Manual Toxicology of Organophosphate & Carbamate Compounds

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The existence, and relevance, of additional targets has been widely used to discuss issues such as of common mechanism of action of OPs and the proposed cumulative risk assessment, possible CNS effects of long-term chronic exposure, as well as developmental neurotoxicity, particularly when effects are seen at OP doses that cause minimal or no AChE inhibition Voorhees et al. OPs do indeed affect hundreds of enzymes, receptors, and other proteins. Various other components of the cholinergic system have been shown to be directly affected by some OPs, and muscarinic M2 receptors in particular have been shown to be a potential target Costa, Several enzymes involved in the metabolism of peptides are inhibited by OPs.

For example, acylpeptide hydrolase APH , responsible for the removal of N-acetylated amino acids from the N-terminus of short peptides, such as beta-endorphin, is inhibited by various oxons eg, dichlorvos, diazoxon at low concentrations, and inhibition was also observed after in vivo exposure Richards et al. Indirect evidence of inhibition of encephalin metabolism by DFP a neuropathic OP, never used as insecticide has also been reported Costa and Murphy, Several OPs have also been shown to inhibit a variety of lipases, which may alter lipid metabolism, particularly in the nervous system Quistad et al.

Toxicology of Organophosphate and Carbamate Compounds - 1st Edition

Two potentially important noncholinergic effects of OPs that have been investigated are oxidative stress and neuroinflammation. Both may be of high relevance as they are known to be involved in the pathogenesis of several neurodevelopmental and neurodegenerative diseases. OP-induced oxidative stress has been observed in experimental animal studies in vivo , in in vitro preparations, as well as in humans Kovacic, ; Milatovic et al. Of relevance is the fact that both the parent compounds as well the oxygen analogs were able to induce oxidative stress, and the fact that this effect did not appear to be related to AChE inhibition.

Acute and chronic exposures to OPs have also been shown to cause neuroinflammation, with microglia activation and increase in pro-inflammatory cytokine levels in mice Banks and Lein, ; Viviani et al. The exact molecular mechanisms involved in OP-induced oxidative stress and neuroinflammation are still elusive, though they may be secondary to mitochondrial toxicity Terry, Overall, though the possibility that novel additional noncholinergic targets or effects may be involved in some adverse effects of OPs is of much interest, the evidence so far linking one or more of the observed effects to significant in vivo end-points is not fully convincing, and more rigorous investigations are needed.

With regard to OPs, findings in animals clearly show that the young are more sensitive to the acute cholinergic toxicity, likely because of lower detoxication abilities Benke and Murphy, ; Mortensen et al. In recent years, accumulating evidence suggests that perinatal exposure to OPs may cause developmental neurotoxicity. Several epidemiological studies have found associations between in utero or early childhood exposure to OPs and behavioral abnormalities, particularly deficits in learning and memory reviewed in Eskenazi et al.

It has been pointed out that exposure to OPs, as shown by biological monitoring in children, though somewhat elevated in inner cities or farming communities, is still at levels below those causing any AChE inhibition. Several animal studies also showed developmental neurotoxicity effects of OPs, however, with few exceptions, effects were observed at levels causing significant AChE inhibition see details in Eaton et al. As indicated earlier, OPs can interact with targets other than AChE, and affect various cellular processes in vitro or ex-vivo , often at dose levels that produced no clear cholinergic signs of toxicity and at times that produce no AChE inhibition reviewed in Eaton et al.

It should be noted that most of the human, animal and in vitro studies have focused on chlorpyrifos, a widely used OP, and to a minor extent on diazinon, leading to regulatory restrictions on their use. However, there is no strong reason to believe that other OP compound may not share similar novel mechanisms of action, and further research in this area is certainly warranted. Table 2. Axonal transport was measured in rat cortical neurons. Adapted from Gao et al.

Insecticides: organochlorines, organophosphates and carbamates

Aging is often associated with a wide variety of clinical and pathological conditions which can be classified as neurodegenerative diseases. The etiology of these diseases is unknown and both environmental and genetic factors may play a role; oxidative stress and neuroinflammatory processes are prominent in most neurodegenerative diseases. Though genetic forms of PD have been associated with specific mutations in a number of genes, the great majority of PD cases is sporadic, and may be due to environmental factors or to gene-environment interactions, ie, exposure of genetically susceptible individuals to neurotoxic substances.

Among the environmental factors believed to be associated with PD there are certain pesticides such as the herbicide paraquat and the insecticide rotenone. However, Chuang et al. The mechanism s by which OPs may cause degeneration of dopaminergic neurons remains elusive, though oxidative stress and neuroinflammation have been suggested Wani et al. The emerging role of gut microbiota in PD Parashar and Udayabanu, and the effects of OPs on the microbiome see below may represent another fruitful avenue for mechanistic investigations. Its most common symptom is memory loss for recent events, with diffuse cortical and hippocampal atrophy, and accumulation of abnormally folded amyloid beta and of tau proteins in amyloid plaques and neuronal tangles Khan and Bloom, ; Selkoe and Hardy, A review of the literature shows that evidence for such association in human studies is weak, and suggested mechanisms are again oxidative stress and neuroinflammation Zaganas et al.

Environmental factors potentially involved in the etiopathogenesis of ALS have been investigated to a very limited degree. Overall, while investigations on possible associations between environmental factors and neurodegenerative diseases remain of much relevance, evidence that OPs may play an etiological role in such diseases remains weak. Over the past 2 decades, aircrew and some passengers on various airlines have complained of ill health following exposures to toxic fumes in airplane cabins Harrison and Mackenzie Ross, Air drawn from outside is circulated around the engine and then pumped into the aircraft; such bleed air may be contaminated with engine oil fumes which contain a number of toxic substances Shehadi et al.

Reported symptoms range from respiratory tract irritation, to gastrointestinal effects, to CNS problems of various types tremors, disorientation, memory loss, and cognitive dysfunction of short-and long-term nature. Several air monitoring studies have identified various toxic substances eg, toluene, carbon monoxide, and N-phenyl-L-naphthylamine , but interest has focused on TCP and TOCP.

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These compounds can be detected in cabin air, but levels are very low de Ree et al. Human exposure, determined by urine metabolite levels and by butyrylcholinesterase adducts, is also very low Schindler et al. No significant inhibition of lymphocytic NTE activity was reported, and erythrocyte AChE activity was also, not surprisingly, unaffected Heutelbeck et al. Nevertheless, any potential role of TCPs would need further, more thorough investigations. A few decades ago attention had focused on the formation of the bicyclophosphate esters upon pyrolysis of trimethylpropane polyesters, which, like the triarylphosphates, were also used as aircraft engine lubricants Kalman et al.

Bicyclic phosphorus esters do not inhibit AChE, but they are potent antagonists of the gamma-aminobutyic acid-A receptors, and hence potent convulsants Bellet and Casida, ; Bowery et al. Issues related to the eventual roles of OPs in the aerotoxic syndrome remain emotionally charged and scientifically weak; perhaps a way forward would be that of developing bleedless aircrafts, as already done with some newer models.

The fact that the human gut contains various organisms such as fungi, parasites, viruses and bacteria has been known for decades. In recent years, attention has focused on the role that perturbation of human microbiota may have on disease Mahana et al. Significant associations have been found for example between alterations in the gut microbiome and diabetes, inflammatory diseases, liver damage, and also neurodevelopmental eg, autism and neurodegenerative eg, PD diseases, in line with the important role of the gut-brain axis ZHu et al. Several chemicals have been shown to perturb the gut microbiota, and a handful of studies have focused on OPs.

Interestingly, the effects were more pronounced in male than in female mice. Examples of observed effects include significant changes in bacterial genera, alterations in bile acids abundance, and a drastic decrease in taurine levels Gao et al. In a follow up study, Gao et al. Of note is that prolonged exposure to diazinon was reported not to cause any AChE inhibition Gao et al. Two similar studies, which utilized this and higher doses of chlorpyrifos 3. Unfortunately, none of these studies with chlorpyrifos indicates whether AChE activity was affected.

A human study by Stanaway et al. As research on the role of microbiota in human disease is rather recent, it would be expected that research on the interactions of OPs with the microbiome will increase, and perhaps provide some novel mechanism for some of the still unexplained effects of these insecticides, particularly as it relates to effects from prolonged low level exposures.

Innumerable epidemiological studies have been carried out with the purpose of determining possible associations between exposure to pesticides and an increased risk of tumors. As a class OPs have not been considered to pose a significant cancer risk Woo et al. Two widely used OPs, chlorpyrifos and diazinon, are classified as unlikely to be carcinogens in humans; yet epidemiological studies have revealed associations between exposure to these 2 OPs and certain cancers Weichenthal et al. For diazinon and malathion, the classification was based on limited to sufficient animal evidence, limited human evidence and some mechanistic evidence genotoxicity, oxidative stress.

For this compound, which is the most widely used pesticide worldwide, particularly because it is used in glyphosate-resistant crops, evidence by IARC was deemed sufficient for animal studies, limited for humans, and supported by evidence of genotoxicity and oxidative stress Guyton et al. At about the same time the European Food Safety Authority concluded instead that glyphosate is unlikely to pose any carcinogenicity risk for humans EFSA, , starting a fiery debate which is still ongoing eg, Williams et al.

As noted previously, the use of OPs as insecticides has been declining in recent years; however, this is not yet the time of their demise Casida and Durkin, Features that keep OPs as major chemicals for pest control include decades of experience on their use, high effectiveness on many pests, availability of generic products of low cost, excellent overall environmental profile Casida and Durkin, , while high toxicity to mammalian species remains a major concern.

Indeed several OP compounds have and are being developed as herbicides eg, glyphosate, glufosinate , fungicides eg, iprobenfos, edifenphos , pharmaceutical drugs eg, the antihypertensive fosinopril or the antineoplastic fotemustine , or flame retardants [eg, tris 1, 3 dichloropropyl phosphate—TDCPP, or tris 2-chloroethyl phosphate—TCEP] Casida, b.

For example, production and use of OP flame retardants have increased significantly in the past 2 decades, particularly since the more popular PBDEs polybrominated diphenylethers have been phased out or banned due to concerns on their potential developmental neurotoxicity Costa and Giordano, In addition, several OP flame retardants have been associated with a number of adverse health effects, as they are suspected carcinogens, developmental neurotoxicants, reproductive toxicants, and endocrine disruptors van der Veen and de Boer, ; Greaves and Letcher, As for insecticidal OPs and for nerve agent OPs ie, primarily AChE inhibitors several toxicological issues still linger and need further investigations, as in part outlined in this review.

Toxicology of organophosphate and carbamate compounds

I would like to dedicate this article to my late mentor Sheldon D. Murphy — who introduced me to the field of OP toxicology and shared his knowledge and wisdom in this area. I also acknowledge my early Italian mentor Corrado L. Galli, who introduced me to the field of toxicology and to Sheldon , and my colleague at the University of Washington, Clement E. Furlong, who kept our OP research on paraoxonases exciting for several decades.

Apologies are due to all colleagues whose important research contributions on OPs could not be cited because of space limitations. Oxford University Press is a department of the University of Oxford.

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Abstract One of the major classes of pesticides is that of the organophosphates OPs. Figure 1. View large Download slide. Figure 2. Search ADS. Organophosphorus compounds: Molecular basis for their biological properties. Is it possible to reverse aged acetylcholinesterase inhibited by organophosphorus compounds. Insight from a theoretical study. Google Preview.

A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation.

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Bicyclic phosphorus esters: High toxicity without cholinesterase inhibition. The influence of age on the toxicity and metabolism of methylparathion and parathion in male and female rats. Bicyclic phosphorus esters that are potent convulsants and GABA antagonists. Inhibition of endocannabinoid-metabolizing enzymes in peripheral tissues following developmental chlorpyrifos exposure in rats.

Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: From clinical findings to preclinical models and potential mechanisms. Organophosphate toxicology: Safety aspects of nonacetylcholinesterase secondary targets. Organophosphorus compounds: An overview. In Organophosphates: Chemistry, Fate, and Effects. Carboxylesterase inhibition as an indicator of malathion potentiation in mice. The toxicity of mixtures of specific organophosphorus compounds is modulated by paraoxonase 1 status.

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Neurobehavioral assessment of mice following repeated postnatal exposures to chlorpyrifos oxon. Cholinergic and opiate involvement in the antinociceptive effect of diisopropylfluorophosphate. Developmental neurotoxicity of polybrominated diphenyl ether PBDE flame retardants.

Paraoxonase 1 PON1 as a genetic determinant of susceptibility to organophosphate toxicity. De Boer. Tricresyl phosphate and the aerotoxic syndrome of flight crew members: Current gaps in knowledge. De Ree. Health risk assessment of exposure to tricresyl phosphates TCPs in aircraft: A commentary.

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In vitro neurotoxic hazard characterization of different tricresyl phosphate TCP isomers and mixtures. Du Bois. Studies on the toxicity and mechanism of action of p-nitrophenyl diethyl thionophosphate parathion. Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment.

Pharmacological treatment of organophosphorus insecticide poisoning: The old and the possible new. Conclusion on the peer review of the pesticide risk assessment of the active substance glyphosate. Exposures of children to organophosphate pesticides and their potential adverse health effects. Chlorpyrifos and chlorpyrifos oxon impair the transport of membrane bound organelles in rat cortical axons. Sex-specific effects of organophosphate diazinon on the gut microbiome and its metabolic functions.

Organophosphate diazinon altered quorum sensing, cell motility, stress response, and carbohydrate metabolism of gut microbiome. Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency. A systematic review of developmental effects of prenatal and postnatal organophosphate pesticide exposure. A review of organophosphate esters in the environment from biological effects to distribution and fate.

Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Systematic review on neurodevelopmental and neurodegenerative disorders linked to pesticide exposure: Methodological features and impact on risk assessment. Acetylcholinesterase and neuropathy target esterase activities in 11 cases of symptomatic flight crew members after fume events. Gregory J. Smith U. Department of the Interior, Fish and Wildlife Service. The use of organophosphorus and carbamate pesticides has increased markedly during the past two decades.

Currently, more than different organophosphorus and carbamate chemicals are registered as the active ingredients in thousands of different pesticide products in the United States. More than million acre-treatments of these pesticides are estimated to be applied to agricultural crops and forests each year. Clearly, these two groups of chemicals constitute a major portion of all pesticides used today. Organophosphorus and carbamate compounds have histories dating back long before their use as pesticides. Carbamates were developed during investigation of "ordeal" poisons used in Africa and made from the calabar bean, which contains the only known naturally occurring carbamate ester Kuhr and Dorough The insecticidal activity of carbamates was discovered in and developed in the mid-to-late 's.

Large quantities were being produced and used by the late 's Kuhr and Dorough Although much research on organophosphorus compounds was done in the 19th century, the insecticidal activity of these chemicals was not discovered until Eto In Germany, during World War II, the compounds were rapidly developed as insecticides, and during the 's the commercial use of organophosphates expanded markedly Eto Presently, organophosphorus and carbamate pesticides are used as insecticides, herbicides, nematicides, acaricides, fungicides, rodenticides, and bird repellents throughout the world.

The discovery that organochlorine pesticides, such as DDT, are highly persistent, bioconcentrate in food chains, and can severely affect whole populations or species of wildlife has led to bans and use restrictions Stickel