Inhibitor Report for: Mevinphos

Organophosphate (OP)-related systemic illnesses reported to the Worker Health and Safety (WH&S) Branch, and restricted OP-related agricultural use data reported to the Information Services Branch at the California Department of Food and Agriculture (CDFA) (now CAL-EPA) during 1984-1988 were used to assess factors associated with OP-related systemic illnesses. Counts of OP-related systemic illnesses (numerator), relative to OP-related use data (denominator), such as pounds applied, number of applications, and acres treated (pounds applied/acres treated), were analyzed by crop treated, season of application, method of application, geographic region, and by specific OP applied. A Relative Illness/Use Ratio (RIUR) was calculated by Poisson regression. The highest risk of systemic illness was associated with OP applications to fleshy fruit (mainly fruit trees) compared to all other crops combined (RIUR = 2.9, 95%CI = 2.2-3.9) using pounds applied in the denominator, followed by vegetables and melons (RIUR = 1.9, 95%CI = 1.4-2.4). Air applications resulted in higher RIURs for systemic illness than did ground applications (RIUR = 2.1, 95%CI = 1.7-2.5). Specific OPs that showed significantly elevated RIURs for systemic illness when compared to other OPs were Mevinphos (RIUR = 5.8, 95%CI = 5.0-6.8), Demeton (RIUR = 4.3, 95%CI = 2.6-7.1), Oxydemeton-Methyl (RIUR = 3.8, 95%CI = 3.0-4.9), Methamidophos (RIUR = 1.6, 95%CI = 1.2-2.0) and Azinphos-Methyl (RIUR = 1.3, 95% CI = 1.1-1.6).

Ten day old chick sympathetic ganglia cultured in a microslide assembly were treated with a selected group of organophosphate pesticides to evaluate their cytotoxicity ranges, and the usefulness of such a model for screening pesticides. Examination by phase contrast and light microscopy for chemically-induced morphological alteration of nerve fibers, glial cells and neurons provided the criteria for quantitation and assessment of the toxic effects. Concentrations that produced half-maximal effects ranged from 1 x 10(-6)M (severely toxic) for methylparathian, diazinon, paraoxon, mevinphos, diisopropylfluorophosphate, tri-o-tolyl phosphate and its mixed isomers to a 1 x 10(-3)M (intermediate) for malathion, leptophos, coumaphos, mono- and dicrotophos. Some or no effects were evident at 1 x 10(2-)M for O'ethyl-O-p-nitrophenyl phenyl phosphonothioate, tri-m-tolylphosphate, chlorpyriphos and triphenyl phosphate. In all instances, nerve fibers were more sensitive than neurons or glial cells to insecticides. All cellular growth was inhibited at 1 x 10(-2)M (except triphenyl phosphate). Below 1 x 10(-7)M, no inhibitory effects were evident. The secondary abnormalities included decreased cellular migration, diffuse cellular growth pattern, increased vacuolization, nerve fiber swelling and cellular degeneration. The cytotoxic effects of these chemicals do not appear to be related to in vivo toxicity or cholinesterase inhibition potential.

As inhibitors of acetylcholinesterase, clinical presentations of poisoning from organophosphate compounds are generally believed to entail overstimulation by the accumulated acetylcholine on muscarinic receptors at peripheral and central synapses. That some patients still yielded to acute organophosphate poisoning despite repeated dosing of atropine suggests that cellular mechanisms that are independent of muscarinic receptor activation may also be engaged in organophosphate poisoning. The present study was undertaken to test the hypothesis that muscarinic receptor-independent activation of cyclic adenosine monophosphate-dependent protein kinase A (PKA) in rostral ventrolateral medulla (RVLM), a medullary site where sympathetic vasomotor tone originates and where the organophosphate poison mevinphos (Mev) acts, is involved in the cardiovascular responses exhibited during organophosphate intoxication. In Sprague-Dawley rats, microinjection bilaterally of Mev (10 nmol) into the RVLM significantly augmented PKA activity in ventrolateral medulla that was not antagonized by coadministration of an equimolar concentration (1 nmol) of atropine or selective muscarinic receptor type M1 (pirenzepine), M2 (methoctramine), M3 (4-diphenyl-acetoxy-N-dimethylpiperidinium), or M4 (tropicamide) inhibitor. Comicroinjection of two selective PKA antagonists (100 pmol), N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide and (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-dii ndolol[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-1][1,6]benzodiazocine-10-carboxylic acid, significantly blunted the initial sympathoexcitatory cardiovascular response and the accompanying augmentation of nitric oxide synthase (NOS I) expression in the ventrolateral medulla exhibited during Mev intoxication; the secondary sympathoinhibitory phase and associated elevation in NOS II expression were unaffected. We conclude that whereas a muscarinic receptor-independent augmentation of PKA activity in the ventrolateral medulla was manifested throughout acute Mev intoxication, this activation was preferentially involved in the sympathoexcitatory phase by an upregulation of NOS I expression.

BACKGROUND Causal antidotal therapy of acute intoxications with organophosphorus compounds involving administration of the parasympatholytic and cholineesterase reactivator (oxime) has not been resolved so far satisfactorily despite knowledge of the basic mechanism of action of these noxious substances. METHODS AND RESULTS: In experiments on mice the therapeutic effect of parasympatholytics atropine, benactyzine and biperidene (Akineton) combined with oxime HI-6 on the toxicity of highly toxic organophosphates soman and substance VX and the organophosphorus insecticide phosdrine was compared as regards their influence on the LD50 of these noxious substances during 24-hour survival of experimental animals. Two levels of antidotes were tested. These findings confirm that the LD50 value of untreated intoxication with all three organophosphorus compounds is most increased by oxime HI-6 combined with benactyzine regardless of the antidote dosage.
CONCLUSIONS: Oxime HI-6 is the most effective against highly toxic organophosphates and organophosphorus insecticides when combined with the centrally acting parasympatholytic benactyzine.

The efficacy of two new monopyridinium oximes (2-PAAM, 2-PAEM) and two bispyridinium oximes (obidoxime. HI-6) was tested in combination with atropine sulphate against acute poisoning with the organophosphorus insecticide mevinphos in mice. When mice were treated two min. after mevinphos poisoning, no significant differences in the therapeutic effect of tested oximes were observed. The oximes increased the 24 hr LD50 values of mevinphos about two times in comparison with the 24 hr LD50 values of mevinphos in mice protected with atropine sulphate alone and more than three times in comparison with non-treated intoxicated animals. On the other hand, both monopyridinium oximes were significantly more efficacious than HI-6 and as efficacious as obidoxime when they were administered 30 sec. after mevinphos poisoning. Both monopyridinium oximes and obidoxime increased the 24 hr values of mevinphos almost three times in comparison with the 24 hr values of mevinphos in mice protected with atropine sulphate alone and about twenty-five times in comparison with non-treated intoxicated animals, while the oxime HI-6 less than two times in comparison with the 24 hr values of mevinphos in mice protected with atropine sulphate alone and about fifteen times in comparison with non-treated intoxicated animals. Use of new monopyridinium oximes seems to be the improvement in the antidotal treatment of poisoning with organophosphorous insecticide mevinphos in comparison with HI-6 but not in comparison with obidoxime when oximes are used in equimolar doses.

Laboratory bioassays with green peach aphids, Myzus persicae (Sulzer), were conducted on samples from field grown spinach and mustard greens to determine the persistence of triazamate, dimethoate, and mevinphos. Treatment with each insecticide resulted in similar mortality initially on both crops. Mortality on samples from mevinphos treated plants declined considerably by 1 d after treatment. Dimethoate persisted for > 4 d at a level that would kill at least some aphids during the allotted time. Persistence of triazamate and dimethoate activities were similar on spinach. Triazamate, however, resulted in greater aphid mortality through time on mustard greens than did dimethoate.

Organophosphate (OP)-related systemic illnesses reported to the Worker Health and Safety (WH&S) Branch, and restricted OP-related agricultural use data reported to the Information Services Branch at the California Department of Food and Agriculture (CDFA) (now CAL-EPA) during 1984-1988 were used to assess factors associated with OP-related systemic illnesses. Counts of OP-related systemic illnesses (numerator), relative to OP-related use data (denominator), such as pounds applied, number of applications, and acres treated (pounds applied/acres treated), were analyzed by crop treated, season of application, method of application, geographic region, and by specific OP applied. A Relative Illness/Use Ratio (RIUR) was calculated by Poisson regression. The highest risk of systemic illness was associated with OP applications to fleshy fruit (mainly fruit trees) compared to all other crops combined (RIUR = 2.9, 95%CI = 2.2-3.9) using pounds applied in the denominator, followed by vegetables and melons (RIUR = 1.9, 95%CI = 1.4-2.4). Air applications resulted in higher RIURs for systemic illness than did ground applications (RIUR = 2.1, 95%CI = 1.7-2.5). Specific OPs that showed significantly elevated RIURs for systemic illness when compared to other OPs were Mevinphos (RIUR = 5.8, 95%CI = 5.0-6.8), Demeton (RIUR = 4.3, 95%CI = 2.6-7.1), Oxydemeton-Methyl (RIUR = 3.8, 95%CI = 3.0-4.9), Methamidophos (RIUR = 1.6, 95%CI = 1.2-2.0) and Azinphos-Methyl (RIUR = 1.3, 95% CI = 1.1-1.6).

Mevinphos (trade name, Phosdrin), a category 1 organophosphorus insecticide, has been used mainly as a cleanup pesticide for vegetable crops. A risk assessment for occupational and dietary exposure to mevinphos was initiated because of the high acute toxicity of the compound. Repetitive dosing with mevinphos did not cause any discernible histopathological effects in mice or rats, nor was it oncogenic in either species. The principal toxic effects of mevinphos, both short- and long term, were due to inhibition of cholinesterase activity. Consequently, potential adverse effects from short-term exposures were the primary concern. A human no-observed-effect level (0.025 mg/kg) for cholinergic signs was used as the regulatory basis for calculating margins of safety (MOSs) for potential acute dietary and short-term occupational exposures. Estimates of exposure to mixer/loaders, pilots, and flaggers associated with aerial application of mevinphos were based on passive dosimetry. Because no acceptable exposure studies for work tasks associated with ground application of mevinphos were available, surrogate data based on ground application of oxydemeton-methyl were used. Exposure estimates for field workers and harvesters relied on measured dislodgeable foliar residues of mevinphos and transfer factors generated from studies of other active ingredients. MOSs for mean acute occupational exposure of mixer/loader/applicators associated with ground application and of harvesters working in fruit trees were less than the value conventionally recommended to protect people from the toxic effects of mevinphos. MOSs for the 95th percentile of short-term worker exposure for all mixer/loader work categories associated with mevinphos application were also inadequate. Calculated MOSs for potential acute dietary exposure to measured residue levels of mevinphos were adequate for the various population subgroups. However, 25 of the USEPA tolerances for mevinphos on agricultural commodities were not adequate to protect for the toxic effects of mevinphos from theoretical acute dietary exposure to one or more population subgroups if commodities are consumed with residues at the tolerance level. When the mean short-term occupational exposures were combined with potential acute dietary exposure, the MOSs for mixer/loaders engaged in aerial applications, as well as ground applications, were inadequate to protect people from the toxic effects of mevinphos. As mitigation of the estimated excessive occupational exposures did not appear possible, both California and the USEPA were preparing to cancel registration of the product. However, an agreement was worked out between the manufacturer and the two agencies that ended production for domestic use but allowed existing stocks in the channels of trade to continue to be used for a limited period.

BACKGROUND Acute pancreatitis as a complication of organophosphate intoxication has been infrequently addressed. Previous reports have suggested that acute pancreatitis may follow the oral ingestion of several organophosphates, including parathion, malathion, difonate, coumaphos, and diazinon, or after cutaneous exposure to dimethoate. No cases of acute pancreatitis following mevinphos (CAS 7786-34-71) poisoning have been reported to date. The possible pathogeneses of the pancreatic insult in organophosphate intoxication are excessive cholinergic stimulation of the pancreas and ductular hypertension. CASE REPORT: We describe a patient presenting with painless acute pancreatitis following an intentional ingestion of large amounts of mevinphos. Serum amylase and lipase values were increased and determination of amylase isoenzymes confirmed a pancreatic origin. A computerized tomograph of the abdomen showed diffuse swelling of the pancreas. The patient was discharged after a seven week clinical course, complicated by a delayed neuropathy.
CONCLUSIONS: As acute pancreatitis in organophosphate intoxication may be more common than reported, serum pancreatic enzymes and appropriate imaging studies should be more liberally utilized. Early recognition and appropriate therapy for acute pancreatitis may lead to an improved prognosis.

In experiments on male mice, the effect of the cholinesterase reactivators obidoxime, methoxime and HI-6 in combination with atropine sulfate on the acute intoxication with the organophosphorous insecticide fosdrine was tested in dependence on the period of administration of drugs after intoxication and on the dose of oxime by influencing the LD50 value in 48-hour survival of experimental animals. It has been demonstrated that the rate of the therapeutic intervention is a much more important factor influencing the effect of oximes than the dose of oximes. A shortening of the period of drug administration from 2 minutes to 30 seconds substantially increases the effects of all three oximes. A comparison of the effects of all three reactivators has shown that the oxime HI-6 is significantly more effective than the remaining two reactivators in the case of therapy of intoxication 30 seconds after the application of the noxa. In the therapy of intoxication 2 minutes after the exposure of experimental animals to fosdrine, the effect of the antidotal therapy was relatively low regardless of the selected oxime.

The efficacy of cholinesterase reactivators tetroxime, HI-6 and obidoxime in combination with atropine against highly toxic organophosphate soman as well as organophosphorus insecticide fosdrin was evaluated in male mice using median lethal dose (LD50) for 48 hours. Oxime HI-6 appears to be considerably more effective than tetroxime as well as obidoxime for the treatment of acute poisonings by soman or fosdrin, although the difference in effect is not significant in the case of poisoning by fosdrin. These findings suggest that HI-6 has definite advantage over obidoxime as well as tetroxime in the treatment of poisoning with not only highly toxic organophosphates but also organophoshorus insecticides.

The exposure of sprayers and plant handlers to mevinphos, a toxic organophosphate insecticide, was evaluated in eight flower-growing greenhouses. The purpose was to assess an appropriate re-entry interval for mevinphos after its application in greenhouses. Inhalational and dermal exposure was measured during two days after application by measuring mevinphos in the greenhouse air and on the foliage. Workers' dermal exposure was measured with patch and handwash samples. The method of application considerably affected the levels of mevinphos in greenhouse air and on the foliage. The occupational exposure was measured with patch and handwash samples. The method of application considerably affected the levels of mevinphos in greenhouse air and on the foliage. The occupational exposure limit for mevinphos in Finland (100 micrograms/m3) was exceeded during the use of nonthermal foggers. Usually, however, the concentration of mevinphos in the breathing zone of the workers was below 10 micrograms/m3 9-12 hr after application. Mevinphos disappeared rapidly from greenhouse air and from the foliage after application, with a half-life of 9.2 hr. These data provide evidence that the main route of exposure to mevinphos is dermal, a conclusion supported by the excellent correlation between dermal exposure and the amount of mevinphos on the foliage. The calculated re-entry interval for mevinphos was approximately 4.5 hr. However, that interval is likely to be too short in practice because the risk of dermal exposure is considerable for more than 10 hr after the application of mevinphos.

A method is described for the analysis of the cis- and trans-isomers of mevinphos in baits and avian tissues. The procedure involves extraction of the mevinphos isomers with acetone-dichloromethane (1:1) followed by clean-up on alumina. Bait samples were initially screened by thin-layer chromatography and identity of extracts confirmed by infrared spectrophotometry and gas chromatography-mass spectrometry.

Evidence is given that the organo-phosphates mevinphos and malathion perturb the retinal functioning of the white mouse by acting 1. directly on the photoreceptors; 2. by a synaptolytic effect due to the inhibition of cholinesterases; 3. likely by a damage of the bipolar and/or the ganglion neurones.

The authors carried out studies on 10 cats, anesthetized by urethane, under atropine protection and under the conditions of artificial respiration and examined the influence of therapeutic antidote of phosphorganic pesticides-Doline on the induced eletromyographic activity during total neuro-muscular block, induced by superlethal doses of phosphadrine. It was established that superlethal doses of phosphadrine induced total block of electropotentials in neuro-muscular conduction of the peripheral musculature, which was removed immediately after venous and muscular administration of the antidote Doline.

Ten day old chick sympathetic ganglia cultured in a microslide assembly were treated with a selected group of organophosphate pesticides to evaluate their cytotoxicity ranges, and the usefulness of such a model for screening pesticides. Examination by phase contrast and light microscopy for chemically-induced morphological alteration of nerve fibers, glial cells and neurons provided the criteria for quantitation and assessment of the toxic effects. Concentrations that produced half-maximal effects ranged from 1 x 10(-6)M (severely toxic) for methylparathian, diazinon, paraoxon, mevinphos, diisopropylfluorophosphate, tri-o-tolyl phosphate and its mixed isomers to a 1 x 10(-3)M (intermediate) for malathion, leptophos, coumaphos, mono- and dicrotophos. Some or no effects were evident at 1 x 10(2-)M for O'ethyl-O-p-nitrophenyl phenyl phosphonothioate, tri-m-tolylphosphate, chlorpyriphos and triphenyl phosphate. In all instances, nerve fibers were more sensitive than neurons or glial cells to insecticides. All cellular growth was inhibited at 1 x 10(-2)M (except triphenyl phosphate). Below 1 x 10(-7)M, no inhibitory effects were evident. The secondary abnormalities included decreased cellular migration, diffuse cellular growth pattern, increased vacuolization, nerve fiber swelling and cellular degeneration. The cytotoxic effects of these chemicals do not appear to be related to in vivo toxicity or cholinesterase inhibition potential.

The authors carried out studies on 18 nonanesthetised and anesthetised cats under the conditions of complete imobilization with tricuran and under artificial respiration and examined the temporary consequence of the effects on the spontaneous and induced cerebral activity after poisoning with lethal doses of phosdrine and treatment with Doline, which is the therapeutic antidote of phosphorganic pesticides. The authors established that after lethal poisoning with phosdrin the secondary induced cerebral hypoxia enhanced deepening of the disintegration in the intercerebral interrelationships, which caused the appearence of epileptiform activity. The antidote Doline within 1-2 minutes, after its muscular administration abolished effectively the generalized epileptic seizure and repaired quickly the electrophysiological indices-peculiar for the normal EEG.

The authors examined the changes in the nerve-muscular conductivit occuring after acute poisoning with phosdrine and treatment with arpenal and oximic reacytivators of HE-toxogonine and TMB-4(Trimedoxime) on 20 cats, anesthethised with urethane and atropine protection under the conditions of artificinal respiration. They found that there was a total nerve-muscular block cessation of the mediation in the myoneural synaptic zones, characterized by complete cessation also of the induced electrical responses after single and serial stimuli, during acute intoxications with phosdrine, used in lethal doses of 300 mg/kg intramuscularly. After treatment with H-cholinolitics (arpenal) there was a quick recovery of the muscle contractions as well as of the evoked myopotentials after stimulation with single electric stimuli. In contrast to the oximnic reactivators of He (toxogonine, TMB-4(Trimedoxime)) during serial electric stimuli (10,20 and 30 per second after treatment with arpenal there was a quick contraction only after the first stimulus, after which a progresive weakening of the induced electric myopotentials followed till the appearence of a total nerve-muscular block. This phenomenon was explained by the lack of reactivating properties of H-cholinolitics to HE, inhibited by FOV.

The interaction of the organophosphate mevinphos and atropine was examined in two pigeons performing in a variable interval schedule of reinforcement. When administered separately, both atropine and mevinphos produced a dose-related decrement in responding. The combined exposure to these drugs produced a performance decrement greater than that caused by exposure to each component drug alone. These findings suggest that prophylactic use of atropine may increase the detrimental behavioral effects of organophosphate exposure and that the atropine exposure alone may produce serious behavioral deficits.

Low doses of the acetylcholinesterase inhibitors, mevinphos and physostigmine, reduce hippocampal inhibitory phenomena, measured in terms of the duration of the poststimulus inhibitory pause seen in individual hippocampal neurones in the pigeon. The cholinergic antagonist, atropine, increased hippocampal inhibition. At near threshold doses, mevinphos could, in part, reverse atropine effects. At higher doses, mevinphos synergized with atropine. In the discussion, it is suggested that any organophosphate or carbamate pesticide and its antidote, atropine, may alter "attention" or "short-term memory" through effects on hippocampus at doses too low to induce grossly detectable peripheral symptomatology. Extreme caution in the use or handling of these compounds by aerial applicators is urged. Since the effects of atropine and mevinphos can synergize, the use of atropine to permit poisoned applicators to resume activity is questioned.

The need for study of the effects on performance of non-lethal organophosphate insecticide exposure is founded on many reports of behavioral difficulties in aerial applicators following exposure. In this study, a different pair of gerbils served in each of the following schedules of reinforcement: FR 25, FR 75, DRL 12-sec, DRL 20-sec, and VI 1-min. Baseline performance in these tasks tended to be comparable to that of more common laboratory species, but was more variable in the case of the VI 1-min task. Mevinphos doses of 0.20 mg/kg and above produced observable somatic signs of poisoning and also produced dose-related decrements in performance in FR and VI tasks. Performance in the DRL schedule was affected only at a dose of 0.30 mg/kg. No performance deficits or overt somatic signs of poisoning were present at mevinphos doses of 0.10 mg/kg or lower. These results do not agree with those of an earlier study which decrements in VI performance of pigeons and squirrel monkeys appeared at low mevinphos doses which did not produce overt somatic signs of poisoning. The possibility of variations in mevinphos effect as a function of species and task was discussed.