A single post-exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides.

Millions of individuals globally suffer from inadvertent, occupational or self-harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP-inhibited AChE. However, animal model studies and recent clinical trials using insecticide-poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood-brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP-inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post-exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1-2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non-invasive treatment, especially in isolated rural settings.

Acute myocardial infarction: can it be a complication of acute organophosphorus compound poisoning?

Organophosphorus compounds are used as pesticides and represent a common cause of poisoning in developing countries including India due to their widespread availability and use. Toxicity due to these agents can affect many organs including heart. Here, we report a case of acute organophosphorus poisoning (parathion), followed by acute myocardial infarction; documented by clinical features, electrocardiographic changes, and elevated cardiac enzymes. Myocardial infarction has been rarely reported with organophosphorus compounds exposure, thus awareness of this complication can reduce morbidity and mortality.

What may be happen after an organophosphate exposure: acute myocardial infarction?

The increase in accidental organophosphate poisoning as well as the rise in the number of cases of suicide attempts with organophosphate compounds is due to primarily to the widespread use of these compounds in agriculture. Organophosphates are anti-acetycholinesterase agents and their toxicity affects many organs, including the pancreas, liver and heart. Cardiac complications often accompany poisoning with these compounds and may be serious and often fatal. However, little is known about the myocardial infarction risk associated with exposure to pesticides. Herein, a rare case of acute myocardial infarction due to acute exposure to organophosphate compound is documented with electrocardiogram, enzyme and clinical characteristics in this report.

An unusual case of attempted suicide by rectal administration of parathion.

Although organophosphate (OP) poisoning is well known, unusual routes of administration of OP compounds are reported occasionally. Herein, a case of self administration of parathion, an OP compound, into the rectum using a six inches (15 cm) nozzle of a sprayer in a 35-year-old man is highlighted along with probable mechanisms for rapid absorption and severe systemic toxicity.

Prior exposure to immunosuppressive organophosphorus or organochlorine compounds aggravates the T(H)1- and T(H)2-type allergy caused by topical sensitization to 2,4-dinitrochlorobenzene and trimellitic anhydride.

Immunosuppressive environmental chemicals may increase the potency of allergens and thereby play a role in the development of allergic diseases. This study's primary objective was to examine the mechanisms behind the relationship between allergic diseases and the immunosuppression induced by some environmental chemicals. We focused on the modulation of allergic potential in vitro and in mice by the organophosphorus pesticide O,O-diethyl-O-4-nitrophenyl-thiophosphate (parathion) and the organochlorine pesticide 1,1,1-trichloro-2,2-bis(4-methoxy-phenyl)ethane (methoxychlor), with respect to the T(H)1-type allergen 2,4-dinitrochlorobenzene (DNCB) and the T(H)2-type allergen trimellitic anhydride (TMA). Mice (4-week-old) were orally administered parathion or methoxychlor. Four weeks after the final dosing, the mice were sensitized to DNCB or TMA, and T-lymphocyte proliferation measured in their (using a local lymph node assay [LLNA]). In addition, we analyzed T-lymphocytes via surface antigen expression and local cytokine production in auricular lymph nodes after treatment with 0.1% DNCB or 0.3% TMA. The estimated concentration of DNCB and TMA to yield a stimulation index (SI) of cell proliferation of three decreased markedly in parathion- and methoxychlor-pre-treated mice. Pesticide pre-treatment induced marked increases in the number of helper and cytotoxic T-cells, levels of T(H)1 and T(H)2 cytokines, and gene expression in lymph node cells. According to our results, T(H)1- and T(H)2-type allergies are aggravated by prior exposure to immunosuppressive environmental chemicals.

Neonatal organophosphorus pesticide exposure alters the developmental trajectory of cell-signaling cascades controlling metabolism: differential effects of diazinon and parathion.

BACKGROUND: Organophosphorus pesticides (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism. OBJECTIVES/METHODS: We administered diazinon (DZN) or parathion (PRT) to rats on postnatal days 14 at doses straddling the threshold for systemic signs of exposure and assessed the effects on hepatic and cardiac cell signaling mediated through the adenylyl cyclase (AC) cascade. RESULTS: In the liver, DZN elicited global sensitization, characterized by parallel up-regulation of AC activity itself and of the responses to stimulants acting at beta-adrenergic receptors, glucagon receptors, or G-proteins. The effects intensified over the course from adolescence to adulthood. In contrast, PRT elicited up-regulation in adolescence that waned by adulthood. Superimposed on these general patterns were effects on glucagon receptor coupling to AC and on responses mediated through the Gi inhibitory protein. The effects on the liver were more substantial than those in the heart, which displayed only transient effects of DZN on AC function in adolescence and no significant effects of PRT. Furthermore, the hepatic effects were greater in magnitude than those in a brain region (cerebellum) that shares similar AC cascade elements. CONCLUSIONS: These findings indicate that OPs alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction. Notably, the various OPs differ in their net impact on peripheral AC signaling, making it unlikely that the effects on signaling reflect their shared property as cholinesterase inhibitors.

Children's exposure to chlorpyrifos and parathion in an agricultural community in central Washington State.

We measured two diethyl organophosphorus (OP) pesticides--chlorpyrifos and parathion--in residences, and their metabolic by-products, in the urine of children 6 years old or younger in a central Washington State agricultural community. Exposures to two dimethyl OP pesticides (azinphos-methyl and phosmet) in this same population have been reported previously. We categorized children by parental occupation and by household proximity to pesticide-treated farmland. Median chlorpyrifos house dust concentrations were highest for the 49 applicator homes (0.4 microg/g), followed by the 12 farm-worker homes (0.3 microg/g) and the 14 nonagricultural reference homes (0.1 microg/g), and were statistically different (p < 0.001); we observed a similar pattern for parathion in house dust. Chlorpyrifos was measurable in the house dust of all homes, whereas we found parathion in only 41% of the homes. Twenty-four percent of the urine samples from study children had measurable 3,5,6-trichloro-2-pyridinol (TCPy) concentrations [limits of quantitation (LOQ) = 8 microg/L], and 7% had measurable 4-nitrophenol concentrations (LOQ = 9 microg/L). Child urinary metabolite concentrations did not differ across parental occupational classifications. Homes in close proximity (200 ft/60 m) to pesticide-treated farmland had higher chlorpyrifos (p = 0.01) and parathion (p = 0.014) house dust concentrations than did homes farther away, but this effect was not reflected in the urinary metabolite data. Use of OP pesticides in the garden was associated with an increase in TCPy concentrations in children's urine. Parathion concentrations in house dust decreased 10-fold from 1992 to 1995, consistent with the discontinued use of this product in the region in the early 1990s.

Protein binding of isofluorophate in vivo after coexposure to multiple chemicals.

Full toxicologic profiles of chemical mixtures, including dose-response extrapolations to realistic exposures, is a prohibitive analytical problem, even for a restricted class of chemicals. We present an approach to probing in vivo interactions of pesticide mixtures at relevant low doses using a monitor compound to report the response of biochemical pathways shared by mixture components. We use accelerator mass spectrometry (AMS) to quantify [14C]-diisopropylfluorophosphate as a tracer at attomole levels with 1-5% precision after coexposures to parathion (PTN), permethrin (PER), and pyridostigmine bromide separately and in conjunction. Pyridostigmine shows an overall protective effect against tracer binding in plasma, red blood cells, muscle, and brain that is not explained as competitive protein binding. PTN and PER induce a significant 25-30% increase in the amount of tracer reaching the brain with or without pyridostigmine. The sensitivity of AMS for isotope-labeled tracer compounds can be used to probe the physiologic responses of specific biochemical pathways to multiple compound exposures.

Parathion, a cholinesterase-inhibiting plaguicide induces changes in tertiary villi of placenta of women exposed: a scanning electron microscopy study.

The objective of this work was to describe the anatomy of placentas from women who were at risk of exposure to parathion during their pregnancy, when examined with the light and scanning electron microscopes. Twenty term placentas were analyzed; 10 from women living in an agricultural area, who were at risk of exposure to parathion during their pregnancy, and 10 from women living in an urban area, not expressly exposed to pesticides. Each sample was examined with both light and scanning electron microscopes. Cholinesterase activity was significantly reduced in blood from women of the exposed group. In some placentas of women exposed to parathion, recent microinfarctions, microcalcifications and increased deposition of fibrinoid material were seen, along with a larger proportion of atypical characteristics of villi, such as bullous and balloon-like formations with nonhomogeneous surface, and other areas devoid of microvilli. These observations suggest that in chronic exposure to pesticides, the rate of atypical characteristics of placental villi increases, which could be related to changes in the fetus biology. In this study, one newborn from the exposed group showed intrauterine growth retardation and another one, some signs of hypoxia.

Effects of parathion on acetylcholinesterase, butyrylcholinesterase, and carboxylesterase in three-spined stickleback (Gasterosteus aculeatus) following short-term exposure.

The sensitivity of butyrylcholinesterase (BChE) toward the inhibition by the organophosphorus insecticide (OP) parathion-ethyl was compared with that of other esterases in the fish three-spined stickleback. Earlier field and in vitro results had suggested the higher sensitivity to OPs of stickleback BChE when compared with acetylcholinesterase (AChE). In the present study, stickleback were exposed in vivo under environmentally realistic conditions using a short duration of exposure (1 h) and parathion concentrations of 0.01, 0.1, and 1.0 microgram/L. Seventy and 80% of nominal concentrations, respectively, were measured in the 0.01 and 0.1 microgram/L treatments. Following exposure, stickleback were maintained in clean water for 48 h (recovery), allowing the metabolic activation of parathion. After recovery, the activities of BChE (axial muscle, gills, liver), AChE (brain, axial muscle, gills), and carboxylesterase (CaE, liver) were determined. Following exposure to 1 microgram/L parathion, the BChE activity was significantly decreased in liver (approximately 60%) and axial muscle (approximately 30%), while its decrease in gills (approximately 30%) was not significant. No effects on BChE activity were observed with 0.1 and 0.01 microgram/L parathion. The AChE and CaE activities remained unaffected with all parathion concentrations used. The results are discussed with respect to the potential application of stickleback BChE as a biomarker of OP exposure.

Efectos de paratión sobre la síntesis proteica testicular / Parathion effects in testicular protein synthesis

El paratión como insecticida de uso masivo en la agricultura, puede afectar el potencial reproductivo de la población humana y animal expuesta. Sus propiedades bioquímicas potencialmente alteral los mecanismos de síntesis proteica testicular, afectando la morfofuncionalidad del aparato reproductor. El objetivo del presente trabajo, es cuantificar la síntesis de proteínas testicular, bajo la presencia de paratión, en ratón CF1, in vitro. Se cultivaron túbulos seminífero de ratones CF-1 e incubaron con concentraciones decrecientes (0,4; 0,04 y 0,004 mM) de paratión (PT) por 4 horas. Leucina tritiada (2 µ Ci) fue agregada después de una hora. Posteriormente se evaluó la síntesis proteica como actividad específica (cpm/µgr proteínas). Los resultados mostraron que el paration induce inhibición significativa de la síntesis proteica en la concentración 0,4 mM, mientras que a dosis menores de paratión disminuye el efecto sobre la inhibición de la síntesis de proteínas

Occupational pesticide exposure and semen quality among Chinese workers.

This study investigated the association between occupational pesticide exposure and semen quality among Chinese workers. Male workers, 32 who were exposed to organophosphate pesticides and 43 who were not exposed were recruited from two nearby factories and interviewed. Following a work shift, semen and urine samples were collected for pesticide metabolite analysis. Semen samples were analyzed for sperm concentration, percentage of motility, and percentage of normal structure. Within the exposed group, the mean end-of-shift urinary p-nitrophenol levels were 0.22 and 0.15 mg/L for the high- and low-exposure subgroups, respectively. Linear regression analysis of individual semen parameters revealed a significant reduction of sperm concentration (35.9 x 10(6) vs 62.8 x 10(6), p < 0.01) and percentage of motility (47% vs 57%, p = 0.03) but not percentage of sperm with normal structure (57% vs 61%, p = 0.13). Multivariate modeling showed a significant overall shift in the mean semen parameter. Occupational exposure to ethylparathion and methamidophos seems to have a moderately adverse effect on semen quality.

Influencias de medidas regulatorias en la morbilidad y mortalidad por Talio y Parathion en Rosario, Argentina / The influence of regulatory steps in the morbility and mortality due to thallium and parathion in Rosario, Argentina

La expanción en el uso de plaguicidas en los últimos 50 años ha sido acompañada por la introducción de regulaciones tendientes a garantizar la seguridad de usuarios, consumidores y medio ambiente. El objeto de este trabajo es mostrar la disminución o supresión de las intoxicacionespor talio y parathion atendidas en Rosario luego de las medidas de prohibición del uso de dichos plaguicidas. En una revisión sobre 1343 intoxicaciones agudas con plaguicidas atendidas en Rosario entre 1977 y 1985, el 25,5 por ciento corresponde a pacientes intoxicados con talio de raticidas (desde 32,6 por ciento en 1977 hasta 7,1 por ciento en 1985) y luego practicamente desaparecen ( la última intoxicación registrada ocurrió en 1990). Nueve de los 10 casos letales por AP entre 1977 y 1985 y 8 de 11 casos letales por AP en el período 1990-1994 corresponden a intoxicacion por parathion. La última intoxicación por talio representaron un problema sanitario grave no sólo por su elevada incidencia sino tambien por la complejidad de los cuadros clínicos y la dudosa eficacia de las medidas terapéuticas disponibles. La gravedad de las intoxicaciones por parathion determinaron la inclusión de variantes en el tratamiento. En las dos situaciones consideradas, la prohibición de su uso determinó un rápido descenso en la morbilidad y mortalidad y las sustancias alternativas a su uso (anticuagulantes y otros compuestos organofosforados anticolinesterasa), si bien no son inocuas, tienen un margen de seguridad más aceptable incluyendo el uso inapropiado

The role of metabolism in determining susceptibility to parathion toxicity in man.

Human liver microsomes (n = 16) activated parathion (O, O, diethyl O-p-nitrophenyl phosphorothioate, 20 and 200 microM) to paraoxon at a rate of 23.3-199.3 and 18.7-310.3 pmol/min per mg protein, respectively. p-Nitrophenol, was also formed, at 321.1-769.2 and 406.2-778.3 pmol/min per mg protein. This represented a 16-fold and 2-fold range in capacity to activate and detoxify parathion, respectively. Parathion was activated with an apparent Km of 9-16 microM (n = 3). The activation of parathion (200 microM) was positively correlated with nifedipine oxidation, indicating the involvement of CYP3A. Correlations were not significant with ethoxyresorufin-O-dealkylation (CYP1A1/2), pentoxyresorufin-O-dealkylation (CYP2B6), p-nitrophenol hydroxylation (CYP2E1), paraoxon hydrolysis (A-esterase) or phenylvalerate hydrolysis (B-esterase). Paraoxon formation from parathion was markedly reduced by CYP3A inhibitors. Experiments with EDTA indicated that A-esterase was not functionally important at low levels of paraoxon. Human P450s 3A4 and 3A5 expressed microsomes were the most efficient at biotransforming parathion to paraoxon, although P450s 1A1, 2B6 and 2C8 also catalysed the reaction. This study has determined wide interindividual variations in capacity to metabolise parathion, mainly by CYP3A, which may influence its manifest toxicity.

Sperm aneuploidy among Chinese pesticide factory workers: scoring by the FISH method.

BACKGROUND: A study of the prevalence of sperm aneuploidy among pesticide factory workers was conducted in Anhui, China. METHODS: We recruited 75 men: 32 subjects from a large pesticide-manufacturing plant and 43 subjects from a nearby textile factory free of pesticide exposure. Each subject met the following criteria: age of 20-40 years; continuous work in the plant for 3 months prior to the study, no congenital anomalies or acquired disease of the external genitalia and no history of recent febrile illness or mumps. Within one hour after collection from each subject, semen was evaluated in terms of several parameters and smear slides were prepared. RESULTS: Exposure assessment revealed that workers in the pesticide plant were exposed to ethyl parathion or methamidophos, each of which is a potent organophosphate pesticide, at a median level of 0.02 mg/m3 (8-hour time weighted average as measured by personal pump) while workers in the control plant had no such occupational exposure. Twenty-nine semen slides (13 from the exposed group and 16 from the unexposed group) were randomly chosen for aneuploidy scoring by the three-color fluorescence in situ hybridization (FISH) method with scorers being unaware of exposure status. Median semen parameters were as follows for exposed (and unexposed) men: abstinence period, 3 days (4 days); sperm concentration, 52.8x10(6)/ml (53.1x10(6)/ml); proportion of sperm with normal motility, 50.5% (61.3%); and proportion of sperm with normal morphology, 59% (61.5%). The specific chromosome abnormalities of interest were disomy for chromosome 18 and the three different types of sex chromosome disomy (i.e. XX, XY, YY disomy). The crude proportion of all aneuploidy combined was 0.30% and 0.19% for sperm from exposed and unexposed men, respectively. Poisson regression with overdispersion adjustment yielded significantly different crude risks of aneuploidy - 3.03 and 1.94 per 1,000 sperm from exposed and unexposed men, respectively - giving a rate ratio of 1.56 (95% CI, 1.06-2.31). The regression coefficients remained statistically significant after adjustment for inter-technician variability giving a rate ratio of 1.51 (95% CI, 1. 04-2.20). CONCLUSIONS: We conclude that occupational exposure to organophosphate pesticides moderately increases the prevalence of sperm aneuploidy.

Reproductive hormone profile among pesticide factory workers.

Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels, as well as urinary levels of FSH, LH, and E1C, a metabolite of testosterone, were measured to investigate the adverse reproductive effects of organophosphate pesticides among Chinese factory workers who were occupationally exposed to ethylparathion and methamidophos. Thirty-four exposed workers were randomly chosen and recruited from a large pesticide factory, and 44 unexposed workers were selected from a nearby textile factory. A quantitative pesticide exposure assessment was performed among a subset of the exposed and unexposed workers. Information on potential confounders was collected in an interview. A single blood sample was collected at the end of a work shift, when each subject also donated a semen sample. Three first-voided urine samples were collected from each worker on 3 consecutive days. Urinary p-nitrophenol level at 1 hour after the work shift correlated with serum (r = 0.71, P < 0.01) and urinary (r = 0.51, P = 0.04) FSH levels. Stratifying by the subjects' exposure status, we found a significant negative correlation among the exposed group between urinary FSH level and sperm count (r = -0.61, P < 0.01) and between urinary FSH level and sperm concentration (r = -0.53, P = 0.03). Pesticide exposure alone was significantly associated with serum LH level (beta [coefficient of exposure effect] = 0.79; 95% confidence interval [CI] = 0.42, 1.16) but not with serum FSH or testosterone or with any urinary hormone levels. With adjustment for age, rotating shift work, current cigarette smoking, and current alcohol consumption, exposure significantly increased the serum LH level by 1.1 mIU/mL (95% CI = 0.34, 1.82). Meanwhile, the serum FSH level was slightly elevated (beta [coefficient of exposure effect] = 1.38; 95% CI = -0.09, 2.85) and the serum testosterone level was decreased (beta = -55.13; 95% CI = -147.24, 37) with increased pesticide exposure. Age and rotating shift work appeared to act as confounders. We conclude that organophosphate pesticides have a small effect on male reproductive hormones, suggestive of a secondary hormonal disturbance after testicular damage.

Chromosomal aberrations induced by methyl parathion in human peripheral lymphocytes of alcoholics and smokers.

1 Two different concentrations (0.08 and 0.16 micrograms ml-1) of methyl parathion (MP), a broad-spectrum insecticide, were tested on peripheral lymphocytes of healthy non-smoking non-alcoholics (CN), chronic smokers (SM) and alcoholics with smoking habit (ALSM). 2 SM and ALSM revealed a significant increase in chromosome aberration frequencies in peripheral lymphocytes compared to the CN group. 3 MP did not induce chromosomal aberrations in vitro in the CN group at either of the concentrations tested. 4 In SM and ALSM, MP induced a significant increase in chromosomal aberrations in vitro in peripheral lymphocytes at a concentration of 0.16 micrograms ml-1. 5 The results indicate that the damage induced by MP in peripheral lymphocytes is potentiated by smoking and alcohol intake.

De novo amplification within a "silent" human cholinesterase gene in a family subjected to prolonged exposure to organophosphorous insecticides.

A 100-fold DNA amplification in the CHE gene, coding for serum butyrylcholinesterase (BtChoEase), was found in a farmer expressing the "silent" CHE phenotype. Individuals homozygous for this gene display a defective serum BtChoEase and are particularly vulnerable to poisoning by agricultural organophosphorous insecticides, to which all members of this family had long been exposed. DNA blot hybridization with regional BtChoEase cDNA probes suggested that the amplification was most intense in regions encoding central sequences within BtChoEase cDNA, whereas distal sequences were amplified to a much lower extent. This is in agreement with the "onion skin" model, based on amplification of genes in cultured cells and primary tumors. The amplification was absent in the grandparents but present at the same extent in one of their sons and in a grandson, with similar DNA blot hybridization patterns. In situ hybridization experiments localized the amplified sequences to the long arm of chromosome 3, close to the site where we previously mapped the CHE gene. Altogether, these observations suggest that the initial amplification event occurred early in embryogenesis, spermatogenesis, or oogenesis, where the CHE gene is intensely active and where cholinergic functioning was indicated to be physiologically necessary. Our findings demonstrate a de novo amplification in apparently healthy individuals within an autosomal gene producing a target protein to an inhibitor. Its occurrence in two generations from a family under prolonged exposure to parathion indicates that organophosphorous poisons may be implicated in previously unforeseen long-term ecological effects.