Organophosphate Exposure Research Articles

ENDOCRINE DISTURBANCES INDUCED BY LOW-DOSE ORGANOPHOSPHATE EXPOSURE IN MALE WISTAR RATS.

Organophosphate exposure induces many endocrine effects. In this study we observed the effects of acute stress induced by cholinesterase inhibition on the main hormonal axes. We included thirteen weanling Wistar rats that were subjected to organophosphate exposure. They were first tested for baseline levels of butyrylcholinesterase, cortisol, free triiodothyronine, thyroxine, thyroid-stimulating hormone and prolactin. Secondly, chlorpyrifos was administered. Next samples were taken to determine the level of all the above-mentioned parameters. Butyrylcholinesterase was significantly decreased after exposure (p<0.001). Cortisol levels were significantly higher after clorpyrifos administration (358.75±43 vs. 241.2±35 nmoL/L)(p<0.01). Although prolactin had a growing trend (450.25±24.65 vs. 423±43.4 uI/mL), the results were not statistically significant. Both free triiodothyronine and thyroxine were significantly higher after exposure. Surprisingly, thyroid-stimulating hormone level almost doubled after exposure with high statistical significance (p<0.001), suggesting a central stimulation of thyroid axis. Butyrylcholinesterase level was proportional with thyroid-stimulating hormone level (p=0.02) and thyroxine level was inversely correlated to the cortisol level (p=0.01). Acute cholinesterase inhibition may induce high levels of cortisol, free triiodothyronine, thyroxine and thyroid-stimulating hormone. From our knowledge this is the first study dedicated to the assessment of acute changes of hormonal status in weanling animals after low-dose organophosphate exposure.Conclusion. Acute cholinesterase inhibition may cause acute phase hormonal disturbances specific to shocked patients.

Paraoxonase-1 (PON1) Status Analysis Using Non-Organophosphate Substrates.

Human paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme with antioxidant, anti-inflammatory, and antiapoptotic roles. The ability of PON1 to hydrolyze specific organophosphate (OP) compounds and prevent accumulation of oxidized lipids in lipoproteins has prompted a large number of studies investigating PON1's role in modulating toxicity and disease. Most of these studies, however, have only focused on PON1 single nucleotide polymorphism analyses and have ignored PON1 activity levels, arguably the most important parameter in determining protection against exposure and disease. We developed a two-substrate activity assay termed "PON1 status" that reveals both the functional PON1192 genotype and plasma PON1 activity levels. While our previous studies with PON1 status demonstrated that both PON1192 functional genotype and enzymatic activity levels obtained exclusively by determining PON1 status are required for a proper evaluation of PON1's role in modulating OP exposures and risk of disease, the original PON1 status assay requires the use of highly toxic OP metabolites. As many laboratories are not prepared to handle such toxic compounds and the associated waste generated, determination of PON1 status has been limited to rather few studies. Here, we describe a PON1 status protocol that uses non-OP substrates with a resolution equivalent to that of the original PON1 status approach. We have also included useful suggestions to ensure the assays can easily be carried out in any laboratory. The protocols described here will enable a proper examination of the risk of exposure or susceptibility to disease in PON1 epidemiological studies without the need to handle highly toxic substrates. © 2021 Wiley Periodicals LLC. Basic Protocol: Determining PON1 status using non-organophosphate substrates Support Protocol 1: Experimental pathlength determination Support Protocol 2: PON1 DNA genotyping for the Q192R (rs662) polymorphism.

Sex-specific acute and chronic neurotoxicity of acute diisopropylfluorophosphate (DFP)-intoxication in juvenile Sprague-Dawley rats

Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of cognitive deficits in juvenile rats acutely intoxicated with OPs.

Inappropriate Use of Risk Assessment in Addressing Health Hazards Posed by Civil Aircraft Cabin Air

Toxicological reviews of data on Aerotoxic Syndrome that have been widely referenced by the airline industry tend to use a toxicological endpoint, Organo-Phosphate Induced Neuropathy (OPIDN), that is acknowledged to be the result of a very high dose of organophosphate exposure. Additionally, the reviews tend to only address one chemical, Tri-Ortho Cresyl Phosphate (TOCP), ignoring the presence of other toxic compounds in a complex mixture. In using this to justify the safety of the continued use of unfiltered engine bleed air to ventilate civil aircraft cabins, this represents a misuse of toxicological risk assessment. The approach totally ignores the scientific literature on repeated low-dose exposure to OPs over extended periods, the constant presence of a complex mixture of OPs in engine bleed air and their overall toxicity and the variable susceptibility of individuals to toxicological damage. This paper lists the above-mentioned studies and reviews a sub-set. We present the scientific literature that should be considered to make a realistic risk assessment of the hazards of aircraft engine bleed air.

Integrating Metapopulation Dynamics into a Bayesian Network Relative Risk Model: Assessing Risk of Pesticides to Chinook Salmon (Oncorhynchus tshawytscha) in an Ecological Context.

The population level is often the biological endpoint addressed in ecological risk assessments (ERAs). However, ERAs tend to ignore the metapopulation structure, which precludes an understanding of how population viability is affected by multiple stressors (e.g., toxicants and environmental conditions) at large spatial scales. Here we integrate metapopulation model simulations into a regional-scale, multiple stressors risk assessment (Bayesian network relative risk model [BN-RRM]) of organophosphate (OP) exposure, water temperature, and DO impacts on Chinook salmon (Oncorhynchus tshawytscha). A matrix metapopulation model was developed for spring Chinook salmon in the Yakima River Basin (YRB), Washington, USA, including 3 locally adapted subpopulations and hatchery fish that interact with those subpopulations. Three metapopulation models (an exponential model, a ceiling density-dependent model, and an exponential model without dispersal) were integrated into the BN-RRM to evaluate the effects of population model assumptions on risk calculations. Risk was defined as the percent probability that the abundance of a subpopulation would decline from their initial abundance (500 000). This definition of risk reflects the Puget Sound Partnership's management goal of achieving "no net loss" of Chinook abundance. The BN-RRM model results for projection year 20 showed that risk (in % probability) from OPs and environmental stressors was higher for the wild subpopulations-the American River (50.9%-97.7%) and Naches (39.8%-84.4%) spring Chinook-than for the hatchery population (CESRF 18.5%-46.5%) and the Upper Yakima subpopulation (21.5%-68.7%). Metapopulation risk was higher in summer (58.1%-68.7%) than in winter (33.6%-53.2%), and this seasonal risk pattern was conserved at the subpopulation level. To reach the management goal in the American River spring Chinook subpopulation, the water temperature conditions in the Lower Yakima River would need to decrease. We demonstrate that 1) relative risk can vary across a metapopulation's spatial range, 2) dispersal among patches impacts subpopulation abundance and risk, and 3) local adaptation within a salmon metapopulation can profoundly impact subpopulation responses to equivalent stressors. Integr Environ Assess Manag 2021;17:95-109. © 2020 SETAC.

Pesticide residue monitoring in the EuropeanUnion Agricultural Sector via modern analyticaltechniques.A review on Organophosphates

Organophosphate exposure, via foodproducts circulated within the EU member states, is monitored byvarious researchers and the results are provided to theircorresponding national authorities or to official European monitoringbodies. Different analytical methods for the detection of pesticideresidues in food products are applied, although the most preferablemethod used lately in private or educational laboratories is theQuEChERS method (a solid phase extraction technique) whereas theultra-high pressure liquid chromatography (UHPLC) system isgradually gaining ground in regard to pesticide residue trace analysis.This review focused on analyzing, from collected published data, thepreferred methods for the detection of organophosphate pesticideresidues in food products from the European Union AgriculturalSector. Even though a European legislation exists and applies strictguidelines, regulations and even bans, in order to reduce the use ofpersistent pesticides and to encourage the development of targetspecific pesticides, this review shows the current state for monitoringand detecting pesticide residues in general, as well as their possibledrawbacks and possible active solutions for pesticide monitoring intoday’s agriculture sector. In addition, results in the existing literatureare sufficient to demonstrate the difference in efficiency formonitoring and detecting organophosphate pesticide residues,however, more studies are needed to evaluate the available analyticaltechniques so as to strengthen the existing literature and to confirmthe existing data.

Cascading effects of insecticides and road salt on wetland communities.

Novel stressors introduced by human activities increasingly threaten freshwater ecosystems. The annual application of more than 2.3 billion kg of pesticide active ingredient and 22 billion kg of road salt has led to the contamination of temperate waterways. While pesticides and road salt are known to cause direct and indirect effects in aquatic communities, their possible interactive effects remain widely unknown. Using outdoor mesocosms, we created wetland communities consisting of zooplankton, phytoplankton, periphyton, and leopard frog (Rana pipiens) tadpoles. We evaluated the toxic effects of six broad-spectrum insecticides from three families (neonicotinoids: thiamethoxam, imidacloprid; organophosphates: chlorpyrifos, malathion; pyrethroids: cypermethrin, permethrin), as well as the potentially interactive effects of four of these insecticides with three concentrations of road salt (NaCl; 44, 160, 1600 Cl- mg/L). Organophosphate exposure decreased zooplankton abundance, elevated phytoplankton biomass, and reduced tadpole mass whereas exposure to neonicotinoids and pyrethroids decreased zooplankton abundance but had no significant effect on phytoplankton abundance or tadpole mass. While organophosphates decreased zooplankton abundance at all salt concentrations, effects on phytoplankton abundance and tadpole mass were dependent upon salt concentration. In contrast, while pyrethroids had no effects in the absence of salt, they decreased zooplankton and phytoplankton density under increased salt concentrations. Our results highlight the importance of multiple-stressor research under natural conditions. As human activities continue to imperil freshwater systems, it is vital to move beyond single-stressor experiments that exclude potentially interactive effects of chemical contaminants.

The Effects of Chronic Low Dose Exposure of Chlorpyrifos on the Rat Kidney

Introduction: An increased incidence of chronic kidney disease (CKD) was reported among agricultural workers who were exposed to organophosphates (OP). There is little information on the effects of chronic low OP exposure on kidney in experimental animals. Chlorpyrifos (CPF) is a common type of OP used in agriculture. Thus, the aim of this study was to assess the effects of chronic low subcutaneous exposure of CPF on the kidney. Methods. Eighteen male Sprague Dawley rats were divided into three groups, with six rats in each group. Group 1 served as a control group, and groups 2 and 3 received a subcutaneous vehicle (3% dimethyl sulfoxide + 97% v/v soy oil) or CPF (18.0 mg/kg) respectively, every other day for 180 days. Serum urea, creatinine, uric acid, cystatin C, electrolyte levels, acetylcholinesterase (AChE), and arylesterase (ArE) activities were measured. Histopathological changes in the kidney tissues were examined. Results. Urea, creatinine, uric acid, and cystatin C levels were significantly increased (p &lt; 0.05), while electrolytes were reduced (p &lt; 0.05) in the CPF-treated rats. Both AChE and ArE activities were depressed in the CPF group (p &lt; 0.01 and p &lt; 0.001, respectively). Diffuse necrosis of proximal tubules and glomerular hypercellularity were observed in the kidney in the CPF group. Conclusion. A chronic low dose of CPF via subcutaneous exposure caused considerable renal tubular necrosis and derangement of glomerular function. These findings suggest that chronic occupational OPs exposure can cause kidney damage.

Association between Organophosphate Pesticide Exposure and Insulin Resistance in Pesticide Sprayers and Nonfarmworkers.

Insulin resistance is a risk factor for various diseases. Chronic organophosphate exposure has been reported to be a cause of insulin resistance in animal models. This cross-sectional study aimed to evaluate the association between organophosphate exposure and insulin resistance in pesticide sprayers and nonfarmworkers. Participants aged 40–60 years, consisting of 150 pesticide sprayers and 150 nonfarmworkers, were interviewed and assessed for their homeostatic model assessment of insulin resistance (HOMA-IR) level. Organophosphate (OP) exposure was measured in 37 sprayers and 46 nonfarmworkers by first morning urinary dialkyl phosphate (DAP) metabolites. The DAP metabolite levels were not different in either group except for diethylthiophosphate (DETP; p = 0.03), which was higher in sprayers. No significant association was observed between DAP metabolite levels and HOMA-IR. Wearing a mask while handling pesticides was associated with lower dimethyl metabolites (95% CI = −11.10, −0.17). Work practices of reading pesticide labels (95% CI = −81.47, −14.99) and washing hands after mixing pesticide (95% CI = −39.97, −3.35) correlated with lower diethyl alkylphosphate level. Overall, we did not observe any association between OP exposure and insulin resistance in pesticide sprayers and the general population. However, personal protective equipment (PPE) utilization and work practice were associated with OP exposure level in sprayers.

Mixture of Organophosphates Chronic Exposure and Pancreatic Dysregulations in Two Different Population Samples.

Organophosphates (OP) are a major agrochemical. The application of OP pesticides is expected to increase multifold in the coming decades. The etiology of diabetic diseases is attributed to multiple factors including OP pesticide exposure. The present study investigates pancreatic dysregulation with respect to exocrine enzymes and diabesity in groups of Pakistani and Cameroonian people exposed to a mixture of OP pesticides. Nine hundred and four OP exposed individuals were enrolled for this cross-sectional study after due consent and approval from an ethical review committee. Pesticides' residues were measured by GC-MS spectrometry. Cholinergic enzymes were measured by Elman's method. Serum glucose, insulin, serum amylase, lipase, and triglyceride were measured by spectrophotometry and ELISA; HOMA-IR was determined in OP exposed and non-exposed participants. Stata 15 and R 3.2.0 software were used for statistical analysis of the data. Malathion, chlorpyrifos, and parathion residues were evident in plasma samples. RBC-acetylcholinesterase was significantly depressed in OP exposed groups. In both population samples, investigated pancreatic functions were found to be statistically significantly more dysregulated than non-exposed. OP exposure indicated risk of diabetes and insulin, glycaemia, adiponectin, triglycerides, and TNF-α dysregulations. The study concludes that both OP exposed population groups exhibited a mixture of OP residues and pancreatic dysregulation, although the effect was more pronounced in the Cameroonian population. In addition, serum lipase has a positive correlation with OP exposure and diabetes and may be suggested as an alternate/additional diagnostic marker for diabesity under OP exposure. However, screening of other environmental co-factors with OP for pancreatic dysregulation is suggested.

Characteristics of Exposure of Reproductive-Age Farmworkers in Chiang Mai Province, Thailand, to Organophosphate and Neonicotinoid Insecticides: A Pilot Study.

Exposure to insecticides containing organophosphate (OP) and neonicotinoid (NEO) compounds has been associated with adverse reproductive health outcomes. This study characterized and identified predictors of exposure to OP and NEO among 100 reproductive-age farmworkers from two intensive farming areas in Chiang Mai Province, Thailand, including 50 each from the Fang (FA) and Chom Thong (CT) districts. OP exposure was determined by measuring the urinary concentrations of six dialkylphosphates (DAPs), whereas NEO exposure was determined by measuring the urinary concentrations of NEO compounds and their metabolites (NEO/m). The most frequently detected OPs were diethylphosphate (DEP) and diethylthiophosphate (DETP), with DETP having the highest geometric mean (GM) concentration, 8.9 μg/g-creatinine. The most frequently detected NEO/m were N-desmethyl-acetamiprid (N-dm-ACE), imidacloprid (IMI), and thiamethoxam (THX), with IMI having the highest GM concentration, 8.7 μg/g-creatinine. Consumption of well water was the predominant determinant of OP and NEO exposure in this population. In addition to encouraging workers to use personal protective equipment, exposure of farmworkers to these compounds may be reduced by nation-wide monitoring agricultural insecticides and other pesticides in community drinking water resources.

Metabolome-wide association study of organophosphate pesticide exposure

Background: Organophosphates (OP) are widely used insecticides that acutely inhibit acetylcholinesterase enzyme activity. There is great interest in improving the understanding of molecular mechanisms related to chronic OP exposure induced toxicity. We aim to elucidate metabolomic changes associated with OP exposure using high-resolution metabolomics (HRM).Methods: In a population-based case control study of Parkinson's disease (PD), we retrieved serum samples of 178 controls and assessed ambient OP exposure via residential and workplace proximity to commercial applications for each subject. We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares regression to select metabolic features associated with OP exposure. Pathway analyses were employed to identify biologic pathways related to OP exposure. Confounders including age, race/ethnicity, sex were controlled a prior.Results: In total we extracted 8,615 and 4,124 metabolic features from serum samples in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 (negative ion mode) columns, respectively. Controlling for confounding factors, 151 and 50 discriminatory metabolic features (HILIC and C18, respectively) were selected (Variable Importance in Projection (VIP) &gt;= 2). Pathway enrichment analysis for discriminatory features associated with OP indicated that in serum fatty acid oxidation and inflammation related pathways were altered, including arachidonic acid, leukotriene, and prostaglandin pathways.Conclusion: This study finds chronic low-level OP exposure is associated with differential metabolomic profiles in serum. Our study results suggest that long-term sub-acute OP exposure influences metabolites enriched for oxidative stress and inflammation pathways.

Prenatal exposure to organophosphate pesticides and longitudinally assessed executive function and attention in childhood and early adolescence

Background: Neurobehavioral functions governed by the prefrontal cortex, including executive function and attention, impact children’s academic and socioeconomic attainment into adulthood. Pesticide exposures may affect these functions. Objective: To investigate whether prenatal exposure to organophosphate (OP) pesticides is associated with children’s executive functioning and attention at ages 7 to 12 years. Methods: We measured dialkyl phosphates (DAPs), metabolites of OP pesticides, in urine samples collected from pregnant women participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a population-based cohort study conducted in an agricultural region of California. We assessed executive functioning and attention via maternal report on behavior and standardized assessments of children. We estimated associations of prenatal OP exposure with these outcomes, longitudinally assessed at ages 7, 9, 10.5 and 12 years (n=310 to 341, depending on the time point), adjusting for sociodemographic factors, home learning environment, and maternal receptive language skills and depressive symptoms. Results: Higher prenatal total DAP concentrations (geometric mean (SD) = 130.3 (2.7)) were associated with more parent-reported executive function and attention problems and poorer performance on child assessment measures. For example, a 10-fold increase in prenatal DAP concentrations was associated with a 3.7 point (95% CI 1.8, 5.6) increase in Behavior Rating Inventory of Executive Function Global Executive Composite T-scores and a 3.9 point reduction (95% CI: -6.4, -1.3) in Weschler Intelligence Scales for Children-IV Working Memory scores. Associations were driven primarily by dimethyl phosphates, which are considerably higher than diethyl phosphates in CHAMACOS. In addition, DAP-related associations with parent-reported behavior were stronger in boys than in girls. Discussion: OP pesticide metabolite concentrations during pregnancy were associated with poorer executive functioning and attention at school age and into adolescence. Reducing prenatal exposure to OP pesticides through public health interventions and policy is an important goal.

Oxidative Stress and Analysis of Selected SNPs of ACHE (rs 2571598), BCHE (rs 3495), CAT (rs 7943316), SIRT1 (rs 10823108), GSTP1 (rs 1695), and Gene GSTM1, GSTT1 in Chronic Organophosphates Exposed Groups from Cameroon and Pakistan.

The detrimental effects of organophosphates (OPs) on human health are thought to be of systemic, i.e., irreversible inhibition of acetylcholinesterase (AChE) at nerve synapses. However, several studies have shown that AChE inhibition alone cannot explain all the toxicological manifestations in prolonged exposure to OPs. The present study aimed to assess the status of antioxidants malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) (reduced), catalase, and ferric reducing antioxidant power (FRAP) in chronic OP-exposed groups from Cameroon and Pakistan. Molecular analysis of genetic polymorphisms (SNPs) of glutathione transferases (GSTM1, GSTP1, GSTT1), catalase gene (CAT, rs7943316), sirtuin 1 gene (SIRT1, rs10823108), acetylcholinesterase gene (ACHE, rs2571598), and butyrylcholinesterase gene (BCHE, rs3495) were screened in the OP-exposed individuals to find the possible causative association with oxidative stress and toxicity. Cholinesterase and antioxidant activities were measured by colorimetric methods using a spectrophotometer. Salting-out method was employed for DNA extraction from blood followed by restriction fragment length polymorphism (RFLP) for molecular analysis. Cholinergic enzymes were significantly decreased in OP-exposed groups. Catalase and SOD were decreased and MDA and FRAP were increased in OP-exposed groups compared to unexposed groups in both groups. GSH was decreased only in Pakistani OPs-exposed group. Molecular analysis of ACHE, BCHE, Catalase, GSTP1, and GSTM1 SNPs revealed a tentative association with their phenotypic expression that is level of antioxidant and cholinergic enzymes. The study concludes that chronic OPs exposure induces oxidative stress which is associated with the related SNP polymorphism. The toxicogenetics of understudied SNPs were examined for the first time to our understanding. The findings may lead to a newer area of investigation on OPs induced health issues and toxicogenetics.

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine.

Organophosphate (OP) exposure induces status epilepticus (SE), a medical emergency with high morbidity and mortality. Current standard medical countermeasures lose efficacy with time so that treatment delays, in the range of tens of minutes, result in increasingly poor outcomes. As part of the Countermeasures Against Chemical Threats Neurotherapeutics Screening Program, we previously developed a realistic model of delayed treatment of OP-induced SE using the OP diisopropyl fluorophosphate (DFP) to screen compounds for efficacy in the termination of SE and elimination of neuronal death. Male rats were implanted for electroencephalogram (EEG) recordings 7 days prior to experimentation. Rats were then exposed to DFP, and SE was induced for 60 minutes and then treated with midazolam (MDZ) plus one of three antiseizure drugs (ASDs)-phenobarbital (PHB), memantine (MEM), or dexmedetomidine (DMT)-in conjunction with antidotes. EEG was recorded for 24 hours, and brains were stained with Fluoro-Jade B for quantification of degenerating neurons. We found that PHB + MDZ induced a prolonged suppression of SE and reduced neuronal death. MEM + MDZ treatment exacerbated SE and increased mortality; however, surviving rats had fewer degenerating neurons. DMT + MDZ significantly suppressed SE with only a minimal reduction in neuronal death. These data demonstrate that delayed treatment of OP-induced SE with other ASDs, when added to MDZ, can achieve greater seizure suppression with additional reduction in degenerating neurons throughout the brain compared with MDZ alone. The effect of a drug on the severity of seizure activity did not necessarily determine the drug's effect on neuronal death under these conditions. SIGNIFICANCE STATEMENT: This study assesses the relative effectiveness of three different delayed-treatment regimens for the control of organophosphate-induced status epilepticus and reduction of subsequent neuronal death. The data demonstrate the potential for highly effective therapies despite significant treatment delay and a potential disconnect between seizure severity and neuronal death.

Cholinesterase Inhibition and Exposure to Organophosphate Esters in Aircraft Maintenance Workers.

INTRODUCTION: Aircraft maintenance workers may be exposed to organophosphates in hydraulic fluid and engine oil. Previous research has indicated that inhalation may not be the primary exposure route. This study sought to measure dermal contact and inhalation in conjunction with cholinesterase inhibition and determine if Air Force Specialty Code serves as an exposure predictor.METHODS: Aircraft maintenance workers were sampled for changes in acetylcholinesterase and butyrylcholinesterase. Dermal contact was measured using wrist-worn silicone passive dosimeters and inhalation exposure was measured using thermal desorption tube air sampling.RESULTS: Overall prevalence of any cholinesterase inhibition in the study population was 25.33%. Prevalence of inhibition of acetylcholinesterase and butyrylcholinesterase was 18.67% and 6.67%, respectively. The mean tributyl phosphate result was 1.71 ng of tributyl phosphate per gram of wristband (ng g1) [95% confidence interval (CI): 5.63, 9.05]. Triphenyl phosphate was more prevalent, with only one sample below the limit of detection (mean 1386.26 ng g1; 95% CI: 7297.78, 10,070.31), and tricresyl phosphate was found in every sample (mean 4311.65 ng g1; 95% CI: 8890.24, 17,512.31). No organophosphates were detected via air sampling.DISCUSSION: Workers experienced organophosphate exposure and cholinesterase inhibition, but the study was not large enough to establish a statistically significant association between exposure and disease. Exposure to organophosphate esters is more likely to occur through contact and absorption of chemicals through the skin than through inhalation of oil mists. Air Force Specialty Code does not appear to be a good predictor of exposure to organophosphates. Future studies should consider using a larger sample size.Hardos JE, Rubenstein M, Pfahler S, Sleight T. Cholinesterase inhibition and exposure to organophosphate esters in aircraft maintenance workers. Aerosp Med Hum Perform. 2020; 91(9):710714.

Quantitative T2 MRI is predictive of neurodegeneration following organophosphate exposure in a rat model

Organophosphorus compounds, such as chemical warfare nerve agents and pesticides, are known to cause neurological damage. This study measured nerve agent-related neuropathology and determined whether quantitative T2 MRI could be used as a biomarker of neurodegeneration. Quantitative T2 MRI was performed using a 9.4 T MRI on rats prior to and following soman exposure. T2 images were taken at least 24 h prior, 1 h and 18–24 h after soman exposure. Rats were pre- and post-treated with HI-6 dimethanesulfonate and atropine methyl nitrate. A multicomponent T2 acquisition and analysis was performed. Brains were stained with Fluoro-Jade C to assess neurodegeneration. Rats exposed to soman developed behavioral expression of electrographic seizures. At 18–24 h after soman exposure, significant increases in T2, a possible marker of edema, were found in multiple regions. The largest changes were in the piriform cortex (before: 47.7 ± 1.4 ms; 18–24 h: 82.3 ± 13.4 ms). Fluoro-Jade C staining showed significant neurodegeneration 18–24 h post exposure. The piriform cortex had the strongest correlation between the change in relaxation rate and percent neurodegeneration (r = 0.96, p < 0.001). These findings indicate there is regionally specific neurodegeneration 24 h after exposure to soman. The high correlation between T2 relaxivity and histopathology supports the use of T2 as a marker of injury.

Glycosylated-imidazole aldoximes as reactivators of pesticides inhibited AChE: Synthesis and in-vitro reactivation study

The present armamentarium of commercially available antidotes provides limited protection against the neurological effects of organophosphate exposure. Hence, there is an urgent need to design and develop molecules that can protect and reactivate inhibited-AChE in the central nervous system. Some natural compounds like glucose and certain amino acids (glutamate, the anion of glutamic acid) can easily cross the blood brain barrier although they are highly polar. Glucose is mainly transported by systems like glucose transporter protein type 1 (GLUT1). For this reason, a series of non-quaternary and quaternary glycosylated imidazolium oximes with different alkane linkers have been designed and synthesized. These compounds were evaluated for their in-vitro reactivation ability against pesticide (paraoxon-ethyl and paraoxon-methyl) inhibited-AChE and compared with standards antidote AChE reactivators pralidoxime and obidoxime. Several physicochemical properties including acid dissociation constant (pKa), logP, logD, HBD and HBA, have also been assessed for reported compounds. Out of the synthesized compounds, three have exhibited comparable potency with a standard antidote (pralidoxime).

Broad Spectrum Treatment for Ocular Insult Induced by Organophosphate Chemical Warfare Agents.

Warfare organophosphates nerve agents constitute one of the prime threats to mankind on the battlefield and in the scenario of civilian terror. Exposure toorganophosphate (OP) nerve agents dose-dependently result in incapacitation. They affect multiple organs, but the eye is one of the first and most frequently affected. Ocular OP insult may result in long-term miosis, impaired visual function, and ocular pain thus inducing functional incapacitation. The currently recommended military medical doctrine of using 1% atropine eye drops is far from being the optimal treatment. Although effective in reducing ocular pain and the miotic response, this treatment induces long-term mydriasis and cycloplegia promoting photophobia and restricted accommodation, which may result in further impairment in visual function. An optimal treatment must ameliorate the long-term ocular insult enabling rapid return of normal visual function, while avoiding the induction of mydriasis and cycloplegia side effects, which could possibly worsen the visual performance. Optimal treatment should also keep effects of misuse to a minimum. Work done in recent years examined treatments with various anticholinergic drugs alone or used in combination with oxime treatments and may offer improved efficacy in ameliorating the ocular insult. This review is a summary of the applied research in animals and will discuss clinical implications and possible alterations in treatment protocols following OP exposure. Taken together the data points toward the use of topical low concentrations of potent anticholinergic ophthalmic drops such as atropine or homatropine, which rapidly ameliorate the long-term OP-induced ocular insult.

Molecular mechanisms for the antidepressant-like effects of a low-dose ketamine treatment in a DFP-based rat model for Gulf War Illness

Exposure to organophosphates (OP) during the First Gulf War is among one of the factors for Gulf War Illness (GWI) development in veterans and it has been challenging to treat GWI symptoms with existing therapies. Ketamine produces a rapid-onset and sustained antidepressant response, but there is no evidence whether ketamine treatment is effective for GWI depression. Repeated, low-dose exposure to diisopropyl fluorophosphate (DFP) mimic Gulf War related OP exposures and produces a chronic depressive state in rats. In this study, DFP-exposed rats treated with ketamine (10 mg/kg, i.p.) exhibited antidepressant-like effect on the Forced Swim Test at 1-h. This effect persisted at 24-h post ketamine, a time-point by which it is eliminated from the brain suggesting involvement of mechanisms that affect long-term synaptic plasticity. Western blot analysis showed significantly lower Brain-Derived Neurotrophic Factor (BDNF) levels in DFP rat brains. Ketamine produced a nonsignificant increase in BDNF expression at 1-h but produced a larger, significant (2.2-fold) increase at 24-h in DFP rats. We previously reported chronic hippocampal calcium elevations ([Ca2+]i) in DFP rats. Ketamine-treated DFP rats exhibited significantly lower [Ca2+]i at 1-h but not at 24-h. Interestingly, treatment with ANA-12, a TrkB-BDNF receptor antagonist, in DFP rats blunted ketamine’s antidepressant-like effect at 24-h but not at 1-h. These experiments suggest that in a rat model of DFP-induced depression, inhibition of the NMDAR-Ca2+ contributes to the rapid-onset antidepressant effects of ketamine while the antidepressant actions that persisted at 24-h post ketamine administration involve upregulation of BDNF signaling.