have shown that PON1 activity is an important marker in individuals who are exposed to OP. Both serum cholinesterase and PON1 activities were measured spectrophotometrically from 18 male agricultural workers who were chronically exposed to azinphos methyl, chlorpyriphos, or malathion and other pesticides during cereal spraying, transportation, and storage. The individuals were classified according to PON1 phenotypes using the antimode 60% stimulation method to determine the dividing point between non-salt-stimulated, A type (homozygotes for the low activity allele), and salt-stimulated AB (heterozygotes) and B types (homozygotes for the high-activity allele). A positive correlation was found between AChE activities and percent of PON1 stimulation. The individuals with phenotype A had the lowest enzyme activities. This study suggests that individuals with phenotype A might be more sensitive to OP-induced toxicity.     

Peripheral cholinesterase inhibition by occupational chlorpyrifos exposure in Australian termiticide applicators.

Occupational exposure to organophosphorus insecticides (OPs), such as chlorpyrifos, may be monitored by the measurement of the activity of peripheral cholinesterase (ChE) enzymes, including erythrocyte acetylcholinesterase (EAChE) and serum cholinesterase (SChE). Lymphocyte neuropathy target esterase (NTE) is thought to have potential as a predictor of organophosphate-induced delayed neuropathy (OPIDN). This paper describes work performed in 39 Australian pest control operators (PCOs) exposed to a termiticide containing chlorpyrifos, and 34 unexposed control subjects. EAChE activities in PCOs did not differ from those of unexposed control workers. Mean NTE activity was slightly higher in PCOs than in controls and mean SChE was 52% of control activity. These results indicate that exposure of Australian PCOs to termiticides containing chlorpyrifos may be monitored using SChE but not EAChE or NTE, and that workers in this industry have sufficiently high OP exposure to significantly depress SChE activity. SChE inhibition of 70-80% may be associated with symptoms. Although no current symptoms were reported to be associated with occupational OP exposure, these workers may be at increased risk of acute effects following inadvertent spills or self-contamination due to their background level of exposure to OPs. While it is preferable to compare ChE enzyme activities between pre- and post-exposure periods to evaluate OP-related effects in individuals, in some cases there is an absence of pre-exposure data. The results of this study suggest that a screening value for SChE of 550 nmol/min/ml in a single blood sample may be useful to identify potentially OP-exposed individuals in the Australian population. Australian control subjects were similar with respect to EAChE, but displayed activities of NTE and SChE approximately 50 and 23% lower than an unexposed UK reference group. While these comparisons are presently speculative, they suggest that there may be differences in SChE and NTE activities in control populations of the two countries. The routine treatment of Australian homes with termiticides containing OPs, or differences in the availability and use of domestic OP-containing insecticides may explain these population differences. Further work is required to examine whether these differences are real, and if so their likely cause.     

A Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans.

A PBPK/PD model was developed for the organophosphate insecticide chlorpyrifos (CPF) (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), and the major metabolites CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP) in rats and humans. This model integrates target tissue dosimetry and dynamic response (i.e., esterase inhibition) describing uptake, metabolism, and disposition of CPF, CPF-oxon, and TCP and the associated cholinesterase (ChE) inhibition kinetics in blood and tissues following acute and chronic oral and dermal exposure. To facilitate model development, single oral-dose pharmacokinetic studies were conducted in rats (0.5-100 mg/kg) and humans (0.5-2 mg/kg), and the kinetics of CPF, CPF-oxon, and TCP were determined, as well as the extent of blood (plasma/RBC) and brain (rats only) ChE inhibition. In blood, the concentration of analytes followed the order TCP > CPF > CPF-oxon; in humans CPF-oxon was not quantifiable. Simulations were compared against experimental data and previously published studies in rats and humans. The model was utilized to quantitatively compare dosimetry and dynamic response between rats and humans over a range of CPF doses. The time course of CPF and TCP in both species was linear over the dose range evaluated, and the model reasonably simulated the dose-dependent inhibition of plasma ChE, RBC acetylcholinesterase (AChE), and brain (rat only) AChE. Model simulations suggest that rats exhibit greater metabolism of CPF to CPF-oxon than humans do, and that the depletion of nontarget B-esterase is associated with a nonlinear, dose-dependent increase in CPF-oxon blood and brain concentration. This CPF PBPK/PD model quantitatively estimates target tissue dosimetry and AChE inhibition and is a strong framework for further organophosphate (OP) model development and for refining a biologically based risk assessment for exposure to CPF under a variety of scenarios.     

Dichlorvos — a 2-year inhalation carcinogenesis study in rats

Summary To determine the effects of dichlorvos vapour on the tumour incidence in rats, 5 week old Carworth Farm E strain rats weighing between 94 and 150 g were exposed to 0, 0.05, 0.5 and 5.0 mg/m³ in a 2-year inhalation study.The growth rate of all treated rats was depressed, particularly in the males. There was increased survival of the rats exposed to 5 mg/m³. There were no consistent differences in food intakes, organ weights, haematological or blood chemistry estimations, except in cholinesterase activities, amongst the various groups of rats.No compound-related differences were seen in acetylcholine and choline estimations carried out on a small number of female rats' brain tissues after two years' exposure. There were no gross or microscopical compound-related changes in the rats' tissues. Ultrastructural examination of the respiratory tissues of the rats from the control and 5 mg/m³ group showed no changes attributable to dichlorvos. The results of a relative risk analysis of the tumour data showed that no dose-related increase in tumour risk was established for rats of either sex.These data confirm the results of earlier studies supporting the safety of insecticidal uses of dichlorvos.     

Relationship between cholinesterase inhibition and thermoregulation following exposure to diisopropyl fluorophosphate in the rat.

This study examined the relationship between inhibition of cholinesterase activity (CA) and thermoregulatory response in the rat following exposure to the organophosphate (OP), diisopropyl fluorophosphate (DFP). Male Long-Evans rats were injected with DFP dissolved in peanut oil in doses ranging from 0 to 1.5 mg/kg (s.c.). Colonic (Tcol) and tail skin temperature (Ttail) were recorded at 0, 1, 2 and 3 h post-injection. At 3 h post-injection the rat was sacrificed and a blood sample was taken by cardiac puncture and analyzed for CA. There was a biphasic dose effect of DFP on Tcol with slight but significant elevation in Tcol in the dose range of 0.01-0.5 mg/kg and a significant depression in Tcol at doses of 1.0 and 1.5 mg/kg. There was a dose-dependent fall in CA with DFP administration in the erythrocyte, plasma, and whole blood fractions. Hypothermia was associated with 80-87% inhibition in CA, whereas the elevation in Tcol was associated with 20-70% inhibition in CA. DFP also elicited significant elevations in Ttail. Overall, the data fail to demonstrate any clear relationship between inhibition of blood CA and thermoregulatory response following exposure to DFP. However, the elevation in Tcol following relatively low doses of DFP may be of relevance to the frequently reported symptom of fever in humans exposed to OP agents.