Inhibitor Report for: Isofenphos

The neuropathic potential of acute and repeated exposures of the phosphoramidates tabun (GA) and isofenphos (IFP), of diisopropyl fluorophosphate (DFP) and paraoxon (PO) were examined in the hen with treatments for up to 90 days via intramuscular injections of the highest tolerated doses with atropine protection. Plasma acetylcholinesterase (AChE), non-specific butyrylcholinesterase (BChE) and creatine kinase (CK) activities were measured in order to monitor whether the compounds were present at biologically active concentrations. Locomotor behavior was observed and tissues from the peripheral and central nervous systems were examined for signs of organophosphate-induced delayed neuropathy (OPIDN). No behavioral or histological evidence of OPIDN was observed after treatments with GA, IFP, PO, saline or atropine sulfate. DFP-treated birds displayed locomotor and neuropathological signs of OPIDN with a no effect level (NOEL) between 25 and 50 micrograms/kg.

Daily dermal administration for 90 days of 0.01 to 10 mg/kg of O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) technical grade (85%) in acetone (0.1 ml) on the unprotected back of the neck produced delayed neurotoxicity. Hens given 2.5 to 10 mg/kg daily doses also received daily doses of atropine sulfate for 5 or 6 days to protect against cholinergic acute toxicity. Severity of the clinical condition depended on the concentration of the daily dermal dose of EPN; i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. The most consistent histopathologic alteration was the degeneration of axons and myelin in the spinal cord which was identical to that found in positive control hens that received daily dermal doses of 5 or 10 mg/kg tri-o-cresyl phosphate (TOCP). Some of the hens treated daily with the smallest tested dose of EPN (0.001 mg/kg) which did not show clinical signs of delayed neurotoxicity showed equivocal histological changes in the spinal cord. EPN and TOCP treatments had a more profound effect on the activity of plasma butyrylcholinesterase than that of brain acetylcholinesterase (AchE). by contrast O,O,-diethyl O-4-nitrophenyl phosphorothioate (parathion) was more inhibitory to brain AChE. Negative control hens that were treated with 90 daily dermal doses of 1 mg/kg of parathion initially showed leg weakness followed by recovery. A group of hens that received the same volume of acetone (0.1 ml) daily remained normal.

A screening method has been developed for determining organophosphorus pesticides at ng/L levels in drinking water. Sixteen organophosphorus pesticides, diazinon, diazinon-oxon, dimethoate, ronnel, beta-phosphamidon, methyl parathion, ethyl parathion, malathion, chlorpyrifos, fenitrothion, ruelene, methidathion, ethion, EPN, phosalone, and phosmet, were extracted by Amberlite XAD-2 resin from 100 and 200 L drinking water previously spiked with these pesticides. The pesticides were eluted from the XAD-2 resin with acetone-hexane (15+85). The concentrated extract was analyzed by gas chromatography using a nitrogen-phosphorus selective detector and by gas chromatography-mass spectrometry using selected ion monitoring. Recoveries at the 10 and 100 ng/L spiking levels were greater than 90%, except recoveries for dimethoate and phosphamidon were 37 and 42%, respectively. The analysis of 300 L Ottawa tap water showed no detectable amounts (less than 1 ng/L) of any of the 16 organophosphorus pesticides.

Organophosphates, a widely used class of insecticidal compounds, have been shown to cross the placental barrier, and thus potentially affect the developing fetus. This study compared the maternal and fetal effects, including cholinesterase inhibition, following gestational exposure to six organophosphates: tribufos, oxydemeton-methyl, azinphos-methyl, fenamiphos, isofenphos, and fenthion in the Sprague-Dawley rat. All test compounds were administered via oral gavage on gestation days 6-15. Maternal cholinesterase activities (plasma, PChe; erythrocyte, RChe; and brain, BChe) were measured on gestation days 16 and 20, and fetal brain cholinesterase activity was measured on gestation day 20. Effects on gestational parameters (clinical signs, food consumption, and body weight) in adult rats, when observed, were only observed at the highest dose tested for each compound. The inhibition of maternal cholinesterase activities associated with these clinical findings was, for all compounds, always greater than 20%. Moreover, cholinesterase activities were inhibited at dose levels below that which elicited clinical effects. Statistically significant inhibition of at least two of the three cholinesterase enzymes (PChe, RChe, or BChe) was observed on gestation day 16, 24 h following exposure, with all of the organophosphates tested. By gestation day 20, the inhibition of cholinesterase activity was reduced; however, the high dose for all test compounds (except BChe in fenamiphos-treated dams) continued to demonstrate statistically significant inhibition of RChe and BChe. Despite significantly affected cholinesterase activity in the dams, no remarkable effects on fetal BChe were observed with any test compound. No embryotoxicity or teratogenicity were observed with any of the test compounds. These results demonstrate that for the six organophosphates tested: (1) inhibition of maternal cholinesterase activity was the most sensitive indicator of organophosphate exposure; (2) the level of cholinesterase inhibition associated with clinical findings was always greater than 20%; and (3) no effect on fetal cholinesterase activity (BChe) was observed, even at dose levels that continued to demonstrate significant inhibition of maternal cholinesterase activity.

To determine the protective effect of pralidoxime on muscle fiber necrosis induced by organophosphate acute intoxication in rats. DESIGN: Adult male Wistar rats were given oral organophosphate compounds dissolved in glycerol formal: dichlorvos, isofenphos, metamidophos, and diazinon. Half of the animals also received pralidoxime mesylate (20 mg/kg, intraperitoneal). Control animals received only the solvent. Twenty-four hours after treatment, the diaphragm muscle was collected for histological counts of necrotic muscle fibers in transverse sections. RESULTS: Metamidophos- and isofenphos-treated animals showed the highest percentage of necrotic muscle fibers: 1.66 +/- 1.112 and 1.34 +/- 0.320, respectively. Diazinon-treated animals had a lower percentage of necrotic fibers: 0.40 +/- 0.032 (p < 0.05) compared to the first 2 products, and dichlorvos-treated animals showed the smallest: 0.05 +/- 0.021 (p < 0.05) when compared to the other 3 products. Pralidoxime reduced necrotic fibers about 20 times in metamidophos-treated animals, 10 times in isofenphos-treated animals and 6 times in diazinon-treated animals. Pralidoxime administration did not increase plasma cholinesterase activity in any group, although symptoms were reduced. CONCLUSIONS: Oxime reduced diaphragmatic muscle necrosis in experimental organophosphate intoxication, despite little effect on plasma cholinesterase. Since respiratory insufficiency is an important cause of mortality and morbidity in organophosphate intoxications, early oxime administration may be particularly beneficial.

A rapid procedure has been developed that allows a single-step, selective extraction and cleanup of organophosphate (OP) pesticide residues from milk dispersed on solid-matrix diatomaceous material filled into disposable cartridges by means of light petroleum saturated with acetonitrile and ethanol. Recovery experiments were carried out on homogenized commercial milk (3.6% fat content) spiked with ethanolic solutions of 24 OP pesticides, viz., ethoprophos, diazinon, dimethoate, chlorpyrifos-methyl, parathion-methyl, chlorpyrifos-ethyl, malathion, isofenphos, quinalphos, ethion, pyrazophos, azinphosethyl, heptenophos, omethoate, fonofos, pirimiphos-methyl, fenitrothion, parathion, chlorfenvinphos, phenthoate, methidathion, triazophos, phosalone, azinphos-methyl, at levels ranging for the different OP pesticides from 0.02 mg/kg to 1.11 mg/kg. Average recoveries of four replicates were in the range 72-109% for the different OP pesticides, with relative standard deviations (R.S.D.) from ca. 1 to 19%, while dimethoate and omethoate were not recovered. Coextracted fatty material amounted to an average of about 4.0 mg/ml of milk. The extraction procedure requires about 30 min. The main advantages are that extraction and cleanup are carried out in a single step, emulsions do not occur, several samples can be run in parallel by a single operator, reusable glassware is not needed and simple operations are required.

In 1990 an outbreak of ataxia occurred in over 700 pigs in the north of England. Epidemiological studies demonstrated that the disorder was associated with the consumption of feed from a particular supplier and that one component (wheat screenings) was common to the batch of feed with which the ataxia was associated. An analysis of the feed demonstrated the presence of an organophosphorus pesticide, later identified as isofenphos, a pesticide not approved for use in the United Kingdom. The wheat screenings had been imported from France and the warehouse in which they had been stored was contaminated with isofenphos, which is approved for restricted use in France. Isofenphos is known to cause delayed neuropathy. The dose to which the pigs were theoretically exposed would be expected to have resulted in neuropathy (manifested as ataxia).

The neuropathic potential of acute and repeated exposures of the phosphoramidates tabun (GA) and isofenphos (IFP), of diisopropyl fluorophosphate (DFP) and paraoxon (PO) were examined in the hen with treatments for up to 90 days via intramuscular injections of the highest tolerated doses with atropine protection. Plasma acetylcholinesterase (AChE), non-specific butyrylcholinesterase (BChE) and creatine kinase (CK) activities were measured in order to monitor whether the compounds were present at biologically active concentrations. Locomotor behavior was observed and tissues from the peripheral and central nervous systems were examined for signs of organophosphate-induced delayed neuropathy (OPIDN). No behavioral or histological evidence of OPIDN was observed after treatments with GA, IFP, PO, saline or atropine sulfate. DFP-treated birds displayed locomotor and neuropathological signs of OPIDN with a no effect level (NOEL) between 25 and 50 micrograms/kg.

The principles and procedures for the assessment of the safety/risk of chemical used by the relevant WHO and EPA expert groups are outlined. The assessment in terms of acceptable daily intakes (ADIs) and reference doses (RfDs) of 25 pesticides is listed. The pesticides assessed are acephate, alachlor, amitrole, azinphos-methyl, benomyl, biphenthrin, bromophos, chlordane, chlorthalonil, cyhalothrin, DDT, EPTC, ethion, folpet, fosetyl-al, glyphosate, isofenphos, methomyl, methyl mercury, paraquat, phosphamidon, systhane, terbutyn, tribultyltin oxide, and vinclozin. In addition, their critical effects, the no-observed-effect levels and the size of the safety/uncertainty factors used are also listed to illustrate the diversity of the toxic effects and the resulting assessments. Furthermore, the enormous amount of data reviewed and the complex scientific judgement involved are also indicated. Considering the various uncertainties existing, the ADIs and RfDs do not differ appreciably in most instances. However, marked differences exist between the ADIs and RfDs of DDT and chlordane. It is suggested that re-evaluation be done on these, and perhaps other, chemicals.

Daily dermal administration for 90 days of 0.01 to 10 mg/kg of O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) technical grade (85%) in acetone (0.1 ml) on the unprotected back of the neck produced delayed neurotoxicity. Hens given 2.5 to 10 mg/kg daily doses also received daily doses of atropine sulfate for 5 or 6 days to protect against cholinergic acute toxicity. Severity of the clinical condition depended on the concentration of the daily dermal dose of EPN; i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. The most consistent histopathologic alteration was the degeneration of axons and myelin in the spinal cord which was identical to that found in positive control hens that received daily dermal doses of 5 or 10 mg/kg tri-o-cresyl phosphate (TOCP). Some of the hens treated daily with the smallest tested dose of EPN (0.001 mg/kg) which did not show clinical signs of delayed neurotoxicity showed equivocal histological changes in the spinal cord. EPN and TOCP treatments had a more profound effect on the activity of plasma butyrylcholinesterase than that of brain acetylcholinesterase (AchE). by contrast O,O,-diethyl O-4-nitrophenyl phosphorothioate (parathion) was more inhibitory to brain AChE. Negative control hens that were treated with 90 daily dermal doses of 1 mg/kg of parathion initially showed leg weakness followed by recovery. A group of hens that received the same volume of acetone (0.1 ml) daily remained normal.

A screening method has been developed for determining organophosphorus pesticides at ng/L levels in drinking water. Sixteen organophosphorus pesticides, diazinon, diazinon-oxon, dimethoate, ronnel, beta-phosphamidon, methyl parathion, ethyl parathion, malathion, chlorpyrifos, fenitrothion, ruelene, methidathion, ethion, EPN, phosalone, and phosmet, were extracted by Amberlite XAD-2 resin from 100 and 200 L drinking water previously spiked with these pesticides. The pesticides were eluted from the XAD-2 resin with acetone-hexane (15+85). The concentrated extract was analyzed by gas chromatography using a nitrogen-phosphorus selective detector and by gas chromatography-mass spectrometry using selected ion monitoring. Recoveries at the 10 and 100 ng/L spiking levels were greater than 90%, except recoveries for dimethoate and phosphamidon were 37 and 42%, respectively. The analysis of 300 L Ottawa tap water showed no detectable amounts (less than 1 ng/L) of any of the 16 organophosphorus pesticides.