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Neurotoxicology Sep 2018Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNA), are threats to the general population as possible weapons of terrorism or...
Evaluating the broad-spectrum efficacy of the acetylcholinesterase oximes reactivators MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against phorate oxon, sarin, and VX in the Hartley guinea pig.
Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNA), are threats to the general population as possible weapons of terrorism or by accidental exposure whether through inadvertent release from manufacturing facilities or during transport. To mitigate the toxicities posed by these threats, a therapeutic regimen that is quick-acting and efficacious against a broad spectrum of OPs is highly desired. The work described herein sought to assess the protective ratio (PR), median effective doses (ED), and therapeutic index (TI = oxime 24-h LD/oxime ED) of MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against the OPs sarin (GB), VX, and phorate-oxon (PHO). All OPs are representative of the broader classes of G and V chemical warfare nerve agents and persistent pesticides. MMB4 DMS and HLö-7 DMS were previously identified as comparative efficacy leads warranting further evaluations. 2-PAM Cl is the U.S. FDA-approved standard-of-care oxime therapy for OP intoxication. Briefly, PRs were determined in male guinea pigs by varying the subcutaneously (SC) delivered OP dose followed then by therapy with fixed levels of the oxime and atropine (0.4 mg/kg; administered intramuscularly [IM]). EDs were determined using a similar approach except the OP dose was held constant at twice the median lethal dose (2 × LD) while the oxime treatment levels were varied. The ED information was then used to calculate the TI for each OP/oxime combination. Both MMB4 DMS and HLö-7 DMS provided significant protection, i.e., higher PR against GB, VX, and PHO when compared to atropine controls, but significance was not readily demonstrated across the board when compared against 2-PAM Cl. The ED values of MMB4 DMS was consistently lower than that of the other oximes against all three OPs. Furthermore, based on those EDs, the TI trend of the various oximes against both GB and VX was MMB4 DMS > HLö-7 DMS > 2-PAM Cl, while against PHO, MMB4 DMS > 2-PAM Cl > HLö-7 DMS.
Topics: Animals; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Guinea Pigs; Insecticides; Male; Organophosphates; Organothiophosphorus Compounds; Oximes; Phorate; Pralidoxime Compounds; Pyridinium Compounds; Sarin
PubMed: 30056178
DOI: 10.1016/j.neuro.2018.07.014 -
Environment International Sep 2018Little is known about modifiable risk factors for thyroid disease. Several pesticides have been implicated in thyroid disruption, but clinical implications are not clear.
BACKGROUND
Little is known about modifiable risk factors for thyroid disease. Several pesticides have been implicated in thyroid disruption, but clinical implications are not clear.
OBJECTIVE
We assessed associations between pesticide use and other farm exposures and incident hypothyroidism and hyperthyroidism in female spouses of farmers in the Agricultural Health Study (AHS).
METHODS
We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals for risk of thyroid disease in 24,092 spouses who completed at least one follow-up questionnaire.
RESULTS
We identified 1627 hypothyroid and 531 hyperthyroid cases over 20 years of follow-up. The fungicides benomyl, maneb/mancozeb, and metalaxyl, the herbicide pendimethalin, and among those over 60 years of age the insecticides parathion and permethrin (applied to crops) were associated with elevated hypothyroidism risk, with HR ranging from 1.56-2.44. Conversely, the insecticide phorate, and the herbicides imazethapyr and metolachlor were associated with decreased risk (HR ranging 0.63-0.73), as were long-term farm residence and other farm-related activities (HR ranging 0.69-0.84). For hyperthyroidism, the insecticide diazinon, the fungicides maneb/mancozeb, and the herbicide metolachlor were associated with increased risk (HR ranging 1.35-2.01) and the herbicide trifluralin with decreased risk (HR: 0.57).
CONCLUSIONS
Several individual pesticides were associated with increased risk of hypothyroidism and hyperthyroidism, although some pesticides were associated with decreased risk. Some of the findings, specifically associations with fungicides, are consistent with results from an earlier analysis of prevalent diseases in AHS spouses.
Topics: Female; Follow-Up Studies; Humans; Male; Occupational Exposure; Pesticides; Spouses; Surveys and Questionnaires; Thyroid Diseases
PubMed: 29908479
DOI: 10.1016/j.envint.2018.05.041 -
Pesticide Biochemistry and Physiology Feb 2018Phorate is a highly toxic agricultural pesticide currently in use throughout the world. Like many other organophosphorus (OP) pesticides, the primary mechanism of the...
Kinetic analysis of oxime-assisted reactivation of human, Guinea pig, and rat acetylcholinesterase inhibited by the organophosphorus pesticide metabolite phorate oxon (PHO).
UNLABELLED
Phorate is a highly toxic agricultural pesticide currently in use throughout the world. Like many other organophosphorus (OP) pesticides, the primary mechanism of the acute toxicity of phorate is acetylcholinesterase (AChE) inhibition mediated by its bioactivated oxon metabolite. AChE reactivation is a critical aspect in the treatment of acute OP intoxication. Unfortunately, very little is currently known about the capacity of various oximes to rescue phorate oxon (PHO)-inhibited AChE. To help fill this knowledge gap, we evaluated the kinetics of inhibition, reactivation, and aging of PHO using recombinant AChE derived from three species (rat, guinea pig and human) commonly utilized to study the toxicity of OP compounds and five oximes that are currently fielded (or have been deemed extremely promising) as anti-OP therapies by various nations around the globe: 2-PAM Cl, HI-6 DMS, obidoxime Cl, MMB4-DMS, and HLö7 DMS. The inhibition rate constants (k) for PHO were calculated for AChE derived from each species and found to be low (i.e., 4.8×10 to 1.4×10Mmin) compared to many other OPs. Obidoxime Cl was the most effective reactivator tested. The aging rate of PHO-inhibited AChE was very slow (limited aging was observed out to 48h) for all three species.
CONCLUSIONS
(1) Obidoxime Cl was the most effective reactivator tested. (2) 2-PAM Cl, showed limited effectiveness in reactivating PHO-inhibited AChE, suggesting that it may have limited usefulness in the clinical management of acute PHO intoxication. (3) The therapeutic window for oxime administration following exposure to phorate (or PHO) is not limited by aging.
Topics: Acetylcholinesterase; Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Guinea Pigs; Humans; Kinetics; Obidoxime Chloride; Oximes; Pesticides; Phorate; Rats
PubMed: 29482737
DOI: 10.1016/j.pestbp.2018.01.009 -
International Journal of Hygiene and... Apr 2018Occupational studies suggest that exposure to organophosphate insecticides (OPs) can lead to vision or hearing loss. Yet the effects of early-life exposure on visual and...
BACKGROUND
Occupational studies suggest that exposure to organophosphate insecticides (OPs) can lead to vision or hearing loss. Yet the effects of early-life exposure on visual and auditory function are unknown. Here we examined associations between prenatal OP exposure and grating visual acuity (VA) and auditory brainstem response (ABR) during infancy.
METHODS
30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Grating visual acuity (VA) (n = 179-200) and auditory brainstem response (ABR) (n = 139-183) were assessed at 6 weeks, 9 months, and 18 months. Outcomes included VA score, ABR wave V latency and central conduction time, and head circumference (HC). Associations between sensory outcomes during infancy and cord OPs were examined using linear mixed models.
RESULTS
Prenatal chlorpyrifos exposure was associated with lower 9-month grating VA scores; scores were 0.64 (95% CI: -1.22, -0.06) points lower for exposed versus unexposed infants (p = 0.03). The OPs examined were not associated with infant ABR latencies, but chlorpyrifos and phorate were both significantly inversely associated with HC at 9 months; HCs were 0.41 (95% CI: 0.75, 0.6) cm and 0.44 (95% CI: 0.88, 0.1) cm smaller for chlorpyrifos (p = 0.02) and phorate (p = 0.04), respectively.
CONCLUSIONS
We found deficits in grating VA and HC in 9-month-old infants with prenatal exposure to chlorpyrifos. The clinical significance of these small but statistically significant deficits is unclear. However, the disruption of visual or auditory pathway maturation in infancy could potentially negatively affect downstream cognitive development.
Topics: Adult; Chlorpyrifos; Cohort Studies; Developmental Disabilities; Environmental Pollutants; Evoked Potentials, Auditory, Brain Stem; Female; Fetal Blood; Hearing; Hearing Disorders; Humans; Infant; Insecticides; Male; Maternal Exposure; Mothers; Organophosphorus Compounds; Phorate; Pregnancy; Prenatal Exposure Delayed Effects; Sensation; Vision Disorders; Vision, Ocular; Visual Acuity
PubMed: 29402694
DOI: 10.1016/j.ijheh.2018.01.010 -
Environmental Health Perspectives Jul 2017Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries. Few studies have investigated its relationship to environmental...
BACKGROUND
Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries. Few studies have investigated its relationship to environmental neurotoxicants. In previous cross-sectional studies, we found an association between pesticide use and self-reported retinal degeneration.
OBJECTIVE
We evaluated the association of pesticide use with physician-confirmed incident AMD.
METHODS
The Agricultural Health Study (AHS) is a prospective cohort of pesticide applicators and their spouses enrolled from 1993-1997 in Iowa and North Carolina. Cohort members reported lifetime use of 50 specific pesticides at enrollment. Self-reports of incident AMD during follow-up through 2007 were confirmed by reports from participants' physicians and by independent evaluation of retinal photographs provided by the physicians. Confirmed cases (=161) were compared with AHS cohort members without AMD (=39,108). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression with adjustment for age, gender, and smoking.
RESULTS
AMD was associated with ever use of organochlorine [OR=2.7 (95% CI: 1.8, 4.0)] and organophosphate [OR=2.0 (95% CI: 1.3, 3.0)] insecticides and phenoxyacetate herbicides [OR=1.9 (95% CI: 1.2, 2.8)]. Specific pesticides consistently associated with AMD included chlordane, dichlorodiphenyltrichloroethane (DDT), malathion, and captan; others with notable but slightly less consistent associations were heptachlor, diazinon, phorate, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and 2,4-dichlorophenoxyacetic acid (2,4-D). Results were similar for men and women. Some specific pesticides were associated with both early- and late-stage AMD, but others were associated with only one stage.
CONCLUSIONS
Exposures to specific pesticides may be modifiable risk factors for AMD. https://doi.org/10.1289/EHP793.
Topics: Aged; Aged, 80 and over; Agricultural Workers' Diseases; Case-Control Studies; Female; Humans; Incidence; Iowa; Logistic Models; Macular Degeneration; Male; Middle Aged; North Carolina; Occupational Exposure; Pesticides; Prospective Studies; Risk Factors
PubMed: 28886597
DOI: 10.1289/EHP793 -
Environment International Sep 2017Organophosphate insecticides (OPs) are used worldwide, yet despite nearly ubiquitous exposure in the general population, few have been studied outside the laboratory....
BACKGROUND
Organophosphate insecticides (OPs) are used worldwide, yet despite nearly ubiquitous exposure in the general population, few have been studied outside the laboratory. Fetal brains undergo rapid growth and development, leaving them susceptible to long-term effects of neurotoxic OPs. The objective here was to investigate the extent to which prenatal exposure to OPs affects infant motor development.
METHODS
30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Motor function was assessed at 6-weeks and 9-months using Peabody Developmental Motor Scales 2nd edition (PDMS-2) (n=199). Outcomes included subtest scores: reflexes, stationary, locomotion, grasping, visual-motor integration (V-M), composite scores: gross (GM), fine (FM), total motor (TM), and standardized motor quotients: gross (GMQ), fine (FMQ), total motor (TMQ).
RESULTS
Naled, methamidophos, trichlorfon, chlorpyrifos, and phorate were detected in ≥10% of samples. Prenatal naled and chlorpyrifos were associated with decreased 9-month motor function. Scores were 0.55, 0.85, and 0.90 points lower per 1ng/mL increase in log-naled, for V-M (p=0.04), FM (p=0.04), and FMQ (p=0.08), respectively. For chlorpyrifos, scores were 0.50, 1.98, 0.80, 1.91, 3.49, 2.71, 6.29, 2.56, 2.04, and 2.59 points lower for exposed versus unexposed infants, for reflexes (p=0.04), locomotion (p=0.02), grasping (p=0.05), V-M (p<0.001), GM (p=0.007), FM (p=0.002), TM (p<0.001), GMQ (p=0.01), FMQ (p=0.07), and TMQ (p=0.008), respectively. Girls appeared to be more sensitive to the negative effects of OPs on 9-month motor function than boys.
CONCLUSIONS
We found deficits in 9-month motor function in infants with prenatal exposure to naled and chlorpyrifos. Naled is being aerially sprayed to combat mosquitoes carrying Zika virus, yet this is the first non-occupational human study of its health effects. Delays in early-motor skill acquisition may be detrimental for downstream development and cognition.
Topics: China; Chlorpyrifos; Cohort Studies; Developmental Disabilities; Female; Fetal Blood; Humans; Infant; Infant, Newborn; Insecticides; Male; Motor Skills; Naled; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 28602489
DOI: 10.1016/j.envint.2017.05.015 -
PloS One 2017The UK's Initial Operational Response (IOR) is a revised process for the medical management of mass casualties potentially contaminated with hazardous materials. A...
The UK's Initial Operational Response (IOR) is a revised process for the medical management of mass casualties potentially contaminated with hazardous materials. A critical element of the IOR is the introduction of immediate, on-scene disrobing and decontamination of casualties to limit the adverse health effects of exposure. Ad hoc cleansing of the skin with dry absorbent materials has previously been identified as a potential means of facilitating emergency decontamination. The purpose of this study was to evaluate the in vitro oil and water absorbency of a range of materials commonly found in the domestic and clinical environments and to determine the effectiveness of a small, but representative selection of such materials in skin decontamination, using an established ex vivo model. Five contaminants were used in the study: methyl salicylate, parathion, diethyl malonate, phorate and potassium cyanide. In vitro measurements of water and oil absorbency did not correlate with ex vivo measurements of skin decontamination. When measured ex vivo, dry decontamination was consistently more effective than a standard wet decontamination method ("rinse-wipe-rinse") for removing liquid contaminants. However, dry decontamination was ineffective against particulate contamination. Collectively, these data confirm that absorbent materials such as wound dressings and tissue paper provide an effective, generic capability for emergency removal of liquid contaminants from the skin surface, but that wet decontamination should be used for non-liquid contaminants.
Topics: Animals; Decontamination; Female; Malonates; Mass Casualty Incidents; Parathion; Phorate; Potassium Cyanide; Salicylates; Skin Absorption; Swine; United Kingdom
PubMed: 28152053
DOI: 10.1371/journal.pone.0170966 -
Pest Management Science Jan 2017Rice is a major field crop of paramount importance for global food security. However, the increased adoption of more profitable and resource-efficient direct-seeded rice...
BACKGROUND
Rice is a major field crop of paramount importance for global food security. However, the increased adoption of more profitable and resource-efficient direct-seeded rice (DSR) systems has contributed to greater weed infestations, including weedy rice, which has become a severe problem in several Asian regions. In this study we have developed a conceptually novel method to protect rice plants at high doses of clomazone and triallate.
RESULTS
The insecticide phorate applied to rice seeds provided a substantial level of protection against the herbicides clomazone or triallate. A quantity of 15 kg phorate ha significantly increased the LD values, which were more than twofold greater than for rice plants treated only with clomazone. A quantity of 20 kg phorate ha in combination with 2000 g triallate ha safened rice plants (80% survival) with LD >3.4-fold greater than in phorate-untreated rice. Weed control efficacy was not lowered by the presence of phorate-treated rice seeds.
CONCLUSION
Weedy rice is one of the most damaging global weeds and a major threat to DSR systems. In this study we have developed a proof-of-concept method to allow selective weedy rice control in rice crops. We call for herbicide discovery programmes and research to identify candidate safener and herbicide combinations to achieve selective herbicide control of weedy rice and alleviate weed infestations in global rice crops. © 2016 Society of Chemical Industry.
Topics: Crops, Agricultural; Herbicides; Isoxazoles; Oryza; Oxazolidinones; Plant Weeds; Seeds; Triallate; Weed Control
PubMed: 27484802
DOI: 10.1002/ps.4411 -
The Journal of Toxicological Sciences 2016Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid,... (Comparative Study)
Comparative Study
Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD50/oxime ED50) from a panel of four oximes deemed most efficacious in a previous study. The oximes tested were pralidoxime chloride (2-PAM Cl), MMB4 DMS, HLö-7 DMS, and obidoxime Cl2. The 24-hr median lethal dose (LD50) for the four by intramuscular (IM) injection and the median effective dose (ED50) were determined. In the ED50 study, male guinea pigs clipped of hair received 2x LD50 topical challenges of undiluted Russian VX (VR), VX, or phorate oxon (PHO) and, at the onset of cholinergic signs, IM therapy of atropine (0.4 mg/kg) and varying levels of oxime. Survival was assessed at 3 hr after onset clinical signs. The 3-hr 90th percentile dose (ED90) for each oxime was compared to the guinea pig pre-hospital human-equivalent dose of 2-PAM Cl, 149 µmol/kg. The TI was calculated for each OP/oxime combination. Against VR, MMB4 DMS had a higher TI than HLö-7 DMS, whereas 2-PAM Cl and obidoxime Cl2 were ineffective. Against VX, MMB4 DMS > HLö-7 DMS > 2-PAM Cl > obidoxime Cl2. Against PHO, all performed better than 2-PAM Cl. MMB4 DMS was the most effective oxime as it was the only oxime with ED90 < 149 µmol/kg against all three topical OPs tested.
Topics: Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Guinea Pigs; Lethal Dose 50; Male; Muscarinic Antagonists; Obidoxime Chloride; Organophosphate Poisoning; Organothiophosphorus Compounds; Oximes; Pesticides; Pralidoxime Compounds; Pyridinium Compounds; Time Factors
PubMed: 27432237
DOI: 10.2131/jts.41.511 -
Fundamental Toxicological Sciences 2016The oral toxicity of phorate oxon (PHO), with emphasis on gender- and age-related effects, was characterized in the Sprague-Dawley rat. The oral LD (95% fiducial limits)...
The oral toxicity of phorate oxon (PHO), with emphasis on gender- and age-related effects, was characterized in the Sprague-Dawley rat. The oral LD (95% fiducial limits) for PHO in corn oil was 0.88 (0.79, 1.04) mg/kg in males and 0.55 (0.46, 0.63) mg/kg in females with a probit slope of 15. Females had higher baseline blood cholinesterase titers, but males were significantly more tolerant. Younger rats generally had lower absolute cholinesterase blood titers. However as PHO challenges increased, baseline-normalized cholinesterase inhibition was independent of age and gender. Butyrylcholinesterase (BChE) and especially acetylcholinesterase (AChE) in brains of younger females were affected more than that in either males or older females. In summary, while female rats, especially older females, had higher titers relative to males, female rats were more susceptible in terms of absolute cholinesterase inhibition and 24-hr lethality data, but the differences were not observed when titers were normalized to baseline levels.
PubMed: 28856079
DOI: 10.2131/fts.3.195