Utilizing alternative developmental and neurotoxicity screening methods to prioritize compounds for further mammalian testing

EPA Science Inventory

Due to their toxicity and persistence in the environment, brominated flame retardants (BFRs) are being phased out of commercial use, leading to the increased use of alternative chemicals such as the organophosphorus flame retardants (OPFRs). Due to the structural similarity of th...

Proteomic analysis of adducted butyrylcholinesterase for biomonitoring organophosphorus exposures

PubMed Central

Marsillach, Judit; Hsieh, Edward J.; Richter, Rebecca J.; MacCoss, Michael J.; Furlong, Clement E.

2014-01-01

Organophosphorus (OP) compounds include a broad group of toxic chemicals such as insecticides, chemical warfare agents and antiwear agents. The liver cytochromes P450 bioactivate many OPs to potent inhibitors of serine hydrolases. Cholinesterases were the first OP targets discovered and are the most studied. They are used to monitor human exposures to OP compounds. However, the assay that is currently used has limitations. The mechanism of action of OP compounds is the inhibition of serine hydrolases by covalently modifying their active-site serine. After structural rearrangement, the complex OP inhibitor-enzyme is irreversible and will remain in circulation until the modified enzyme is degraded. Mass spectrometry is a sensitive technology for analyzing protein modifications, such as OP-adducted enzymes. These analyses also provide some information about the nature of the OP adduct. Our aim is to develop high-throughput protocols for monitoring OP exposures using mass spectrometry. PMID:23123252

The comparative toxicity of phosphoramidothionates and phosphoramidates to susceptible and insecticide-resistant houseflies and mosquitos*

PubMed Central

March, R. B.; Georghiou, G. P.; Metcalf, R. L.; Printy, G. E.

1964-01-01

Studies of the comparative toxicity of a number of homologous X-chlorophenyl phosphoramidothionates and phosphoramidates and related analogues to susceptible and insecticide-resistant houseflies (Musca domestica L.) and mosquitos (Culex pipiens quinquefasciatus Say and Anopheles albimanus Wied.) have shown that the 2,4,5-trichlorophenyl series is the most active and the 4-chlorophenyl series the least active. Toxicity decreases in general with increasing chain length of the alkoxy and alkylamido moieties, maximum toxicity residing in methoxy, ethoxy, amido, methylamido, and ethylamido homologues. Toxicity is greatest to the susceptible strain but the alkylamido and X-chlorophenyl structures confer toxicological advantages from the standpoint of relative effectiveness against organophosphorus-resistance and organophosphorus vigour-tolerance. Many of the phosphoramidates are less toxic than their phosphoramidothionate analogues, probably due to less favourable physical properties. Certain of these compounds show promise against both susceptible and insecticide-resistant housefly adults and it is suggested that they be further evaluated in broad-spectrum field trials. Although some show promise as mosquito larvicides, in general the introduction of an alkyl-amido group markedly decreases residual toxicity from a filter-paper residue to mosquito adults in comparison with the corresponding dialkoxy analogues. PMID:14122443

S-alkynyl esters of phosphorus thioacids as inhibitors of cholinesterases and as promising physiologically active compounds

NASA Astrophysics Data System (ADS)

Brestkin, A. P.; Vikhreva, L. A.; Godovikov, Nikolai N.; Zhukovskii, Yu G.; Kabachnik, Martin I.; Moralev, S. N.; Rosengart, V. I.; Sherstobitov, O. E.

1991-08-01

Data are given in the review on the anticholinesterase activity of 58 specially synthesised esters of phosphorus thioacids containing an acetylenic bond in the thioester group. It was established that compounds containing an acetylenic group in the β and especially in the α position of the thioester residue display an inhibitory action many times greater than that of their saturated analogues. A phosphorylated enzyme is formed by the reaction of the acetylenic organophosphorus inhibitors (OPIs) with the enzymes as in the case of reaction with the saturated analogues. It was shown that the acetylenic organophosphorus inhibitors possess high biological activity both for mammals and for arthropods. On replacing the phosphoryl oxygen (P=O) by sulphur (P=S) the toxicity of the acetylenic organophosphorus inhibitors for mammals was sharply reduced but was little changed for arthropods. This raises the possibility of obtaining highly selective insecto-acaricides. The mechanism of the antienzymic action of the acetylenic OPIs and the mechanism of detoxication of diethyl S-hexynyl dithiophosphate are considered. The bibliography includes 44 references.

Acute organo-phosphorus pesticide poisoning in North Karnataka, India: oxidative damage, haemoglobin level and total leukocyte.

PubMed

Hundekari, I A; Suryakar, A N; Rathi, D B

2013-03-01

Pesticide poisoning is an important cause of morbidity and mortality in India. To assess the oxidative damage, hemoglobin level and leukocyte count in acute organophosphorus pesticide poisoning. Plasma cholinesterase was assessed as a toxicity marker. Oxidative damage was assessed by estimating serum malondialdehyde (MDA) levels, plasma total antioxidant capacity (TAC), erythrocyte superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels. Progressive and significant decline (p< 0.001) in plasma cholinesterase in correlation with the severity of organophosphorus poisoning was observed. Serum MDA levels significantly increased (p< 0.001) in all grades of organophosphorus poisoning cases as compared to controls. Erythrocyte SOD, CAT and GPx were significantly increased (p< 0.05) in earlier grade and (p< 0.001) in later grades of organophosphorus poisoning cases as compared to controls. While plasma TAC (p<0.001) was significantly decreased in all grades of organophosphorus poisoning cases as compared to controls. Leucocytosis observed in these cases signifies the activation of defense mechanism which could be a positive response for survival. Organophosphorus compounds inhibit cholinesterase action leading to cholinergic hyperactivity. Increased MDA level may lead to peroxidative damages deteriorating the structural and functional integrity of neuronal membrane. Increased erythrocyte SOD, CAT and GPx activities suggest an adaptive measure to tackle the pesticide accumulation. Hence it is concluded that cholinesterase inhibition may initiate cellular dysfunction leading to acetylcholine induced oxidative damage.

Immobilization of Enzymes in Nanoporous Host Materials: A Nanobiotechnological Approach to Decontamination and Demilitarization of Chemical and Biological Warfare Agents

DTIC Science & Technology

2002-05-06

Organophosphorus compounds (OPs) are highly toxic and found extensive use as pesticides , insecticides and potential chemical warfare (CW) agents . Recently...commonly used substrate, the serine protease inhibitor diisopropyl fluorophosphates (DFP), and different fluoride-containing G-type nerve agents such as...

Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care

PubMed Central

Hulse, Elspeth J.; Davies, James O. J.; Simpson, A. John; Sciuto, Alfred M.

2014-01-01

Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities. PMID:25419614

Persistent and High-Level Expression of Human Liver Prolidase in Vivo in Mice Using Adenovirus

DTIC Science & Technology

2013-01-01

types of nerve agents and pesticide compounds, is mostly exported into the circulation [11]. Similarly, human paraoxonase1, a promising enzyme in the...of human butyrylcholinesetrase results in persistent high-level transgene expression in vivo, Chem. Biol. Interact. 175 (2008) 327– 331. [11] K...paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon, Gene Ther. 18 (2011) 250–257. [14

[Perspectives in the treatments of poisonings by organophosphorus insecticides and warfare nerve agents].

PubMed

Sogorb-Sánchez, M A; Vilanova-Gisbert, E; Carrera-González, V

Organophosphorus compounds are worldwide employed as insecticides and are yearly responsible of several millions of poisonings. The chemical structure of most of the warfare nerve agents also corresponds with an organophosphorus compound. Organophosphorus insecticides and warfare nerve agents exert their main toxicological effects through inhibition of acetylcholinesterase. Current treatments of patients poisoned with organophosphorus compounds include atropine (in order to protect muscarinic receptors), oximes (in order to accelerate the reactivation of the inhibited acetylcholinesterase) and benzodiazepines (in order to avoid convulsions). The administration of phosphotriesterases (enzymes involved in the detoxication of organophosphorus compounds through hydrolysis) is a very effective treatment against poisonings by organophosphorus insecticides and warfare nerve agents. There are experimental preventive treatments based on the simultaneous administration of carbamates and certain antimuscarinic drugs, different from atropine, which notably improve the efficacy of the classical treatments applied after poisonings by warfare nerve agents. The treatments based in the administration of phosphotriesterases might be the response to the call of the World Health Organization for searching new treatments with capability to reduce the high mortality recorded in the cases of poisonings by organophosphorus compounds. These treatments can be applied in a preventive way without the intrinsic neurotoxicity associated to the preventive treatments based on carbamates and antimuscarinic drugs. Therefore, these treatments are specially interesting for people susceptible to suffer severe exposures, i.e. sprayers in the farms.

Acute toxicity of some nerve agents and pesticides in rats.

PubMed

Misik, Jan; Pavlikova, Ruzena; Cabal, Jiri; Kuca, Kamil

2015-01-01

Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD50, mg kg(-1)) 2, 4, and 24 hours post exposure. V-agents were the most toxic presented with LD50 ranged from 0.0082 mg kg(-1) (VX, i.m.) to 1.402 mg kg(-1) (Russian VX, p.o.), followed by G-agents (LD50 = 0.069 mg kg(-1)/soman, i.m./ - 117.9 mg kg(-1)/sarin, p.c./), organophosphate POX and DFP (LD50 = 0.321 mg kg(-1)/POX, i.m./ - 420 mg kg(-1)/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD50 = 0.0082 mg kg(-1)/VX/ - 1.399 mg kg(-1)/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD50 = 0.085 mg kg(-1)/VX/ - 420 mg kg(-1)/DFP/). The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents.

PubMed

Albuquerque, Edson X; Pereira, Edna F R; Aracava, Yasco; Fawcett, William P; Oliveira, Maristela; Randall, William R; Hamilton, Tracey A; Kan, Robert K; Romano, James A; Adler, Michael

2006-08-29

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

PubMed Central

Albuquerque, Edson X.; Pereira, Edna F. R.; Aracava, Yasco; Fawcett, William P.; Oliveira, Maristela; Randall, William R.; Hamilton, Tracey A.; Kan, Robert K.; Romano, James A.; Adler, Michael

2006-01-01

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer’s disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning. PMID:16914529

Method for purifying bidentate organophosphorus compounds

DOEpatents

Schulz, Wallace W.

1977-01-01

Bidentate organophosphorus compounds useful for extracting actinide elements from acidic nuclear waste solutions are purified of undesirable acidic impurities by contacting the compounds with ethylene glycol which preferentially extracts the impurities found in technical grade bidentate compounds.

Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain.

PubMed

Pizarro, Jose M; Chang, Wenling E; Bah, Mariama J; Wright, Linnzi K M; Saviolakis, George A; Alagappan, Arun; Robison, Christopher L; Shah, Jinesh D; Meyerhoff, James L; Cerasoli, Douglas M; Midboe, Eric G; Lumley, Lucille A

2012-04-01

The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

Structural Insights into the Dual Activities of the Nerve Agent Degrading Organophosphate Anhydrolase/Prolidase

DTIC Science & Technology

2009-12-11

class of bimetalloenzymes that hydrolyze a variety of toxic acetylcholinesterase-inhibiting organophosphorus compounds, including fluorine ... electrophilicity of the phosphorus center. Similar interactions and functions have been proposed for the carbonyl oxygen of the scissile peptide bond...163, 261–276. 2. Mazur, A. (1946) An enzyme in animal tissues capable of hydrolyzing the phosphorus- fluorine bond of alkyl fluorophosphate. J. Biol

[Interest of the cholinesterase assay during organophosphate poisonings].

PubMed

Jalady, A-M; Dorandeu, F

2013-12-01

Cholinesterases are the main targets of organophosphorus compounds. The two enzymes present in the blood (butyrylcholinesterase, BChE; acetylcholinesterase, AChE) are biomarkers of their systemic toxicity. Activity of the plasma BChE is very often determined as it allows a rapid diagnostic of poisoning and is a marker of the persistence of the toxicant in the blood. The activity of the red blood cell AChE gives a better picture of the synaptic inhibition in the nervous system but the assay is less commonly available in routine laboratories. Better biomarker of the exposure, it allows a diagnosis of the severity of the poisoning and helps to assess the efficacy of oxime therapy. Besides the practical aspects of blood collection and sample processing, and the interpretation of the assays, this review stresses the complementarity of both enzyme assays and recalls their crucial interest for the confirmation of poisoning with an organophosphorus in a situation of war or terrorist attack and for the monitoring of occupational exposures. Copyright © 2013. Published by Elsevier SAS.

Recent Developments in Organophosphorus Flame Retardants Containing P-C Bond and Their Applications

PubMed Central

Wendels, Sophie; Chavez, Thiebault; Bonnet, Martin; Gaan, Sabyasachi

2017-01-01

Organophosphorus compounds containing P-C bonds are increasingly developed as flame retardant additives due to their excellent thermal and hydrolytic stability and ease of synthesis. The latest development (since 2010) in organophosphorus flame retardants containing P-C bonds summarized in this review. In this review, we have broadly classified such phosphorus compounds based on the carbon unit linked to the phosphorus atom i.e., could be a part of either an aliphatic or an aromatic unit. We have only considered those published literature where a P-C bond was created as a part of synthetic strategy to make either an intermediate or a final organophosphorus compound with an aim to use it as a flame retardant. General synthetic strategies to create P-C bonds are briefly discussed. Most popular synthetic strategies used for developing P-C containing phosphorus based flame retardants include Michael addition, Michaelis–Arbuzov, Friedels–Crafts and Grignard reactions. In general, most flame retardant derivatives discussed in this review have been prepared via a one- to two-step synthetic strategy with relatively high yields greater than 80%. Specific examples of P-C containing flame retardants synthesized via suitable synthetic strategy and their applications on various polymer systems are described in detail. Aliphatic phosphorus compounds being liquids or low melting solids are generally applied in polymers via coatings (cellulose) or are incorporated in the bulk of the polymers (epoxy, polyurethanes) during their polymerization as reactive or non-reactive additives. Substituents on the P atoms and the chemistry of the polymer matrix greatly influence the flame retardant behavior of these compounds (condensed phase vs. the gas phase). Recently, aromatic DOPO based phosphinate flame retardants have been developed with relatively higher thermal stabilities (>250 °C). Such compounds have potential as flame retardants for high temperature processable polymers such as polyesters and polyamides. A vast variety of P-C bond containing efficient flame retardants are being developed; however, further work in terms of their economical synthetic methods, detailed impact on mechanical properties and processability, long term durability and their toxicity and environmental impact is much needed for their potential commercial exploitations. PMID:28773147

Surface-water-quality assessment of the Yakima River basin, Washington; distribution of pesticides and other organic compounds in water, sediment, and aquatic biota, 1987-91; with a section on dissolved organic carbon in the Yakima River basin

USGS Publications Warehouse

Rinella, Joseph F.; McKenzie, Stuart W.; Crawford, J. Kent; Foreman, William T.; Fuhrer, Gregory J.; Morace, Jennifer L.; Aiken, George R.

1999-01-01

During 1987-91, chemical data were collected for pesticides and other organic compounds in surface water, streambed sediment, suspended sediment, agricultural soil, and aquatic biota to determine the occurrence, distribution, transport, and fate of organic compounds in the Yakima River basin in Washington. The report describes the chemical and physical properties of the compounds most frequently detected in the water column; organochlorine compounds including DDT, organophosphorus compounds, thiocarbamate and sulfite compounds, acetamide and triazine compounds, and chlorophenoxy-acetic acid and benzoic compounds. Concentrations are evaluated relative to chronic-toxicity water quality criteria and guidelines for the protection of human health and freshwater aquatic life.

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

PubMed Central

Čolović, Mirjana B; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M

2013-01-01

Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases. PMID:24179466

IN VITRO EFFECTS OF CHLORPYRIFOS, PARATHION, METHYL PARATHION AND THEIR OXONS ON CARDIAC MUSCARINIC RECEPTOR BINDING IN NEONATAL AND ADULT RATS. (R825811)

EPA Science Inventory

Organophosphorus insecticides elicit toxicity by inhibiting acetylcholinesterase. Young animals are generally more sensitive than adults to these toxicants. A number of studies reported that some organophosphorus agents also bind directly to muscarinic receptors, in particular...

A role for solvents in the toxicity of agricultural organophosphorus pesticides

PubMed Central

Eddleston, Michael; Street, Jonathan M.; Self, Ian; Thompson, Adrian; King, Tim; Williams, Nicola; Naredo, Gregorio; Dissanayake, Kosala; Yu, Ly-Mee; Worek, Franz; John, Harald; Smith, Sionagh; Thiermann, Horst; Harris, John B.; Eddie Clutton, R.

2012-01-01

Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12 h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4 [0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates. PMID:22365945

Organophosphorus poisoning (acute).

PubMed

Blain, Peter G

2011-05-17

Acetylcholinesterase inhibition by organophosphorus pesticides or organophosphate nerve agents can cause acute parasympathetic system dysfunction, muscle weakness, seizures, coma, and respiratory failure. Prognosis depends on the dose and relative toxicity of the specific compound, as well as pharmacokinetic factors. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute organophosphorus poisoning? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 62 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: activated charcoal (single or multiple doses), alpha(2) adrenergic receptor agonists, atropine, benzodiazepines, butyrylcholinesterase replacement therapy, cathartics, extracorporeal clearance, gastric lavage, glycopyrronium bromide (glycopyrrolate), ipecacuanha (ipecac), magnesium sulphate, milk or other home remedy immediately after ingestion, N-methyl-D-aspartate receptor antagonists, organophosphorus hydrolases, oximes, removing contaminated clothes and washing the poisoned person, and sodium bicarbonate.

Structural Analysis and Bioengineering of Thermostable Pyrococcus furiosus Prolidase for the Optimization of Organophosphorus Nerve Agent Detoxification

DTIC Science & Technology

2012-04-26

in the following categories: PaperReceived TOTAL: (b) Papers published in non-peer-reviewed journals (N/A for none) Number of ... biodegradable , yet they are extremely toxic to mammals because they bind to acetyl cholinesterase and render it inactive leading to a buildup of the ...respiratory complications, respiratory failure, coma and death. OP compounds exist mainly in the form of pesticides and chemical warfare agents

Discovery and identification of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) as a novel mode of action of organophosphorus insecticides.

PubMed

Zeng, Zhigang; Yan, Ying; Wang, Bingfeng; Liu, Niu; Xu, Hanhong

2017-06-15

Organophosphorus (OP) insecticides play an important role in pest control. Many OP insecticides have been removed from the market because of their high toxicity to humans. We designed and synthesized a new OP insecticide with the goal of providing a low cost, and less toxic insecticide. The mode of action of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) was studied in Drosophila melanogaster. Bioassays showed that XP-1408 at a concentration of 50 mg/L delayed larval development. Molecular docking into Drosophila acetylcholinesterase (AChE) and voltage-gated sodium channels suggested that XP-1408 fitted into their active sites and could be inhibitory. Whole-cell patch clamp recordings indicated that XP-1408 exhibited synergistic effects involving the inhibition of cholinergic synaptic transmission and blockage of voltage-gated potassium (K v ) channels and sodium (Na v ) channels. In conclusion, the multiple actions of XP-1408 rendered it as a lead compound for formulating OP insecticides with a novel mode of action.

[Decontamination of organophosphorus compounds: Towards new alternatives].

PubMed

Poirier, L; Jacquet, P; Elias, M; Daudé, D; Chabrière, E

2017-05-01

Organophosphorus coumpounds (OP) are toxic chemicals mainly used for agricultural purpose such as insecticides and were also developed and used as warfare nerve agents. OP are inhibitors of acetylcholinesterase, a key enzyme involved in the regulation of the central nervous system. Chemical, physical and biological approaches have been considered to decontaminate OP. This review summarizes the current and emerging strategies that are investigated to tackle this issue with a special emphasis on enzymatic remediation methods. During the last decade, many studies have been dedicated to the development of biocatalysts for OP removal. Among these, recent reports have pointed out the promising enzyme SsoPox isolated from the archaea Sulfolobus solfataricus. Considering both its intrinsic stability and activity, this hyperthermostable enzyme is highly appealing for the decontamination of OP. Copyright © 2017 Académie Nationale de Pharmacie. All rights reserved.

Spectroscopic and Computational Investigation of Room-Temperature Decomposition of a Chemical Warfare Agent Simulant on Polycrystalline Cupric Oxide

DOE PAGES

Trotochaud, Lena; Tsyshevsky, Roman; Holdren, Scott; ...

2017-08-21

Certain organophosphorus molecules are infamous due to their use as highly toxic nerve agents. The filtration materials currently in common use for protection against chemical warfare agents were designed before organophosphorus compounds were used as chemical weapons. A better understanding of the surface chemistry between simulant molecules and the individual filtration-material components is a critical precursor to the development of more effective materials for filtration, destruction, decontamination, and/or sensing of nerve agents. Here, we report on the surface adsorption and reactions of a sarin simulant molecule, dimethyl methylphosphonate (DMMP), with cupric oxide surfaces. In situ ambient pressure X-ray photoelectron andmore » infrared spectroscopies are coupled with density functional calculations to propose mechanisms for DMMP decomposition on CuO. We find extensive room temperature decomposition of DMMP on CuO, with the majority of decomposition fragments bound to the CuO surface. We observe breaking of PO-CH3, P-OCH3, and P-CH3bonds at room temperature. On the basis of these results, we identify specific DMMP decomposition mechanisms not seen on other metal oxides. Participation of lattice oxygen in the decomposition mechanism leads to significant changes in chemical and electronic surface environment, which are manifest in the spectroscopic and computational data. This study establishes a computational baseline for the study of highly toxic organophosphorous compounds on metal oxide surfaces.« less

Spectroscopic and Computational Investigation of Room-Temperature Decomposition of a Chemical Warfare Agent Simulant on Polycrystalline Cupric Oxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trotochaud, Lena; Tsyshevsky, Roman; Holdren, Scott

Certain organophosphorus molecules are infamous due to their use as highly toxic nerve agents. The filtration materials currently in common use for protection against chemical warfare agents were designed before organophosphorus compounds were used as chemical weapons. A better understanding of the surface chemistry between simulant molecules and the individual filtration-material components is a critical precursor to the development of more effective materials for filtration, destruction, decontamination, and/or sensing of nerve agents. Here, we report on the surface adsorption and reactions of a sarin simulant molecule, dimethyl methylphosphonate (DMMP), with cupric oxide surfaces. In situ ambient pressure X-ray photoelectron andmore » infrared spectroscopies are coupled with density functional calculations to propose mechanisms for DMMP decomposition on CuO. We find extensive room temperature decomposition of DMMP on CuO, with the majority of decomposition fragments bound to the CuO surface. We observe breaking of PO-CH3, P-OCH3, and P-CH3bonds at room temperature. On the basis of these results, we identify specific DMMP decomposition mechanisms not seen on other metal oxides. Participation of lattice oxygen in the decomposition mechanism leads to significant changes in chemical and electronic surface environment, which are manifest in the spectroscopic and computational data. This study establishes a computational baseline for the study of highly toxic organophosphorous compounds on metal oxide surfaces.« less

Cloning of a Novel Aldo-Keto Reductase Gene from Klebsiella sp. Strain F51-1-2 and Its Functional Expression in Escherichia coli▿

PubMed Central

Jiang, Hong; Yang, Chao; Qu, Hong; Liu, Zheng; Fu, Q. S.; Qiao, Chuanling

2007-01-01

A soil bacterium capable of metabolizing organophosphorus compounds by reducing the P=S group in the molecules was taxonomically identified as Klebsiella sp. strain F51-1-2. The gene involved in the reduction of organophosphorus compounds was cloned from this strain by the shotgun technique, and the deduced protein (named AKR5F1) showed homology to members of the aldo-keto reductase (AKR) superfamily. The intact coding region for AKR5F1 was subcloned into vector pET28a and overexpressed in Escherichia coli BL21(DE3). Recombinant His6-tagged AKR5F1 was purified in one step using Ni-nitrilotriacetic acid affinity chromatography. Assays for cofactor specificity indicated that reductive transformation of organophosphorus compounds by the recombinant AKR5F1 specifically required NADH. The kinetic constants of the purified recombinant AKR5F1 toward six thion organophosphorus compounds were determined. For example, the Km and kcat values of reductive transformation of malathion by the purified recombinant AKR5F1 are 269.5 ± 47.0 μΜ and 25.7 ± 1.7 min−1, respectively. Furthermore, the reductive transformation of organophosphorus compounds can be largely explained by structural modeling. PMID:17575004

Influence of polychlorinated aromatic compounds on the biotransformation and toxicity of organophosphorus pesticides (OP) to the Daphnia magna

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tonkopii, V.; Zagrebin, A.; Sherstneva, L.

1995-12-31

The effect of different polychlorinated aromatics (DDT, Aroclor 1254, certain polychlorinated biphenyls and dibenzofurans) on the toxicity of OP (DDVP paraoxon, malaoxon) to Daphnia magna was studied. Pretreatment of daphnids with chlorinated compounds during 72 hours in nontoxic concentrations (1/5--1/20 CL{sub 50}) has been shown to reduce the toxicity of OP for hydrobionts. For study of influence of chlorinated compounds on biotransformation of OP the activity of enzymes which are hydrolyzing the OP was investigated in Daphnia`s homogenates or microsomes. The activity of carboxylesterase (tributyrinase, aliesterase) and arylesterase (phosphorylphosphatase) with usage as substrates accordingly {alpha}-naphthylacetate and paraoxon was measured. Besidesmore » that the activity of cholinesterase with application of propionylthiocholine as substrate was determined. After polychlorinated aromatic compounds treatment of daphnids activities of both aryl-and carboxylesterase increased markedly. It decreased the inhibition of Daphnia`s cholinesterase caused by incubation with OP in concentrations 0.5--1.0 CL{sub 50}. Thus the induction by chlorinate aromatics of OP metabolizing enzymes seems to play the important role in reduction of OP toxicity to Daphnia magna. Perhaps the aryl- and carboxylesterase of Daphnia can be used as biomarkers of pollution by polychlorinated aromatics in water.« less

EFFECT OF ORGANOPHOSPHORUS FLAME RETARDANTS ON NEURONAL DEVELOPMENT IN VITRO

EPA Science Inventory

The increased use of organophosphorus compounds as alternatives to brominated flame retardants (BFRs) has led to widespread human exposure, There is, however, limited information on their potential health effects. This study compared the effects of nii ne organophosphorus flame...

Protective Effect of Selenium-Based Medicines on Toxicity of Three Common Organophosphorus Compounds in Human Erythrocytes In Vitro

PubMed Central

Mostafalou, Sara; Navaei-Nigjeh, Mona; Baeeri, Maryam; Mohammadirad, Azadeh; Abdollahi, Mohammad

2016-01-01

Objective Organophosphorus (OP) compounds are used to control pests, however they can reach the food chain and enter the human body causing serious health problems by means of acetylcholinesterase (AChE) inhibition and oxidative stress (OS). Among the OPs, chlorpyrifos (CHP), malathion (MAL), and diazinon (DIA) are commonly used for commercial extermination purposes, in addition to veterinary practices, domestic, agricul- ture and public health applications. Two new recently registered medicines that contain selenium and other antioxidants, IMOD and angipars (ANG), have shown beneficial ef- fects for OS related disorders. This study examines the effect of selenium-based medi- cines on toxicity of three common OP compounds in erythrocytes. Materials and Methods In the present experimental study, we determined the ef- ficacy of IMOD and ANG on OS induced by three mentioned OP pesticides in human erythrocytes in vitro. After dose-response studies, AChE, lipid peroxidation (LPO), total antioxidant power (TAP) and total thiol molecules (TTM) were measured in eryth- rocytes after exposure to OPs alone and in combined treatment with IMOD or ANG. Results AChE activity, TAP and TTM reduced in erythrocytes exposed to CHP, MAL and DIA while they were restored in the presence of ANG and IMOD. ANG and IMOD reduced the OPs-induced elevation of LPO. Conclusion The present study shows the positive effects of IMOD and ANG in re- duction of OS and restoration of AChE inhibition induced by CHP, MAL and DIA in erythrocytes in vitro. PMID:26862533

DETERMINATION OF ORGANOPHOSPHORUS COMPOUNDS BY GC-ICPMS

EPA Science Inventory

Accidental or intentional release of neurotoxic organophosphorus (OP) pesticides and OP chemical warfare agents (CWAs) are potential threats to public health and the environment. Such a release could involve any number of a large suite of OP chemicals. These compounds, as well a...

Effects of an organophosphorus pesticide on reproduction in the rat.

DOT National Transportation Integrated Search

1970-01-01

The toxic effects of organophosphorus insecticides are commonly ascribed to cholinesterase (CHE) inhibition. A search of the scientific literature revealed the well-established fact that a number of chlorinated pesticides adversely affect reproductio...

Organophosphorus and carbamate pesticides

USGS Publications Warehouse

Glaser, L.C.

1999-01-01

The insecticidal properties of organophosphorus (OP) and carbamate compounds were first discovered in the 1930s, and the compounds were developed for pesticide use in the 1940s. They have been used increasingly since the 1970s when environmentally persistent organochlorine pesticides, such as DDT and dieldrin, were banned for use in the United States. Organophosphorus and carbamate pesticides are generally short-lived in the environment (usually lasting only days to months instead of years) and, generally, chemical breakdown is accelerated as temperatures or pH or both increase.

Time course of electrophysiologic effects induced by di-n-butyl-2,2-dichlorovinyl phosphate (DBCV) in the adult hen.

PubMed

Robertson, D G; Mattson, A M; Bestervelt, L L; Richardson, R J; Anderson, R J

1988-01-01

Previous work in our laboratory indicated that di-n-butyl-2,2-dichlorovinyl phosphate (DBCV) produced electrophysiologic changes in hen peripheral nerve that coincided with the development of histopathologic changes and neurologic signs of peripheral neuropathy. The purpose of the present study was to follow the time course for the development of the electrophysiologic changes and to determine whether pretreatment with the phosphinate analog of DBCV (DBCV-P), a nonageable organophosphorus compound, prevented these effects. Although significant electrophysiologic deficits occurred in the tibial and sciatic nerve 24 h after DBCV treatment, the most marked changes coincided with the onset of clinical signs of organophosphorus-induced delayed neuropathy (14-21 d). The sciatic and tibial nerves were equally susceptible to DBCV in producing deficits characterized by changes in the relative refractory period and an increased strength-duration threshold. Pretreatment with DBCV-P prevented the clinical signs and also attenuated the electrophysiologic deficits induced by DBCV treatment. These data suggest that electrophysiologic deficits occur before clinical signs of organophosphorus-induced delayed neuropathy (OPIDN) and may be indicative of a link between neurotoxic esterase (NTE) inhibition and onset of overt clinical toxicity.

Microbial degradation of an organophosphate pesticide, malathion.

PubMed

Singh, Baljinder; Kaur, Jagdeep; Singh, Kashmir

2014-05-01

Organophosphorus pesticide, malathion, is used in public health, residential, and agricultural settings worldwide to control the pest population. It is proven that exposure to malathion produce toxic effects in humans and other mammals. Due to high toxicity, studies are going on to design effective methods for removal of malathion and its associated compounds from the environment. Among various techniques available, degradation of malathion by microbes proves to be an effective and environment friendly method. Recently, research activities in this area have shown that a diverse range of microorganisms are capable of degrading malathion. Therefore, we aimed at providing an overview of research accomplishments on this subject and discussed the toxicity of malathion and its metabolites, various microorganisms involved in its biodegradation and effect of various environmental parameters on its degradation.

Role of the P-F bond in fluoride-promoted aqueous VX hydrolysis: an experimental and theoretical study.

PubMed

Marciano, Daniele; Columbus, Ishay; Elias, Shlomi; Goldvaser, Michael; Shoshanim, Ofir; Ashkenazi, Nissan; Zafrani, Yossi

2012-11-16

Following our ongoing studies on the reactivity of the fluoride ion toward organophosphorus compounds, we established that the extremely toxic and environmentally persistent chemical warfare agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is exclusively and rapidly degraded to the nontoxic product EMPA (ethyl methylphosphonic acid) even in dilute aqueous solutions of fluoride. The unique role of the P-F bond formation in the reaction mechanism was explored using both experimental and computational mechanistic studies. In most cases, the "G-analogue" (O-ethyl methylphosphonofluoridate, Et-G) was observed as an intermediate. Noteworthy and of practical importance is the fact that the toxic side product desethyl-VX, which is formed in substantial quantities during the slow degradation of VX in unbuffered water, is completely avoided in the presence of fluoride. A computational study on a VX-model, O,S-diethyl methylphosphonothioate (1), clarifies the distinctive tendency of aqueous fluoride ions to react with such organophosphorus compounds. The facility of the degradation process even in dilute fluoride solutions is due to the increased reactivity of fluoride, which is caused by the significant low activation barrier for the P-F bond formation. In addition, the unique nucleophilicity of fluoride versus hydroxide toward VX, in contrast to their relative basicity, is discussed. Although the reaction outcomes were similar, much slower reaction rates were observed experimentally for the VX-model (1) in comparison to VX.

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication.

PubMed

Faria, Melissa; Prats, Eva; Padrós, Francesc; Soares, Amadeu M V M; Raldúa, Demetrio

2017-04-01

Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included "standard therapy" drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-D-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC 50 )] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication.

Influence of N-P base fiber reactive organophosphorus flame retardant on cotton thermal behavior

USDA-ARS?s Scientific Manuscript database

An efficient synergistic effect between a nitrogen-containing organophosphorus compound in the presence of a catalytic amount of chlorine is proposed based on the cyanuric chloride-linked organophosphorus flame retardant, tetraethyl-2,2'-(6-chloro-1,3,5-triazine-2,4-diyl)bis(azanediyl)bis(ethane-2,1...

31P-edited diffusion-ordered 1H NMR spectroscopy for the spectral isolation and identification of organophosphorus compounds related to chemical weapons agents and their degradation products.

PubMed

Mayer, Brian P; Valdez, Carlos A; Hok, Saphon; Chinn, Sarah C; Hart, Bradley R

2012-12-04

Organophosphorus compounds represent a large class of molecules that include pesticides, flame-retardants, biologically relevant molecules, and chemical weapons agents (CWAs). The detection and identification of organophosphorus molecules, particularly in the cases of pesticides and CWAs, are paramount to the verification of international treaties by various organizations. To that end, novel analytical methodologies that can provide additional support to traditional analyses are important for unambiguous identification of these compounds. We have developed an NMR method that selectively edits for organophosphorus compounds via (31)P-(1)H heteronuclear single quantum correlation (HSQC) and provides an additional chromatographic-like separation based on self-diffusivities of the individual species via (1)H diffusion-ordered spectroscopy (DOSY): (1)H-(31)P HSQC-DOSY. The technique is first validated using the CWA VX (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate) by traditional two-dimensional DOSY spectra. We then extend this technique to a complex mixture of VX degradation products and identify all the main phosphorus-containing byproducts generated after exposure to a zinc-cyclen organometallic homogeneous catalyst.

Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings

PubMed Central

Kuca, Kamil; Karasova, Jana Zdarova; Soukup, Ondrej; Kassa, Jiri; Novotna, Eva; Sepsova, Vendula; Horova, Anna; Pejchal, Jaroslav; Hrabinova, Martina; Vodakova, Eva; Jun, Daniel; Nepovimova, Eugenie; Valis, Martin; Musilek, Kamil

2018-01-01

Background Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity. PMID:29563775

CUMULATIVE EFFECTS OF ORGANOPHOSPHORUS OR CARBAMATE PESTICIDES.

EPA Science Inventory

This book chapter strives to summarize the body of literature exploring the toxic interaction of organophosphorus and carbamate pesticides in mixtures. This review represents one of the only reviews of the subject that has been published within the last 20 years. Specifically, th...

A Common Mechanism for Resistance to Oxime Reactivation of Acetylcholinesterase Inhibited by Organophosphorus Compounds

DTIC Science & Technology

2013-01-01

application of the Hammett equation with the constants rph in the chemistry of organophosphorus compounds, Russ. Chem. Rev. 38 (1969) 795–811. [13...of oximes and OP compounds and the ability of oximes to reactivate OP- inhibited AChE. Multiple linear regression equations were analyzed using...phosphonate pairs, 21 oxime/ phosphoramidate pairs and 12 oxime/phosphate pairs. The best linear regression equation resulting from multiple regression anal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rohrbaugh, Wayne Joseph

Results are reported from an investigation of correlations between molecular structural parameters of selected organophosphorus insecticides and their corresponding toxic effectiveness. The crystal and molecular structures of azinphos-methyl, emidithion, and tetrachlorvinphos were determined via three-dimensional x-ray analysis. Acetylcholinesterase (AChE) in nerve cells was identified as the target for organophosphorus insecticides.

Toxicity of parathion to captive European starlings (Sturnus vulgaris)-absence of seasonal effects

USGS Publications Warehouse

Rattner, B.A.; Grue, C.E.

1990-01-01

The effects of season on the toxicity of the prototypic organophosphorus insecticide parathion was evaluated using adult European starlings (Sturnus vulgaris) housed in outdoor pens. Groups of birds received oral doses of parathion in the fall, winter, spring and summer. Median lethal dosage, and brain and plasma cholinesterase inhibition, were found to be quite similar among seasons. Parathion may have been more toxic during hot weather (winter vs. summer LD50 estimate: 160 vs. 118 mg/kg; p < 0.1). In view of previous reports in which ambient temperature extremes and harsh weather have enhanced organophosphorus insecticide toxicity to birds, it is concluded that circannual toxicity studies should include measures of sensitivity (acute oral exposure) and vulnerability (dietary exposure) to better predict responses of free-ranging birds.

A quantum chemical study of molecular properties and QSPR modeling of oximes, amidoximes and hydroxamic acids with nucleophilic activity against toxic organophosphorus agents

NASA Astrophysics Data System (ADS)

Alencar Filho, Edilson B.; Santos, Aline A.; Oliveira, Boaz G.

2017-04-01

The proposal of this work includes the use of quantum chemical methods and cheminformatics strategies in order to understand the structural profile and reactivity of α-nucleophiles compounds such as oximes, amidoximes and hydroxamic acids, related to hydrolysis rate of organophosphates. Theoretical conformational study of 41 compounds were carried out through the PM3 semiempirical Hamiltonian, followed by the geometry optimization at the B3LYP/6-31+G(d,p) level of theory, complemented by Polarized Continuum Model (PCM) to simulate the aqueous environment. In line with the experimental hypothesis about hydrolytic power, the strength of the Intramolecular Hydrogen Bonds (IHBs) at light of the Bader's Quantum Theory of Atoms in Molecules (QTAIM) is related to the preferential conformations of α-nucleophiles. A set of E-Dragon descriptors (1,666) were submitted to a variable selection through Ordered Predictor Selection (OPS) algorithm. Five descriptors, including atomic charges obtained from the Natural Bond Orbitals (NBO) protocol jointly with a fragment index associated to the presence/absence of IHBs, provided a Quantitative Structure-Property Relationship (QSPR) model via Multiple Linear Regression (MLR). This model showed good validation parameters (R2 = 0.80, Qloo2 = 0.67 and Qext2 = 0.81) and allowed the identification of significant physicochemical features on the molecular scaffold in order to design compounds potentially more active against organophosphorus poisoning.

Use of Alternative Assays to Identify and Prioritize Organophosphorus Flame Retardants for Potential Developmental and Neurotoxicity

EPA Science Inventory

Due to their toxicity and persistence in the environment, brominated flame retardants (BFRs) are being phased out of commercial use, leading to the increased use of alternative chemicals such as the organophosphorus flame retardants (OPFRs). There is, however, limited information...

Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giordano, Gennaro; Afsharinejad, Zhara; Guizzetti, Marina

2007-03-15

Over the past several years evidence has been accumulating from in vivo animal studies, observations in humans, and in vitro studies, that organophosphorus (OP) insecticides may induce oxidative stress. Such effects may contribute to some of the toxic manifestations of OPs, particularly upon chronic or developmental exposures. The aim of this study was to investigate the role of oxidative stress in the neurotoxicity of two commonly used OPs, chlorpyrifos (CPF) and diazinon (DZ), their oxygen analogs (CPO and DZO), and their 'inactive' metabolites (TCP and IMP), in neuronal cells from a genetic model of glutathione deficiency. Cerebellar granule neurons frommore » wild type mice (Gclm +/+) and mice lacking the modifier subunit of glutamate cysteine ligase (Gclm -/-), the first and limiting step in the synthesis of glutathione (GSH), were utilized. The latter display very low levels of GSH and are more susceptible to the toxicity of agents that increase oxidative stress. CPO and DZO were the most cytotoxic compounds, followed by CPF and DZ, while TCP and IMP displayed lower toxicity. Toxicity was significantly higher (10- to 25-fold) in neurons from Gclm (-/-) mice, and was antagonized by various antioxidants. Depletion of GSH from Gclm (+/+) neurons significantly increased their sensitivity to OP toxicity. OPs increased intracellular levels of reactive oxygen species and lipid peroxidation and in both cases the effects were greater in neurons from Gclm (-/-) mice. OPs did not alter intracellular levels of GSH, but significantly increased those of oxidized glutathione (GSSG). Cytotoxicity was not antagonized by cholinergic antagonists, but was decreased by the calcium chelator BAPTA-AM. These studies indicate that cytotoxicity of OPs involves generation of reactive oxygen species and is modulated by intracellular GSH, and suggest that it may involve disturbances in intracellular homeostasis of calcium.« less

Use of individual auto-injector kits ‘IZAS-05’ on the contemporary battlefield

PubMed Central

Ziemba, Radosław

2012-01-01

Summary In crisis situations, such as transportation catastrophes, terrorist attacks or contamination with chemical warfare agents, it is crucial to properly organize and sensibly conduct rescue operations. Among chemical warfare agents, the most toxic ones are the derivatives of organophosphorus compounds. An individual auto-injector kit ‘IZAS-05’ contains auto-injectors, which are devices designed for intramuscular administration of drugs in self-aid or buddy-aid on the battlefield. This paper describes in detail the components of the ‘IZAS-05’ kit, as well as its mode of use and possible contraindications. PMID:22207129

Homolytic substitution at phosphorus for C–P bond formation in organic synthesis

PubMed Central

2013-01-01

Summary Organophosphorus compounds are important in organic chemistry. This review article covers emerging, powerful synthetic approaches to organophosphorus compounds by homolytic substitution at phosphorus with a carbon-centered radical. Phosphination reagents include diphosphines, chalcogenophosphines and stannylphosphines, which bear a weak P–heteroatom bond for homolysis. This article deals with two transformations, radical phosphination by addition across unsaturated C–C bonds and substitution of organic halides. PMID:23843922

Evaluation of Chemically-Sensitive Field-Effect Transistors for Detection of Organophosphorus Compounds

DTIC Science & Technology

1989-12-05

during past decade. In order to understand the basic operation of these sensors, especially of the CHEMFET, the appropriate background information will...during the past decade for detecting organophosphorus compounds, the chemically- sensitive thin films investigated in this thesis, and finally, the...reactivate the phosphorylated cholinesterase enzyme. Solid State Chemical Sensors During the past decade, a number of solid state chemical sensors have been

Environmental contaminants

USGS Publications Warehouse

Hoffman, D.J.; Rattner, B.A.; Scheunert, I.; Korte, F.; Shore, Richard F.; Rattner, Barnett A.

2001-01-01

The purpose of this chapter is to provide an overview of the ecotoxicology of major classes of environmental contaminants, with respect to sources, environmental chemistry, most likely routes of exposure, potential bioaccumulation and biomagification, mechanisms of toxicity, and effects on potentially vulnerable species of mammalian wildlife. Major contaminants reviewed were selected on the basis of their use patterns, availability and potential toxicity to wild mammals. These included pesticides used in agroecosystems (organochlorines, organophosphorus and carbamate compounds, anticoagulants, herbicides and fungicides), various organic pollutants (chlorobenzenes, chlorophenols, polychlorinated biphenyls, dibenzodioxins and dibenzofurans, and polycyclic aromatic hydrocarbons), heavy metals (lead, mercury, and cadmium), agricultural drainwater mixtures, leachates and radionuclides. Many of the above aspects of ecotoxicology and contaminants will be expanded upon in subsequent chapters of this book as they relate to distinct mammalian species and potential risk.

HI-6 assisted Catalytic Scavenging of VX by Acetylcholinesterase Choline Binding Site Mutants

PubMed Central

Hrvat, Nikolina Maček; Žunec, Suzana; Taylor, Palmer; Radić, Zoran; Kovarik, Zrinka

2016-01-01

The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein, we demonstrate an efficient HI-6-assisted VX detoxification, both ex vivo in human blood and in vivo in mice by hAChE mutants modified at the choline binding site (Y337A and Y337A/F338A). The catalytic scavenging of VX in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms. PMID:27083141

Environmental Fate of Organophosphorus Compounds Related to Chemical Weapons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davisson, M L; Love, A H; Vance, A

2005-02-08

Man-made organophosphorus compounds have been widely distributed throughout our environment as pesticides since their development during and after WWII. Many important studies have documented their relative persistence and toxicity. Development and use of some organophosphorus compounds as nerve agents gave rise to a separate but parallel effort to understand environmental persistence. In this latter case, the experiments have focused mainly on evaporation rates and first-order reaction kinetics. However, because organophosphorus compounds are easily polarized, the ionic content of a surrounding media directly factors into these reaction rates, but limited work in this regard has been done under environmentally relevant conditions.more » Furthermore, limited experiments investigating persistence of these agents on soil has resulted in widely varying degradation rates. Not surprisingly, no studies have investigated affinities of organophosphorus nerve agents to mineral or organic matter typically found in soil. As a result, we initiated laboratory experiments on dilute concentrations of nerve agent O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) to quantify persistence in simulated environmental aqueous conditions. A quantitative analytical method was developed for VX and its degradation products using High Performance Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (HPLC-ESI-MS). VX hydrolysis rate is known to have a pH-dependency, however, the type of buffer and the relative proportion of different nucleophiles in solution significantly affect the overall rate and mechanism of degradation. For example, dissolved carbonate, a weak nucleophile dominating natural water, yielded pseudo-first order rate constants of {approx} 8 x 10{sup -3}/hr at pH 5 and 2 x 10{sup -2}/hr at pH 11. This small pH-dependent variation departs significantly from widely accepted rates at this pH range (4 x 10{sup -4}/hr to 8 x 10{sup -2}/hr) that were based on chloride and hydroxyl (strong nucleophile) dominated experimental solutions. Because of its overwhelming abundance in solution relative to hydroxyl ion, bicarbonate likely effectively competes in nucleophilic attack on phosphorus. The addition of natural dissolved organic matter at 100 mg/L in pH 7 bicarbonate buffered solution slowed VX hydrolysis rates {approx}2 times relative to controls, suggesting hydrophobic interaction. Adsorption experiments derived isotherms from batch aqueous experiments on montmorillonite clay, iron-oxyhydroxide goethite, and on amorphous silica. VX had moderate affinity for montmorillonite and amorphous silica, and very low affinity toward goethite. The addition of dissolved organic matter into solution enhanced VX adsorption to goethite, consistent with its high affinity for hydrophobic organic matter (log K{sub oc} = 2.52). Diisopropylaminoethylthiol (DESH), a hydrolysis product of VX showed equivalent adsorption to montmorillonite, and poor affinity to goethite and silica. However, hydrolysis products O-Ethylmethylphosphonic acid (EMPA) and methylphosphonic acid (MPA) strongly adsorbed on goethite, but not on montmorillonite or silica, suggesting a ligand-exchange mechanism. VX degraded rapidly when completely dried onto goethite followed by rehydration, consistent with an irreversible chemical adsorption mechanism.« less

Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides.

PubMed

Musilek, Kamil; Dolezal, Martin; Gunn-Moore, Frank; Kuca, Kamil

2011-07-01

Organophosphate pesticides (OPPs; e.g. chlorpyrifos, diazinon, paraoxon) are a wide and heterogeneous group of organophosphorus compounds. Their biological activity of inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) ranks them as life endangering agents. The necessary treatment after OPP exposure involves the use of parasympatolytics (e.g. atropine), oxime reactivators (e.g. obidoxime), and anticonvulsive drugs (e.g. diazepam). Therefore, the reactivators of AChE are essential compounds in the treatment of OPP intoxications. Commercial AChE reactivators (e.g. pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) were originally developed for other members of the organophosphate family, such as nerve agents (e.g. sarin, soman, tabun, VX). Pralidoxime, HI-6, and methoxime were found to be weak reactivators of OPP-inhibited AChE. Obidoxime and trimedoxime showed satisfactory reactivation against various OPPs with minor toxicity issues. During the last two decades, the treatment of OPP exposure has become more widely discussed because of growing agricultural production, industrialization, and harmful social issues (e.g. suicides). In this review is the summarized design, evaluation, and structure-activity relationship studies of recently produced AChE reactivators. Since pralidoxime, over 300 oximes have been produced or tested against OPP poisoning, and several novel compounds show very promising abilities as comparable (or higher) to commercial oximes. Some of these are highlighted for their further testing of OPP exposure and, additionally, the main structure-activity relationship of AChE reactivators against OPP is discussed. © 2009 Wiley Periodicals, Inc.

Supercritical Fluid Extraction of Toxic Heavy Metals and Uranium from Acidic Solutions with Sulfur-Containing Organophosphorus Reagents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Yuehe; Liu, Chongxuan; Wu, Hong

2003-03-02

The feasibility of using sulfur-containing organophosphorus reagents for the chelation-supercritical fluid extraction (SFE) of toxic heavy metals and uranium from acidic media was investigated. The SFE experiments were conducted in a specially-designed flow-through liquid extractor. Effective extraction of the metal ions from various acidic media was demonstrated. The effect of ligand concentration in supercritical CO{sub 2} on the kinetics of metal extraction was studied. A simplified model is used to describe the extraction kinetics and the good agreement of experimental data with the equilibrium-based model is achieved.

Phospholipase B activity and organophosphorus compound toxicity in cultured neural cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Read, David J.; Langford, Lynda; Barbour, Helen R.

2007-03-15

Organophosphorus compounds (OP) such as phenyl saligenin phosphate (PSP) and mipafox (MPX) which cause delayed neuropathy, inhibit neuropathy target esterase (NTE), while OPs such as paraoxon (PXN) react more readily with acetylcholinesterase. In yeast and mammalian cell lines, NTE has been shown to have phospholipase B (PLB) activity which deacylates intracellular phosphatidylcholine to glycerophosphocholine (GroPCho) and can be detected by metabolic labeling with [{sup 14}C]choline. Here we investigated PLB activity in primary cultures of mouse neural cells. In cortical and cerebellar granule neurons and astrocytes, [{sup 14}C]GroPCho labeling was inhibited by PSP and MPX: phenyl dipentylphosphinate (PDPP), a non-neuropathic NTEmore » inhibitor, was more potent, while PXN, was substantially less so. In all three cell types, conversion of [{sup 14}C]phosphatidylcholine to [{sup 14}C]GroPCho over 24 h was relatively small (2.3-14%). Consequently, even with > 80% inhibition of [{sup 14}C]GroPCho production, increased [{sup 14}C]phosphatidylcholine was not detected. At concentrations of 1-10 {mu}M, only PSP was cytotoxic to cortical and cerebellar granule neurons after 24-h exposure. Moreover, dramatic changes in glial cell morphology were induced by PSP, but not PDPP or MPX, with rapid (2-3 h) rounding up of astrocytes and of Schwann cells in cultures of dissociated mouse dorsal root ganglia. We conclude that PLB activity is present in a variety of cultured mouse neural cell types but that acute loss of this activity is not cytotoxic. Conversely, the rapid toxic effects of PSP in vitro suggest that a serine hydrolase distinct from NTE is required continuously by neurons and glia.« less

[The VR, the Russian version of the nerve agent VX].

PubMed

Cuquel, A-C; Dorandeu, F; Ceppa, F; Renard, C; Burnat, P

2015-05-01

A product of the arms race during the Cold War, the Russian VX, or VR, is an organophosphorus compound that is a structural isomer of the western VX compound (or A4), with which it shares a very high toxicity. It is much less studied and known than VX because the knowledge of its existence is relatively recent. A very low volatility and high resistance in the environment make it a persistent agent. Poisoning occurs mainly following penetration through skin and mucosa but vapour inhalation is a credible risk in some circumstances. The clinical presentation may be differed by several hours and despite the absence of signs and symptoms, the casualty should not be considered as contamination or intoxication-free. This agent has a long residence time in blood, a characteristics that clearly differentiates it from other compounds such as sarin. The protocols for antidote administration may thus have to be changed accordingly. The fact that VR poisoned individuals will less respond to the current oxime therapy used in France, the 2-PAM and that VR represents a higher threat than VX, being probably possessed by some proliferating states, justify the interest for this toxic product. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Sorption of Organophosphorus Flame Retardants (OPFRs) on ...

EPA Pesticide Factsheets

Organophosphorus flame retardants (OPFRs) are widely used as additives in industrial and consumer products such as electrical and electronic products, furniture, plastics, textiles, and building/construction materials. Due to human exposure and potential health effects, OPFRs including tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCPP), and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) are EPA Action Plan chemicals for chemical assessments under the Toxic Substances Control Act (TSCA). This work investigated the sorption of these three compounds from the air to settled Arizona Test Dust (ATD) and house dust (HD) in a dual small chamber system. The OPFR exposed dust was analyzed to determine the sorption concentration and sorption rate of OPFRs on the dust. The effect of the composition of the dust on OPFR sorption was evaluated. The results showed that ATD and HD have varied sorption capacity for OPFRs from air. This work explores the relationship between OPFR concentrations in settled dust and air. The data can be used to determine partitioning of OPFRs between the gas phase and settled dust indoors and to inform strategies to reduce exposure and risk.

Zebrafish as a model for acetylcholinesterase-inhibiting organophosphorus agent exposure and oxime reactivation

PubMed Central

Koenig, Jeffrey A.; Dao, Thuy L.; Kan, Robert K.; Shih, Tsung-Ming

2016-01-01

The current research progression efforts for investigating novel treatments for exposure to organophosphorus (OP) compounds that inhibit acetylcholinesterase (AChE), including pesticides and chemical warfare nerve agents (CWNAs), rely solely on in vitro cell assays and in vivo rodent models. The zebrafish (Danio rerio) is a popular, well-established vertebrate model in biomedical research that offers high-throughput capabilities and genetic manipulation not readily available with rodents. A number of research studies have investigated the effects of subacute developmental exposure to OP pesticides in zebrafish, observing detrimental effects on gross morphology, neuronal development, and behavior. Few studies, however, have utilized this model to evaluate treatments, such as oxime reactivators, anticholinergics, or anticonvulsants, following acute exposure. Preliminary work has investigated the effects of CWNA exposure. The results clearly demonstrated relative toxicity and oxime efficacy similar to that reported for the rodent model. This review surveys the current literature utilizing zebrafish as a model for OP exposure and highlights its potential use as a high-throughput system for evaluating AChE reactivator antidotal treatments to acute pesticide and CWNA exposure. PMID:27123828

Functionalization of P4 through Direct P-C Bond Formation.

PubMed

Borger, Jaap E; Ehlers, Andreas W; Slootweg, J Chris; Lammertsma, Koop

2017-09-04

Research on chlorine-free conversions of P 4 into organophosphorus compounds (OPCs) has a long track record, but methods that allow desirable, direct P-C bond formations have only recently emerged. These include the use of metal organyls, carbenes, carboradicals, and photochemical approaches. The versatile product scope enables the preparation of both industrially relevant organophosphorus compounds, as well as a broad range of intriguing new compound classes. Herein we provide a concise overview of recent breakthroughs and outline the acquired fundamental insights to aid future developments. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Priority and emerging flame retardants in rivers: occurrence in water and sediment, Daphnia magna toxicity and risk assessment.

PubMed

Cristale, Joyce; García Vázquez, Alejandro; Barata, Carlos; Lacorte, Silvia

2013-09-01

The occurrence, partitioning and risk of eight polybrominated diphenyl ethers (PBDEs), nine new brominated (NBFRs) and ten organophosphorus flame retardants (OPFRs) were evaluated in three Spanish rivers suffering different anthropogenic pressures (Nalón, Arga and Besòs). OPFRs were ubiquitous contaminants in water (ΣOPFRs ranging from 0.0076 to 7.2μgL(-1)) and sediments (ΣOPFRs ranging 3.8 to 824μgkg(-1)). Brominated flame retardants were not detected in waters, whereas ΣPBDEs ranged from 88 to 812μgkg(-1) and decabromodiphenyl ethane (DBDPE) reached 435μgkg(-1) in sediments from the River Besòs, the most impacted river. The occurrence of flame retardants in river water and sediment was clearly associated with human activities, since the highest levels occurred near urban and industrial zones and after wastewater treatment plants discharge. Daphnia magna toxicity was carried out for OPFRs, the most ubiquitous flame retardants, considering individual compounds and mixtures. Toxicity of nine tested OPFRs differed largely among compounds, with EC50 values ranging over three magnitude orders (0.31-381mgL(-1)). Results evidenced that these compounds act by non-polar narcosis, since their toxicity was proportional to their lipophilicity (Kow). Furthermore, their joint toxicity was additive, which means that single and joint toxicity can be predicted knowing their concentration levels in water using quantitative structure activity relationships (QSARs) and predictive mixture models. Based on these results, a risk assessment considering joint effect was performed calculating and summing risk quotients (RQs) for the water and sediment samples. No significant risk to D. magna (ΣRQs <1) was observed for any of the monitored rivers. © 2013.

DEVELOPMENT OF RISK ASSESSMENT TECHNIQUES FOR SOIL BIOAVAILABILITY AND BIOACCUMULATION OF AN ORGANOPHOSPHORUS PESTICIDE

EPA Science Inventory

There is increased concern about the effects of organophosphorus (OP) pesticides on human and animal health. This class of chemicals has been shown to affect the immune function of macrophages and lymphocytes. Malathion, an OP compound, is one of the most widely used pesticides...

A SAW-based chemical sensor for detecting sulfur-containing organophosphorus compounds using a two-step self-assembly and molecular imprinting technology.

PubMed

Pan, Yong; Yang, Liu; Mu, Ning; Shao, Shengyu; Wang, Wen; Xie, Xiao; He, Shitang

2014-05-19

This paper presents a new effective approach for the sensitive film deposition of surface acoustic wave (SAW) chemical sensors for detecting organophosphorus compounds such as O-ethyl-S-2-diisopropylaminoethyl methylphosphonothiolate (VX) containing sulfur at extremely low concentrations. To improve the adsorptive efficiency, a two-step technology is proposed for the sensitive film preparation on the SAW delay line utilizing gold electrodes. First, mono[6-deoxy-6-[(mercaptodecamethylene)thio

A SAW-Based Chemical Sensor for Detecting Sulfur-Containing Organophosphorus Compounds Using a Two-Step Self-Assembly and Molecular Imprinting Technology

PubMed Central

Pan, Yong; Yang, Liu; Mu, Ning; Shao, Shengyu; Wang, Wen; Xie, Xiao; He, Shitang

2014-01-01

This paper presents a new effective approach for the sensitive film deposition of surface acoustic wave (SAW) chemical sensors for detecting organophosphorus compounds such as O-ethyl-S-2-diisopropylaminoethyl methylphosphonothiolate (VX) containing sulfur at extremely low concentrations. To improve the adsorptive efficiency, a two-step technology is proposed for the sensitive film preparation on the SAW delay line utilizing gold electrodes. First, mono[6-deoxy-6-[(mercaptodecamethylene)thio

Toward antibody-catalyzed hydrolysis of organophosphorus poisons

PubMed Central

Vayron, Philippe; Renard, Pierre-Yves; Taran, Frédéric; Créminon, Christophe; Frobert, Yveline; Grassi, Jacques; Mioskowski, Charles

2000-01-01

We report here our preliminary results on the use of catalytic antibodies as an approach to neutralizing organophosphorus chemical weapons. A first-generation hapten, methyl-α-hydroxyphosphinate Ha, was designed to mimic the approach of an incoming water molecule for the hydrolysis of exceedingly toxic methylphosphonothioate VX (1a). A moderate protective activity was first observed on polyclonal antibodies raised against Ha. The results were further confirmed by using a mAb PAR 15 raised against phenyl-α-hydroxyphosphinate Hb, which catalyzes the hydrolysis of PhX (1b), a less toxic phenylphosphonothioate analog of VX with a rate constant of 0.36 M−1⋅min−1 at pH 7.4 and 25°C, which corresponds to a catalytic proficiency of 14,400 M−1 toward the rate constant for the uncatalyzed hydrolysis of 1b. This is a demonstration on the organophosphorus poisons themselves that mAbs can catalytically hydrolyze nerve agents, and a significant step toward the production of therapeutically active abzymes to treat poisoning by warfare agents. PMID:10860971

Non-aqueous electrolyte for lithium-ion battery

DOEpatents

Amine, Khalil; Zhang, Lu; Zhang, Zhengcheng

2016-01-26

A substantially non-aqueous electrolyte solution includes an alkali metal salt, a polar aprotic solvent, and an organophosphorus compound of Formula IA, IB, or IC: ##STR00001## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, alkenoxy, alkynoxy, cycloalkoxy, aryloxy, heterocyclyloxy, heteroaryloxy, siloxyl, silyl, or organophosphatyl; R.sup.5 and R.sup.6 are each independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; R.sup.7 is ##STR00002## and R.sup.8, R.sup.9 and R.sup.10 are each independently alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; provided that if the organophosphorus compound is of Formula IB, then at least one of R.sup.5, and R.sup.6 are other than hydrogen, alkyl, or alkenyl; and if the organophosphorus compound is of Formula IC, then the electrolyte solution does not include 4-methylene-1,3-dioxolan-2-one or 4,5-dimethylene-1,3-dioxolan-2-one.

Accumulation, metabolism and toxicity of parathion in tadpoles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hall, R.J.

1990-04-01

Earlier work exposing tadpoles to organophosphorus pesticides indicated the great resistance of tadpoles of the bullfrog (Rana catesbeiana) to these chemicals and their surprising ability to accumulate parathion and fenthion from water. These qualities seemed to make them an ideal model with which to test a hypothesis advanced by Burke and Ferguson, who noted that parathion is more toxic to resistant mosquitofish in static water than in flowing water--a reversal of the pattern normally seen. They believed that highly toxic metabolite paraoxon was produced by the fish and that its buildup in static systems resulted in the unexpected mortality. Amphibiansmore » have been shown to produce paraoxon and to accumulate the parent compound parathion to levels that are potentially hazardous to other organisms. In the course of examining paraoxon production by tadpoles, it would also be possible to learn more about their patterns of parathion uptake and elimination. Retention of residues is also a matter of concern given the high levels observed in the earlier studies.« less

Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity.

PubMed

Behl, Mamta; Hsieh, Jui-Hua; Shafer, Timothy J; Mundy, William R; Rice, Julie R; Boyd, Windy A; Freedman, Jonathan H; Hunter, E Sidney; Jarema, Kimberly A; Padilla, Stephanie; Tice, Raymond R

2015-01-01

Due to their toxicity and persistence in the environment, brominated flame retardants (BFRs) are being phased out of commercial use, leading to the increased use of alternative chemicals such as the organophosphorus flame retardants (OPFRs). There is, however, limited information on the potential health effects of OPFRs. Due to the structural similarity of the OPFRs to organophosphorus insecticides, there is concern regarding developmental toxicity and neurotoxicity. In response, we evaluated a set of OPFRs (triphenyl phosphate [TPHP]), isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], (tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl)phosphate [TCEP]) in a battery of cell-based in vitro assays and alternative model organisms and compared the results to those obtained for two classical BFRs (3,3',5,5'-tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). The assays used evaluated the effects of chemicals on the differentiation of mouse embryonic stem cells, the proliferation and growth of human neural stem cells, rat neuronal growth and network activity, and development of nematode (Caenorhabditis elegans) and zebrafish (Danio rerio). All assays were performed in a concentration-response format, allowing for the determination of the point of departure (POD: the lowest concentration where a chemically-induced response exceeds background noise). The majority of OPFRs (8/9) were active in multiple assays in the range of 1-10 μM, most of which had comparable activity to the BFRs TBBPA and BDE-47. TCEP was negative in all assays. The results indicate that the replacement OPFRs, with the exception of TCEP, showed comparable activity to the two BFRs in the assays tested. Based on these results, more comprehensive studies are warranted to further characterize the potential hazard of some of these OPFR compounds. Published by Elsevier Inc.

HI-6 assisted catalytic scavenging of VX by acetylcholinesterase choline binding site mutants.

PubMed

Maček Hrvat, Nikolina; Žunec, Suzana; Taylor, Palmer; Radić, Zoran; Kovarik, Zrinka

2016-11-25

The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein, we demonstrate an efficient HI-6-assisted VX detoxification, both ex vivo in human blood and in vivo in mice by hAChE mutants modified at the choline binding site (Y337A and Y337A/F338A). The catalytic scavenging of VX in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Structure–efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds

PubMed Central

Letort, Sophie; Bosco, Michaël; Cornelio, Benedetta; Brégier, Frédérique; Daulon, Sébastien; Gouhier, Géraldine

2017-01-01

New derivatives of cyclodextrins were prepared in order to determine the relative importance of the structural key elements involved in the degradation of organophosphorus nerve agents. To avoid a competitive inclusion between the organophosphorus substrate and the iodosobenzoate group, responsible for its degradation, the latter group had to be covalently bound to the cyclodextrin scaffold. Although the presence of the α nucleophile iodosobenzoate was a determinant in the hydrolysis process, an imidazole group was added to get a synergistic effect towards the degradation of the agents. The degradation efficiency was found to be dependent on the relative position of the heterocycle towards the reactive group as well as on the nature of the organophosphorus derivative. PMID:28382180

Structure-efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds.

PubMed

Letort, Sophie; Bosco, Michaël; Cornelio, Benedetta; Brégier, Frédérique; Daulon, Sébastien; Gouhier, Géraldine; Estour, François

2017-01-01

New derivatives of cyclodextrins were prepared in order to determine the relative importance of the structural key elements involved in the degradation of organophosphorus nerve agents. To avoid a competitive inclusion between the organophosphorus substrate and the iodosobenzoate group, responsible for its degradation, the latter group had to be covalently bound to the cyclodextrin scaffold. Although the presence of the α nucleophile iodosobenzoate was a determinant in the hydrolysis process, an imidazole group was added to get a synergistic effect towards the degradation of the agents. The degradation efficiency was found to be dependent on the relative position of the heterocycle towards the reactive group as well as on the nature of the organophosphorus derivative.

Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain

DTIC Science & Technology

2012-01-01

NUMBER activates BDNF expression in mouse brain 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Pizarro, JM, Chang, WE, Bah, MJ...of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain Jose M. Pizarro,*,† Wenling E. Chang,†,‡ Mariama J. Bah,† Linnzi K. M...triphosphate and UTP, and 2 ll modified cytidine triphosphate solution [2mM]), 33P-UTP (specific activity of 5 3 109 cpm/lg), 2 ll RNA polymerase, 2 ll of

DEVELOPMENT OF A RISK ASSESSMENT MODEL FOR THE EFFECTS OF ORGANOPHOSPHORUS PESTICIDES ON INFECTIOUS DISEASE SUSCEPTIBILITY AND THE IMMUNE SYSTEM

EPA Science Inventory

There is increased concern about the sublethal effects of organophosphorus (OP) pesticides on human and animal health. This class of chemicals has been shown to affect the immune function of macrophages and lymphocytes. Malathion, an OP compound, is one of the most widely used ...

AGE-RELATED EFFECTS OF CHLORPYRIFOS ON ACETYLCHOLINE RELEASE IN RAT BRAIN. (R825811)

EPA Science Inventory

Chlorpyrifos (CPF) is an organophosphorus insecticide that elicits toxicity through inhibition of acetylcholinesterase (AChE). Young animals are markedly more sensitive than adults to the acute toxicity of CPF. We evaluated acetylcholine (ACh) release and its muscarinic recept...

Risk assessment of the cumulative acute exposure of Hungarian population to organophosphorus pesticide residues with regard to consumers of plant based foods.

PubMed

Zentai, Andrea; Szabó, István J; Kerekes, Kata; Ambrus, Árpád

2016-03-01

Based on the Hungarian pesticide residues monitoring data of the last five years and the consumption data collected within a 3-day dietary record survey in 2009 (more than 2 million pesticide residue results and almost 5000, 0-101-year-old consumers 3 non-consecutive-day personal fruit and vegetable consumption data), the cumulative acute exposure of organophosphorus pesticide residues was evaluated. The relative potency factor approach was applied, with acephate chosen as index compound. According to our conservative calculation method, applying the measured residues only, the 99.95% of the 99th percentiles of calculated daily intakes was at or below 87 μg/kgbwday, indicating that the cumulative acute exposure of the whole Hungarian population (including all age classes) to organophosphorus compounds was not a health concern. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quantitative 31P NMR for Simultaneous Trace Analysis of Organophosphorus Pesticides in Aqueous Media Using the Stir Bar Sorptive Extraction Method

NASA Astrophysics Data System (ADS)

Ansari, S.; Talebpour, Z.; Molaabasi, F.; Bijanzadeh, H. R.; Khazaeli, S.

2016-09-01

The analysis of pesticides in water samples is of primary concern for quality control laboratories due to the toxicity of these compounds and their associated public health risk. A novel analytical method based on stir bar sorptive extraction (SBSE), followed by 31P quantitative nuclear magnetic resonance (31P QNMR), has been developed for simultaneously monitoring and determining four organophosphorus pesticides (OPPs) in aqueous media. The effects of factors on the extraction efficiency of OPPs were investigated using a Draper-Lin small composite design. An optimal sample volume of 4.2 mL, extraction time of 96 min, extraction temperature of 42°C, and desorption time of 11 min were obtained. The results showed reasonable linearity ranges for all pesticides with correlation coefficients greater than 0.9920. The limit of quantification (LOQ) ranged from 0.1 to 2.60 mg/L, and the recoveries of spiked river water samples were from 82 to 94% with relative standard deviation (RSD) values less than 4%. The results show that this method is simple, selective, rapid, and can be applied to other sample matrices.

Fourth Indo-US Workshop on Mathematical Chemistry Held in Pune, Maharastra, India on 8-12 January 2005

DTIC Science & Technology

2005-01-12

Designing of less toxic to non target organophosphorus pesticide through multiple correlation analysis (MRA), a part of QSAR Rini Roy, Aditi Nag...of Organophosphorus Pesticide (OPs) in biological system and environment have implicated wide use of these types of pesticides in agriculture in...having minimal effect on any part of mammalian brain. In our study, we have dealt with the effects of phosphorothionate pesticides like methyl parathion

A systems-level approach for investigating organophosphorus pesticide toxicity.

PubMed

Zhu, Jingbo; Wang, Jing; Ding, Yan; Liu, Baoyue; Xiao, Wei

2018-03-01

The full understanding of the single and joint toxicity of a variety of organophosphorus (OP) pesticides is still unavailable, because of the extreme complex mechanism of action. This study established a systems-level approach based on systems toxicology to investigate OP pesticide toxicity by incorporating ADME/T properties, protein prediction, and network and pathway analysis. The results showed that most OP pesticides are highly toxic according to the ADME/T parameters, and can interact with significant receptor proteins to cooperatively lead to various diseases by the established OP pesticide -protein and protein-disease networks. Furthermore, the studies that multiple OP pesticides potentially act on the same receptor proteins and/or the functionally diverse proteins explained that multiple OP pesticides could mutually enhance toxicological synergy or additive on a molecular/systematic level. To the end, the integrated pathways revealed the mechanism of toxicity of the interaction of OP pesticides and elucidated the pathogenesis induced by OP pesticides. This study demonstrates a systems-level approach for investigating OP pesticide toxicity that can be further applied to risk assessments of various toxins, which is of significant interest to food security and environmental protection. Copyright © 2017 Elsevier Inc. All rights reserved.

THE ANTICHOLINESTERASE INSECTICIDE, DIAZINON, MAY POTENTIATE THE TOXICITY OF THE PYRETHROID INSECTICIDE DELTAMETHRIN AT LOW DOSAGES.

EPA Science Inventory

This present study explores the interaction of the toxicity induced by an organophosphorus insecticide, diazinon (diethyl 2-isopropyl-6methyl-4-pyrimidal phosphorothionate), with a pyrethroid insecticide, deltamethrin ((S)-a-cyano-3-phenoxybenzyl (1R,3R)-3-(2,2-dibromovinyl)-2,...

Age-related differences in acetylcholinesterase inhibition produced by organophosphorus and N-methyl carbamate pesticides

EPA Science Inventory

Introduction The concern that infants and children may be more susceptible to the toxic effects of chemicals, including pesticides, has received much attention in the scientific literature and the public media. Greater toxicity may be evident as long-term adverse outcomes, e.g.,...

Parenteral organophosphorus poisoning in a rural emergency department: a case report

PubMed Central

2013-01-01

Background Poisoning is a common presentation in the emergency department. Oral exposures to organophosphorus compounds are especially frequent in rural and agricultural regions of South Asia and throughout the developing world. Case presentation Here we report a case of deliberate self-harm with an organophosphorus pesticide via the relatively uncommon parenteral route. A young woman injected herself with chlorpyriphos. Although the cholinergic effects were mild, cellulitis and abscess development were noted as a result. Conclusion Resource limited agricultural countries like Nepal present health care workers with numerous challenges in poisoning management. This case represents a rare but potentially morbid method of agrochemical poison exposure. PMID:24321121

Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Read, David J.; Li Yong; Chao, Moses V.

2010-05-15

Single doses of organophosphorus compounds (OP) which covalently inhibit neuropathy target esterase (NTE) can induce lower-limb paralysis and distal damage in long nerve axons. Clinical signs of neuropathy are evident 3 weeks post-OP dose in humans, cats and chickens. By contrast, clinical neuropathy in mice following acute dosing with OPs or any other toxic compound has never been reported. Moreover, dosing mice with ethyloctylphosphonofluoridate (EOPF) - an extremely potent NTE inhibitor - causes a different (subacute) neurotoxicity with brain oedema. These observations have raised the possibility that mice are intrinsically resistant to neuropathies induced by acute toxic insult, but maymore » incur brain oedema, rather than distal axonal damage, when NTE is inactivated. Here we provide the first report that hind-limb dysfunction and extensive axonal damage can occur in mice 3 weeks after acute dosing with a toxic compound, bromophenylacetylurea. Three weeks after acutely dosing mice with neuropathic OPs no clinical signs were observed, but distal lesions were present in the longest spinal sensory axons. Similar lesions were evident in undosed nestin-cre:NTEfl/fl mice in which NTE had been genetically-deleted from neural tissue. The extent of OP-induced axonal damage in mice was related to the duration of NTE inactivation and, as reported in chickens, was promoted by post-dosing with phenylmethanesulfonylfluoride. However, phenyldipentylphosphinate, another promoting compound in chickens, itself induced in mice lesions different from the neuropathic OP type. Finally, EOPF induced subacute neurotoxicity with brain oedema in both wild-type and nestin-cre:NTEfl/fl mice indicating that the molecular target for this effect is not neural NTE.« less

[The mechanism of the transport of organophosphorus compounds across the histo-hematic barriers].

PubMed

Miroshkina, V N; Kosmachev, A B; Salova, L S

1999-01-01

It was demonstrated in experiments on mice [correction of rats] that the transport of organophosphorus compounds (OPC) through membranes of the histohematic barriers (HHB) of the organism occurs by means of diffusion. The rate of this process depends on the interaction of OPC with the specific sites of binding with the tissues, among which the enzyme carboxylesterase plays an important part. It is suggested that both the rate and direction of OPC diffusion are determined by the relationship between the values of affinity of the ligands for the sites of their specific binding found on both sides of the HHB.

Toxicity of carbamates for mammals

PubMed Central

Vandekar, M.; Pleština, R.; Wilhelm, K.

1971-01-01

Toxicity studies have been carried out with a number of monomethylcarbamates, most of which reached an advanced stage in the World Health Organization insecticide evaluation programme. Both quantitative and qualitative distinctions have been found between the carbamates studied, and certain common characteristics that distinguish them in several important aspects from organophosphorus insecticides have been demonstrated. PMID:4999482

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2010 CFR

2010-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2013 CFR

2013-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2014 CFR

2014-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2012 CFR

2012-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2011 CFR

2011-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

Can hydroxylamine be a more potent nucleophile for the reactivation of tabun-inhibited AChE than prototype oxime drugs? An answer derived from quantum chemical and steered molecular dynamics studies.

PubMed

Lo, Rabindranath; Ganguly, Bishwajit

2014-07-29

Organophosphorus nerve agents are highly toxic compounds which strongly inhibit acetylcholinesterase (AChE) in the blood and in the central nervous system (CNS). Tabun is one of the highly toxic organophosphorus (OP) compounds and is resistant to many oxime drugs formulated for the reactivation of AChE. The reactivation mechanism of tabun-conjugated AChE with various drugs has been examined with density functional theory and ab initio quantum chemical calculations. The presence of a lone-pair located on the amidic group resists the nucleophilic attack at the phosphorus center of the tabun-conjugated AChE. We have shown that the newly designed drug candidate N-(pyridin-2-yl)hydroxylamine, at the MP2/6-31+G*//M05-2X/6-31G* level in the aqueous phase with the polarizable continuum solvation model (PCM), is more effective in reactivating the tabun-conjugated AChE than typical oxime drugs. The rate determining activation barrier with N-(pyridin-2-yl)hydroxylamine was found to be ∼1.7 kcal mol(-1), which is 7.2 kcal mol(-1) lower than the charged oxime trimedoxime (one of the most efficient reactivators in tabun poisonings). The greater nucleophilicity index (ω(-)) and higher CHelpG charge of pyridinylhydroxylamine compared to TMB4 support this observation. Furthermore, we have also examined the reactivation process of tabun-inhibited AChE with some other bis-quaternary oxime drug candidates such as methoxime (MMB4) and obidoxime. The docking analysis suggests that charged bis-quaternary pyridinium oximes have greater binding affinity inside the active-site gorge of AChE compared to the neutral pyridinylhydroxylamine. The peripheral ligand attached to the neutral pyridinylhydroxylamine enhanced the binding with the aromatic residues in the active-site gorge of AChE through effective π-π interactions. Steered molecular dynamics (SMD) simulations have also been performed with the charged oxime (TMB4) and the neutral hydroxylamine. From protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometry and the orientation of the drug candidates, the hydroxylamine is suggested to orchestrate the reactivation process better than TMB4. Furthermore, the calculated log P values show the effective penetration of the neutral drug candidate through the blood-brain barrier. The toxicity measurements and the IC50 values (a measure of the intrinsic affinity toward AChE) suggest that the pyridinylhydroxylamine compound could have similar toxic behavior compared to the prototype oxime antidotes used for reactivation purposes. The newly designed pyridinylhydroxylamine drug candidate can be an effective antidote both kinetically and structurally to reactivate the tabun-inhibited enzyme.

Pesticide intoxications in the Centre of Portugal: three years analysis.

PubMed

Teixeira, Helena; Proença, Paula; Alvarenga, Margarida; Oliveira, Margarida; Marques, Estela P; Vieira, Duarte Nuno

2004-07-16

Pesticides are used in most countries around the world to protect agricultural and horticultural crops against damage. Poisoning by these toxicant agents occurs as a result of misuse or accidental exposure, and also by oral ingestion (voluntary or not). In Portugal, pesticide intoxications are still a cause of death, found in a considerable number of cases. The authors retrospectively examined the cases of pesticide poisoning in the Centre of Portugal, from autopsies performed in the Forensic Pathology Service of Coimbra's Delegation of the National Institute of Legal Medicine (NILM) and from other autopsies carried out in the Centre of Portugal, as well as some samples taken in hospitals in cases of suspected intoxication. In this study, the positive cases have been especially studied, in order to identify the pesticide used, as well as the etiology. The frequency of intoxications and its distribution by sex and age were also analyzed. Between January 2000 and December 2002, the Forensic Toxicology Laboratory received 639 pesticide analysis requests. In 2000, in a total of 149 analysis requests, 30 cases were positive, 63.3% from male individuals and 36.7% from female. In 2001, the analysis requests increased to 240 as well as the positive cases (43), 74.4% from male individuals and 25.6% from female and in 2002, the total cases analyzed also increased to 250, with 38 positive (73.6% from male individuals and 26.4% from female). Among the pesticides, organophosphorus insecticides still constitute the most important class detected in forensic intoxications, representing 63% of the total positive cases, followed by herbicides, with 33% of the positive results. Quinalphos is the most important organophosphorus insecticide, present in 32 of the 111 positive cases, followed by the herbicide paraquat, detected in 31 cases. The study emphasizes the increasing number of pesticide analyses, particularly relevant for the organophosphorus compounds and herbicides. Intoxication suspicion, accidental or voluntary, seems to be the most common cause of the incidents, for which analyses are requested, but it is also evident that the putative cause is unknown in a large number of cases. Therefore, more stringent legislation and enforcement regarding the sale and distribution of these toxic substances are needed.

The relationship between the chemical structure and neurotoxicity of alkyl organophosphorus compounds

PubMed Central

Davies, D. R.; Holland, P.; Rumens, M. J.

1960-01-01

Thirty-six alkyl organophosphorus compounds have been tested for neurotoxicity in the chicken. The individual compounds were chosen to enable the importance of each portion of the molecule to be assessed in relation to the property of neurotoxicity. Seventeen substances were found to be neurotoxic, fifteen for the first time. All of these contained fluorine. On the basis of the results reported, certain predictions have been made about the chemical structure of compounds which would be expected to be neurotoxic. The importance of fluorine suggests that it plays a direct role in the development of the biochemical lesion, and this may occur as the result of its being carried by the molecule as a whole to specific areas in the nervous system. By the action of cholinesterase, the P-F bond may be ruptured and ionic fluorine liberated where it blocks some metabolic cycle. PMID:13814387

Organophosphorus Compounds at 80: Some Old and New Issues.

PubMed

Costa, Lucio G

2018-03-01

One of the major classes of pesticides is that of the organophosphates (OPs). Initial developments date back almost 2 centuries but it was only in the mid-1940s that OPs reached a prominent status as insecticides, a status that, albeit declining, is still ongoing. OPs are highly toxic to nontarget species including humans, the primary effects being an acute cholinergic toxicity (responsible for thousands of poisoning each year) and a delayed polyneuropathy. Several issues of current debate and investigation on the toxicology of OPs are discussed in this brief review. These include (1) possible additional targets of OPs, (2) OPs as developmental neurotoxicants, (3) OPs and neurodegenerative diseases, (4) OPs and the "aerotoxic syndrome," (5) OPs and the microbiome, and (6) OPs and cancer. Some of these issues have been debated and studied for some time, while others are newer, suggesting that the study of the toxicology of OPs will remain an important scientific and public health issue for years to come.

Percutaneous toxicity and decontamination of soman, VX, and paraoxon in rats using detergents.

PubMed

Misík, Jan; Pavliková, Růžena; Kuča, Kamil

2013-06-01

Highly toxic organophosphorus compounds (OPs) were originally developed for warfare or as agricultural pesticides. Today, OPs represent a serious threat to military personnel and civilians. This study investigates the in vivo decontamination of male Wistar rats percutaneously exposed to paraoxon and two potent nerve agents--soman (GD) and VX. Four commercial detergents were tested as decontaminants--Neodekont(TM), Argos(TM), Dermogel(TM), and FloraFree(TM). Decontamination performed 2 min after exposure resulted in a higher survival rate in comparison with non-decontaminated controls. The decontamination effectiveness was expressed as protective ratio (PR, median lethal dose of agent in decontaminated animals divided by the median lethal dose of agent in untreated animals). The highest decontamination effectiveness was consistently achieved with Argos(TM) (PR=2.3 to 64.8), followed by Dermogel(TM) (PR=2.4 to 46.1). Neodekont(TM) and FloraFree(TM) provided the lowest decontamination effectiveness, equivalent to distilled water (PR=1.0 to 43.2).

Validation of an SPME method, using PDMS, PA, PDMS-DVB, and CW-DVB SPME fiber coatings, for analysis of organophosphorus insecticides in natural waters.

PubMed

Lambropoulou, D A; Sakkas, V A; Albanis, T A

2002-11-01

Solid-phase microextraction (SPME) has been optimized and applied to the determination of the organophosphorus insecticides diazinon, dichlofenthion, parathion methyl, malathion, fenitrothion, fenthion, parathion ethyl, bromophos methyl, bromophos ethyl, and ethion in natural waters. Four types of SPME fiber coated with different stationary phases (PDMS, PA, PDMS-DVB, and CW-DVB) were used to examine their extraction efficiencies for the compounds tested. Conditions that might affect the SPME procedure, such as extraction time and salt content, were investigated to determine the analytical performance of these fiber coatings for organophosphorus insecticides. The optimized procedure was applied to natural waters - tap, sea, river, and lake water - spiked in the concentration range 0.5 to 50 micro g L(-1) to obtain the analytical characteristics. Recoveries were relatively high - >80% for all types of aqueous sample matrix - and the calibration plots were reproducible and linear (R(2)>0.982) for all analytes with all the fibers tested. The limits of detection ranged from 2 to 90 ng L(-1), depending on the detector and the compound investigated, with relative standard deviations in the range 3-15% at all the concentration levels tested. The SPME partition coefficients (K(f)) of the organophosphorus insecticides were calculated experimentally for all the polymer coatings. The effect of organic matter such as humic acids on extraction efficiency was also studied. The analytical performance of the SPME procedure using all the fibers in the tested natural waters proved effective for the compounds.

Hydrolysis of VX and related compounds by organophosphorus hydrolase. Final report, Februray-December 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kolakowski, J.E.; DeFrank, J.J.; Lai, K.

1995-11-01

Organophosphorus Hydrolase (OPH) is a fully characterized and cloned enzyme, derived from Pseudomonas diminuta, consisting of 365 amino acids with a total molecular weight of 38,0(X). The enzyme has a leader sequence of 29 amino acids which has been removed in the construction used in this study. OPH was evaluated for its effectiveness in catalyzing the S-(2-diisopwpylaminoethyl) methylphosphonothioate (VX) and its analogs.

Chiral separation of G-type chemical warfare nerve agents via analytical supercritical fluid chromatography.

PubMed

Kasten, Shane A; Zulli, Steven; Jones, Jonathan L; Dephillipo, Thomas; Cerasoli, Douglas M

2014-12-01

Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(-) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(-) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc.

Insecticide resistance resulting from sequential selection of houseflies in the field by organophosphorus compounds*

PubMed Central

Georghiou, George P.; Hawley, Marilyn K.

1971-01-01

Although cross-resistance in houseflies to the organophosphates has eliminated numerous potentially useful compounds from field use, the ”subgroup” specificity of this phenomenon has permitted housefly control to be carried out for nearly a quarter of a century by changing from one toxicant to another within this class of insecticides. A question of considerable importance in insect control is whether the development of resistance to one subgroup of organophosphates will be at the expense of resistance to a subgroup applied previously. The development over several years of resistance in a field population selected sequentially by a number of organophosphates was studied. It was observed that the resistance spectrum expanded progressively to include, finally, organophosphates originally thought to belong to more than one subgroup—namely, malathion (resistance greater than 100 times), fenchlorphos (114 times), diazinon (163 times), coumaphos (greater than 100 times), Ciodrin (greater than 100 times), fenthion (18 times) and naled (9.3 times). Resistance to each compound continued to rise to levels considerably higher than those achieved at the time when the field use of the compound ended. The possible coexistence of subgroup cross-resistance in a population is discussed in the light of these results. PMID:5316852

Localization of cholinesterases in the chicken nervous system and the problem of the selective neurotoxicity of organophosphorus compounds

PubMed Central

Cavanagh, J. B.; Holland, P.

1961-01-01

Using the thiocholine method, a restricted survey has been made of cholinesterases in the spinal cord and brain stem of the chicken. No simple relation between sites of selective damage in organophosphorus neurotoxicity and centres of cholinesterase activity could be adduced. Moreover, no significant differences between species susceptible and insusceptible to poisoning by these compounds were found by this method. It is concluded that, while cholinesterase may well play an intermediary role in the intoxication, other factors determine the selective damage to certain neurones and their processes. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 PMID:13691740

Study of a QCM dimethyl methylphosphonate sensor based on a ZnO-modified nanowire-structured manganese dioxide film.

PubMed

Pei, Zhifu; Ma, Xingfa; Ding, Pengfei; Zhang, Wuming; Luo, Zhiyuan; Li, Guang

2010-01-01

Sensitive, selective and fast detection of chemical warfare agents is necessary for anti-terrorism purposes. In our search for functional materials sensitive to dimethyl methylphosphonate (DMMP), a simulant of sarin and other toxic organophosphorus compounds, we found that zinc oxide (ZnO) modification potentially enhances the absorption of DMMP on a manganese dioxide (MnO(2)) surface. The adsorption behavior of DMMP was evaluated through the detection of tiny organophosphonate compounds with quartz crystal microbalance (QCM) sensors coated with ZnO-modified MnO(2) nanofibers and pure MnO(2) nanofibers. Experimental results indicated that the QCM sensor coated with ZnO-modified nanostructured MnO(2) film exhibited much higher sensitivity and better selectivity in comparison with the one coated with pure MnO(2) nanofiber film. Therefore, the DMMP sensor developed with this composite nanostructured material should possess excellent selectivity and reasonable sensitivity towards the tiny gaseous DMMP species.

Experimental and in silico investigations of organic phosphates and phosphonates sorption on polymer-ceramic monolithic materials and hydroxyapatite.

PubMed

Pietrzyńska, Monika; Zembrzuska, Joanna; Tomczak, Rafał; Mikołajczyk, Jakub; Rusińska-Roszak, Danuta; Voelkel, Adam; Buchwald, Tomasz; Jampílek, Josef; Lukáč, Miloš; Devínsky, Ferdinand

2016-10-10

A method based on experimental and in silico evaluations for investigating interactions of organic phosphates and phosphonates with hydroxyapatite was developed. This quick and easy method is used for determination of differences among organophosphorus compounds of various structures in their mineral binding affinities. Empirical sorption evaluation was carried out using liquid chromatography with tandem mass spectrometry or UV-VIS spectroscopy. Raman spectroscopy was used to confirm sorption of organic phosphates and phosphonates on hydroxyapatite. Polymer-ceramic monolithic material and bulk hydroxyapatite were applied as sorbent materials. Furthermore, a Polymer-ceramic Monolithic In-Needle Extraction device was used to investigate both sorption and desorption steps. Binding energies were computed from the fully optimised structures utilising Density Functional Theory (DFT) at B3LYP/6-31+G(d,p) level. Potential pharmacologic and toxic effects of the tested compounds were estimated by the Prediction of the Activity Spectra of Substances using GeneXplain software. Copyright © 2016 Elsevier B.V. All rights reserved.

Study of a QCM Dimethyl Methylphosphonate Sensor Based on a ZnO-Modified Nanowire-Structured Manganese Dioxide Film

PubMed Central

Pei, Zhifu; Ma, Xingfa; Ding, Pengfei; Zhang, Wuming; Luo, Zhiyuan; Li, Guang

2010-01-01

Sensitive, selective and fast detection of chemical warfare agents is necessary for anti-terrorism purposes. In our search for functional materials sensitive to dimethyl methylphosphonate (DMMP), a simulant of sarin and other toxic organophosphorus compounds, we found that zinc oxide (ZnO) modification potentially enhances the absorption of DMMP on a manganese dioxide (MnO2) surface. The adsorption behavior of DMMP was evaluated through the detection of tiny organophosphonate compounds with quartz crystal microbalance (QCM) sensors coated with ZnO-modified MnO2 nanofibers and pure MnO2 nanofibers. Experimental results indicated that the QCM sensor coated with ZnO-modified nanostructured MnO2 film exhibited much higher sensitivity and better selectivity in comparison with the one coated with pure MnO2 nanofiber film. Therefore, the DMMP sensor developed with this composite nanostructured material should possess excellent selectivity and reasonable sensitivity towards the tiny gaseous DMMP species. PMID:22163653

Overexpression of Human Senescence Marker Protein 30 in Mice Fails to Offer Protection Against Challenge with Organophosphorus Compounds

DTIC Science & Technology

2011-09-01

poisoning. Toxicology 233: 145-154. 2. Gray AP (1984) Design and structure- activity relationships of antidotes to organophosphorus anticholinesterase ...and is being actively pursued. One approach under investigation is the development of human proteins as bioscavengers that sequester or hydrolyze...the major roles described for SMP30 is in maintaining Ca2+ homeostasis by activating enzymes involved in the regulation of Ca2+ pumps localized in

Gas chromatography/mass spectrometry comprehensive analysis of organophosphorus, brominated flame retardants, by-products and formulation intermediates in water.

PubMed

Cristale, Joyce; Quintana, Jordi; Chaler, Roser; Ventura, Francesc; Lacorte, Silvia

2012-06-08

A multiresidue method based on gas chromatography coupled to quadrupole mass spectrometry was developed to determine organophosphorus flame retardants, polybromodiphenyl ethers (BDEs 28, 47, 99, 100, 153, 154, 183 and 209), new brominated flame retardants, bromophenols, bromoanilines, bromotoluenes and bromoanisoles in water. Two ionization techniques (electron ionization--EI, and electron capture negative ionization--ECNI) and two acquisition modes (selected ion monitoring--SIM, and selected reaction monitoring--SRM) were compared as regards to mass spectral characterization, sensitivity and quantification capabilities. The highest sensitivity, at expenses of identification capacity, was obtained by GC-ECNI-MS/SIM for most of the compounds analyzed, mainly for PBDEs and decabromodiphenyl ethane while GC-EI-MS/MS in SRM was the most selective technique and permitted the identification of target compounds at the pg level, and identification capabilities increased when real samples were analyzed. This method was further used to evaluate the presence and behavior of flame retardants within a drinking water treatment facility. Organophosphorus flame retardants were the only compounds detected in influent waters at levels of 0.32-0.03 μg L⁻¹, and their elimination throughout the different treatment stages was evaluated. Copyright © 2012 Elsevier B.V. All rights reserved.

INFLUENCE OF ENVIRONMENTAL CHANGES ON DEGRADATION OF CHIRAL POLLUTANTS IN SOILS

EPA Science Inventory

Numerous anthropogenic chemicals of environmental concern- including some phenoxy acid herbicides, organophosphorus insecticides, polychlorinated biphenyls, phthalates, freon substi- tutes and some DDT derivatives- are chiral. Their potential biological effects, such as toxicity,...

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication

PubMed Central

Soares, Flávia V.; de Castro, Alexandre A.; Pereira, Ander F.; Leal, Daniel H. S.; Mancini, Daiana T.; da Cunha, Elaine F. F.; Kuca, Kamil

2018-01-01

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways. PMID:29690585

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication.

PubMed

Soares, Flávia V; de Castro, Alexandre A; Pereira, Ander F; Leal, Daniel H S; Mancini, Daiana T; Krejcar, Ondrej; Ramalho, Teodorico C; da Cunha, Elaine F F; Kuca, Kamil

2018-04-23

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways.

[Comparative analysis of sensitivity of proteases (chymotrypsin and trypsin) and cholinesterases of different origin to some organophosphorus inhibitors].

PubMed

Rozengart, E V

2009-01-01

The antichymotrypsin, antitrypsin, and anticholinesterase efficiencies of four homologous series of organophosphorus inhibitors are compared: O-ethyl-S-(n-alkyl)methylthiophosphonates, O-(n-alkyl)-S-(n-butyl)methylthiophosphonates, O-(n-alkyl)-S-beta-(ethylmercaptoethylene)methylthiophosphonates, and their methylsulfomethylates. As sources of a-chymotrypsin and trypsin, commercial compounds of Worthington Biochemical Corporation and Leningrad Myasokombinat were tested. Bimolecular constant of the reaction rate was used as the measure of antienzyme efficiency. In all cases, the antichymotrypsin efficiency was lower, while the antitrypsin--essentially higher than the anticholinesterase activity of the studied inhibitors. These differences were found to much depend both on the inhibitor structure and on nature of the cholinesterase compounds.

Preparation, in vitro screening and molecular modelling of symmetrical 4-tert-butylpyridinium cholinesterase inhibitors--analogues of SAD-128.

PubMed

Musilek, Kamil; Roder, Jan; Komloova, Marketa; Holas, Ondrej; Hrabinova, Martina; Pohanka, Miroslav; Dohnal, Vlastimil; Opletalova, Veronika; Kuca, Kamil; Jung, Young-Sik

2011-01-01

Carbamate inhibitors (e.g., pyridostimine bromide) are used as a pre-exposure treatment for the prevention of organophosphorus poisoning. They work by blocking acetylcholinesterase's (AChE) native function and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for many undesirable side-effects related to the carbamylation of AChE. In this Letter, 19 analogues of SAD-128 were prepared and evaluated as cholinesterase inhibitors. The screening results showed promising inhibitory ability of four compounds better to used standards (pralidoxime, obidoxime, BW284c51, ethopropazine, SAD-128). Four most promising compounds were selected for further molecular docking studies. The SAR was stated from obtained data. The former receptor studies were reported and discussed. The further in vivo studies were recommended in the view of OP pre-exposure treatment. Copyright © 2010 Elsevier Ltd. All rights reserved.

URANIUM EXTRACTION PROCESS USING SYNERGISTIC REAGENTS

DOEpatents

Schmitt, J.M.; Blake, C.A. Jr.; Brown, K.B.; Coleman, C.F.

1958-11-01

Improved methods are presented for recovering uranium values from aqueous solutions by organic solvent extraction. The improvement lies in the use, in combination, of two classes of organic compounds so that their extracting properties are enhanced synergistically. The two classes of organic compounds are dialkylphosphoric acid and certain neutral organophosphorus compounds such as trialkylphosphates, trialkylphosphonates, trlalkylphosphinates and trialkylphosphine oxides.

Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds Along Two Different Reaction Pathways: Implica-tions for Engineering Bioscavengers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wymore, Troy W; Langan, Paul; Smith, Jeremy C

Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ( bioscavengers ) is an emerging prophylactic approach to diminishing their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical (QM/MM) umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalentmore » intermediate. P F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily due to the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed -propeller folds for more efficient degradation of OP compounds.« less

Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds along Two Different Reaction Pathways: Implications for Engineering Bioscavengers

PubMed Central

2015-01-01

Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents (“bioscavengers”) is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P–F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds. PMID:24720808

Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Quistad, Gary B.; Klintenberg, Rebecka; Caboni, Pierluigi

2006-02-15

Three components of the cannabinoid system are sensitive to selected organophosphorus (OP) compounds: monoacylglycerol (MAG) lipase that hydrolyzes the major endogenous agonist 2-arachidonoylglycerol (2-AG); fatty acid amide hydrolase (FAAH) that cleaves the agonist anandamide present in smaller amounts; the CB1 receptor itself. This investigation considers which component of the cannabinoid system is the most likely contributor to OP-induced hypomotility in mice. Structure-activity studies by our laboratory and others rule against major involvement of a direct toxicant-CB1 receptor interaction for selected OPs. Attention was therefore focused on the OP sensitivities of MAG lipase and FAAH, assaying 19 structurally diverse OP chemicalsmore » (pesticides, their metabolites and designer compounds) for in vitro inhibition of both enzymes. Remarkably high potency and low selectivity is observed with three O-alkyl (C{sub 1}, C{sub 2}, C{sub 3}) alkylphosphonofluoridates (C{sub 8}, C{sub 12}) (IC50 0.60-3.0 nM), five S-alkyl (C{sub 5}, C{sub 7}, C{sub 9}) and alkyl (C{sub 1}, C{sub 12}) benzodioxaphosphorin oxides (IC50 0.15-5.7 nM) and one OP insecticide metabolite (chlorpyrifos oxon, IC50 34-40 nM). In ip-treated mice, the OPs at 1-30 mg/kg more potently inhibit brain FAAH than MAG lipase, but FAAH inhibition is not correlated with hypomotility. However, the alkylphosphonofluoridate-treated mice show dose-dependent increases in severity of hypomotility, inhibition of MAG lipase activity and elevation of 2-AG. Moderate to severe hypomotility is accompanied by 64 to 86% MAG lipase inhibition and about 6-fold elevation of brain 2-AG level. It therefore appears that OP-induced MAG lipase inhibition leads to elevated 2-AG and the associated hypomotility.« less

Oxime-Induced Reactivation of Carboxylesterase Inhibited by Organophosphorus Compounds

DTIC Science & Technology

1993-05-13

detoxication enzyme for OP compounds (Maxwell, 1992a), when in the presence of an uncharged oxime, becomes even more effective because it is easily...Wolring, 1984). Therefore, oxime-induced reactivation of OP-inhibited CaE for protection by enhancement of OP detoxication occurs at approximately the

Chiral Separation of G-type Chemical Warfare Nerve Agents via Analytical Supercritical Fluid Chromatography

PubMed Central

Kasten, Shane A; Zulli, Steven; Jones, Jonathan L; Dephillipo, Thomas; Cerasoli, Douglas M

2014-01-01

Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(–) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(–) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. Chirality 26:817–824, 2014. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc. PMID:25298066

Current and emerging strategies for organophosphate decontamination: special focus on hyperstable enzymes.

PubMed

Jacquet, Pauline; Daudé, David; Bzdrenga, Janek; Masson, Patrick; Elias, Mikael; Chabrière, Eric

2016-05-01

Organophosphorus chemicals are highly toxic molecules mainly used as pesticides. Some of them are banned warfare nerve agents. These compounds are covalent inhibitors of acetylcholinesterase, a key enzyme in central and peripheral nervous systems. Numerous approaches, including chemical, physical, and biological decontamination, have been considered for developing decontamination methods against organophosphates (OPs). This work is an overview of both validated and emerging strategies for the protection against OP pollution with special attention to the use of decontaminating enzymes. Considerable efforts have been dedicated during the past decades to the development of efficient OP degrading biocatalysts. Among these, the promising biocatalyst SsoPox isolated from the archaeon Sulfolobus solfataricus is emphasized in the light of recently published results. This hyperthermostable enzyme appears to be particularly attractive for external decontamination purposes with regard to both its catalytic and stability properties.

Anticholinesterases: Medical applications of neurochemical principles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Millard, C.B.; Broomfield, C.A.

1995-12-31

Cholinesterases form a family of serine esterases that arise in animals from at least two distinct genes. Multiple forms of these enzymes can be precisely localized and regulated by alternative mRNA splicing and by co- or posttranslational modifications. The high catalytic efficiency of the cholinesterases is quelled by certain very selective reversible and irreversible inhibitors. Owing largely to the important role of acetylcholine hydrolysis in neurotransmission, cholinesterase and its inhibitors have been studied extensively in vivo. In parallel, there has emerged an equally impressive enzyme chemistry literature. Cholinesterase inhibitors are used widely as pesticides; in this regard the compounds aremore » beneficial with concomitant health risks. Poisoning by such compounds can result in an acute but usually manageable medical crisis and may damage the ONS and the PNS, as well as cardiac and skeletal muscle tissue. Some inhibitors have been useful for the treatment of glaucoma and myasthenia gravis, and others are in clinical trials as therapy for Alzheimer`s dementia. Concurrently, the most potent inhibitors have been developed as highly toxic chemical warfare agents. We review treatments and sequelae of exposure to selected anticholinesterases, especially organophosphorus compounds and carbamates, as they relate to recent progress in enzyme chemistry.« less

Organophosphorus Flame Retardants Inhibit Specific Liver Carboxylesterases and Cause Serum Hypertriglyceridemia

PubMed Central

2015-01-01

Humans are prevalently exposed to organophosphorus flame retardants (OPFRs) contained in consumer products and electronics, though their toxicological effects and mechanisms remain poorly understood. We show here that OPFRs inhibit specific liver carboxylesterases (Ces) and cause altered hepatic lipid metabolism. Ablation of the OPFR target Ces1g has been previously linked to dyslipidemia in mice. Consistent with OPFR inhibition of Ces1g, we also observe OPFR-induced serum hypertriglyceridemia in mice. Our findings suggest novel toxicities that may arise from OPFR exposure and highlight the utility of chemoproteomic and metabolomic platforms in the toxicological characterization of environmental chemicals. PMID:24597639

[Rapid identification of 22 abused drugs and organophosphorus pesticides in blood by LC-MS/MS].

PubMed

Liu, Hong-tao; Ma, An-de

2009-08-01

To develop a method for rapid identification of 22 abused drugs and organophosphorus pesticides in the blood. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) in multiple-reaction monitoring mode (MRM) was employed for detecting the drugs and pesticides in the blood. The MRM database and criteria for identification were established, and ethyl acetate was used for extraction of the drugs. After 3 rounds of extractions of the blood sample (1 mL) using 2 mL ethyl acetate, the extract was vortexed for 3 min and centrifuged at 5000 r/min. Each organic phase was combined and evaporated by gentle N2 gas. The residue was re-dissolved in 100 L mobile phase, from which 5 L was taken for LC-MS/MS detection. The detection of the 22 target compounds could be completed within 10 min. The limit of detection of the target compound ranged from 0.03 to 6.00 ng/ml. Satisfactory results were obtained in proficiency testing program organized by China National Accreditation Service for Conformity Assessment. The method we established is rapid, selective and sensitive for detecting the 22 abused drugs and organophosphorus pesticides.

Isolation of the opdE gene that encodes for a new hydrolase of Enterobacter sp. capable of degrading organophosphorus pesticides.

PubMed

Chino-Flores, Concepción; Dantán-González, Edgar; Vázquez-Ramos, Alejandra; Tinoco-Valencia, Raunel; Díaz-Méndez, Rafael; Sánchez-Salinas, Enrique; Castrejón-Godínez, Maria Luisa; Ramos-Quintana, Fernando; Ortiz-Hernández, Maria Laura

2012-06-01

Microbial enzymes that can hydrolyze organophosphorus compounds have been isolated, identified and characterized from different microbial species in order to use them in biodegradation of organophosphorus compounds. We isolated a bacterial strain Cons002 from an agricultural soil bacterial consortium, which can hydrolyze methyl-parathion (MP) and other organophosphate pesticides. HPLC analysis showed that strain Cons002 is capable of degrading pesticides MP, parathion and phorate. Pulsed-field gel electrophoresis and 16S rRNA amplification were performed for strain characterization and identification, respectively, showing that the strain Cons002 is related to the genus Enterobacter sp. which has a single chromosome of 4.6 Mb and has no plasmids. Genomic library was constructed from DNA of Enterobacter sp. Cons002. A gene called opdE (Organophosphate Degradation from Enterobacter) consists of 753 bp and encodes a protein of 25 kDa, which was isolated using activity methods. This gene opdE had no similarity to any genes reported to degrade organophosphates. When kanamycin-resistance cassette was placed in the gene opdE, hydrolase activity was suppressed and Enterobacter sp. Cons002 had no growth with MP as a nutrients source.

Anticholinesterase exposure of white-winged doves breeding in lower Rio Grande valley, Texas

USGS Publications Warehouse

Tacha, T.C.; Schacht, S.J.; George, R.R.; Hill, E.F.

1994-01-01

We studied exposure of breeding white-winged doves (Zenaida asiatica) to anticholinesterase compounds (organophosphorus and carbamate pesticides) in the Lower Rio Grande Valley (LRGV), Texas. Widespread use of organophosphorus pesticides and dove population declines prompted the study. We collected breeding adult doves in May and July 1991 (n = 28) and July 1992 (n = 33) at 6 locations. We used depression of whole-brain cholinesterase (ChE) activity (2 SD below control mean) to detect exposure; values from 4 hand-reared doves fed commercial pigeon chow served as the control. Mean brain ChE activity was lower (P lt 0.027) than the control sample at all 6 locations in 1991; 79% of the birds were diagnostic of exposure ( gt 16.1% ChE depression). Pooled 1992 field samples also were lower (P lt 0.036) than were control samples; doves from 4 of the 6 locations had brain ChE activity below (P lt 0.088) controls. Overall, 39% of 1992 doves were diagnostic of exposure to anticholinesterase compounds. Higher exposure rates in 1991 were probably due to increased use of organophosphorus pesticides. Research is needed documenting effects of sublethal exposure on white-winged dove productivity.

Evaluation and refinement of a field-portable drinking water toxicity sensor utilizing electric cell-substrate impedance sensing and a fluidic biochip.

PubMed

Widder, Mark W; Brennan, Linda M; Hanft, Elizabeth A; Schrock, Mary E; James, Ryan R; van der Schalie, William H

2015-07-01

The US Army's need for a reliable and field-portable drinking water toxicity sensor was the catalyst for the development and evaluation of an electric cell-substrate impedance sensing (ECIS) device. Water testing technologies currently available to soldiers in the field are analyte-specific and have limited capabilities to detect broad-based water toxicity. The ECIS sensor described here uses rainbow trout gill epithelial cells seeded on fluidic biochips to measure changes in impedance for the detection of possible chemical contamination of drinking water supplies. Chemicals selected for testing were chosen as representatives of a broad spectrum of toxic industrial compounds. Results of a US Environmental Protection Agency (USEPA)-sponsored evaluation of the field portable device were similar to previously published US Army testing results of a laboratory-based version of the same technology. Twelve of the 18 chemicals tested following USEPA Technology Testing and Evaluation Program procedures were detected by the ECIS sensor within 1 h at USEPA-derived human lethal concentrations. To simplify field-testing methods further, elimination of a procedural step that acclimated cells to serum-free media streamlined the test process with only a slight loss of chemical sensitivity. For field use, the ECIS sensor will be used in conjunction with an enzyme-based sensor that is responsive to carbamate and organophosphorus pesticides. Copyright © 2014 John Wiley & Sons, Ltd.

Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview.

PubMed

Becker, Christian; Worek, Franz; John, Harald

2010-10-01

Poisoning with organophosphorus compounds (OP), e.g. pesticides and nerve agents, causes inhibition of acetylcholinesterase (AChE) by phosphylation of the active site serine residue. Consequently, accumulation of stimulating acetylcholine in the synaptic cleft induces cholinergic crisis which ultimately may lead to death. For standard causal therapy, enzyme reactivators are administered representing oxime derivatives of quarternary pyridinium compounds, e.g. pralidoxime (2-PAM), obidoxime and HI 6. The mechanism of action includes removal of the phosphyl moiety by a nucleophilic attack of the oximate molecule substituting the enzyme and forming a phosphylated oxime (POX). POX is produced in stoichiometric amounts of reactivated enzyme and exhibits a significantly enhanced toxicity (inhibition rate constant) when compared to the parent OP. However, stability of POX under physiological conditions appears to be highly limited. Nevertheless, the presence of POX reveals a potential critical issue for both therapeutic efficacy in vivo and pharmacokinetic and pharmacodynamic (PK-PD) modelling based on cholinesterase activity data. Detailed characterization represents an important need for elaboration of the entire oxime pharmacology.Nevertheless, reports on POX toxicity and analysis are quite rare and may therefore be indicative of the challenge of POX analysis. This review provides a concise overview of chromatographic approaches applied to POX separation. Chromatography represents the key technology for POX purification and quantification in kinetic in vitro studies using buffers and biological fluids. Applications based on reversed-phase chromatography (RPC), ion pair chromatography (IPC) and an affinity approach as well as thin layer chromatography (TLC) are discussed and novel applications and data are presented. Copyright © 2010 John Wiley & Sons, Ltd.

Sol-gel niobia sorbent with a positively charged octadecyl ligand providing enhanced enrichment of nucleotides and organophosphorus pesticides in capillary microextraction for online HPLC analysis.

PubMed

Kesani, Sheshanka; Malik, Abdul

2018-04-01

A niobia-based sol-gel organic-inorganic hybrid sorbent carrying a positively charged C 18 ligand (Nb 2 O 5 -C 18 (+ve)) was synthesized to achieve enhanced enrichment capability in capillary microextraction of organophosphorus compounds (which include organophosphorus pesticides and nucleotides) before their online analysis by high-performance liquid chromatography. The sorbent was designed to simultaneously provide three different types of molecular level interactions: electrostatic, Lewis acid-base, and van der Waals interactions. To understand relative contributions of various molecular level analyte-sorbent interactions in the extraction process, two other sol-gel niobia sorbents were also created: (a) a purely inorganic sol-gel niobia sorbent (Nb 2 O 5 ) and (b) an organic-inorganic hybrid sol-gel niobia sorbent carrying an electrically neutral-bonded octadecyl ligand (Nb 2 O 5 -C 18 ). The extraction efficiency of the created sol-gel niobia sorbent (Nb 2 O 5 -C 18 (+ve)) was compared with that of analogously designed and synthesized titania-based sol-gel sorbent (TiO 2 -C 18 (+ve)), taking into consideration that titania-based sorbents present state-of-the-art extraction media for organophosphorus compounds. In capillary microextraction with high-performance liquid chromatography analysis, Nb 2 O 5 -C 18 (+ve) had shown 40-50% higher specific extraction values (a measure of extraction efficiency) over that of TiO 2 -C 18 (+ve). Compared to TiO 2 -C 18 (+ve), Nb 2 O 5 -C 18 (+ve) also provided superior analyte desorption efficiency (96 vs. 90%) during the online release of the extracted organophosphorus pesticides from the sorbent coating in the capillary microextraction capillary to the chromatographic column using reversed-phase high-performance liquid chromatography mobile phase. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A multiresidue method by high performance liquid chromatography-based fractionation and gas chromatographic determination of trace levels of pesticides in air and water.

PubMed

Seiber, J N; Glotfelty, D E; Lucas, A D; McChesney, M M; Sagebiel, J C; Wehner, T A

1990-01-01

A multiresidue analytical method is described for pesticides, transformation products, and related toxicants based upon high performance liquid chromatographic (HPLC) fractionation of extracted residue on a Partisil silica gel normal phase column followed by selective-detector gas chromatographic (GC) determination of components in each fraction. The HPLC mobile phase gradient (hexane to methyl t-butyl ether) gave good chromatographic efficiency, resolution, reproducibility and recovery for 61 test compounds, and allowed for collection in four fractions spanning polarities from low polarity organochlorine compounds (fraction 1) to polar N-methylcarbamates and organophosphorus oxons (fraction 4). The multiresidue method was developed for use with air samples collected on XAD-4 and related trapping agents, and water samples extracted with methylene chloride. Detection limits estimated from spiking experiments were generally 0.3-1 ng/m3 for high-volume air samples, and 0.01-0.1 microgram/L for one-liter water samples. Applications were made to determination of pesticides in fogwater and air samples.

Multidimensional profiling platforms reveal metabolic dysregulation caused by organophosphorus pesticides.

PubMed

Medina-Cleghorn, Daniel; Heslin, Ann; Morris, Patrick J; Mulvihill, Melinda M; Nomura, Daniel K

2014-02-21

We are environmentally exposed to countless synthetic chemicals on a daily basis, with an increasing number of these chemical exposures linked to adverse health effects. However, our understanding of the (patho)physiological effects of these chemicals remains poorly understood, due in part to a general lack of effort to systematically and comprehensively identify the direct interactions of environmental chemicals with biological macromolecules in mammalian systems in vivo. Here, we have used functional chemoproteomic and metabolomic platforms to broadly identify direct enzyme targets that are inhibited by widely used organophosphorus (OP) pesticides in vivo in mice and to determine metabolic alterations that are caused by these chemicals. We find that these pesticides directly inhibit over 20 serine hydrolases in vivo leading to widespread disruptions in lipid metabolism. Through identifying direct biological targets of OP pesticides, we show heretofore unrecognized modes of toxicity that may be associated with these agents and underscore the utility of using multidimensional profiling approaches to obtain a more complete understanding of toxicities associated with environmental chemicals.

New insights on molecular interactions of organophosphorus pesticides with esterases.

PubMed

Mangas, Iris; Estevez, Jorge; Vilanova, Eugenio; França, Tanos Celmar Costa

2017-02-01

Organophosphorus compounds (OPs) are a large and diverse class of chemicals mainly used as pesticides and chemical weapons. People may be exposed to OPs in several occasions, which can produce several distinct neurotoxic effects depending on the dose, frequency of exposure, type of OP, and the host factors that influence susceptibility and sensitivity. These neurotoxic effects are mainly due to the interaction with enzyme targets involved in toxicological or detoxication pathways. In this work, the toxicological relevance of known OPs targets is reviewed. The main enzyme targets of OPs have been identified among the serine hydrolase protein family, some of them decades ago (e.g. AChE, BuChE, NTE and carboxylesterases), others more recently (e.g. lysophospholipase, arylformidase and KIA1363) and others which are not molecularly identified yet (e.g. phenylvalerate esterases). Members of this family are characterized by displaying serine hydrolase activity, containing a conserved serine hydrolase motif and having an alpha-beta hydrolase fold. Improvement in Xray-crystallography and in silico methods have generated new data of the interactions between OPs and esterases and have established new methods to study new inhibitors and reactivators of cholinesterases. Mass spectrometry for AChE, BChE and APH have characterized the active site serine adducts with OPs being useful to detect biomarkers of OPs exposure and inhibitory and postinhibitory reactions of esterases and OPs. The purpose of this review is focus specifically on the interaction of OP with esterases, mainly with type B-esterases, which are able to hydrolyze carboxylesters but inhibited by OPs by covalent phosphorylation on the serine or tyrosine residue in the active sites. Other related esterases in some cases with no-irreversible effect are also discussed. The understanding of the multiple molecular interactions is the basis we are proposing for a multi-target approach for understanding the organophosphorus toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Counteracting desensitization of human α7-nicotinic acetylcholine receptors with bispyridinium compounds as an approach against organophosphorus poisoning.

PubMed

Scheffel, Corinna; Niessen, Karin V; Rappenglück, Sebastian; Wanner, Klaus T; Thiermann, Horst; Worek, Franz; Seeger, Thomas

2018-09-01

Irreversible inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and overstimulation of muscarinic and nicotinic receptors accounts for the acute toxicity of organophosphorus compounds (OP). Accordingly, the mainstay pharmacotherapy against poisoning by OP comprises the competitive muscarinic acetylcholine receptor antagonist atropine to treat muscarinic effects and, in addition, oximes to reactivate inhibited AChE. A therapeutic gap still remains in the treatment of desensitized nicotinic acetylcholine receptors following OP exposure. Hereby, nicotinic effects result in paralysis of the central and peripheral respiratory system if untreated. Thus, these receptors pose an essential target for therapeutic indication to address these life-threatening nicotinic symptoms of the cholinergic crisis. Identification of ligands regulating dynamic transitions between functional states by binding to modulatory sites appears to be a promising strategy for therapeutic intervention. In this patch clamp study, the ability of differently substituted bispyridinium non-oximes to "resensitize" i.e. to recover the activity of desensitized human homomeric α7-type nAChRs stably transfected in CHO cells was investigated and compared to the already described α7-specific positive allosteric modulator PNU-120596. The structures of these bispyridinium analogues were based on the lead structure of the tert-butyl-substituted bispyridinium propane MB327, which has been shown to have a positive therapeutic effect due to a non-competitive antagonistic action at muscle-type nAChRs in vivo and has been found to have a positive allosteric activity at neuronal receptors in vitro. Prior to test compounds, desensitization of hα7-nAChRs was verified by applying an excess of nicotine revealing activation at low, and desensitization at high concentrations. Thereby, desensitization could be reduced by modulation with PNU-120596. Desensitization was further verified by dose-response profiles of agonists, carbamoylcholine and epibatidine in the absence and presence of PNU-120596. Although less pronounced than PNU-120596 and the lead structure MB327, bispyridinium compounds, particularly those substituted at position 3 and 4, resensitized the nicotine desensitized hα7-nAChRs in a concentration-dependent manner and prolonged the mean channel open time. In summary, identification of more potent compounds able to restore nAChR function in OP intoxication is needed for development of a putative efficient antidote. Copyright © 2017 Elsevier B.V. All rights reserved.

[Phosphoric acid ester preparations used in cattle, swine and sheep with special reference to cholinesterase activity. 4. Use of phosphoric acid esters and their effect on acetylcholinesterase activity in sheep].

PubMed

Mieth, K; Beier, D; Losch, K

1975-01-01

The use of organophosphorus preparations for the control of ectoparasites and endoparasites of sheep, particularly systemic application, is discussed. Experiments on 13 groups of sheep with five preparations produced in the German Democratic Republic in various formulations and concentrations showed that external application had good contact activity, but little was absorbed. Acetylcholinesterase activity was not inhibited, except by pour-on application of doses several times the normal dose. The preparations were arranged in order of cholinesterase inhibition. In contrast to cattle, diminished cholinesterase activity was unreliable as in indicator of systemic toxicity of organophosphorus preparations in sheep.

Different approaches to acute organophosphorus poison treatment.

PubMed

Nurulain, Syed Muhammad

2012-07-01

Organophosphorus compounds (OPCs) have a wide variety of applications and are a serious threat for self-poisoning, unintentional misuse, terrorist attack, occupational hazard and warfare attack. The present standard treatment has been reported to be unsatisfactory. Many novel approaches are being used and tested for acute organophosphorus (OP) poison treatment. The bioscavenger concept captured high attention among the scientific community during the last few decades. Other approaches like alkalinisation of blood plasma/serum and use of weak inhibitors against strong inhibitors, though it showed promising results, did not get such wide attention. The introduction of a novel broad-spectrum oxime has also been in focus. In this mini-review, an update of the overview of four different approaches has been discussed. The standard therapy that is atropine+oxime+benzodiazepine along with supportive measures will continue to be the best option with only the replacement of a single oxime to improve its broad-spectrum efficacy.

Impact of prechlorination on organophosphorus pesticides during drinking water treatment: Removal and transformation to toxic oxon byproducts.

PubMed

Li, Wei; Wu, Ruiqing; Duan, Jinming; Saint, Christopher P; van Leeuwen, John

2016-11-15

Prechlorination is commonly used to minimize operational problems associated with biological growth as well as taste and odor control during drinking water treatment. However, prechlorination can also oxidise micropollutants into intermediate byproducts. This could impose profound effects on the safety of the finished water if the transformed byproducts are more toxic and less removable. This study investigated the effect of prechlorination on decomposition and subsequent removal of the four organophosphorus pesticides (OPPs): chlorpyrifos, diazinon, malathion and tolclofos-methyl using a simulated conventional water treatment process of powdered activated carbon assisted coagulation-sedimentation-filtration (PAC-CSF) and postchlorination. It was found that, following prechlorination, not only did the percentage of OPPs oxidation vary significantly, but also the concentration of transformed oxons, which are more toxic than their parent compounds, increased as the major identified oxidation byproducts in water. Removal of these oxons proved to be more difficult by the PAC-CSF than their parent OPPs, because they are more water soluble and more hydrophilic. Both the OPP oxidation and oxon formation increased with chlorine dose during prechlorination. Meanwhile, the continuing chlorination of OPPs by residual free chlorine during PAC-CSF further complicated the pesticide removal processes, generally resulting in a gradually increased formation of oxons. Moreover, in the final treatment stage of postchlorination, the more chlorine-reactive pesticides, malathion and diazinon, were completely oxidised and the formation of corresponding oxons was increased with the prechlorine dose. In contrast, a certain amount of the less chlorine-reactive pesticide tolclofos-methyl still remained in solution after postchlorination, accompanied by an increased formation of tolclofos-methyl oxon with prechlorine dose. Since the oxons are resistant to further oxidation and less adsorbable during the PAC-CSF process, the gross removal of these pesticides and their oxons decreased with increase of the prechlorine dose. This led to an accumulation of the more toxic oxons in the finished water, especially at higher chlorine doses during prechlorination. The significance of this work is the demonstration that, under circumstances where prechlorination is used and source water contains traces of OPPs, alternative practices should be prioritized to avoid the potential risks involved in consumption of the treated water. Copyright © 2016 Elsevier Ltd. All rights reserved.

SELECTED PESTICIDE RESIDUES AND METABOLITES IN URINE FROM A SURVEY OF THE U.S. GENERAL POPULATION

EPA Science Inventory

Residues of toxic chemicals in human tissues and fluids can be important indicators of exposure. Urine collected from a subsample of the second National Health and Nutrition Examination Survey was analyzed for organochlorine, organophosphorus, and chlorophenoxy pesticides or the...

THE INTERACTION OF AN ANTICHOLINESTERASE INSECTICIDE, DIAZINON, WITH A PYRETHROID INSECTICIDE, DELTAMETHRIN.

EPA Science Inventory

This present study explores the interaction of the toxicity induced by an organophosphorus insecticide, diazinon (diethyl 2-isopropyl-6methyl-4-pyrimidal phosphorothionate), with a pyrethroid insecticide, deltamethrin ((S)-a-cyano-3-phenoxybenzyl (1R,3R)-3-(2,2-dibromovinyl)-2,...

The preparation, in vitro screening and molecular docking of symmetrical bisquaternary cholinesterase inhibitors containing a but-(2E)-en-1,4-diyl connecting linkage.

PubMed

Musilek, Kamil; Pavlikova, Ruzena; Marek, Jan; Komloova, Marketa; Holas, Ondrej; Hrabinova, Martina; Pohanka, Miroslav; Dohnal, Vlastimil; Dolezal, Martin; Gunn-Moore, Frank; Kuca, Kamil

2011-04-01

Carbamate inhibitors (e.g. pyridostigmine bromide) are used as a pre-treatment for the prevention of organophosphorus poisoning. They work by blocking the native function of acetylcholinesterases (AChE) and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for their many undesirable side effects related to the carbamylation of AChE. In this paper, we describe 17 novel bisquaternary compounds and have analysed their effect on AChE inhibition. The newly prepared compounds were evaluated in vitro using both human erythrocyte AChE and human plasmatic butyrylcholinesterase. Their inhibitory ability was expressed as the half maximal inhibitory concentration (IC₅₀) and then compared to the standard carbamate drugs and two AChE reactivators. One of these novel compounds showed promising AChE inhibition in vitro (nM range) and was better than the currently used standards. Additionally, a kinetic assay confirmed the non-competitive inhibition of hAChE by this novel compound. Consequently, the docking results confirmed the apparent π-π or π-cationic interactions with the key amino acid residues of hAChE and the binding of the chosen compound at the enzyme catalytic site.

Structural connotations of bioactivity in a series of organophosphinates

NASA Astrophysics Data System (ADS)

King, James W.; Molnar, Stephen P.

Pretreatment before exposure is one of the options for temporarily protecting persons liable to exposure to toxic organophosphorus compounds in agricultural or warfare situations. It is known that organophosphinates interact with neuronal cholinesterases, but that the latter may spontaneously reactivate in time. Before that reactivation, the enzyme is protected against comlexation with organophosphates. In this study, geometrically optimized unitary molecular indices, i.e., the molecular transforms, FTm, FTe, and FTc, indicating general, electronic, and charge properties, respectively, and the analogous normalized molecular moments, Mn, Me, and Mc, were calculated for a number of phosphinates. These indices were subsequently used in correlation trials with spontaneous reactivation percentages at specific elapsed times, as well as in clustering procedures, to evaluate the effect of structure variations on the reactivation percentages. The results of these studies are discussed, as is the effect of the octanol/water partition coefficient on the noted bioactivity.

Novel choline esterase based sensor for monitoring of organophosphorus pollutants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilkins, E.S.; Ghindilis, A.L.; Atanasov, P.

1996-12-31

Organophosphorus compounds are significant major environmental pollutants due to their intensive use as pesticides. The modern techniques based on inhibition of choline esterase enzyme activity are discussed. Potentiometric electrodes based on detection of choline esterase inhibition by analytes has been developed. The detection of choline esterase activity is based on the novel principle of molecular transduction. Immobilized peroxidase acting as the molecular transducer, catalyzes the electroreduction of hydrogen peroxide by direct (mediatorless) electron transfer. The sensing element consists of a carbon based electrode containing an assembly of co-immobilized enzymes: choline esterase, choline oxidase and peroxidase.

Anticholinesterase poisoning of birds: Field monitoring and diagnosis of acute poisoning

USGS Publications Warehouse

Hill, E.F.; Fleming, W.J.

1982-01-01

Organophosphorus and carbamate pesticides are cholinesterase (ChE) inhibiting chemicals that have been responsible for avian die-offs. Identification of chemicals implicated in these die-offs is difficult and sometimes conclusions are solely circumstantial. However, when marked depression (inhibition) of brain ChE activity accompanies organophosphorus or carbamate residues in body tissues or ingesta, cause-effect diagnosis is enhanced. To achieve this end, normal brain ChE activity is estimated for controls of the affected species and then die-off specimens are individually evaluated for evidence of ChE inhibition. This approach to evaluation of antiChE poisoning may also be used to monitor exposure of vertebrates to field application of organophosphorus or carbamate pesticides. Problems associated with this kind of evaluation, and the main topic of this report, include variability of brain ChE activity among species, postmortem influences of ambient conditions (storage or field) on ChE activity, and differential patterns of ChE activity when inhibited by organophosphorus or carbamate compounds. Other topics discussed are the ChE assay procedure, example case reports and interpretation, and research needed for improving the diagnostic utility of ChE activity in a field situation.

Organophosphorus (OP) Pesticide Degradation in the Presence of Chlorinated Oxidants: Kinetics, Modeling, and Structure-Activity Relationships

EPA Science Inventory

The rates and pathways for pesticide transformation during drinking water treatment are known for only a few pesticides and under limited conditions. The resulting oxons are more toxic than the parent pesticides. The transformation rates and pathways for chlorpyrifos, an OP pest...

PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES

EPA Science Inventory

Physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) models are particularly suited for interpretation of cumulative risk via the dermal route for which aggregate exposure must be assessed for chemicals having a common mechanism of toxicity. To this end, a quantita...

Recent Developments in the Addition of Phosphinylidene-Containing Compounds to Unactivated Unsaturated Hydrocarbons: Phosphorus-Carbon Bond-Formation via Hydrophosphinylation and Related Processes

PubMed Central

Coudray, Laëtitia

2012-01-01

Summary The reactions of phosphinylidene-containing compounds with unactivated unsaturated hydrocarbons are reviewed. The review is organized by phosphorus-containing functional group types. Free-radical and metal-catalyzed additions of R1R2P(O)H to alkenes, alkynes, and related compounds, deliver functionalized organophosphorus compounds RP(O)R1R2, including H-phosphinates, phosphinates, tertiary phosphine oxides, and phosphonates. The review covers the literature up to February 2008. PMID:23308039

Pattern of organophosphorous poisoning: a retrospective community based study.

PubMed

Chataut, J; Adhikari, R K; Sinha, N P; Marahatta, S B

2011-01-01

Pesticide poisoning is very common in Nepal. Hospital based studies from various parts of Nepal have shown that poisoning with organophosphorus compounds is the most common type of poisoning. Current study is undertaken to see the pattern of organophosphorus poisoning and to identify the common risk factors among the cases. If the risk factors are modifiable, attempts in addressing the risk factors and decreasing the likelihood of poisoning will certainly be fruitful in reducing the morbidity and mortality associated with organophosphorus poisoning. To assess the risk factors of organophosphorus poisoning which is major public health problem in Nepal. A community based retrospective study of 75 cases of organophosphate poisoning who were brought to the emergency department of Dhulikhel hospital over the period of 3 years. Basic information was collected from hospital records and home visits were made to study the risk factors. Data were collected through interviews of the study population and their family members using a pre-designed questionnaire. In this study 75 cases and their families were interviewed of which there were 59% males and 42% females (M/F ratio of 1:1.4). The majority (40%) of the poisoning cases were in the age group 25-34 years. Lower literacy level showed positive association with the incidence of poisoning. Occupation wise vast majority (80%) of the cases were engaged in agricultural work. Suicidal attempts by ingesting organophosphate compounds were high in farmers and females. In this study, majority of the poisoning were attempts of intentional self harm. Agriculture workers and females are high risk groups and may be associated with the fact that they have easy access to the poison. Interventions directed towards health education, counseling, and enforcement of laws restricting the availability and use of harmful pesticides may help in reducing such events in future.

A Review of Experimental Evidence Linking Neurotoxic Organophosphorus Compounds and Inflammation

PubMed Central

Banks, Christopher N.; Lein, Pamela J.

2012-01-01

Organophosphorus (OP) nerve agents and pesticides inhibit acetylcholinesterase (AChE), and this is thought to be a primary mechanism mediating the neurotoxicity of these compounds. However, a number of observations suggest that mechanisms other than or in addition to AChE inhibition contribute to OP neurotoxicity. There is significant experimental evidence that acute OP intoxication elicits a robust inflammatory response, and emerging evidence suggests that chronic repeated low-level OP exposure also upregulates inflammatory mediators. A critical question that is just beginning to be addressed experimentally is the pathophysiologic relevance of inflammation in either acute or chronic OP intoxication. The goal of this article is to provide a brief review of the current status of our knowledge linking inflammation to OP intoxication, and to discuss the implications of these findings in the context of therapeutic and diagnostic approaches to OP neurotoxicity. PMID:22342984

Field tests on the residual effectiveness of deposits of malathion and Bayer 29493 against resistant Anopheles albimanus in El Salvador*

PubMed Central

Schoof, H. F.; Mathis, Willis; Austin, J. R.

1961-01-01

The appearance of resistance to both dieldrin and DDT in several malaria vectors has intensified investigations on the potential of organophosphorus compounds for residual application. This report describes the final year's activities of a three-year study on malathion. Water-wettable formulations of malathion and of Bayer 29493 were evaluated against DDT/dieldrin-resistant Anopheles albimanus in El Salvador. The results indicate that neither compound at a dosage of 0.5 g/m2 offers any promise as a residual agent. At dosages of 1.0 g/m2 or 2.0 g/m2 the two toxicants gave effective kills (70%-100%) for periods of 21/2-3 months, based on 1-hour exposure to the treated surfaces. Up to 3 months, both compounds gave similar levels of effectiveness on wood, thatch, and mud. On whitewash and plaster surfaces, Bayer 29493 was superior to malathion. The findings indicate that each insecticide has considerable potential value for residual treatment in areas where the malaria vector cannot be killed effectively by either DDT or dieldrin. In such areas, further investigation into their utility as replacements for the chlorinated hydrocarbon insecticides is warranted. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5 PMID:13748489

Kinetics of the inhibitory interaction of organophosphorus neuropathy inducers and non-inducers in soluble esterases in the avian nervous system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mangas, Iris; Vilanova, Eugenio; Estevez, Jorge, E-mail: jorge.estevez@umh.es

2011-11-15

Some published studies suggest that low level exposure to organophosphorus esters (OPs) may cause neurological and neurobehavioral effects at long term exposure. These effects cannot be explained by action on known targets. In this work, the interactions (inhibition, spontaneous reactivation and 'ongoing inhibition') of two model OPs (paraoxon, non neuropathy-inducer, and mipafox, neuropathy-inducer) with the chicken brain soluble esterases were evaluated. The best-fitting kinetic model with both inhibitors was compatible with three enzymatic components. The amplitudes (proportions) of the components detected with mipafox were similar to those obtained with paraoxon. These observations confirm the consistency of the results and themore » model applied and may be considered an external validation. The most sensitive component (E{alpha}) for paraoxon (11-23% of activity, I{sub 50} (30 min) = 9-11 nM) is also the most sensitive for mipafox (I{sub 50} (30 min) = 4 nM). This component is spontaneously reactivated after inhibition with paraoxon. The second sensitive component to paraoxon (E{beta}, 71-84% of activity; I{sub 50} (30 min) = 1216 nM) is practically resistant to mipafox. The third component (E{gamma}, 5-8% of activity) is paraoxon resistant and has I{sub 50} (30 min) of 3.4 {mu}M with mipafox, similar to NTE (neuropathy target esterase). The role of these esterases remains unknown. Their high sensitivity suggests that they may either play a role in toxicity in low-level long-term exposure of organophosphate compounds or have a protective effect related with the spontaneous reactivation. They will have to be considered in further metabolic and toxicological studies. -- Research Highlights: Black-Right-Pointing-Pointer Paraoxon and mipafox interactions have been evaluated with chicken soluble brain esterases. Black-Right-Pointing-Pointer The paraoxon inhibition was analyzed considering the simultaneous spontaneous reactivation. Black-Right-Pointing-Pointer The best-fitting kinetic models were compatible with a three enzymatic components. Black-Right-Pointing-Pointer The amplitudes of the components were similar in paraoxon and mipafox experiments. Black-Right-Pointing-Pointer It is suggested they may play a role in toxicity in low-level long-term exposure of these compounds.« less

The Electrochemistry of Organophosphorus Compounds.

DTIC Science & Technology

1988-01-20

of hydrogen on the electrode surface. Mechanistkc views are further developed with the addition of water resulting in the formation of...the exclusive vlide product. Furthermore, carbonvl compounds were added to the electrolyses to react with the electrochemically-generated ylides via...the Wittig reaction. The resulting olefins were found to catalytically isomerize from the Z isomer to the E isomer upon reduction. The role of water

Rodentia and lagomorpha

USGS Publications Warehouse

Sheffield, S.R.; Sawicka-Kapusta, K.; Cohen, J.B.; Rattner, B.A.; Shore, Richard F.; Rattner, Barnett A.

2001-01-01

This comprehensive review examines the extensive literature on wild rodents and lagomorphs as biomonitors of environmental contamination. This chapter covers studies dealing with exposure and effects of environmental contaminants on rodent and lagomorph species, including pesticides (organochlorines, organophosphorus and carbamate compounds, herbicides, plant growth regulators, fungicides, and rodenticides), other organic chemicals, metals, radionuclides, and other miscellaneous contaminants. Many research needs become evident when reviewing ecotoxicological data for rodents and lagomorphs, the most striking being the paucity of information on rodent families other than Muridae (mice and rats). While our ability to qualitatively extrapolate effects observed in laboratory studies to field situations is good for a variety of contaminants, quantitative predictions of dose-response relationships are poor because inter-specific variation and differences in exposure patterns between laboratory and wild species to toxicants are for the most part unknown. More sophisticated comparative toxicity studies need to be undertaken that build on previous work in order to develop a database of information, to account for and model differences in exposure pathways, to document interactions among multiple stressors, to generate data establishing thresholds, critical concentrations, and diagnostic guidelines, and even to develop physiologically-based toxicokinetic models. Such efforts may enhance our ability to predict effects on wild populations, including threatened and endangered species.

Immobilization of Russian VX skin depots by localized cooling: implications for decontamination and medical countermeasures.

PubMed

Mikler, J; Tenn, C; Worek, F; Reiter, G; Thiermann, H; Garrett, M; Bohnert, S; Sawyer, T W

2011-09-25

The chemical weapon nerve agent known as Russian VX (VR) is a potent organophosphorus (OP) compound that is much less studied than its VX analogue with respect to toxicity, as well as to the effectiveness of several known countermeasures against it. An anaesthetized domestic swine model was utilized to assess several approaches in mitigating its toxicity, including the utility of cooling VR treated skin to increase the therapeutic window for treatment. The 6h LD₅₀ for VR topically applied on the ear was 100 μg/kg. Treatment of VR exposed animals (5 × LD₅₀) with pralidoxime (2PAM) very poorly regenerated inhibited blood cholinesterase activity, but was partially effective in preventing signs of OP poisoning and increasing survival. In contrast, treatment with the Hagedorn oxime HI-6 reactivated cholinesterase, eliminated all signs of poisoning and prevented death. Decontamination with the Reactive Skin Decontaminant Lotion (RSDL) 15 min after VR exposure was completely effective in preventing death. Cooling of the VR exposure sites for 2 or 6h prevented signs of OP poisoning and death during the cooling period. However, these animals died very quickly after the cessation of cooling, unless they were treated with oxime or decontaminated with RSDL. Blood analyses showed that cooling of agent exposure sites delayed the entry of VR into the bloodstream. Medical treatment with HI-6 and to a lesser extent 2PAM, or decontamination with RSDL are effective in protecting against the toxic effects of cutaneous exposure to VR. Immobilizing this agent (and related compounds) within the dermal reservoir by cooling the exposure sites, dramatically increases the therapeutic window in which these medical countermeasures are effective. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

PubMed

Voorhees, Jaymie R; Rohlman, Diane S; Lein, Pamela J; Pieper, Andrew A

2016-01-01

Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.

Inhibition of Phenylamide Hydrolysis by Bacillus sphaericus with Methylcarbamate and Organophosphorus Insecticides

PubMed Central

Engelhardt, G.; Wallnöfer, P. R.

1975-01-01

The degradation of the phenylamide herbicides monolinuron, linuron, and solan by cultures of Bacillus sphaericus ATCC 12123 was inhibited by the methylcarbamate insecticides metmercapturon, aldicarb, propoxur, and carbaryl and by the organophosphorus insecticides fenthion and parathion. The extent of inhibition was largest with metmercapturon and smallest with parathion. Inhibition of hydrolysis of the two phenylurea herbicides was greater than of the acylanilide compound. Tests with crude enzyme preparations of aryl acylamidase derived from B. sphaericus showed that the inhibition of the hydrolysis of linuron with methylcarbamates is a competitive one. The insecticides tested did not induce the enzyme, nor could they serve as its substrate. PMID:1155931

Remedial Investigation/Feasibility Study/Interim Response Actions

DTIC Science & Technology

1988-03-25

organosulfur compounds (CC/FP), organophosphorus compounds (CC/FPD), hydrocarbons (CC/FID), volatile aromatic compounds (GC/ PID ), volatile halogenated...ICP metals, mercury and arsenic (AA). Water samples are being analyzed for volatile halogenated organics (GC/CON), volatile aromatic organics (GC/ PID ...Feb Mar Apr May Jun Jul Aug SepSI - I I I I I • .. I I I ----+----- 685 27-90 so ONSITE DISPOSAL FACILITY .i * 686 27-01 Prep FLUE Plan Fz=m8u> 6e7

Management of acute organophosphorus pesticide poisoning.

PubMed

Eddleston, Michael; Buckley, Nick A; Eyer, Peter; Dawson, Andrew H

2008-02-16

Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200,000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available. Medical management is difficult, with case fatality generally more than 15%. We describe the limited evidence that can guide therapy and the factors that should be considered when designing further clinical studies. 50 years after first use, we still do not know how the core treatments--atropine, oximes, and diazepam--should best be given. Important constraints in the collection of useful data have included the late recognition of great variability in activity and action of the individual pesticides, and the care needed cholinesterase assays for results to be comparable between studies. However, consensus suggests that early resuscitation with atropine, oxygen, respiratory support, and fluids is needed to improve oxygen delivery to tissues. The role of oximes is not completely clear; they might benefit only patients poisoned by specific pesticides or patients with moderate poisoning. Small studies suggest benefit from new treatments such as magnesium sulphate, but much larger trials are needed. Gastric lavage could have a role but should only be undertaken once the patient is stable. Randomised controlled trials are underway in rural Asia to assess the effectiveness of these therapies. However, some organophosphorus pesticides might prove very difficult to treat with current therapies, such that bans on particular pesticides could be the only method to substantially reduce the case fatality after poisoning. Improved medical management of organophosphorus poisoning should result in a reduction in worldwide deaths from suicide.

Management of acute organophosphorus pesticide poisoning

PubMed Central

Eddleston, Michael; Buckley, Nick A; Eyer, Peter; Dawson, Andrew H

2008-01-01

Summary Organophosphorus pesticide self-poisoning is an important clinical problem in rural regions of the developing world, and kills an estimated 200 000 people every year. Unintentional poisoning kills far fewer people but is a problem in places where highly toxic organophosphorus pesticides are available. Medical management is difficult, with case fatality generally more than 15%. We describe the limited evidence that can guide therapy and the factors that should be considered when designing further clinical studies. 50 years after first use, we still do not know how the core treatments—atropine, oximes, and diazepam—should best be given. Important constraints in the collection of useful data have included the late recognition of great variability in activity and action of the individual pesticides, and the care needed cholinesterase assays for results to be comparable between studies. However, consensus suggests that early resuscitation with atropine, oxygen, respiratory support, and fluids is needed to improve oxygen delivery to tissues. The role of oximes is not completely clear; they might benefit only patients poisoned by specific pesticides or patients with moderate poisoning. Small studies suggest benefit from new treatments such as magnesium sulphate, but much larger trials are needed. Gastric lavage could have a role but should only be undertaken once the patient is stable. Randomised controlled trials are underway in rural Asia to assess the effectiveness of these therapies. However, some organophosphorus pesticides might prove very difficult to treat with current therapies, such that bans on particular pesticides could be the only method to substantially reduce the case fatality after poisoning. Improved medical management of organophosphorus poisoning should result in a reduction in worldwide deaths from suicide. PMID:17706760

Interaction of organophosphorus compounds with carboxylesterases in the rat.

PubMed

Jokanović, M; Kosanović, M; Maksimović, M

1996-01-01

Carboxylesterases (CarbE) are involved in detoxication of organophosphorus compounds (OPC) through two mechanisms: hydrolysis of ester bonds in OPC which contain them and binding of OPC at the active site of CarbE which reduces the amount of OPC available for acetylcholinesterase inhibition. This study of the interaction of rat plasma and liver CarbE with dichlorvos, soman and sarin in vitro and in vivo was undertaken in order to contribute to better understanding of the role of CarbE in detoxication of OPC. The results obtained have shown that inhibitory potency (I50) of dichlorvos, sarin and soman towards rat liver CarbE was 0.2 microM, 0.5 microM and 4.5 microM, respectively, for 20-min incubation at 25 degrees C. Second-order rate constants (k(a)) for liver CarbE inhibition were 2.3 x 10(5) M-1 min-1, 6.9 x 10(4) M-1 min-1 and 1.1 x 10(4) M-1 min-1 for dichlorvos, sarin and soman, respectively. The corresponding values for plasma CarbE could not be calculated because of dominant spontaneous reactivation of inhibited CarbE. CarbE inhibited with these OPC in vitro spontaneously reactivate with half-times of 18, 143 and 497 min for sarin, dichlorvos and soman in plasma and 111, 163 and 297 min for sarin, soman and dichlorvos in liver, respectively. These results were also confirmed in experiments in vivo in which rats were subcutaneously treated with 0.5 LD50 of these agents. The half-times of spontaneous reactivation of rat plasma CarbE in vivo were 1.2, 2.0 and 2.7 h for dichlorvos, sarin and soman, respectively. These findings have changed current understanding of the mechanism of interaction of CarbE with OPC and involvement of the enzymes in detoxication of OPC, suggesting an active and important role of the enzymes in metabolic conversions of OPC to their less toxic metabolites.

Occurrence and human exposure to brominated and organophosphorus flame retardants via indoor dust in a Brazilian city.

PubMed

Cristale, Joyce; Aragão Belé, Tiago Gomes; Lacorte, Silvia; Rodrigues de Marchi, Mary Rosa

2018-06-01

Indoor dust is considered an important human exposure route to flame retardants (FRs), which has arised concern due the toxic properties of some of these substances. In this study, ten organophosphorus flame retardants (OPFRs), eight polybrominated diphenyl ethers (PBDEs) and four new brominated flame retardants (NBFRs) were determined in indoor dust from different places in Araraquara-SP (Brazil). The sampled places included houses, apartments, offices, primary schools and cars. The analysis of the sample extracts was performed by gas chromatography coupled to mass spectrometry and two ionization techniques were used (electron ionization - EI; electron capture negative ionization - ECNI). OPFRs were the most abundant compounds and tris(2-butoxyethyl) phosphate (TBOEP), tris(phenyl) phosphate (TPHP), tris(1,3-dichloroisopropyl) phosphate (TDCIPP) and tris(2-chloroisopropyl) phosphate (TCIPP) were present at the highest concentrations. Among the brominated FRs, the most ubiquitous compounds were BDE-209, bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP) and decabromodiphenyl ethane (DBDPE). Statistical analysis revealed that there were differences among dust typologies for TBOEP, TDCIPP, ethylhexyl diphenyl phosphate (EHDPHP), BDE-209, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB), BEH-TEBP and DBDPE, which were attributed to different construction materials in each particular environment and to the age of the buildings. The highest levels of brominated FRs were observed in offices, TBOEP was at high concentration in primary schools, and TDCIPP was at high concentration in cars. A preliminary risk assessment revealed that toddlers were exposed to TBOEP levels higher than the reference dose when considering the worst case scenario. The results obtained in this study showed for the first time that although Brazil does not regulate the use of FRs, these substances are present in indoor dust at levels similar to the observed in countries that have strict fire safety standards, and that humans are exposed to complex mixtures of these contaminants via indoor dust. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells.

PubMed

Sogorb, Miguel A; Fuster, Encarnación; Del Río, Eva; Estévez, Jorge; Vilanova, Eugenio

2016-11-25

Chlorpyrifos (CPS) is an organophosphorus compound (OP) capable of causing well-known cholinergic and delayed syndromes through the inhibition of acetylcholinesterase and Neuropathy Target Esterase (NTE), respectively. CPS is also able to induce neurodevelopmental toxicity in animals. NTE is codified by the Pnpla6 gene and plays a central role in differentiation and neurodifferentiation. We tested, in D3 mouse embryonic stem cells under differentiation, the effects of the NTE inhibition by the OPs mipafox, CPS and its main active metabolite chlorpyrifos-oxon (CPO) on the expression of genes Vegfa, Bcl2, Amot, Nes and Jun, previously reported to be under- or overexpressed after Pnpla6 silencing in this same cellular model. Mipafox did not significantly alter the expression of such genes at concentrations that significantly inhibited NTE. However, CPS and CPO at concentrations that caused NTE inhibition at similar levels to mipafox statistically and significantly altered the expression of most of these genes. Paraoxon (another OP with capability to inhibit esterases but not NTE) caused similar effects to CPS and CPO. These findings suggest that the molecular mechanism for the neurodevelopmental toxicity induced by CPS is not based on NTE inhibition, and that other unknown esterases might be potential targets of neurodevelopmental toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Molecular Modeling in Drug Design for the Development of Organophosphorus Antidotes/Prophylactics.

DTIC Science & Technology

1986-06-01

multidimensional statistical QSAR analysis techniques to suggest new structures for synthesis and evaluation. C. Application of quantum chemical techniques to...compounds for synthesis and testing for antidotal potency. E. Use of computer-assisted methods to determine the steric constraints at the active site...modeling techniques to model the enzyme acetylcholinester-se. H. Suggestion of some novel compounds for synthesis and testing for reactivating

Consumption of fruits and vegetables and probabilistic assessment of the cumulative acute exposure to organophosphorus and carbamate pesticides of schoolchildren in Slovenia.

PubMed

Blaznik, Urška; Yngve, Agneta; Eržen, Ivan; Hlastan Ribič, Cirila

2016-02-01

Adequate consumption of fruits and vegetables is a part of recommendations for a healthy diet. The aim of the present study was to assess acute cumulative dietary exposure to organophosphorus and carbamate pesticides via fruit and vegetable consumption by the population of schoolchildren aged 11-12 years and the level of risk for their health. Cumulative probabilistic risk assessment methodology with the index compound approach was applied. Slovenia, primary schools. Schoolchildren (n 1145) from thirty-one primary schools in Slovenia. Children were part of the PRO GREENS study 2009/10 which assessed 11-year-olds' consumption of fruit and vegetables in ten European countries. The cumulative acute exposure amounted to 8.3 (95% CI 7.7, 10.6) % of the acute reference dose (ARfD) for acephate as index compound (100 µg/kg body weight per d) at the 99.9th percentile for daily intake and to 4.5 (95% CI 3.5, 4.7) % of the ARfD at the 99.9th percentile for intakes during school time and at lunch. Apples, bananas, oranges and lettuce contributed most to the total acute pesticides intake. The estimations showed that acute dietary exposure to organophosphorus and carbamate pesticides is not a health concern for schoolchildren with the assessed dietary patterns of fruit and vegetable consumption.

Mass Spectral Detection of Diethoxyphospho-Tyrosine Adducts on Proteins from HEK293 Cells Using Monoclonal Antibody depY for Enrichment

PubMed Central

2018-01-01

Chronic illness from exposure to organophosphorus toxicants is hypothesized to involve modification of unknown proteins. Tyrosine in proteins that have no active site serine readily reacts with organophosphorus toxicants. We developed a monoclonal antibody, depY, that specifically recognizes diethoxyphospho-tyrosine in proteins and peptides, independent of the surrounding amino acid sequence. Our goal in the current study was to identify diethoxyphosphorylated proteins in human HEK293 cell lysate treated with chlorpyrifos oxon. Cell lysates treated with chlorpyrifos oxon were recognized by depY antibody in ELISA and capillary electrophoresis based Western blot. Tryptic peptides were analyzed by liquid chromatography tandem mass spectrometry. Liquid chromatography tandem mass spectrometry identified 116 diethoxyphospho-tyrosine peptides from 73 proteins in immunopurified samples, but found only 15 diethoxyphospho-tyrosine peptides from 12 proteins when the same sample was not immunopurified on depY. The most abundant proteins in the cell lysate, histone H4, heat shock 70 kDa protein 1A/1B, heat shock protein HSP 90 β, and α-enolase, were represented by several diethoxyphospho-tyrosine peptides. It was concluded that use of immobilized depY improved the number of diethoxyphospho-tyrosine peptides identified in a complex mixture. The mass spectrometry results confirmed the specificity of depY for diethoxyphospho-tyrosine peptides independent of the context of the modified tyrosine, which means depY could be used to analyze modified proteins in any species. Use of the depY antibody could lead to an understanding of chronic illness from organophosphorus pesticide exposure. PMID:29775289

Organophosphorus pesticides effect on early stages of the axolotl Ambystoma mexicanum (Amphibia: Caudata).

PubMed

Robles-Mendoza, C; García-Basilio, C; Cram-Heydrich, S; Hernández-Quiroz, M; Vanegas-Pérez, C

2009-02-01

Ambystoma mexicanum is an endemic salamander of Xochimilco, a wetland of the basin of Mexico valley. Nowadays, axolotl populations are decreasing due environmental stressors. Particularly, studies about organophosphorus pesticides (OPPs; i.e. chlorpyrifos and malathion) toxicity are of great importance due to their intensive use in agricultural activities in Xochimilco. Thus, the aim of this study was to evaluate under controlled conditions the toxicity of chlorpyrifos (CPF) and malathion (MLT) on embryos and larvae (stage 44 and 54) of A. mexicanum. Embryos and larvae were exposure 96h from 0.5 to 3mg CPFL(-1) and from 10 to 30mg MLTL(-1) in independent tests. Embryos at the end of this period were maintained 9d without pesticide in order to identify possible recuperation. Differences obtained in mortality, hatching success, development, morphological abnormalities, behaviour and activity, suggest that toxicity of CPF and MLT differs in embryos and larval stages. Embryos were less sensitive to OPPs acute exposure than axolotl larvae; additionally, toxicity of CPF in larval stages was greater than MLT. On the other hand, data obtained in axolotl embryos during the period of recuperation to CPF in particular as delay and inhibition of development, malformations and success of hatching, indicated that these responses turned out more sensitive than mortality. This study allowed to identify the toxicological potential of OPPs on early developmental stages of A. mexicanum and it is a valuable contribution for the future management of the axolotl wild population.

Adenovirus-mediated human paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon.

PubMed

Duysen, E G; Parikh, K; Aleti, V; Manne, V; Lockridge, O; Chilukuri, N

2011-03-01

Human paraoxonase1 (hPON1) is a potential therapeutic against the toxicity of organophosphorus (OP) pesticides and chemical warfare nerve agents. We tested whether PON1 gene transfer using adenovirus provides protection against the toxicity of the OP diazoxon. Using an adenovirus construct containing hPON1 gene, we showed elevated levels of recombinant hPON1 in vitro in 293A cells and in vivo in mice. The recombinant enzyme was secreted by 293A cells into culture medium and into the systemic circulation of mice. Western blotting revealed that the virally expressed hPON1 had the expected molecular weight of 45 kDa. Recombinant hPON1 in mice was in complex with mouse high-density lipoprotein (HDL) and migrated more slowly than endogenous hPON1 in the human HDL complex. Mice injected with adenovirus expressed PON1 at 600-3480 U ml(-1) on day 5 post-treatment, which is 8-50-fold above endogenous. Six mice expressing hPON1 survived 2LD(50) doses of diazoxon. Four of the six mice survived a second dose of diazoxon (for a total of 4LD(50)) administered 24 h later. In contrast, none of the three mice in the control group survived one 2LD(50) dose. These results show that hPON1 in mice functions as a prophylactic and offers significant protection against lethal doses of diazoxon.

Evidence that microplastics aggravate the toxicity of organophosphorus flame retardants in mice (Mus musculus).

PubMed

Deng, Yongfeng; Zhang, Yan; Qiao, Ruxia; Bonilla, Melvin M; Yang, Xiaoliang; Ren, Hongqiang; Lemos, Bernardo

2018-06-08

This study was performed to reveal the health risks of co-exposure to organophosphorus flame retardants (OPFRs) and microplastics (MPs). We exposed mice to polyethylene (PE) and polystyrene (PS) MPs and OPFRs [tris (2-chloroethy) phosphate (TCEP) and tris (1,3-dichloro-2-propyl) phosphate (TDCPP)] for 90 days. Biochemical markers and metabolomics were used to determine whether MPs could enhance the toxicity of OPFRs. Superoxide dismutase (SOD) and catalase (CAT) increased (p < 0.05) by 21% and 26% respectively in 10 μg/L TDCPP + PE group compared to TDCPP group. Lactate dehydrogenase (LDH) in TDCPP + MPs groups were higher (18%-30%) than that in TDCPP groups (p < 0.05). Acetylcholinesterase (AChE) in TCEP + PE groups were lower (10%-19%) than those in TCEP groups (p < 0.05). These results suggested that OPFR co-exposure with MPs induced more toxicity than OPFR exposure alone. Finally, in comparison to controls we observed that 29, 41, 41, 26, 40 and 37 metabolites changed significantly (p < 0.05; fold-change > 1.2) in TCEP, TCEP + PS, TCEP + PE, TDCPP, TDCPP + PS and TDCPP + PE groups, respectively. Most of these metabolites are related to pathways of amino acid and energy metabolism. Our results indicate that MPs aggravate the toxicity of OPFRs and highlight the health risks of MP co-exposure with other pollutants. Copyright © 2018 Elsevier B.V. All rights reserved.

Isolation and Identification of Persistent Chlorinated Organophosphorus Flame Retardant-Degrading Bacteria ▿

PubMed Central

Takahashi, Shouji; Satake, Ikuko; Konuma, Isao; Kawashima, Koji; Kawasaki, Manami; Mori, Shingo; Morino, Jun; Mori, Junichi; Xu, Hongde; Abe, Katsumasa; Yamada, Ryo-hei; Kera, Yoshio

2010-01-01

Tris(2-chloroethyl) and tris(1,3-dichloro-2-propyl) phosphates are chlorinated persistent flame retardants that have recently emerged as environmental pollutants. Two bacterial strains that can degrade the compounds when they are the sole phosphorus sources have been isolated and identified as members of the sphingomonads. The strains can be useful for the bioremediation of environments contaminated with these compounds. PMID:20525857

In vitro techniques for the assessment of neurotoxicity.

PubMed Central

Harry, G J; Billingsley, M; Bruinink, A; Campbell, I L; Classen, W; Dorman, D C; Galli, C; Ray, D; Smith, R A; Tilson, H A

1998-01-01

Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected through specific mechanisms of neurotoxicity. For example, in vitro systems may be useful for certain structurally defined compounds and mechanisms of toxicity, such as organophosphorus compounds and delayed neuropathy, for which target cells and the biochemical processes involved in the neurotoxicity are well known. For other compounds and the different types of neurotoxicity, a mechanism of toxicity needs to be identified first. Once identified, by either in vivo or in vitro methods, a system can be developed to detect and to evaluate predictive ability for the type of in vivo neurotoxicity produced. Therefore, in vitro tests have their greatest potential in providing information on basic mechanistic processes in order to refine specific experimental questions to be addressed in the whole animal. Images Figure 1 PMID:9539010

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

PubMed Central

Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

2017-01-01

Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

Fragmentation pathways and structural characterization of organophosphorus compounds related to the Chemical Weapons Convention by electron ionization and electrospray ionization tandem mass spectrometry.

PubMed

Hosseini, Seyed Esmaeil; Saeidian, Hamid; Amozadeh, Ali; Naseri, Mohammad Taghi; Babri, Mehran

2016-12-30

For unambiguous identification of Chemical Weapons Convention (CWC)-related chemicals in environmental samples, the availability of mass spectra, interpretation skills and rapid microsynthesis of suspected chemicals are essential requirements. For the first time, the electron ionization single quadrupole and electrospray ionization tandem mass spectra of a series of O-alkyl N-[bis(dimethylamino)methylidene]-P-methylphosphonamidates (Scheme 1, cpd 4) were studied for CWC verification purposes. O-Alkyl N-[bis(dimethylamino)methylidene]-P-methylphosphonamidates were prepared through a microsynthetic method and were analyzed using electron ionization and electrospray ionization mass spectrometry with gas and liquid chromatography, respectively, as MS-inlet systems. General EI and ESI fragmentation pathways were proposed and discussed, and collision-induced dissociation studies of the protonated derivatives of these compounds were performed to confirm proposed fragment ion structures by analyzing mass spectra of deuterated analogs. Mass spectrometric studies revealed some interesting fragmentation pathways during the ionization process, such as McLafferty rearrangement, hydrogen rearrangement and a previously unknown intramolecular electrophilic aromatic substitution reaction. The EI and ESI fragmentation routes of the synthesized compounds 4 were investigated with the aim of detecting and identifying CWC-related chemicals during on-site inspection and/or off-site analysis and toxic chemical destruction monitoring. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Transcriptional regulation of human Paraoxonase 1 by nuclear receptors.

PubMed

Ponce-Ruiz, N; Murillo-González, F E; Rojas-García, A E; Mackness, Mike; Bernal-Hernández, Y Y; Barrón-Vivanco, B S; González-Arias, C A; Medina-Díaz, I M

2017-04-25

Paraoxonase 1 (PON1) is a calcium-dependent lactonase synthesized primarily in the liver and secreted into the plasma, where it is associates with high density lipoproteins (HDL). PON1 acts as antioxidant preventing low-density lipoprotein (LDL) oxidation, a process considered critical in the initiation and progression of atherosclerosis. Additionally, PON1 hydrolyzes and detoxifies some toxic metabolites of organophosphorus compounds (OPs). Thus, PON1 activity and expression levels are important for determining susceptibility to OPs intoxication and risk of developing diseases related to inflammation and oxidative stress. Increasing evidence has demonstrated the modulation of PON1 expression by many factors is due to interaction with nuclear receptors (NRs). Here, we briefly review the studies in this area and discuss the role of nuclear receptors in the regulation of PON1 expression, as well as how understanding these mechanisms may allow us to manipulate PON1 levels to improve drug efficacy and treat disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Mitochondrial dysfunction and organophosphorus compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karami-Mohajeri, Somayyeh; Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Kerman University of Medical Sciences, Kerman; Abdollahi, Mohammad, E-mail: Mohammad.Abdollahi@UToronto.Ca

2013-07-01

Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen frommore » dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP.« less

Hazard evaluation of ten organophosphorous insecticides against the midge, Chironomus riparius via QSAR

USGS Publications Warehouse

Landrum, Peter F.; Fisher, Susan W.; Hwang, Haejo; Hickey, James P.

1999-01-01

Toxicities of ten organophosphorus (OP) insecticides were measured against midge larvae (Chironomus riparius) under varying temperature (11, 18, and 25°C) and pH (6, 7, and 8) conditions and with and without sediment. Toxicity usually increased with increasing temperature and was greater in the absence of sediment. No trend was found with varying pH. A series of unidimensional parameters and multidimensional models were used to describe the changes in toxicity. Log Kow was able to explain about 40–60% of the variability in response data for aqueous exposures while molecular volume and aqueous solubility were less predictive. Likewise, the linear solvation energy relationship (LSER) model only explained 40–70% of the response variability, suggesting that factors other than solubility were most important for producing the observed response. Molecular connectivity was the most useful for describing the variability in the response. In the absence of sediment, 1χv and 3κ were best able to describe the variation in response among all compounds at each pH (70–90%). In the presence of sediment, even molecular connectivity could not describe the variability until the partitioning potential to sediment was accounted for by assuming equilibrium partitioning. After correcting for partitioning, the same molecular connectivity terms as in the aqueous exposures described most of the variability, 61–87%, except for the 11°C data where correlations were not significant. Molecular connectivity was a better tool than LSER or the unidimensional variables to explain the steric fitness of OP insecticides which was crucial to the toxicity.

In vitro study of the neuropathic potential of the organophosphorus compounds trichlorfon and acephate.

PubMed

Fernandes, Laís S; Emerick, Guilherme L; dos Santos, Neife Aparecida G; de Paula, Eloísa Silva; Barbosa, Fernando; dos Santos, Antonio Cardozo

2015-04-01

Organophosphorus-induced delayed neuropathy (OPIDN) is a central and peripheral distal axonopathy characterized by ataxia and paralysis. Trichlorfon and acephate are two organophosphorus compounds (OPs) used worldwide as insecticide and which cause serious effects to non-target species. Despite that, the neuropathic potential of these OPs remains unclear. The present study addressed the neurotoxic effects and the neuropathic potential of trichlorfon and acephate in SH-SY5Y human neuroblastoma cells, by evaluating inhibition and aging of neuropathy target esterase (NTE), inhibition of acetylcholinesterase (AChE), neurite outgrowth, cytotoxicity and intracellular calcium. Additionally, the effects observed were compared to those of two well-studied OPs: mipafox (known as neuropathic) and paraoxon (known as non-neuropathic). Trichlorfon and mipafox presented the lowest percentage of reactivation of inhibited NTE and the lowest ratio IC50 NTE/IC50 AChE. Moreover, they caused inhibition and aging of at least 70% of the activity of NTE at sub-lethal concentrations. All these effects have been associated with induction of OPIDN. When assayed at these concentrations, trichlorfon and mipafox reduced neurite outgrowth and increased intracellular calcium, events implicated in the development of OPIDN. Acephate caused effects similar to those caused by paraoxon (non-neuropathic OP) and was only able to inhibit 70% of NTE activity at lethal concentrations. These findings suggest that trichlorfon is potentially neuropathic, whereas acephate is not. Copyright © 2015 Elsevier Ltd. All rights reserved.

Design and Synthesis of Candidate Prophylactic and Therapeutic Compounds for Use in the Management of Organophosphorus Poisoning.

DTIC Science & Technology

1985-01-01

resynthesis. The Grignard reagent , prepared from 4- chlorobromobenzene and magnesium metal, was treated with NN-diethyl-P- methylphosphonamidic chloride and the...ref. 26-28). Thus, diethylaminodichlorophosphine was treated with two equivalents of butyl Grignard reagent to give phosphinous amide 1 in 63% yield...compound following a general method developed by Ash Stevens Inc. for the synthesis of substituted aryl methylphosphinates. Thus, the Grignard reagent

Recent advances in evaluation of oxime efficacy in nerve agent poisoning by in vitro analysis.

PubMed

Worek, F; Eyer, P; Aurbek, N; Szinicz, L; Thiermann, H

2007-03-01

The availability of highly toxic organophosphorus (OP) warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is primarily caused by inhibition of acetylcholinesterase (AChE). Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents, e.g. soman and cyclosarin. This led to the synthesis and investigation of numerous oximes in the past decades. Reactivation of OP-inhibited AChE is considered to be the most important reaction of oximes. Clinical data from studies with pesticide-poisoned patients support the assumption that the various reactions between AChE, OP and oxime, i.e. inhibition, reactivation and aging, can be investigated in vitro with human AChE. In contrast to animal experiments such in vitro studies with human tissue enable the evaluation of oxime efficacy without being affected by species differences. In the past few years numerous in vitro studies were performed by different groups with a large number of oximes and methods were developed for extrapolating in vitro data to different scenarios of human nerve agent poisoning. The present status in the evaluation of new oximes as antidotes against nerve agent poisoning will be discussed.

A novel organophosphorus hydrolase-based biosensor using mesoporous carbons and carbon black for the detection of organophosphate nerve agents.

PubMed

Lee, Joon Hwan; Park, Jae Yeon; Min, Kyoungseon; Cha, Hyung Joon; Choi, Suk Soon; Yoo, Young Je

2010-03-15

To detect organophosphate chemicals, which are used both as pesticides and as nerve agents, a novel biosensor based on organophosphorus hydrolase was developed. By using mesoporous carbon (MC) and carbon black (CB) as an anodic layer, the sensitivity of the sensor to p-nitrophenol (PNP), which is the product of the organophosphorus hydrolase reaction, was greatly improved. The MC/CB/glass carbon (GC) layer exhibited an enhanced amperometric response relative to a carbon nanotube (CNT)-modified electrode because it promoted electron transfer of enzymatically generated phenolic compounds (p-nitrophenol). The well-ordered nanopores, many edge-plane-like defective sites (EDSs), and high surface area of the MC resulted in increased sensitivity, and allowed for nanomolar-range detection of the analyte paraoxon. Thus, MCs are suitable for use in real-time biosensors. Under the optimized experimental conditions, the biosensor had a detection limit of 0.12 microM (36 ppb) and a sensitivity of 198 nA/microM for paraoxon. (c) 2009 Elsevier B.V. All rights reserved.

Biosensor Detection of Neuropathy Target Esterase in Whole Blood as a Biomarker of Exposure to Neuropathic Organophosphorus Compounds

DTIC Science & Technology

2002-10-15

Chernogolovka, Moscow Region, Russia Arkady V. Eremenko Research Center for Molecular Diagnostics and Therapy, Moscow, Russia Ilya N. Kurochkin...Faculty of Chemistry, M. V. Lomonosov Moscow State University, and Research Center for Molecular Diagnostics and Therapy, Moscow, Russia Vladimir V

Proline/pipecolinic acid-promoted copper-catalyzed P-arylation.

PubMed

Huang, Cheng; Tang, Xu; Fu, Hua; Jiang, Yuyang; Zhao, Yufen

2006-06-23

We have developed a convenient and efficient approach for P-arylation of organophosphorus compounds containing P-H. Using commercially available and inexpensive proline and pipecolinic acid as the ligands greatly improved the efficiency of the coupling reactions, so the method can provide an entry to arylphosphonates, arylphosphinates and arylphosphine oxides.

Functional analysis of Torpedo californica nicotinic acetylcholine receptors in multiple activation states by SSM-based electrophysiology.

PubMed

Niessen, K V; Muschik, S; Langguth, F; Rappenglück, S; Seeger, T; Thiermann, H; Worek, F

2016-04-15

Organophosphorus compounds (OPC), i.e. nerve agents or pesticides, are highly toxic due to their strong inhibition potency against acetylcholinesterase (AChE). Inhibited AChE results in accumulation of acetylcholine in the synaptic cleft and thus the desensitisation of the nicotinic acetylcholine receptor (nAChR) in the postsynaptic membrane is provoked. Direct targeting of nAChR to reduce receptor desensitisation might be an alternative therapeutic approach. For drug discovery, functional properties of potent therapeutic candidates need to be investigated in addition to affinity properties. Solid supported membrane (SSM)-based electrophysiology is useful for functional characterisation of ligand-gated ion channels like nAChRs, as charge translocations via capacitive coupling of the supporting membrane can be measured. By varying the agonist (carbamoylcholine) concentration, different functional states of the nAChR were initiated. Using plasma membrane preparations obtained from Torpedo californica electric organ, functional properties of selected nAChR ligands and non-oxime bispyridinium compounds were investigated. Depending on overall-size, the bispyridinium compounds enhanced or inhibited cholinergic signals induced by 100 μM carbamoylcholine. Applying excessive concentrations of the agonist carbamoylcholine provoked desensitisation of the nAChRs, whereas addition of bispyridinium compounds bearing short alkyl linkers exhibited functional recovery of previously desensitised nAChRs. The results suggest that these non-oxime bispyridinium compounds possibly interacted with nAChR subtypes in a manner of a positive allosteric modulator (PAM). The described newly developed functional assay is a valuable tool for the assessment of functional properties of potential compounds such as nAChR modulating ligands, which might be a promising approach in the therapeutically treatment of OPC-poisonings. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.

PubMed

Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A; Mishin, Vladimir; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

2015-10-01

Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. Copyright © 2015 Elsevier Inc. All rights reserved.

Organophosphorus Insecticide Pharmacokinetics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timchalk, Charles

2010-01-01

This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific andmore » dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.« less

Multiresidue analysis of endocrine-disrupting compounds and perfluorinated sulfates and carboxylic acids in sediments by ultra-high-performance liquid chromatography-tandem mass spectrometry.

PubMed

Cavaliere, Chiara; Capriotti, Anna Laura; Ferraris, Francesca; Foglia, Patrizia; Samperi, Roberto; Ventura, Salvatore; Laganà, Aldo

2016-03-18

A multiresidue analytical method for the determination of 11 perfluorinated compounds and 22 endocrine-disrupting compounds (ECDs) including 13 natural and synthetic estrogens (free and conjugated forms), 2 alkylphenols, 1 plasticiser, 2 UV-filters, 1 antimicrobial, and 2 organophosphorus compounds in sediments has been developed. Ultrasound-assisted extraction followed by solid phase extraction (SPE) with graphitized carbon black (GCB) cartridge as clean-up step were used. The extraction process yield was optimized in terms of solvent composition. Then, a 3(2) experimental design was used to optimize solvent volume and sonication time by response surface methodology, which simplifies the optimization procedure. The final extract was analyzed by ultra-high performance liquid chromatography coupled with tandem mass spectrometry. The optimized sample preparation method is simple and robust, and allows recovery of ECDs belonging to different classes in a complex matrix such as sediment. The use of GCB for SPE allowed to obtain with a single clean-up procedure excellent recoveries ranging between 75 and 110% (relative standard deviation <16%). The developed methodology has been successfully applied to the analysis of ECDs in sediments from different rivers and lakes of the Lazio Region (Italy). These analyses have shown the ubiquitous presence of chloro-substituted organophosphorus flame retardants and bisphenol A, while other analyzed compounds were occasionally found at concentration between the limit of detection and quantification. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparedness for the Evaluation and Management of Mass Casualty Incidents Involving Anticholinesterase Compounds: A Survey of Emergency Department Directors in the 12 Largest Cities in the United States

DTIC Science & Technology

2010-11-01

ORIGINAL ARTICLE Preparedness for the evaluation and management of mass casualty incidents involving anticholinesterase compounds: A survey of...Greenberg, MD, MPH Abstract Objectives: Anticholinesterases include carba- mate and organophosphorus (OP) insecticides and nerve agents. Release of...counterpart to REMM would be either moderately or very helpful for MCIs involving anticholinesterases . DOI:IO.5055/ajdm.2010.0035

Vapor Pressure Data and Analysis for Selected Organophosphorus Compounds, CMMP, DPMP, DMEP, and DEEP: Extrapolation of High-Temperature Data

DTIC Science & Technology

2018-04-01

EXTRAPOLATION OF HIGH -TEMPERATURE DATA ECBC-TR-1507 Ann Brozena Patrice Abercrombie-Thomas RESEARCH AND TECHNOLOGY DIRECTORATE David E. Tevault...Compounds, CMMP, DPMP, DMEP, and DEEP: Extrapolation of High - Temperature Data 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...22060-6201 10. SPONSOR/MONITOR’S ACRONYM(S) DTRA 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT Approved

Organophosphorus pesticide and ester analysis by using comprehensive two-dimensional gas chromatography with flame photometric detection.

PubMed

Liu, Xiangping; Li, Dengkun; Li, Jiequan; Rose, Gavin; Marriott, Philip J

2013-12-15

Thirty-seven phosphorus (P)-containing compounds comprising organophosphorus pesticides and organophosphate esters were analyzed by using comprehensive two-dimensional gas chromatography with flame photometric detection in P mode (GC × GC-FPD(P)), with a non-polar/moderately polar column set. A suitable modulation temperature and period was chosen based on experimental observation. A number of co-eluting peak pairs on the (1)D column were well separated in 2D space. Excellent FPD(P) detection selectivity, responding to compounds containing the P atom, produces clear 2D GC × GC plots with little interference from complex hydrocarbon matrices. Limits of detection (LOD) were within the range of 0.0021-0.048 μmol L(-1), and linear calibration correlation coefficients (R(2)) for all 37 P-compounds were at least 0.998. The P-compounds were spiked in 2% diesel and good reproducibility for their response areas and retention times was obtained. Spiked recoveries were 88%-157% for 5 μg L(-1) and 80%-138% for 10 μg L(-1) spiked levels. Both (1)tR and (2)tR shifts were noted when the content of diesel was in excess of 5% in the matrix. Soil samples were analyzed by using the developed method; some P-compounds were positively detected. In general, this study shows that GC × GC-FPD(P) is an accurate, sensitive and simple method for P-compound analysis in complicated environmental samples. Copyright © 2013 Elsevier B.V. All rights reserved.

Reliable Prescreening of Candidate NerveAgent Prophylaxes via 3D QSAR

DTIC Science & Technology

2005-12-31

recognize and predict prospective toxicity among covalent -binding AChE inhibitors of potential application to nerve agent prophylaxis and...is below since many authors do not follow the 200 word limit 14. SUBJECT TERMS nerve agents , acetylcholinesterase, prophylaxis, QSAR, virtual...Report: Reliable Prescreening of Candidate NerveAgent Prophylaxes via 3D QSAR Report Title ABSTRACT Organophosphorus (OP) nerve agents are among the

Relationship Between Organophosphate Toxicity and Choline Metabolism

DTIC Science & Technology

1986-06-06

E.M.G. Voltage and motor nerve conduction velocity in organophosphorus Pesticide factroy workers. Int. Arch. Occup. Environ. Health 36: 267-274. 62...internal standard, and prepared for the determination of the concentration of choline by pyrolysis gas chromatography (18,19). The rate of choline...those by which they affect ACh metabolism. Diisopropylfluorophosphate (DFP) is the agent most often studied, and data show that after acute or

Reconnaissance of chemical and physical characteristics of selected bottom sediments of the Caloosahatchee River and estuary, tributaries, and contiguous bays, Lee County, Florida, July 20-30, 1998

USGS Publications Warehouse

Fernandez, Mario; Marot, M.E.; Holmes, C.W.

1999-01-01

This report summarizes a reconnaissance study, conducted July 20-30, 1998, of chemical and physical characteristics of recently deposited bottom sediments in the Caloosahatchee River and Estuary. Recently deposited sediments were identified using an isotopic chronometer, Beryllium-7 (7Be), a short-lived radioisotope. Fifty-nine sites were sampled in an area that encompasses the Caloosahatchee River (River) about three miles upstream from the Franklin Lock (S-79), the entire tidally affected length of the river (estuary), and the contiguous water bodies of Matlacha Pass, San Carlos Bay, Estero Bay, Tarpon Bay, and Pine Island Sound in Lee County, Florida. Bottom sediments were sampled for 7Be at 59 sites. From the results of the 7Be analysis, 30 sites were selected for physical and chemical analysis. Sediments were analyzed for particle size, total organic carbon (TOC), trace elements, and toxic organic compounds, using semiquantitative methods for trace elements and organic compounds. The semiquantitative scans of trace elements indicated that cadmium, copper, lead, and zinc concentrations, when normalized to aluminum, were above the natural background range at 24 of 30 sites. Particle size and TOC were used to characterize sediment deposition patterns and organic content. Pesticides, polychlorinated biphenyls (PCBs), and carcinogenic polycyclic aromatic hydrocarbons (CaPAHs) were determined at 30 sites using immunoassay analysis. The semiquantitative immunoassay analyses of toxic organic compounds indicated that all of the samples contained DDT, cyclodienes as chlordane (pesticides), and CaPAHs. PCBs were not detected. Based on analyses of the 30 sites, sediments at 10 of these sites were analyzed for selected trace elements and toxic organic compounds, including pesticides, PCBs, and PAHs, using quantitative laboratory procedures. No arsenic or cadmium was detected. Zinc was detected at two sites with concentrations greater than the lower limit of the range of sediment contaminant concentrations that are usually or always associated with adverse effects (Florida Department of Environmental Protection's Sediment Quality Assessment Guidelines). Organochlorine pesticides were detected at four sites at concentrations below the reporting limits; there were no organophosphorus pesticides or PCBs detected. PAHs were detected at eight sites; however, only four sites had concentrations above the reporting limit.

An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timchalk, Chuck; Kousba, Ahmed A.; Poet, Torka S.

2007-08-01

Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometricallymore » scale both metabolism and tissue ChE levels. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent non-linear increase in CPF-oxon concentration may potentially result from the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that the PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.« less

A Comprehensive Evaluation of the Efficacy of Leading Oxime Therapies in Guinea Pigs Exposed to Organophosphorus Chemical Warfare Agents or Pesticides

PubMed Central

Wilhelm, Christina M.; Snider, Thomas H.; Babin, Michael C.; Jett, David A.; Platoff, Gennady E.; Yeung, David T.

2014-01-01

The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 hours post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman’s method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. PMID:25448441

A High-Throughput UHPLC-MS/MS Method for the Quantification of Five Aged Butyrylcholinesterase Biomarkers from Human Exposure to Organophosphorus Nerve Agents

PubMed Central

Graham, Leigh Ann; Johnson, Darryl; Carter, Melissa D.; Stout, Emily G.; Erol, Huseyin A.; Isenberg, Samantha L.; Mathews, Thomas P.; Thomas, Jerry D.; Johnson, Rudolph C.

2017-01-01

Organophosphorus nerve agents (OPNAs) are toxic compounds that are classified as prohibited Schedule 1 chemical weapons. In the body, OPNAs bind to butyrylcholinesterase (BChE) to form nerve agent adducts (OPNA-BChE). OPNA-BChE adducts can provide a reliable, long-term protein biomarker for assessing human exposure. A major challenge facing OPNA-BChE detection is hydrolysis (aging), which can continue to occur after a clinical specimen has been collected. During aging, the o-alkyl phosphoester bond hydrolyzes, and the specific identity of the nerve agent is lost. To better identify OPNA exposure events, a high throughput method for the detection of five aged OPNA-BChE adducts was developed. This is the first diagnostic panel to allow for the simultaneous quantification of any Chemical Weapons Convention Schedule 1 OPNA by measuring the aged adducts methyl phosphonate (MeP-BChE), ethyl phosphonate (EtP-BChE), propyl phosphonate (PrP-BChE), ethyl phosphoryl (ExP-BChE), phosphoryl (P-BChE), and unadducted BChE. The calibration range for all analytes is 2.00 – 250. ng/mL, which is consistent with similar methodologies used to detect unaged OPNA-BChE adducts. Each analytical run is three minutes making the time to first unknown results, including calibration curve and quality controls, less than one hour. Analysis of commercially purchased individual serum samples demonstrated no potential interferences with detection of aged OPNA-BChE adducts, and quantitative measurements of endogenous levels of BChE were similar to those previously reported in other OPNA-BChE adduct assays. PMID:27572107

The significance of the measurement of serum xanthine oxidase and oxidation markers in patients with acute organophosphorus pesticide poisoning.

PubMed

Zhang, J-W; Lv, G-C; Zhao, Y

2010-01-01

This study investigated whether xanthine oxidase (XO) plays an important role in the mechanism of toxicity of acute organophosphorus pesticide poisoning (AOPP). The serum activities of XO, superoxide dismutase (SOD), paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and malondialdehyde (MDA) were compared in 49 patients with AOPP and 50 age- and gender-matched healthy controls. Serum XO and MDA activities were higher and the serum SOD, PON1 and BChE activities were lower in the AOPP patients compared with the controls. Pearson correlation analysis demonstrated a significant negative correlation between XO activity and the SOD, PON1 and BChE activities, but a significant positive correlation between XO activity and MDA. These results suggest that increased activity of XO and decreased antioxidant enzyme activity contribute to the development of oxidative injury in AOPP patients. Thus, effective antioxidant therapy may be a therapeutic option following AOPP.

A FOURIER TRANSFORM INFRARED PHOTOACOUSTIC SPECTROSCOPY (FTIR-PAS) STUDY OF THE ADSORPTION OF ORGANOPHOSPHORUS COMPOUNDS ON HEAT-TREATED MAGNESIUM OXIDE. (R825549C015)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Exposure to toxic chemicals in the diet: is the Brazilian population at risk?

PubMed

Caldas, Eloisa Dutra; Jardim, Andreia Nunes Oliveira

2012-01-01

In Brazil, in the last 20 years, dietary risk assessments have been conducted on pesticides, mycotoxins, food additives, heavy metals (mainly mercury), environmental contaminants (mainly DDT) and acrylamide, a compound formed during food processing. The objectives of this paper were to review these studies, discuss their limitations and uncertainties and identify the most critical chemicals that may pose a health risk to Brazilian consumers. The studies have shown that the cumulative intake of organophosphorus and carbamate pesticides by high consumers of fruits and vegetables may represent a health concern (up to 169% of the ARfD), although the benefits of consuming large portions of those foods most probably overcome the risks. High consumers of maize products may also be at risk due to the presence of fumonisin (355% of the PMTDI), a mycotoxin present at high levels in Brazilian maize. The studies conducted in the Brazilian Amazon have shown that riparian fish consumers are exposed to unsafe levels of mercury. However, this is a more complex issue, as mercury levels in the region are naturally high and the health benefits of a fish-based diet are well known. Studies conducted both in Brazil and internationally on acrylamide have shown that the exposure to this genotoxic compound, mainly from the consumption of French fries and potato chips, is of health concern. Reducing the population dietary exposure to toxic chemicals is a challenge for government authorities and food producers in all countries. Management strategies aimed at decreasing exposure to the critical chemicals identified in this review involve limiting the use or eliminating highly toxic pesticides, implementing good agricultural practices to decrease maize contamination by fumonisins, educating local fish-eating communities toward a fish diet less contaminated by mercury, and changing dietary habits concerning the consumption of fried potatoes, the main processed food containing acrylamide.

Survey of pesticide residues in maize, cowpea and millet from northern Cameroon: part I.

PubMed

Sonchieu, Jean; Benoit Ngassoum, Martin; Bosco Tchatchueng, Jean; Srivastava, Ashutosh Kumar; Srivastava, Laxman Prasad

2010-01-01

In northern Cameroon, the misuse of pesticides for pest control is common among small-scale farmers. Therefore, monitoring of pesticide residues was carried out on stored maize, cowpea and millet from eight localities. The determination of residues of organochlorines (lindane, α-endosulfan and β-endosulfan), organophosphorus compounds (malathion and pirimiphos-methyl), synthetic pyrethroids (permethrin) and carbamates (carbufuran) was performed using GC-ECD/NPD and GC-MS for confirmation. Organochlorine pesticides were detected more frequently and in higher concentrations, ranging from 0.02 ± 0.01 mg kg(-1) for β-endosulfan in millet to 9.53 ± 4.00 mg kg(-1) lindane in maize, than organophosphorus compounds, with concentrations varying from 0.04 ± 0.03 mg kg(-1) for pirimiphos methyl to 0.23 ± 0.38 mg kg(-1) for malathion in maize. Permethrin was found only in maize at 0.39 ± 0.23 mg kg(-1). No carbofuran was found. More than 75% of samples contained pesticide residues above the maximum residue limit (MRL); showing a potential human dietary risk related to consumption of these grains.

Development of square wave voltammetry method for the assessment of organophosphorus compound impact on the cholinesterase of Pheretima with 2,6-dichloroindophenol as a redox indicator.

PubMed

Qiu, Jingxia; Chen, Jin; Ma, Qianqian; Miao, Yuqing

2009-09-01

A square wave voltammetry method was developed for the assessment of organophosphorus (OPs) compound impact on the cholinesterase of Pheretima with 2,6-dichloroindophenol (2,6-DCIP) as a redox indicator. The substrate of acetylthiocholine is hydrolysed by the cholinesterase (ChE) from soil animal pheretima, and the produced thiocholine reacts with the 2,6-DCIP to give obvious shift of electrochemical signal. The inhibition of ChE was assessed by measuring the enzyme activity before and after incubating with parathion-methyl. The reduction peak current of 2,6-DCIP decreases with the time of enzymatical reaction. The ChE loses almost 32.74% activity after 10 min incubation with 1ng mL(-1) paraoxon and 54.62% with 10 microg mL(-1) paraoxon, while the activity that corresponds to 100 microg mL(-1) paraoxon was nearly completely inhibited. This method can be employed to assess the inhibition of ChE and investigate OPs impact on environmental animals.

Bio-remediation of acephate-Pb(II) compound contaminants by Bacillus subtilis FZUL-33.

PubMed

Lin, Wenting; Huang, Zhen; Li, Xuezhen; Liu, Minghua; Cheng, Yangjian

2016-07-01

Removal of Pb(2+) and biodegradation of organophosphorus have been both widely investigated respectively. However, bio-remediation of both Pb(2+) and organophosphorus still remains largely unexplored. Bacillus subtilis FZUL-33, which was isolated from the sediment of a lake, possesses the capability for both biomineralization of Pb(2+) and biodegradation of acephate. In the present study, both Pb(2+) and acephate were simultaneously removed via biodegradation and biomineralization in aqueous solutions. Batch experiments were conducted to study the influence of pH, interaction time and Pb(2+) concentration on the process of removal of Pb(2+). At the temperature of 25°C, the maximum removal of Pb(2+) by B.subtilis FZUL-33 was 381.31±11.46mg/g under the conditions of pH5.5, initial Pb(2+) concentration of 1300mg/L, and contact time of 10min. Batch experiments were conducted to study the influence of acephate on removal of Pb(2+) and the influence of Pb(2+) on biodegradation of acephate by B.subtilis FZUL-33. In the mixed system of acephate-Pb(2+), the results show that biodegradation of acephate by B.subtilis FZUL-33 released PO4(3+), which promotes mineralization of Pb(2+). The process of biodegradation of acephate was affected slightly when the concentration of Pb(2+) was below 100mg/L. Based on the results, it can be inferred that the B.subtilis FZUL-33 plays a significant role in bio-remediation of organophosphorus-heavy metal compound contamination. Copyright © 2016. Published by Elsevier B.V.

Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jan, Yi-Hua; Richardson, Jason R., E-mail: jricha3@eohsi.rutgers.edu; Baker, Angela A.

Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling,more » a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40 mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation. - Highlights: • Menadione redox cycles with cytochrome P450 reductase and generates reactive oxygen species. • Redox cycling inhibits cytochrome P450-mediated parathion metabolism. • Short term administration of menadione inhibits parathion toxicity by inhibiting paraoxon formation.« less

Analysis and occurrence of endocrine-disrupting compounds and estrogenic activity in the surface waters of Central Spain.

PubMed

Esteban, S; Gorga, M; Petrovic, M; González-Alonso, S; Barceló, D; Valcárcel, Y

2014-01-01

Endocrine-disrupting compounds (EDCs) are chemical compounds with the ability to alter the hormonal systems of organisms. Such compounds are used in several industrial and domestic activities and reach the aquatic environment via wastewater discharge. The aim of this study is to assess the occurrence of 30 EDCs and related compounds in the surface waters of central Spain and to determine the overall estrogenic activity of environmental samples. This study analyzed a large number of EDCs and other emergent or suspected compounds with endocrine-disrupting activity. The results have shown the presence of 19 EDCs at concentrations ranging from 2 to 5928 ng L(-1). Organophosphorus-based flame retardants, alkylphenolic compounds and anticorrosives were found at the highest concentrations. Furthermore, although insufficient data are available to calculate an average over time, these preliminary results show the need to monitor the waters in both rivers studied. Alkylphenolic compounds, particularly nonylphenol, were the main contributors to overall estrogenicity. A higher concentration of the compounds studied was detected in the river Jarama, although the estrogenicity expressed as estradiol equivalents (EEQs) was higher in the river Manzanares due to a higher concentration of nonylphenol. However, the total estrogenicity did not exceed 1 ng L(-1) (EEQ), which is the level that may cause estrogenic effects in aquatic organisms, in any of the samples. In conclusion, the potential estrogenic risk in both rivers is low, although organophosphorus-based flame retardants may increase this risk as they were found at high levels in all samples. Unfortunately, these compounds could not be taken into account when calculating the estrogenic activity due to the lack of activity data for them. For future investigations, it will be important to assess the estrogenicity provided by these flame retardants. Due to the significant concentrations of EDCs detected in both rivers, further studies in this region are required. © 2013.

Organochlorine and organophosphorus pesticide residues in fodder and milk samples along Musi river belt, India.

PubMed

Kotinagu, Korrapati; Krishnaiah, Nelapati

2015-04-01

The present study was conducted to find the organochlorine pesticide (OCP) and organophosphorus pesticide (OPP) residues in fodder and milk samples along Musi river belt, India. Fodder and milk samples collected from the six zones of Musi river belt, Hyderabad India were analyzed by gas chromatography with electron capture detector for OCP residues and pulsated flame photometric detector for the presence of OPP residues. The gas chromatographic analysis of fodder samples of Zone 5 of Musi river showed the residues of dicofol at concentration of 0.07±0.0007 (0.071-0.077). Among organophosphorus compounds, dimetheoate was present in milk samples collected from Zone 6 at a level of 0.13±0.006 (0.111-0.167). The residues of OCPs, OPPs and cyclodies were below the detection limit in the remaining fodder and milk samples collected from Musi river belt in the present study. The results indicate that the pesticide residues in fodder and milk samples were well below the maximum residue level (MRL) values, whereas dicofol in fodder and dimethoate in milk were slightly above the MRL values specified by EU and CODEX.

Organochlorine and organophosphorus pesticide residues in fodder and milk samples along Musi river belt, India

PubMed Central

Kotinagu, Korrapati; Krishnaiah, Nelapati

2015-01-01

Aim: The present study was conducted to find the organochlorine pesticide (OCP) and organophosphorus pesticide (OPP) residues in fodder and milk samples along Musi river belt, India. Materials and Methods: Fodder and milk samples collected from the six zones of Musi river belt, Hyderabad India were analyzed by gas chromatography with electron capture detector for OCP residues and pulsated flame photometric detector for the presence of OPP residues. Results: The gas chromatographic analysis of fodder samples of Zone 5 of Musi river showed the residues of dicofol at concentration of 0.07±0.0007 (0.071-0.077). Among organophosphorus compounds, dimetheoate was present in milk samples collected from Zone 6 at a level of 0.13±0.006 (0.111-0.167). The residues of OCPs, OPPs and cyclodies were below the detection limit in the remaining fodder and milk samples collected from Musi river belt in the present study. Conclusion: The results indicate that the pesticide residues in fodder and milk samples were well below the maximum residue level (MRL) values, whereas dicofol in fodder and dimethoate in milk were slightly above the MRL values specified by EU and CODEX. PMID:27047132

Separating esterase targets of organophosphorus compounds in the brain by preparative chromatography.

PubMed

Mangas, I; Vilanova, E; Benabent, M; Estévez, J

2014-02-10

Low level exposure to organophosphorus esters (OPs) may cause long-term neurological effects and affect specific cognition domains in experimental animals and humans. Action on known targets cannot explain most of these effects by. Soluble carboxylesterases (EC 3.1.1.1) of chicken brain have been kinetically discriminated using paraoxon, mipafox and phenylmethyl sulfonylfluoride as inhibitors and phenyl valerate as a substrate. Three different enzymatic components were discriminated and called Eα, Eβ and Eγ. In this work, a fractionation procedure with various steps was developed using protein native separation methods by preparative HPLC. Gel permeation chromatography followed by ion exchange chromatography allowed enriched fractions with different kinetic behaviors. The soluble chicken brain fraction was fractionated, while total esterase activity, proteins and enzymatic components Eα, Eβ and Eγ were monitored in each subfraction. After the analysis, 13 fractions were pooled and conserved. Preincubation of the soluble chicken brain fraction of with the organophosphorus mipafox gave rise to a major change in the ion exchange chromatography profile, but not in the molecular exchanged chromatography profile, which suggest that mipafox permanently modifies the ionic properties of numerous proteins. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Low-concentration exposure to glyphosate-based herbicide modulates the complexes of the mitochondrial respiratory chain and induces mitochondrial hyperpolarization in the Danio rerio brain.

PubMed

Pereira, Aline G; Jaramillo, Michael L; Remor, Aline P; Latini, Alexandra; Davico, Carla E; da Silva, Mariana L; Müller, Yara M R; Ammar, Dib; Nazari, Evelise M

2018-06-11

Glyphosate (N-phosphonomethyl-glycine) (GLY) is the active ingredient of the most used herbicides in the world. GLY is applied in formulated products known as glyphosate-based herbicides (GBH), which could induce effects that are not predicted by toxicity assays with pure GLY. This herbicide is classified as organophosphorus compound, which is known to induce neurotoxic effects. Although this compound is classified as non-neurotoxic by regulatory agencies, acute exposure to GBH causes neurological symptoms in humans. However, there is no consensus in relation to neurotoxic effects of GBH. Thus, the aim of this study was to investigate the neurotoxic effects of the GBH in the zebrafish Danio rerio, focusing on acute toxicity, the activity and transcript levels of mitochondrial respiratory chain complexes, mitochondrial membrane potential, reactive species (RS) formation, and behavioral repertoire. Adult zebrafish were exposed in vivo to three concentrations of GBH Scout ® , which contained GLY in formulation (fGLY) (0.065, 1.0 and 10.0 mg L -1 fGLY) for 7 d, and an in vitro assay was performed using also pure GLY. Our results show that GBH induced in zebrafish brain a decrease in cell viability, inhibited mitochondrial complex enzymatic activity, modulated gene expression related to mitochondrial complexes, induced an increase in RS production, promoted hyperpolarization of mitochondrial membrane, and induced behavioral impairments. Together, our data contributes to the knowledge of the neurotoxic effects of GBH. Mitochondrial dysfunction has been recognized as a relevant cellular response that should not be disregarded. Moreover, this study pointed to the mitochondria as an important target of GBH. Copyright © 2018 Elsevier Ltd. All rights reserved.

Absence of circannual toxicity of parathion to starlings

USGS Publications Warehouse

Rattner, B.A.; Grue, C.E.

1990-01-01

Ambient temperature and season have been observed to influence the toxicity of several environmental pollutants in homeotherms. The circannual toxicity of ethyl parathion (EP) was examined in adult European starlings (Sturnus vulgaris). Groups of birds housed in outdoor pens received oral doses of EP (20-150 mg/kg body weight) in fall, winter, spring and summer (temperature range -3.3 to 36.7?C). The median lethal dosage (LD50), and brain and plasma cholinesterase inhibition, were found to be quite similar among seasons. There was some suggestion that EP may have been more toxic during hot weather (winter versus summer LD50 estimate [95% confidence interval]:160 [114-225] vs. 118 [102-136] mg/kg; P<0.10). In view of previous reports in which ambient temperature extremes and harsh weather have enhanced organophosphorus insecticide toxicity to birds, it is concluded that circannual toxicity studies should include measures of sensitivity (acute oral exposure) and vulnerability (dietary exposure) to better predict responses of free-ranging birds

The design and synthesis of biologically active organophosphorus compounds--the role of a central research laboratory.

PubMed

Hall, Roger G

2010-01-01

The properties and benefits offered by incorporating phosphorus into molecules are varied and numerous as shown by the many divisional research programs within Ciba-Geigy in the early eighties. This paper describes how a Central Research Group developed new materials in organophosphorous chemistry and identified new leads for life science applications.

Determination of the Partition Coefficients of Organophosphorus Compounds Using High-Performance Liquid Chromatography.

DTIC Science & Technology

1987-12-01

have claimed an advantage to deter- mining values of k’ in 100% aqueous mobile phases by extrapolation of linear plots of log k’ vs. percent organic...im parti- cle size chemically bonded octadecylsilane (ODS) packing ( Alltech Econo- sphere). As required, this column was saturated with I-octanol by in

DOE Office of Scientific and Technical Information (OSTI.GOV)

Worek, Franz, E-mail: franzworek@bundeswehr.org; Wille, Timo; Aurbek, Nadine

Treatment of poisoning by highly toxic organophosphorus compounds (OP, nerve agents) is a continuous challenge. Standard treatment with atropine and a clinically used oxime, obidoxime or pralidoxime is inadequate against various nerve agents. For ethical reasons testing of oxime efficacy has to be performed in animals. Now, it was tempting to investigate the reactivation kinetics of MMB-4, a candidate oxime to replace pralidoxime, with nerve agent-inhibited acetylcholinesterase (AChE) from human and animal origin in order to provide a kinetic basis for the proper assessment of in vivo data. By applying a modified kinetic approach, allowing the use of necessary highmore » MMB-4 concentrations, it was possible to determine the reactivation constants with sarin-, cyclosarin-, VX-, VR- and tabun-inhibited AChE. MMB-4 exhibited a high reactivity and low affinity towards OP-inhibited AChE, except of tabun-inhibited enzyme where MMB-4 had an extremely low reactivity. Species differences between human and animal AChE were low (Cynomolgus) to moderate (swine, guinea pig). Due to the high reactivity of MMB-4 a rapid reactivation of inhibited AChE can be anticipated at adequate oxime concentrations which are substantially higher compared to HI-6. Additional studies are necessary to determine the in vivo toxicity, tolerability and pharmacokinetics of MMB-4 in humans in order to enable a proper assessment of the value of this oxime as an antidote against nerve agent poisoning.« less

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans.

PubMed

Chedik, Lisa; Mias-Lucquin, Dominique; Bruyere, Arnaud; Fardel, Olivier

2017-06-30

Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides ( n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines ( n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds ( n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non-permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects.

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans

PubMed Central

Chedik, Lisa; Mias-Lucquin, Dominique; Bruyere, Arnaud; Fardel, Olivier

2017-01-01

Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides (n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines (n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds (n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non-permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects. PMID:28665355

Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice.

PubMed

Graziani, S; Christin, D; Daulon, S; Breton, P; Perrier, N; Taysse, L

2014-05-01

In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.

Proteomics screening of adenosine triphosphate-interacting proteins in the liver of diazinon-treated rats.

PubMed

Pourtaji, A; Robati, R Yazdian; Lari, P; Hosseinzadeh, H; Ramezani, M; Abnous, K

2016-10-01

Diazinon (DZN) is one of the most important organophosphorus compounds used to control pests in agriculture in many countries. Several studies have shown that exposure to DZN may alter protein expression in the liver. In order to further investigate the mechanism of DZN toxicity, differentially expressed ATP-interacting proteins, following subacute exposure to toxin, were separated and identified in rat liver. Male rats were equally divided into four groups: control (corn oil) and DZN (15 mg/kg) by gavage once a day for 4 weeks. After homogenization of liver tissue, lysates were incubated ATP-sepharose beads. After several washes, ATP-interacting proteins were eluted and separated on 2-D polyacrylamide gels. Deferentially expressed proteins were cut and identified using matrix-assisted laser desorption/ionization/time-of-flight and Mascot database. Identified proteins were classified according to their biological process using protein analysis through evolutionary relationships (PANTHER) Web site. In this work, we showed that several key proteins involved in biological processes such as antioxidant system, oxidative stress, apoptosis, and metabolism were differentially expressed after subacute exposure to DZN. © The Author(s) 2015.

Field studies on pesticides and birds: Unexpected and unique relations

USGS Publications Warehouse

Blus, L.J.; Henny, Charles J.

1997-01-01

We review the advantages and disadvantages of experimental and field studies for determining effects of pesticides on birds. Important problems or principles initially discovered in the field include effects of DDT (through its metabolite DDE) on eggshell thickness, reproductive success, and population stability; trophic-level bioaccumulation of the lipid-soluble organochlorine pesticides; indirect effects on productivity and survival through reductions in the food supply and cover by herbicides and insecticides; unexpected toxic effects and routes of exposure of organophosphorus compounds such as famphur and dimethoate; effects related to simultaneous application at full strength of several pesticides of different classes; and others. Also, potentially serious bird problems with dicofol, based on laboratory studies, later proved negligible in the field. In refining field tests of pesticides, the selection of a species or group of species to study is important, because exposure routes may vary greatly, and 10-fold interspecific differences in sensitivity to pesticides are relatively common. Although there are limitations with field investigations, particularly uncontrollable variables that must be addressed, the value of a well-designed field study far outweighs its shortcomings.

Field studies on pesticides and birds: unexpected and unique relations

USGS Publications Warehouse

Blus, L.J.; Henny, C.J.

1997-01-01

We review the advantages and disadvantages of experimental and field studies for determining effects of pesticides on birds. Important problems or principles initially discovered in the field include effects of DDT (through its metabolite DDE) on eggshell thickness, reproductive success, and population stability; trophic-level bioaccumulation of the lipid-soluble organochlorine pesticides; indirect effects on productivity and survival through reductions in the food supply and cover by herbicides and insecticides; unexpected toxic effects and routes of exposure of organophosphorus compounds such as famphur and dimethoate; effects related to simultaneous application at full strength of several pesticides of different classes; and others. Also, potentially serious bird problems with dicofol, based on laboratory studies, later proved negligible in the field. In refining field tests of pesticides, the selection of a species or group of species to study is important, because exposure routes may vary greatly, and 10-fold interspecific differences in sensitivity to pesticides are relatively common. Although there are limitations with field investigations, particularly uncontrollable variables that must be addressed, the value of a well-designed field study far outweighs its shortcomings

Exposure of nonbreeding migratory shorebirds to cholinesterase-inhibiting contaminants in the western hemisphere

USGS Publications Warehouse

Strum, K.M.; Hooper, M.J.; Johnson, K.A.; Lanctot, Richard B.; Zaccagnini, M.E.; Sandercock, B.K.

2010-01-01

Migratory shorebirds frequently forage and roost in agricultural habitats, where they may be exposed to cholinesterase-inhibiting pesticides. Exposure to organophosphorus and carbamate compounds, common anti-cholinesterases, can cause sublethal effects, even death. To evaluate exposure of migratory shorebirds to organophosphorus and carbamates, we sampled birds stopping over during migration in North America and wintering in South America. We compared plasma cholinesterase activities and body masses of individuals captured at sites with no known sources of organophosphorus or carbamates to those captured in agricultural areas where agrochemicals were recommended for control of crop pests. In South America, plasma acetylcholinesterase and butyrylcholinesterase activity in Buff-breasted Sandpipers was lower at agricultural sites than at reference sites, indicating exposure to organophosphorus and carbamates. Results of plasma cholinesterase reactivation assays and foot-wash analyses were inconclusive. A meta-analysis of six species revealed no widespread effect of agricultural chemicals on cholinesterase activity. however, four of six species were negative for acetylcholinesterase and one of six for butyrylcholinesterase, indicating negative effects of pesticides on cholinesterase activity in a subset of shorebirds. Exposure to cholinesterase inhibitors can decrease body mass, but comparisons between treatments and hemispheres suggest that agrochemicals did not affect migratory shorebirds' body mass. Our study, one of the first to estimate of shorebirds' exposure to cholinesterase-inhibiting pesticides, suggests that shorebirds are being exposed to cholinesterase- inhibiting pesticides at specific sites in the winter range but not at migratory stopover sites. future research should examine potential behavioral effects of exposure and identify other potential sitesand levels of exposure. ?? The Cooper Ornithological Society 2010.

Effects of cadmium, naphthalene, and DDVP on gut carbohydrases activity in bream (Abramis brama L. ) and Mozambique tilapia (Oreochromis mossambicus Peters)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Golovanova, I.L.; Chuiko, G.M.; Pavlov, D.F.

1994-03-01

Previous research has shown that sublethal concentrations of cadmium, naphthalene and dichlorvos (DDVP) decreased growth rates in bream and Mozambique tilapia. One of the factors known to affect fish growth is the activity of gut digestive enzymes such as of lipases, proteases, carbohydrases. We assumed that toxicant-induced inhibition of the digestive enzyme activity and, consequently, the impaired digestion of food may contribute to the reduction of growth in fish exposed to toxicants. However, the influence of toxicants on digestive enzyme activities is poorly studied. The contribution of toxicant-induced changes of digestive enzymes activity to growth rate retardation in exposed fishmore » remains unknown. The goal of this study was to examine the influence of an organophosphorus insecticide DDVP, a polyaromatic hydrocarbon naphthalene, and a metal cadmium on fish gut carbohydrase (CH) activity. 14 refs., 2 tabs.« less

The role of oxidative stress in organophosphate and nerve agent toxicity

PubMed Central

Pearson, Jennifer N.; Patel, Manisha

2016-01-01

Organophosphate nerve agents exert their toxicity through inhibition of acetylcholinesterase. The excessive stimulation of cholinergic receptors rapidly causes neuronal damage, seizures, death, and long-term neurological impairment in those that survive. Owing to the lethality of organophosphorus agents and the growing risk they pose, medical interventions that prevent organophosphate toxicity and the delayed injury response are much needed. Studies have shown that oxidative stress occurs in models of subacute, acute, and chronic exposure to organophosphate agents. Key findings of these studies include alterations in mitochondrial function and increased free radical–mediated injury, such as lipid peroxidation. This review focuses on the role of reactive oxygen species in organophosphate neurotoxicity and its dependence on seizure activity. Understanding the sources, mechanisms, and pathological consequences of organophosphate-induced oxidative stress can lead to the development of rational therapies for treating toxic exposures. PMID:27371936

Comparative toxicity of chlorpyrifos, diazinon, malathion and their oxon derivatives to larval Rana boylii

USGS Publications Warehouse

Sparling, D.W.; Fellers, G.

2007-01-01

Organophosphorus pesticides (OPs) are ubiquitous in the environment and are highly toxic to amphibians. They deactivate cholinesterase, resulting in neurological dysfunction. Most chemicals in this group require oxidative desulfuration to achieve their greatest cholinesterase-inhibiting potencies. Oxon derivatives are formed within liver cells but also by bacterial decay of parental pesticides. This study examines the toxicity of chlorpyrifos, malathion and diazinon and their oxons on the foothill yellow-legged frog (Rana boylii). R. boylii is exposed to agricultural pesticides in the California Central Valley. Median lethal concentrations of the parental forms during a 96 h exposure were 3.00 mg/L (24 h) for chlorpyrifos, 2.14 mg/L for malathion and 7.49 mg/L for diazinon. Corresponding oxons were 10 to 100 times more toxic than their parental forms. We conclude that environmental concentrations of these pesticides can be harmful to R. boylii populations. ?? 2006 Elsevier Ltd. All rights reserved.

Case histories of bald eagles and other raptors killed by organophosphorus insecticides topically applied to livestock

USGS Publications Warehouse

Henny, C.J.; Kolbe, E.J.; Hill, E.F.; Blus, L.J.

1987-01-01

Since 1982 when secondary poisoning of a red-tailed hawk (Buteo jamaicensis) was documented following the recommended use of famphur applied topically to cattle, the Patuxent Wildlife Research Center has tested dead birds of prey for poisoning by famphur and other pour-on organophosphorus (OP) insecticides. Brain cholinesterase (ChE) activity was first determined, then if ChE was depressed greater than or equal to 50%, stomach and/or crop contents were evaluated for anti-ChE compounds. This report presents the circumstances surrounding the OP-caused deaths of eight bald eagles (Haliaeetus leucocephalus), two red-tailed hawks, and one great horned owl (Bubo virginianus) between March 1984 and March 1985. OP poisoning of raptors by pour-on insecticides in the United States is widespread, but its magnitude is unknown.

Case histories of bald eagles and other raptors killed by organophosphorus insecticides topically applied to livestock.

PubMed

Henny, C J; Kolbe, E J; Hill, E F; Blus, L J

1987-04-01

Since 1982 when secondary poisoning of a red-tailed hawk (Buteo jamaicensis) was documented following the recommended use of famphur applied topically to cattle, the Patuxent Wildlife Research Center has tested dead birds of prey for poisoning by famphur and other pour-on organophosphorus (OP) insecticides. Brain cholinesterase (ChE) activity was first determined, then if ChE was depressed greater than or equal to 50%, stomach and/or crop contents were evaluated for anti-ChE compounds. This report presents the circumstances surrounding the OP-caused deaths of eight bald eagles (Haliaeetus leucocephalus), two red-tailed hawks, and one great horned owl (Bubo virginianus) between March 1984 and March 1985. OP poisoning of raptors by pour-on insecticides in the United States is widespread, but its magnitude is unknown.

Rhodium-Catalyzed Insertion Reaction of PhP Group of Pentaphenylcyclopentaphosphine with Acyclic and Cyclic Disulfides.

PubMed

Arisawa, Mieko; Sawahata, Kyosuke; Yamada, Tomoki; Sarkar, Debayan; Yamaguchi, Masahiko

2018-02-16

Organophosphorus compounds with a phosphorus atom attached to a phenyl group and two organothio/organoseleno groups were synthesized using the rhodium-catalyzed insertion reaction of the PhP group of pentaphenylcyclopentaphosphine (PhP) 5 with acyclic disulfides and diselenides. The method was applied to the synthesis of heterocyclic compounds containing the S-P-S group by the reaction of (PhP) 5 and cyclic disulfides such as 1,2-dithietes, 1,2-dithiocane, 1,4,5-dithiopane, and 1,2-dithiolanes.

Vapor Pressure Data and Analysis for Selected Organophosphorus Compounds: DIBMP, DCMP, IMMP, IMPA, EMPA, and MPFA

DTIC Science & Technology

2017-04-01

Methodology, Statistics, and Applications; CRDEC-TR-386; U.S. Army Chemical Research, Development and Engineering Center: Aberdeen Proving Ground...Approved for public release; distribution unlimited. 13. SUPPLEMENTARY NOTES 14. ABSTRACT: Recent work from our laboratory has focused on chemical ...vaporization Volatility Differential scanning calorimetry (DSC) Vapor saturation Boiling point Diisobutyl methylphosphonate (DIBMP), Chemical Abstracts

Human Metabolism and Interactions of Deployment-Related Chemicals

DTIC Science & Technology

2003-08-01

with individual test compounds (final concentration, 100 PM), agent pyridostigmine bromide to protect against possible nerve gas NADPH-generating system...an insect repellent (N,N-diethyl-m- toluamide) a nerve gas prophyllactic (pyridostigmine bromide) did not cause the inhibition of trans-permethrin...mechanism of organophosphorus anticholinesterase agents , namely; covalent modification of the active site of the esterases in question. Carbaryl, another

Infrared analysis of vapor phase deposited tricresylphosphate (TCP)

NASA Technical Reports Server (NTRS)

Morales, Wilfredo; Hanyaloglu, Bengi; Graham, Earl E.

1994-01-01

Infrared transmission was employed to study the formation of a lubricating film deposited on two different substrates at 700 C. The deposit was formed from tricresylphosphate vapors and collected onto a NaCl substrate and on an iron coated NaCl substrate. Analysis of the infrared data suggests that a metal phosphate is formed initially, followed by the formation of organophosphorus polymeric compounds.

Activity-Based Protein Profiling of Organophosphorus and Thiocarbamate Pesticides Reveals Multiple Serine Hydrolase Targets in Mouse Brain

PubMed Central

NOMURA, DANIEL K.; CASIDA, JOHN E.

2010-01-01

Organophosphorus (OP) and thiocarbamate (TC) agrochemicals are used worldwide as insecticides, herbicides, and fungicides, but their safety assessment in terms of potential off-targets remains incomplete. In this study, we used a chemoproteomic platform, termed activity-based protein profiling, to broadly define serine hydrolase targets in mouse brain of a panel of 29 OP and TC pesticides. Among the secondary targets identified, enzymes involved in degradation of endocannabinoid signaling lipids, monoacylglycerol lipase and fatty acid amide hydrolase, were inhibited by several OP and TC pesticides. Blockade of these two enzymes led to elevations in brain endocannabinoid levels and dysregulated brain arachidonate metabolism. Other secondary targets include enzymes thought to also play important roles in the nervous system and unannotated proteins. This study reveals a multitude of secondary targets for OP and TC pesticides and underscores the utility of chemoproteomic platforms in gaining insights into biochemical pathways that are perturbed by these toxicants. PMID:21341672

Evolution of catalytic centers of antibodies by virtual screening of broad repertoire of mutants using supercomputer.

PubMed

Golovin, A V; Smirnov, I V; Stepanova, A V; Zalevskiy, A O; Zlobin, A S; Ponomarenko, N A; Belogurov, A A; Knorre, V D; Hurs, E N; Chatziefthimiou, S D; Wilmanns, M; Blackburn, G M; Khomutov, R M; Gabibov, A G

2017-07-01

It is proposed to perform quantum mechanical/molecular dynamics calculations of chemical reactions that are planned to be catalyzed by antibodies and then conduct a virtual screening of the library of potential antibody mutants to select an optimal biocatalyst. We tested the effectiveness of this approach by the example of hydrolysis of organophosphorus toxicant paraoxon using kinetic approaches and X-ray analysis of the antibody biocatalyst designed de novo.

Muscarinic receptors mediate the endocrine-disrupting effects of an organophosphorus insecticide in zebrafish.

PubMed

Santos da Rosa, João Gabriel; Alcântara Barcellos, Heloísa Helena de; Fagundes, Michele; Variani, Cristiane; Rossini, Mainara; Kalichak, Fabiana; Koakoski, Gessi; Acosta Oliveira, Thiago; Idalencio, Renan; Frandoloso, Rafael; Piato, Angelo L; José Gil Barcellos, Leonardo

2017-07-01

The glucocorticoid cortisol, the end product of hypothalamus-pituitary-interrenal axis in zebrafish (Danio rerio), is synthesized via steroidogenesis and promotes important physiological regulations in response to a stressor. The failure of this axis leads to inability to cope with environmental challenges preventing adaptive processes in order to restore homeostasis. Pesticides and agrichemicals are widely used, and may constitute an important class of environmental pollutants when reach aquatic ecosystems and nontarget species. These chemical compounds may disrupt hypothalamus-pituitary-interrenal axis by altering synthesis, structure or function of its constituents. We present evidence that organophosphorus exposure disrupts stress response by altering the expression of key genes of the neural steroidogenesis, causing downregulation of star, hsp70, and pomc genes. This appears to be mediated via muscarinic receptors, since the muscarinic antagonist scopolamine blocked these effects. © 2017 Wiley Periodicals, Inc.

Changes in Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to Nerve Against in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Changes in extracellular striatal acetylcholine and brain seizure activity following...Acetylcholine, acetylcholinesterase, choline, guinea pig, in vivo microdialysis, nerve agents, organophosphorus compounds, sarin, seizure activity ...RESEARCH ARTICLE Changes in extracellular striatal acetylcholine and brain seizure activity following acute exposure to nerve agents in freely

Generation and Evaluation of PEGylated Recombinant Human Acetylcholinesterase as an Optimal OP-Bioscavenger

DTIC Science & Technology

2009-04-27

intramuscularly and then monitored at various time points for body weight and temperature, blood glucose levels, blood biochemistry and hematology. No...means for therapeutic treatment of OP compound poisoning without exerting any deleterious effect on the treated subjects...R.P., Castro, C.A., Finger, A.V. and Lenz, D.E. (1991). Protection by butyrylcholinesterase against organophosphorus poisoning in nonhuman primates

Effects of a provincial ban of two toxic organophosphorus insecticides on pesticide poisoning hospital admissions.

PubMed

Eddleston, Michael; Adhikari, Sriyantha; Egodage, Samitha; Ranganath, Hasantha; Mohamed, Fahim; Manuweera, Gamini; Azher, Shifa; Jayamanne, Shaluka; Juzczak, Edmund; Sheriff, Mh Rezvi; Dawson, Andrew H; Buckley, Nick A

2012-03-01

Pesticide self-poisoning causes one third of global suicides. Sri Lanka halved its suicide rate by banning WHO Class I organophosphorus (OP) insecticides and then endosulfan. However, poisoning with Class II toxicity OPs, particularly dimethoate and fenthion, remains a problem. We aimed to determine the effect and feasibility of a ban of the two insecticides in one Sri Lankan district. Sale was banned in June 2003 in most of Polonnaruwa District, but not Anuradhapura District. Admissions with pesticide poisoning to the district general hospitals was prospectively recorded from 2002. Hospital admissions for dimethoate and fenthion poisoning fell by 43% after the ban in Polonnaruwa, while increasing by 23% in Anuradhapura. The pesticide case fatality fell from 14.4% to 9.0% in Polonnaruwa (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.41-0.84) and 11.3% to 10.6% in Anuradhapura (OR 0.93, 95%CI 0.70-1.25; p = 0.051). This reduction was not sustained, with case fatality in Polonnaruwa rising to 12.1% in 2006-2007. Further data analysis indicated that the fall in case fatality had actually been due to a coincidental reduction in case fatality for pesticide poisoning overall, in particular for paraquat poisoning. We found that the insecticides could be effectively banned from agricultural practice, as shown by the fall in hospital admissions, with few negative consequences. However, the ban had only a minor effect on pesticide poisoning deaths because it was too narrow. A study assessing the agricultural and health effects of a more comprehensive ban of highly toxic pesticides is necessary to determine the balance between increased costs of agriculture and reduced health care costs and fewer deaths.

Effects of a provincial ban of two toxic organophosphorus insecticides on pesticide poisoning hospital admissions

PubMed Central

2012-01-01

Background. Pesticide self-poisoning causes one third of global suicides. Sri Lanka halved its suicide rate by banning WHO Class I organophosphorus (OP) insecticides and then endosulfan. However, poisoning with Class II toxicity OPs, particularly dimethoate and fenthion, remains a problem. We aimed to determine the effect and feasibility of a ban of the two insecticides in one Sri Lankan district. Methods. Sale was banned in June 2003 in most of Polonnaruwa District, but not Anuradhapura District. Admissions with pesticide poisoning to the district general hospitals was prospectively recorded from 2002. Results. Hospital admissions for dimethoate and fenthion poisoning fell by 43% after the ban in Polonnaruwa, while increasing by 23% in Anuradhapura. The pesticide case fatality fell from 14.4% to 9.0% in Polonnaruwa (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.41–0.84) and 11.3% to 10.6% in Anuradhapura (OR 0.93, 95%CI 0.70–1.25; p = 0.051). This reduction was not sustained, with case fatality in Polonnaruwa rising to 12.1% in 2006–2007. Further data analysis indicated that the fall in case fatality had actually been due to a coincidental reduction in case fatality for pesticide poisoning overall, in particular for paraquat poisoning. Conclusions. We found that the insecticides could be effectively banned from agricultural practice, as shown by the fall in hospital admissions, with few negative consequences. However, the ban had only a minor effect on pesticide poisoning deaths because it was too narrow. A study assessing the agricultural and health effects of a more comprehensive ban of highly toxic pesticides is necessary to determine the balance between increased costs of agriculture and reduced health care costs and fewer deaths. PMID:22372788

Presence of organophosphorus pesticide oxygen analogs in air samples

NASA Astrophysics Data System (ADS)

Armstrong, Jenna L.; Fenske, Richard A.; Yost, Michael G.; Galvin, Kit; Tchong-French, Maria; Yu, Jianbo

2013-02-01

A number of recent toxicity studies have highlighted the increased potency of oxygen analogs (oxons) of several organophosphorus (OP) pesticides. These findings were a major concern after environmental oxons were identified in environmental samples from air and surfaces following agricultural spray applications in California and Washington State. This paper reports on the validity of oxygen analog measurements in air samples for the OP pesticide, chlorpyrifos. Controlled environmental and laboratory experiments were used to examine artificial formation of chlorpyrifos-oxon using OSHA Versatile Sampling (OVS) tubes as recommended by NIOSH method 5600. Additionally, we compared expected chlorpyrifos-oxon attributable to artificial transformation to observed chlorpyrifos-oxon in field samples from a 2008 Washington State Department of Health air monitoring study using non-parametric statistical methods. The amount of artificially transformed oxon was then modeled to determine the amount of oxon present in the environment. Toxicity equivalency factors (TEFs) for chlorpyrifos-oxon were used to calculate chlorpyrifos-equivalent air concentrations. The results demonstrate that the NIOSH-recommended sampling matrix (OVS tubes with XAD-2 resin) was found to artificially transform up to 30% of chlorpyrifos to chlorpyrifos-oxon, with higher percentages at lower concentrations (<30 ng m-3) typical of ambient or residential levels. Overall, the 2008 study data had significantly greater oxon than expected by artificial transformation, but the exact amount of environmental oxon in air remains difficult to quantify with the current sampling method. Failure to conduct laboratory analysis for chlorpyrifos-oxon may result in underestimation of total pesticide concentration when using XAD-2 resin matrices for occupational or residential sampling. Alternative methods that can accurately measure both OP pesticides and their oxygen analogs should be used for air sampling, and a toxicity equivalent factor approach should be used to determine potential health risks from exposures.

BIODEGRADATION OF ORGANOPHOSPHORUS PESTICIDES BY SURFACE-EXPRESSED ORGANOPHOSPHORUS HYDROLASE. (R823663)

EPA Science Inventory

Organophosphorus hydrolase (OPH) was displayed and anchored onto the surface of
Escherichia coli using an Lpp-OmpA fusion system. Production of the fusion proteins in membrane
fractions was verified by immunoblotting with OmpA antisera. inclusion of the organophosphorus
...

Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition.

PubMed

Fawcett, William P; Aracava, Yasco; Adler, Michael; Pereira, Edna F R; Albuquerque, Edson X

2009-02-01

This study was designed to test the hypothesis that the acute toxicity of the nerve agents S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate (VX), O-pinacolyl methylphosphonofluoridate (soman), and O-isopropyl methylphosphonofluoridate (sarin) in guinea pigs is age- and sex-dependent and cannot be fully accounted for by the irreversible inhibition of acetylcholinesterase (AChE). The subcutaneous doses of nerve agents needed to decrease 24-h survival of guinea pigs by 50% (LD(50) values) were estimated by probit analysis. In all animal groups, the rank order of LD(50) values was sarin > soman > VX. The LD(50) value of soman was not influenced by sex or age of the animals. In contrast, the LD(50) values of VX and sarin were lower in adult male than in age-matched female or younger guinea pigs. A colorimetric assay was used to determine the concentrations of nerve agents that inhibit in vitro 50% of AChE activity (IC(50) values) in guinea pig brain extracts, plasma, red blood cells, and whole blood. A positive correlation between LD(50) values and IC(50) values for AChE inhibition would support the hypothesis that AChE inhibition is a major determinant of the acute toxicity of the nerve agents. However, such a positive correlation was found only between LD(50) values and IC(50) values for AChE inhibition in brain extracts from neonatal and prepubertal guinea pigs. These results demonstrate for the first time that the lethal potencies of some nerve agents in guinea pigs are age- and sex-dependent. They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents.

Solvent for the simultaneous recovery of radionuclides from liquid radioactive wastes

DOEpatents

Romanovskiy, Valeriy Nicholiavich; Smirnov, Igor V.; Babain, Vasiliy A.; Todd, Terry A.; Brewer, Ken N.

2002-01-01

The present invention relates to solvents, and methods, for selectively extracting and recovering radionuclides, especially cesium and strontium, rare earths and actinides from liquid radioactive wastes. More specifically, the invention relates to extracting agent solvent compositions comprising complex organoboron compounds, substituted polyethylene glycols, and neutral organophosphorus compounds in a diluent. The preferred solvent comprises a chlorinated cobalt dicarbollide, diphenyl-dibutylmethylenecarbamoylphosphine oxide, PEG-400, and a diluent of phenylpolyfluoroalkyl sulfone. The invention also provides a method of using the invention extracting agents to recover cesium, strontium, rare earths and actinides from liquid radioactive waste.

Method for the simultaneous recovery of radionuclides from liquid radioactive wastes using a solvent

DOEpatents

Romanovskiy, Valeriy Nicholiavich; Smirnov, Igor V.; Babain, Vasiliy A.; Todd, Terry A.; Brewer, Ken N.

2001-01-01

The present invention relates to solvents, and methods, for selectively extracting and recovering radionuclides, especially cesium and strontium, rare earths and actinides from liquid radioactive wastes. More specifically, the invention relates to extracting agent solvent compositions comprising complex organoboron compounds, substituted polyethylene glycols, and neutral organophosphorus compounds in a diluent. The preferred solvent comprises a chlorinated cobalt dicarbollide, diphenyl-dibutylmethylenecarbamoylphosphine oxide, PEG-400, and a diluent of phenylpolyfluoroalkyl sulfone. The invention also provides a method of using the invention extracting agents to recover cesium, strontium, rare earths and actinides from liquid radioactive waste.

Searching for the Cases of Acute Organophosphorus Pesticides Poisoning by JOIS

NASA Astrophysics Data System (ADS)

Futagami, Kojiro; Fujii, Toshiyuki; Horioka, Masayoshi; Asakura, Hajime; Fukagawa, Mitsuro

Cholinesterase reactivator PAM (Pralidoxime) is used in the treatment of organophosphates poisoning with anticholinergic agent atropine. However, some reports demonstrated recently that PAM has inefficacy in some cases of so-called low toxicity organophosphates poisoning. So, to atempt to discuss the efficacy of PAM in clinical treatment, we searched for the case reports of these poisoning by JOIS. In this time, we compared with the specificity of each data bases and presented some examples in this on-line information retrieval.

Trace Detection of Organophosphorus Chemical Warfare Agents in Wastewater and Plants by Luminescent UIO-67(Hf) and Evaluating the Bioaccumulation of Organophosphorus Chemical Warfare Agents.

PubMed

Lian, Xiao; Yan, Bing

2018-05-02

Organophosphorus chemical warfare agents (OPCWAs) are a group of organic pollutants characterized by high toxicity and chemical stability, and they are very difficult to be degraded. The trace quality of OPCWAs in water and food will cause great harm to the human body. Therefore, the detection of OPCWAs is a difficult challenge, which has become the research hotspot over the world. In this work, a Hf-based luminescent metal-organic framework (Eu@1) is prepared, and the reactivity of Hf 12 results in a methanephosphonic acid (MPA)-induced luminescence quenching and the charge transfer from MPA to Hf(IV) and generated exciplexes which are responsible for this quenching effect. The excellent performance of Eu@1 in the detection of MPA, with its finer selectivity, high sensitivity (LOD = 0.4 ppm), and large linear range (10 -7 to 10 -3 M), is encouraging for application in wastewater detection. Importantly, MPA is a pollutant that can be absorbed by plants and causes the bioaccumulation effect, and thus, the detection of MPA in real plant samples is a purposeful topic. Eu@1 also achieved satisfactory results in actual plant sample testing, and the bioaccumulation of MPA in onions, turnips, and cabbages is determined via our sensor. This fabricated detector provides a feasible path for the detection of ppm-level OPCWAs in a complex environment, which will help humans to avoid OPCWA-contaminated foods.

The first evidence of cholinesterases in skin mucus of carps and its applicability as biomarker of organophosphate exposure.

PubMed

Nigam, Ashwini Kumar; Srivastava, Nidhi; Rai, Amita Kumari; Kumari, Usha; Mittal, Ajay Kumar; Mittal, Swati

2014-05-01

The presence of cholinesterase (ChE) activity in skin mucus of three carps, Cirrhinus mrigala, Labeo rohita, and Catla catla and its applicability as biomarker of the organophosphorus insecticide exposure were investigated. Biochemical characterization, using specific substrates and inhibitors, indicated that measured esterase activity in skin mucus was mainly owing to ChEs. Significant difference in the proportion of acetylcholinesterase and butyrylcholinesterase activities was observed in skin mucus of three carps. Enzyme kinetic analysis, using the substrate acetylthiocholine iodide revealed significantly high Vmax value in C. catla compared to that in L. rohita and C. mrigala. In contrast, Vmax value using the substrate butyrylthiocholine iodide was significantly high in C. mrigala than in L. rohita and C. catla. In vitro treatment of skin mucus of three carps, with the organophosphorus insecticide Nuvan®, showed strong inhibition of ChE activities. In vivo experiments conducted using C. mrigala and exposing the fish to the sublethal test concentrations (5 and 15 mg/L) of the insecticide also revealed significant inhibition of ChE activity in mucus. In C. mrigala, exposed to the sublethal test concentrations of the insecticide for 4 days and then kept for recovery for 16 days, mucus ChE activity recovered to the control level. Thus, ChE activity in skin mucus could be considered a good biomarker of the organophosphorus insecticide exposure to fish and a useful tool in monitoring environmental toxicity. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Diet composition modifies the toxicity of repeated soman exposure in rats.

PubMed

Langston, Jeffrey L; Myers, Todd M

2011-12-01

It was previously demonstrated that diet potently modulates the toxic effects of an acute lethal dose of the nerve agent soman. The current investigation was undertaken to examine the influence of diet on the cumulative toxicity of repeated soman administration. Rats were fed one of four distinct diets (standard, choline-enriched, glucose-enriched, or ketogenic) for four weeks prior to and throughout a repeated soman dosing and recovery regimen. Each diet group included animals exposed to an equivalent volume of saline that served as negative controls. In exposure Week 1, animals received three consecutive daily doses of 0.4 LD(50) soman. In exposure Week 2, animals received four consecutive daily doses of 0.5 LD(50) soman. In exposure Week 3, animals received five consecutive daily doses of 0.5 LD(50) soman. Week 4 constituted a post-exposure recovery evaluation. Throughout the experiment, behavioral function was assessed by a discriminated avoidance test that required intact sensory and motor function. Survival and body weight changes were recorded daily. Differences in toxicity as a function of diet composition became apparent during the first week. Specifically, rats fed the glucose-enriched diet showed pronounced intoxication during Week 1, resulting in imperfect survival, weight loss, and deteriorated avoidance performance relative to all other groups. All rats fed the glucose-enriched diet died by the end of exposure Week 2. In contrast, only 10% of animals fed the standard diet died by the end of Week 2. Also in Week 2, weight loss and disrupted avoidance performance were apparent for all groups except for those fed the ketogenic diet. This differential effect of diet composition became even more striking in Week 3 when survival in the standard and choline diet groups approximated 50%, whereas survival equaled 90% in the ketogenic diet group. Avoidance performance and weight loss measures corroborated the differential toxicity observed across diet groups. Upon cessation of soman exposure during the final week, recovery of weight and avoidance performance in survivors was comparable across diet groups. These results systematically replicate previous findings demonstrating that diet composition exacerbates or attenuates toxicity in rodents exposed acutely to organophosphorus compounds. Published by Elsevier B.V.

[Decontamination of chemical and biological warfare agents].

PubMed

Seto, Yasuo

2009-01-01

Chemical and biological warfare agents (CBWA's) are diverse in nature; volatile acute low-molecular-weight toxic compounds, chemical warfare agents (CWA's, gaseous choking and blood agents, volatile nerve gases and blister agents, nonvolatile vomit agents and lacrymators), biological toxins (nonvolatile low-molecular-weight toxins, proteinous toxins) and microbes (bacteria, viruses, rickettsiae). In the consequence management against chemical and biological terrorism, speedy decontamination of victims, facilities and equipment is required for the minimization of the damage. In the present situation, washing victims and contaminated materials with large volumes of water is the basic way, and additionally hypochlorite salt solution is used for decomposition of CWA's. However, it still remains unsolved how to dispose large volumes of waste water, and the decontamination reagents have serious limitation of high toxicity, despoiling nature against the environments, long finishing time and non-durability in effective decontamination. Namely, the existing decontamination system is not effective, nonspecifically affecting the surrounding non-target materials. Therefore, it is the urgent matter to build up the usable decontamination system surpassing the present technologies. The symposiast presents the on-going joint project of research and development of the novel decontamination system against CBWA's, in the purpose of realizing nontoxic, fast, specific, effective and economical terrorism on-site decontamination. The projects consists of (1) establishment of the decontamination evaluation methods and verification of the existing technologies and adaptation of bacterial organophosphorus hydrolase, (2) development of adsorptive elimination technologies using molecular recognition tools, and (4) development of deactivation technologies using photocatalysis.

Reactivation of organophosphate-inhibited human, Cynomolgus monkey, swine and guinea pig acetylcholinesterase by MMB-4: a modified kinetic approach.

PubMed

Worek, Franz; Wille, Timo; Aurbek, Nadine; Eyer, Peter; Thiermann, Horst

2010-12-15

Treatment of poisoning by highly toxic organophosphorus compounds (OP, nerve agents) is a continuous challenge. Standard treatment with atropine and a clinically used oxime, obidoxime or pralidoxime is inadequate against various nerve agents. For ethical reasons testing of oxime efficacy has to be performed in animals. Now, it was tempting to investigate the reactivation kinetics of MMB-4, a candidate oxime to replace pralidoxime, with nerve agent-inhibited acetylcholinesterase (AChE) from human and animal origin in order to provide a kinetic basis for the proper assessment of in vivo data. By applying a modified kinetic approach, allowing the use of necessary high MMB-4 concentrations, it was possible to determine the reactivation constants with sarin-, cyclosarin-, VX-, VR- and tabun-inhibited AChE. MMB-4 exhibited a high reactivity and low affinity towards OP-inhibited AChE, except of tabun-inhibited enzyme where MMB-4 had an extremely low reactivity. Species differences between human and animal AChE were low (Cynomolgus) to moderate (swine, guinea pig). Due to the high reactivity of MMB-4 a rapid reactivation of inhibited AChE can be anticipated at adequate oxime concentrations which are substantially higher compared to HI-6. Additional studies are necessary to determine the in vivo toxicity, tolerability and pharmacokinetics of MMB-4 in humans in order to enable a proper assessment of the value of this oxime as an antidote against nerve agent poisoning. Copyright © 2010 Elsevier Inc. All rights reserved.

[Meta-analysis of association between organophosphorus pesticides and aplastic anemia].

PubMed

Zhang, Ji; Yang, Tubao

2015-09-01

To evaluate the association between organophosphorus pesticides and aplastic anemia, and provide scientific evidence for the primary prevention of aplastic anemia. The published papers of case control studies on the association between organophosphorus pesticides and aplastic anemia from January 1990 to August 2014 were collected from Chinese BioMedical Literature Base (CBM), Chinese National Knowledge Infrastructure (CNKI), PubMed and EMBASE. The papers which met the inclusion criteria were evaluated. The pooled odds ratios (OR) and 95% confidence interval (CI) of organophosphorus pesticides were calculated with software Review Manager 5.0. Subgroup analysis were conducted for different population and different usage of organophosphorus pesticides. A total of 9 papers were selected, involving 5 833 subjects (1 404 cases and 4 429 controls). The results showed that organophosphorus pesticides could increase the risk of aplastic anemia (OR=1.97, 95% CI: 1.60-2.44) . Subgroup analysis showed that Asian (OR=2.01, 95% CI: 1.52-2.66) had higher risk of aplastic anemia than American or European (OR=1.93, 95% CI: 1.39-2.67) . Using pure organophosphorus pesticides (OR=2.15, 95% CI: 1.60-2.88) was more prone to cause aplastic anemia than using the mixture of organophosphorus pesticides (OR=1.82, 95% CI: 1.34-2.47). The analysis indicated that organophosphorus pesticides might be a risk factor for aplastic anemia. Reducing organophosphorus pesticides exposure in daily life and industrial or agricultural production could prevent the incidence of aplastic anemia.

Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koplovitz, I.; Menton, R.; Matthews, C.

1995-12-31

H1-6 (1-2-hydrnxyiminomethyl-1 pyridino-3-(4-carbameyl- 1--pyddino)-2- oxaprnpane dichioride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OPmore » and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI-6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman.« less

Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus

PubMed Central

Rojas, Asheebo; Ganesh, Thota; Lelutiu, Nadia; Gueorguieva, Paoula; Dingledine, Raymond

2015-01-01

Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats. PMID:25656476

Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX.

PubMed

Rice, Helen; Dalton, Christopher H; Price, Matthew E; Graham, Stuart J; Green, A Christopher; Jenner, John; Groombridge, Helen J; Timperley, Christopher M

2015-04-08

To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM-VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro . The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved.

Development of Reactive Topical Skin Protectants against Sulfur Mustard and Nerve Agents

DTIC Science & Technology

1997-06-01

Inorganic pollutants such as hydrogen cyanide, cyanogen chloride, and acid gases are not adsorbed well by activated carbon, and (3) Clean-up and...with Fe203 caused an increase in destructive adsorbent capacity of chlorocarbons, acid gases, and organophosphorus compounds. We attribute this...solution of distilled water, concentrated nitric acid , and methanol were added to methanol and neat titanium (IV) butoxide. The formed gel was aged

Metagenomic Functional Potential Predicts Degradation Rates of a Model Organophosphorus Xenobiotic in Pesticide Contaminated Soils

PubMed Central

Jeffries, Thomas C.; Rayu, Smriti; Nielsen, Uffe N.; Lai, Kaitao; Ijaz, Ali; Nazaries, Loic; Singh, Brajesh K.

2018-01-01

Chemical contamination of natural and agricultural habitats is an increasing global problem and a major threat to sustainability and human health. Organophosphorus (OP) compounds are one major class of contaminant and can undergo microbial degradation, however, no studies have applied system-wide ecogenomic tools to investigate OP degradation or use metagenomics to understand the underlying mechanisms of biodegradation in situ and predict degradation potential. Thus, there is a lack of knowledge regarding the functional genes and genomic potential underpinning degradation and community responses to contamination. Here we address this knowledge gap by performing shotgun sequencing of community DNA from agricultural soils with a history of pesticide usage and profiling shifts in functional genes and microbial taxa abundance. Our results showed two distinct groups of soils defined by differing functional and taxonomic profiles. Degradation assays suggested that these groups corresponded to the organophosphorus degradation potential of soils, with the fastest degrading community being defined by increases in transport and nutrient cycling pathways and enzymes potentially involved in phosphorus metabolism. This was against a backdrop of taxonomic community shifts potentially related to contamination adaptation and reflecting the legacy of exposure. Overall our results highlight the value of using holistic system-wide metagenomic approaches as a tool to predict microbial degradation in the context of the ecology of contaminated habitats. PMID:29515526

Sorption and degradation of chlorophenols, nitrophenols and organophosphorus pesticides in the subsoil under landfills — laboratory studies

NASA Astrophysics Data System (ADS)

Kjeldsen, Peter; Kjølholt, Jesper; Schultz, Birgit; Christensen, Thomas H.; Tjell, Jens Christian

1990-09-01

Landfills and old industrial plant sites have been identified in an increasing number of cases as point sources of groundwater pollution, dissipating a wide range of industrial chemicals and pesticides. To study the fate of co-disposed chemicals in the subsoil of landfills, anaerobic soil columns loaded with anaerobic leachate from a municipal landfill were set up. The leachate was spiked with eleven compounds representing three groups of chemicals: chlorophenols, nitrophenols and organophosphates. Two subsoils were used in the study. The columns were maintained at Danish groundwater temperature (8-10°C), and were run for a period of 10 months. Analysis of the influent leachate concentrations of the spiked compounds showed that the concentrations were constant during the entire experimental period. Many of the compounds showed delayed breakthrough (compared to chloride breakthrough) in both soils, followed by a constant effluent concentration ratio of less than unity indicating that degradation was occuring. The velocities for the chloro- and nitrophenols were in the range of 10-100% of the water velocity in the two subsoils. The distribution coefficient for the specific phenol, the acidity and the pH of the soil apparently governed the retardation of the phenolic compounds. Degradation of most of the phenols was observed with half-like values of 30-150 days. The four organophosphorus pesticides, Dimethoate ®, Malathion ®, Sulfotep ® and Fenitrothion ®, showed relative velocities from < 10% to ≈ 100%. Malathion ® and Sulfotep ® were degraded with half-life values of 10-20 days, while Dimethoate ® was not significantly degraded in the two soil columns. Fenitrothion ® did not appear in the effluent from the columns within the experimental period of time, probably due to high retardation.

Evaluating Cumulative OP Pesticide Body Burden of Children: A National Case Study

PubMed Central

Payne-Sturges, Devon; Cohen, Jonathan; Castorina, Rosemary; Axelrad, Daniel A.; Woodruff, Tracey J.

2009-01-01

Biomonitoring is a valuable tool for identifying exposures to chemicals that pose potential harm to human health. However, to date there has been little published on ways to evaluate the relative public health significance of biomonitoring data for different chemicals, and even less on cumulative assessment of multiple chemicals. The objectives of our study are to develop a methodology for a health risk interpretation of biomonitoring data, and to apply it using NHANES 1999–2002 body burden data for organophosphorus (OP) pesticides. OP pesticides present a particularly challenging case given the non-specificity of many metabolites monitored through NHANES. We back-calculate OP pesticide exposures from urinary metabolite data, and compare cumulative dose estimates with available toxicity information for a common mechanism of action (brain cholinesterase inhibition) using data from U.S. EPA. Our results suggest that approximately 40% of children in the United States may have had insufficient margins of exposure (MOEs) for neurological impacts from cumulative exposures to OP pesticides (MOE less than 1,000). Limitations include uncertainty related to assumptions about likely precursor pesticide compounds of the urinary metabolites, sources of exposure, and intra-individual and temporal variability. PMID:19921915

Protection by butyrylcholinesterase against organophosphorus poisoning in nonhuman primates. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Broomfield, C.A.; Maxwell, D.M.; Solana, R.P.

1991-12-31

Butyrylcholinesterase (BuChE) was examined as an in vivo exogenous scavenger for highly toxic organophosphorus (OP) poisons. Protection studies with equine BuChE were carried out in rhesus monkeys trained to perform a Serial Probe Recognition task. The pharmacokinetics of equine BuChE administered i.v. in rhesus monkeys revealed an elimination T1/2 of -620 hr. Animals given 503 nmol of BuChE i.v. and then challenged with 220 to 260 nmol of soman (two LD50; a lethal dose in untreated animals) all survived with no clinical signs of OP poisoning. Serial Probe Recognition performance was depressed after enzyme administration and at 1 hr postsoman.more » However, all monkeys performed the task at base-line levels at 8 hr after soman and throughout the remainder of the experimental period. Two different monkeys each were given two doses of sarin, 183 nmol/ dose (one LD50) after 460 nmol of BuChE. No signs were observed. A third group of monkeys given 253 or 340 nmol (three and four LD50, respectively) of soman after 460 nmol of BuChE required 1 mg/kg of atropine i.v. 1 0 min postsoman, but recovered completely within 24 hr. Our results indicate that BuChE has the required properties to function as a biological scavenger to protect against the pharmacological and behavioral toxicity of OP poisons. Exogenous scavenger, butyrylcholinesterase, nerve agent.« less

Development and validation of a multiresidue method for the simultaneous determination of organophosphorus insecticides and their toxic metabolites in sugarcane juice and refined sugar by gas chromatography with flame photometric detection.

PubMed

Ramasubramanian, Thirumalaiandi; Paramasivam, Mariappan

2016-06-01

A multiresidue method has been developed and validated for the simultaneous determination of organophosphorus insecticides and their toxic metabolites in sugarcane juice and refined sugar by gas chromatography with flame photometric detection. Limits of quantification of the method varied between 0.007 and 0.01 μg/g. Ethyl acetate based extraction followed by dispersive solid-phase extraction cleanup with primary secondary amine yielded internationally acceptable recoveries of acephate, chlorpyrifos, dichlorvos, monocrotophos, malathion, malaoxon, phorate, phorate-sulfoxide, phorate-oxon, phorate-sulfone, and quinalphos from selected matrices. The recoveries of target analytes from cane juice were 75.55 ± 0.5-102.57 ± 4.2, 77.45 ± 4.7-103.33 ± 3.3, and 80.55 ± 6.6-105.82 ± 9.8% at 0.01, 0.02, and 0.1 μg/g levels of fortification, respectively. The recoveries from cane sugar were 73.24 ± 3.5-104.47 ± 1.9, 75.23 ± 1.5-116.10 ± 3.7, and 70.75 ± 5.7-110.15 ± 2.7%, respectively at 0.01, 0.02, and 0.1 μg/g levels of fortification. Matrix effect and measurement uncertainty were within the permissible limit (less than 20%) as prescribed for pesticide residue analysis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Blood cholinesterases as human biomarkers of organophosphorus pesticide exposure.

PubMed

Nigg, H N; Knaak, J B

2000-01-01

The organophosphorus pesticides of this review were discovered in 1936 during the search for a replacement for nicotine for cockroach control. The basic biochemical characteristics of RBC AChE and BChE were determined in the 1940s. The mechanism of inhibition of both enzymes and other serine esterases was known in the 1940s and, in general, defined in the 1950s. In 1949, the death of a parathion mixer-loader dictated blood enzyme monitoring to prevent acute illness from organophosphorus pesticide intoxication. However, many of the chemical and biochemical steps for serine enzyme inhibition by OP compounds remain unknown today. The possible mechanisms of this inhibition are presented kinetically beginning with simple (by comparison) Michaelis-Menten substrate enzyme interaction kinetics. As complicated as the inhibition kinetics appear here, PBPK model kinetics will be more complex. The determination of inter- and intraindividual variation in RBC ChE and BChE was recognized early as critical knowledge for a blood esterase monitoring program. Because of the relatively constant production of RBCs, variation in RBC AChE was determined by about 1970. The source of plasma (or serum) BChE was shown to be the liver in the 1960s with the change in BChE phenotype to the donor in liver transplant patients. BChE activity was more variable than RBC AChE, and only in the 1990s have BChE individual variation questions been answered. We have reviewed the chemistry, metabolism, and toxicity of organophosphorus insecticides along with their inhibitory action toward tissue acetyl- and butyrylcholinesterases. On the basis of the review, a monitoring program for individuals mixing-loading and applying OP pesticides for commercial applicators was recommended. Approximately 41 OPs are currently registered for use by USEPA in the United States. Under agricultural working conditions, OPs primarily are absorbed through the skin. Liver P-450 isozymes catalyze the desulfurization of phosphorothioates and phosphorodithioates (e.g., parathion and azinphosmethyl, respectively) to the more toxic oxons (P = O(S to O)). In some cases, P-450 isozymes catalyze the oxidative cleavage of P-O-aryl bonds (e.g., parathion, methyl parathion, fenitrothion, and diazinon) to form inactive water-soluble alkyl phosphates and aryl leaving groups that are readily conjugated with glucuronic or sulfuric acids and excreted. In addition to the P-450 isozymes, mammalian tissues contain ('A' and 'B') esterases capable of reacting with OPs to produce hydrolysis products or phosphorylated enzymes. 'A'-esterases hydrolyze OPs (i.e., oxons), while 'B'-esterases with serine at the active center are inhibited by OPs. OPs possessing carboxylesters, such as malathion and isofenphos, are hydrolyzed by the direct action of 'B'-esterases (i.e., carboxylesterase, CaE). Metabolic pathways shown for isofenphos, parathion, and malathion define the order in which these reactions occur, while Michaelis-Menten kinetics define reaction parameters (Vmax, K(m)) for the enzymes and substrates involved, and rates of inhibition of 'B'-esterases (kis, bimolecular rate constants) by OPs and their oxons. OPs exert their insecticidal action by their ability to inhibit AChE at the cholinergic synapse, resulting in the accumulation of acetylcholine. The extent to which AChE or other 'B'-esterases are inhibited in workers is dependent upon the rate the OP pesticide is activated (i.e., oxon formation), metabolized to nontoxic products by tissue enzymes, its affinity for AChE and other 'B'-esterases, and esterase concentrations in tissues. Rapid recovery of OP BChE inhibition may be related to reactivation of inhibited forms. AChE, BChE, and CaE appear to function in vivo as scavengers, protecting workers against the inhibition of AChE at synapses. Species sensitivity to OPs varies widely and results in part from binding affinities (Ka) and rates of phosphorylation (kp) rather than rates of activation and detoxif

Surface-water-quality assessment of the upper Illinois River Basin in Illinois, Indiana, and Wisconsin; data on agricultural organic compounds, nutrients, and sediment in water, 1988-90

USGS Publications Warehouse

Sullivan, D.J.; Terrio, P.J.

1994-01-01

This report describes the sampling design and methods and presents data collected to determine the distribution of agricultural organic compounds, nutrients, and sediment in selected areas of the upper Illinois River Basin as part of the National Water-Quality Assessment program. Four stations in small watersheds (two urban, two agricultural) were sampled in 1988 and 1989. Seventeen stations in an agricultural subbasin were sampled in 1990. Samples were collected before, during, and after runoff events from late spring to midsummer to determine concentrations of agricultural organic compounds in surface waters resulting from storm runoff, as well as background concentrations. Over 200 water samples were analyzed for agricultural organic compound, nutrient, and suspended-sediment concentrations. The agricultural organic compounds included triazine and chlorophenoxy-acid herbicides, and organo-phosphorus insecticides.

Acute soman poisoning in primates neither pretreated nor receiving immediate therapy: value of gacyclidine (GK-11) in delayed medical support.

PubMed

Lallement, G; Clarençon, D; Galonnier, M; Baubichon, D; Burckhart, M F; Peoc'h, M

1999-03-01

Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible.

Cross-Dehydrogenative Coupling Reactions Between P(O)-H and X-H (X = S, N, O, P) Bonds.

PubMed

Hosseinian, Akram; Farshbaf, Sepideh; Fekri, Leila Zare; Nikpassand, Mohammad; Vessally, Esmail

2018-05-26

P(O)-X (X = S, N, O, P) bond-containing compounds have extensive application in medicinal chemistry, agrochemistry, and material chemistry. These useful organophosphorus compounds also have many applications in organic synthesis. In light of the importance of titled compounds, there is continuing interest in the development of synthetic methods for P(O)-X bonds construction. In the last 4 years, the direct coupling reaction of P(O)-H compounds with thiols, alcohols, and amines/amides has received much attention because of the atom-economic character. This review aims to give an overview of new developments in cross-dehydrogenative coupling reactions between P(O)-H and X-H (X = S, N, O, P) bonds, with special emphasis on the mechanistic aspects of the reactions.

Phosphorus sorption on marine carbonate sediment: phosphonate as model organic compounds.

PubMed

Huang, Xiao-Lan; Zhang, Jia-Zhong

2011-11-01

Organophosphonate, characterized by the presence of a stable, covalent, carbon to phosphorus (C-P) bond, is a group of synthetic or biogenic organophosphorus compounds. The fate of these organic phosphorus compounds in the environment is not well studied. This study presents the first investigation on the sorption of phosphorus (P) in the presence of two model phosphonate compounds, 2-aminothylphosphonoic acid (2-AEP) and phosphonoformic acid (PFA), on marine carbonate sediments. In contrast to other organic P compounds, no significant inorganic phosphate exchange was observed in seawater. P was found to adsorb on the sediment only in the presence of PFA, not 2-AEP. This indicated that sorption of P from phosphonate on marine sediment was compound specific. Compared with inorganic phosphate sorption on the same sediments, P sorption from organic phosphorus is much less in the marine environment. Further study is needed to understand the potential role of the organophosphonate compounds in biogeochemical cycle of phosphorus in the environment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Wearable Flexible and Stretchable Glove Biosensor for On-Site Detection of Organophosphorus Chemical Threats

DTIC Science & Technology

2017-03-03

finger enables rapid on-site detection of organophosphate (OP) nerve-agent compounds on suspicious surfaces and agricultural products following their...used as pesticides in agricultural and domestic settings.21,22 These OP neurotoxins severely affect the nervous system and lead to rapid death. Due to...The “on-hand” detection of different OP chemical agents on a variety of surfaces and agricultural foodstuffs demonstrate that the new wireless glove

APPROXIMATE ENZYMIC METHOD OF MICROANALYSIS FOR IDENTIFYING RESIDUAL AMOUNTS OF ORGANOPHOSPHORUS INSECTICIDES,

DTIC Science & Technology

plant extracts gradually increases. This is evidently explained by a conversion of the insecticide into a compound possessing high anticholinesterase activity . (Author)...possible to determine from 1 to 100 micrograms of insecticide per 1 ml. It was established that the anticholinesterase activity of chlorphos when...inherent anticholinesterase action, was developed. In order to realize this method a portable kit was constructed which contains a rack for the storage

Geminal difunctionalization of α-diazo arylmethylphosphonates: synthesis of fluorinated phosphonates.

PubMed

Zhou, Yujing; Zhang, Yan; Wang, Jianbo

2016-11-08

A general approach towards diverse fluorinated phosphonates via geminal difunctionalization reactions of α-diazo arylmethylphosphonates is described. The diazo functionality (RR'C[double bond, length as m-dash]N 2 ) is successfully converted to RR'CF 2 , RR'CHF, RR'CFBr or RR'CFNR'' 2 groups by employing different fluorination reagents. A variety of fluorinated organophosphorus compounds were readily accessed in good to excellent yields from a common type of precursor.

The chemistry of cationic polyphosphorus cages – syntheses, structure and reactivity

PubMed Central

Holthausen, Michael H.

2014-01-01

The aim of this review is to provide a comprehensive view of the chemistry of cationic polyphosphorus cages. The synthetic protocols established for their preparation, which are all based on the functionalization of P4, and their intriguing follow-up chemistry are highlighted. In addition, this review intends to foster the interest of the inorganic, organic, catalytic and material oriented chemical communities in the versatile field of polyphosphorus cage compounds. In the long term, this is envisioned to contribute to the development of new synthetic procedures for the functionalization of P4 and its transformation into (organo-)phosphorus compounds and materials of added value. PMID:24740160

Atmospheric influence on the distribution of organic pollutants in the Guadalquivir River estuary, SW Spain.

PubMed

Fernández-Gómez, Cristal; López-López, José Antonio; Matamoros, Victor; Díez, Sergi; García-Vargas, Manuel; Moreno, Carlos

2013-04-01

In the lower Guadalquivir river basin, a system stressed by a wide variety of anthropogenic activities, eight pesticides (four triazines, two chloroacetanilide herbicides, one organochlorine, and one organophosphorus insecticide); and four emerging pollutants (two personal care products, one organophosphorous flame retardant, and one xanthine alkaloid) were analyzed in river water during a 2-year monitoring program, and after rain episodes. Samples were extracted using the solid phase extraction (SPE) technique prior to determination of compounds using gas chromatograph coupled to a mass spectrometer detector. Except for caffeine, recoveries were mostly above 80 %, while limits of detection and quantification were in the low nanograms per liter level (except for dimethoate). Terbuthylazine, simazine (triazine herbicides), and dimethoate (organophosphorus insecticide), present in agrochemicals, were predominant in the river water, although concentrations were below the quality standards established by the EU Water-Framework-Directive. A general trend to increase concentration was observed after rain events, in particular for pesticides, possibly as a consequence of surface runoff.

Metals, pesticides, and semivolatile organic compounds in sediment in Valley Forge National Historical Park, Montgomery County, Pennsylvania

USGS Publications Warehouse

Reif, Andrew G.; Sloto, Ronald A.

1997-01-01

The Schuylkill River flows through Valley Forge National Historical Park in Lower Providence and West Norriton Townships in Montgomery County, Pa. The concentration of selected metals, pesticides, semivolatile organic compounds, and total carbon in stream-bottom sediments from Valley Forge National Historical Park were determined for samples collected once at 12 sites in and around the Schuylkill River.Relatively low concentrations of arsenic, chromium, copper, and lead were detected in all samples. The concentrations of these metals are similar to concentrations in other stream-bottom sediment samples collected in the region. The concentrations of iron, manganese, and zinc were elevated in samples from four sites in the Schuylkill River, and the concentration of mercury was elevated in a sample from an impoundment along the river.The organophosphorus insecticide diazinon was detected in relatively low concentrations in half of the 12 samples analyzed. The organo-chlorine insecticide DDE was detected in all 12 samples analyzed; dieldrin was detected in 10 samples, chlordane, DDD, and DDT were detected in 9 samples, and heptachlor epoxide was detected in one sample. The concentrations of organo-chlorine and organophosphorus insecticides were relatively low and similar to concentrations in samples collected in the region.Detectable concentrations of 17 semivolatile organic compounds were measured in the 12 samples analyzed. The most commonly detected compounds were fluoranthene, phenanthrene, and pyrene. The maximum concentration detected was 4,800 micrograms per kilogram of phenanthrene. The highest concentrations of compounds were detected in Lamb Run, a small tributary to the Schuylkill River with headwaters in an industrial corporate center. The concentration of compounds in the Schuylkill River below Lamb Run is higher than the Schuylkill River above Lamb Run, indicating that sediment from Lamb Run is increasing the concentration of semivolatile organic compounds in sediment from the Schuylkill River. Concentrations of semivolatile organic compounds are lower in sediment from the Schuylkill River below Myer's Run than above Myer's Run because of the addition of relatively clean sediment from Myer's Run. Samples collected from the floodplain, impounding basin, and wetland along the Schuylkill River contained the lowest concen-trations of semivolatile organic compounds.Detectable concentrations of polychlorinated biphenyls (PCB's) were measured in 11 of the 12 samples analyzed. The maximum PCB concentration was 37 micrograms per kilogram. Sediment samples from Lamb Run contained the highest concentrations of semivolatile organic compounds and PCB's.

Investigation on modes of toxic action to rats based on aliphatic and aromatic compounds and comparison with fish toxicity based on exposure routes.

PubMed

He, Jia; Li, Jin J; Wen, Yang; Tai, Hong W; Yu, Yang; Qin, Wei C; Su, Li M; Zhao, Yuan H

2015-06-01

The modes of toxic action (MOAs) play an important role in the assessment of the ecotoxicity of organic pollutants. However, few studies have been reported on the MOAs in rat toxicity. In this paper, the toxic contributions of functional groups in 1255 aromatic compounds were calculated from regression and were then compared with the toxic contributions in aliphatic compounds. The results show that some functional groups have same toxic contributions both in aromatic and aliphatic compounds, but some have not. To investigate the MOAs in rat toxicity, the distribution of toxic ratio (TR) was examined for well-known baseline and less inert compounds and thresholds of log TR=0.3 and 0.5 were used to classify baseline, less inert and reactive compounds. The results showed that some compounds identified as baseline compounds in fish toxicity were also classified as baseline compounds in rat toxicity. Except for phenols and anilines which were identified as less inert compounds in fish toxicity, aromatic compounds with functional groups such as ether, nitrile, nitrophenol, isocyanatoe and chloro were identified as less inert chemicals in rat toxicity. Reactive compounds identified in fish toxicity exhibit greater toxicity to rats. These compounds can undergo nucleophilic substitution, acylation and Schiff base formation with biological macromolecules. The critical body residues (CBRs) calculated from absorption and bioconcentration show that log 1/CBRs in rat toxicity are not equal to that in fish for some compounds. It suggests that the exposure route can affect the identification of MOAs between these two species for these compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

The role of glutathione S-transferases in the detoxification of some organophosphorus insecticides in larvae and pupae of the yellow mealworm, Tenebrio molitor (Coleoptera: Tenebrionidae).

PubMed

Kostaropoulos, I; Papadopoulos, A I; Metaxakis, A; Boukouvala, E; Papadopoulou-Mourkidou, E

2001-06-01

The correlation between the natural levels of glutathione S-transferase (GST) and the tolerance to the organophosphorus insecticides parathion-methyl and paraoxon-methyl, as well as the interaction of affinity-purified enzyme and the insecticides were investigated in order to collect further information on the role of the glutathione S-transferase system as a mechanism of defence against insecticides in insects. The studies were carried out on the larvae and pupae of the coleopteran Tenebrio molitor L, which exhibit varying natural levels of GST activity. Stage-dependent susceptibility of the insect against insecticides was observed during the first 24 h. However, 48 h after treatment, the KD50 value increased significantly due to the recovery of some individuals. Simultaneous injection of insecticide with compounds which inhibit GST activity in vitro caused an alteration in susceptibility of insects 24 or 48 h post-treatment, depending on stage and insecticide used. Inhibition studies combined with competitive fluorescence spectroscopy revealed that the insecticides probably bind to the active site of the enzyme, thus inhibiting its activity towards 1-chloro-2,4-dinitrobenzene in a competitive manner. High-performance liquid chromatography and gas chromatography revealed that T molitor GST catalyses the conjugation of the insecticides studied to a reduced form of glutathione (GSH). From the above experimental results, it is considered that GST offers a protection against the organophosphorus insecticides studied by active site binding and subsequent conjugation with GSH.

Comparison of Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to the Nerve Agents Cyclosarin and Tabun in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Comparison of extracellular striatal acetylcholine and brain seizure activity following...lethality; nerve agents; organophosphorus compounds; seizure activity ; tabun 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER...acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs John C

Optical detection of organophosphorus compounds based on Mn-doped ZnSe d-dot enzymatic catalytic sensor.

PubMed

Gao, Xue; Tang, Guangchao; Su, Xingguang

2012-01-01

In this paper, we report a sensitive and selective method for detection of organophosphorus compounds (OPs) based on Mn:ZnSe d-dots-enzyme-hydrogen peroxide (H(2)O(2)) fluorescence quenching system. Acetylcholine esterase (AChE) can hydrolyze acetylcholine (ACh) to choline. Subsequently, choline oxidase (ChOx) oxidizes choline to generate H(2)O(2). The enzyme-generated H(2)O(2) can quench the fluorescence of Mn:ZnSe d-dots. When paraoxon are introduced in solution, it can interact with the active centers of AChE and decrease the enzyme activity. This leads to the decrease of the H(2)O(2) production and then the fluorescence quenching rate of Mn:ZnSe d-dots. Experimental results showed that the enzyme inhibition percentage of Mn:ZnSe d-dots-ChOx-AChE-ACh system was proportional to the logarithm of paraoxon in the range 4.84×10(-11) to 4.84×10(-6) mol/L with the detection limit (S/N=3) of 1.31×10(-11) mol/L. The proposed biosensor has been employed for quick determination of paraoxon in tap water and milk samples with satisfactory reproducibility and accuracy. This nano-biosensor was proved to be sensitive, rapid, simple and tolerance of most interfering substances. Copyright © 2012 Elsevier B.V. All rights reserved.

Organophosphorus flame retardants and plasticizers in air from various indoor environments.

PubMed

Marklund, Anneli; Andersson, Barbro; Haglund, Peter

2005-08-01

Eleven organophosphorus compounds (OPs) that are used as plasticizers and flame retardants were analysed in duplicate samples of indoor air from 17 domestic and occupational environments. Solid-phase extraction (SPE) columns were used as adsorbents and analysis was performed using GC with a nitrogen phosphorus selective detector. The total amounts of OPs in the air samples ranged between 36 and 950 ng m(-3); tris(chloropropyl) phosphate (TCPP) and tris(2-chloroethyl) phosphate (TCEP) being the most abundant (0.4 to 730 ng m(-3)), followed by tributyl phosphate (0.5-120 ng m(-3)). Public buildings tended to have about 3-4 times higher levels of OPs than domestic buildings. The relative amounts of individual OPs varied between the sites and generally reflected the building materials, furniture and consumer products used in the sampled environments. Potential sources of these compounds include, inter alia, acoustic ceilings, upholstered furniture, wall coverings, floor polish and polyvinylchloride floor coverings. A correlation was observed between the TCEP concentrations in the air in the sampled environments and previously reported concentrations in dust, but no such correlation was seen for the heavier and less volatile tris(2-butoxyethyl) phosphate (TBEP). Based on estimated amounts of indoor air inhaled and dust ingested, adults and children in the sampled environments would be exposed to up to 5.8 microg kg(-1) day(-1) and 57 microg kg(-1) day(-1) total OPs, respectively.

Fast Gas Chromatography with Tandem Mass Spectrometry Analysis of Selected Persistent Organic Pollutants and Organophosphorus and Synthetic Pyrethroid Pesticides in Indian Prawn (Fenneropenaeus indicus) in Compliance with the EU-MRLs.

PubMed

Sawant, Durvesh; Kelkar, Jitendra; Rasam, Pratap; Datar, Ajit; Hase, Prashant; Handique, Dheeraj; Bhone, Ankush; Chiplunkar, Sanket; Hate, Manish

2017-05-01

A fast GC with tandem MS method was developed and validated for multiresidue determination of 95 chemical contaminants (24 synthetic pyrethroids, 17 organochlorines, 17 organophosphorus compounds, 18 polycyclic aromatic hydrocarbons, and 19 polychlorinated biphenyls) in Indian prawns (Fenneropenaeus indicus) as per the European Union maximum residual limit requirements. Chromatographic separation and MS determination were achieved within a short run time of 18 min, without compromising sensitivity and specificity. Our findings revealed a 2.5× reduction in the run time compared with conventional GC methods. Sample preparation involved a QuEChERS-based extraction of 10 g sample with 10 mL acidified acetonitrile (1% acetic acid) and phase separation with 6 g anhydrous magnesium sulfate and 1.5 g sodium acetate. The extract was cleaned in two steps, first by dispersive cleanup with primary secondary amine and then by C18 SPE cartridge. The regression coefficients of linearity (r2) for the concentration range of 5-50 ng/mL were >0.99 for all the compounds. Recoveries at 5 and 10 ng/g levels were within the acceptable range of 70-120%. The repeatability (RSDr) and within-laboratory reproducibility (RSDwR) precisions were ≤20%. The method was successfully applied for analysis of the real world samples for incurred residues.

Reactivation of organophosphate-inhibited human acetylcholinesterase by isonitrosoacetone (MINA): a kinetic analysis.

PubMed

Worek, Franz; Thiermann, Horst

2011-11-15

Treatment of poisoning by highly toxic organophosphorus compounds (OP) with atropine and an acetylcholinesterase (AChE) reactivator (oxime) is of limited effectiveness in case of different nerve agents and pesticides. One challenge is the reactivation of OP-inhibited brain AChE which shows inadequate success with charged pyridinium oximes. Recent studies with high doses of the tertiary oxime isonitrosoacetone (MINA) indicated a beneficial effect on central and peripheral AChE and on survival in nerve agent poisoned guinea pigs. Now, an in vitro study was performed to determine the reactivation kinetics of MINA with tabun-, sarin-, cyclosarin-, VX- and paraoxon-inhibited human AChE. MINA showed an exceptionally low affinity to inhibited AChE but, with the exception of tabun-inhibited AChE, a moderate to high reactivity. In comparison to the pyridinium oximes obidoxime, 2-PAM and HI-6 the affinity and reactivity of MINA was in most cases lower and in relation to the most effective reactivators, the second order reactivation constant of MINA was 500 to 3400-fold lower. Hence, high in vivo MINA concentrations would be necessary to achieve at least partial reactivation. This assumption corresponds to in vivo data showing a dose-dependent effect on reactivation and survival in animals. In view, of the toxic potential of MINA in animals human studies would be necessary to determine the tolerability and pharmacokinetics of MINA in order to enable a proper assessment of the value of this oxime as an antidote in OP poisoning. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Effects of pesticides on Canada Geese

USGS Publications Warehouse

Blus, L.J.; Rusch, Donald H.; Samuel, Michael D.; Humburg, Dale D.; Sullivan, Brian D.

1998-01-01

This paper summarizes published and unpublished sources relating to exposure of Canada geese (Branta canadensis) to pesticides, emphasizing documented episodes of poisoning by organochlorine (OC), organophosphorus (OP), and carbamate compounds. Canada geese accumulate the lipid-soluble OC compounds, although they have a lower potential for biomagnification of these pesticides than animals at higher trophic levels in food webs. Low residues of p,p'-DDT and its metabolite p,p'-DDE were frequently found in tissues and eggs of Canada geese, but they had no apparent adverse effects on reproductive success or eggshell thickness. Likewise, in an orchard system in central Washington state, the OC rodenticide endrin accumulated in tissues and eggs of Canada geese without apparent adverse effect. In contrast, ingestion of seeds treated with the OC heptachlor caused mortality, lowered reproductive success, and caused a local population decline of geese in Oregon and Washington. In recent years, the most persistent OC's have been banned by law and replaced with less persistent carbamate and OP compounds that do not readily accumulate in animal tissues. However, many of these compounds are acutely toxic and have caused numerous die-offs of Canada geese. Among OP compounds, diazinon was responsible for most reported die-offs (41 incidents involving >535 geese), whereas parathion applied alone or jointly with methyl parathion accounted for most reported mortalities (8 incidents involving >3,000 geese). Three other OP's, a carbamate (carbofuran), zinc phosphide, and strychnine also caused goose die-offs. Mortality from anticholinesterase (antiChE) compounds occurs relatively soon after exposure and death can usually be diagnosed by evaluation of brain cholinesterase (thE) activity. Because geese are primarily grazers, the main route of exposure to antiChE's is apparently ingestion of contaminated grasses and forbs; dermal absorption and inhalation are other routes. Despite the widespread die-offs of Canada geese from antiChE insecticides, there is no evidence of adverse effects on population levels. It is not known how sublethal antiChE exposure relates to long-term survival and reproductive success of birds.

Insect nicotinic receptor interactions in vivo with neonicotinoid, organophosphorus, and methylcarbamate insecticides and a synergist

PubMed Central

Shao, Xusheng; Xia, Shanshan; Durkin, Kathleen A.; Casida, John E.

2013-01-01

The nicotinic acetylcholine (ACh) receptor (nAChR) is the principal insecticide target. Nearly half of the insecticides by number and world market value are neonicotinoids acting as nAChR agonists or organophosphorus (OP) and methylcarbamate (MC) acetylcholinesterase (AChE) inhibitors. There was no previous evidence for in vivo interactions of the nAChR agonists and AChE inhibitors. The nitromethyleneimidazole (NMI) analog of imidacloprid, a highly potent neonicotinoid, was used here as a radioligand, uniquely allowing for direct measurements of house fly (Musca domestica) head nAChR in vivo interactions with various nicotinic agents. Nine neonicotinoids inhibited house fly brain nAChR [3H]NMI binding in vivo, corresponding to their in vitro potency and the poisoning signs or toxicity they produced in intrathoracically treated house flies. Interestingly, nine topically applied OP or MC insecticides or analogs also gave similar results relative to in vivo nAChR binding inhibition and toxicity, but now also correlating with in vivo brain AChE inhibition, indicating that ACh is the ultimate OP- or MC-induced nAChR active agent. These findings on [3H]NMI binding in house fly brain membranes validate the nAChR in vivo target for the neonicotinoids, OPs and MCs. As an exception, the remarkably potent OP neonicotinoid synergist, O-propyl O-(2-propynyl) phenylphosphonate, inhibited nAChR in vivo without the corresponding AChE inhibition, possibly via a reactive ketene metabolite reacting with a critical nucleophile in the cytochrome P450 active site and the nAChR NMI binding site. PMID:24108354

In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate.

PubMed

O'Donnell, John C; McDonough, John H; Shih, Tsung-Ming

2011-12-01

Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents' propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure.

Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX

PubMed Central

Rice, Helen; Dalton, Christopher H.; Price, Matthew E.; Graham, Stuart J.; Green, A. Christopher; Jenner, John; Groombridge, Helen J.; Timperley, Christopher M.

2015-01-01

To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM–VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro. The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved. PMID:27547080

Methyl parathion and fenvalerate toxicity in American kestrels: Acute physiological responses and effects of cold

USGS Publications Warehouse

Rattner, B.A.; Franson, J.C.

1984-01-01

Physiological and toxicological effects of p.o. methyl parathion (0.375-3.0 mg/kg) or fenvalerate (1000-4000 mg/kg) were examined over a 10-h period in American kestrels (Falco sparverius) maintained in thermoneutral (22?C) and cold (-5?C) environments. Methyl parathion was highly toxic (estimated median lethal dose of 3.08 mg/kg, 95% confidence limits of 2.29 -4.14 mg/kg), producing dose-dependent inhibition of brain and plasma cholinesterase activity, hyperglycemia, and elevated plasma corticosterone concentration. Brain and plasma cholinesterase inhibition in excess of 50% was associated with transient but pronounced hypothermia 2 h after intubation, although the magnitude of this response was yariable. Fenvalerate, at doses far exceeding those encountered in the environment, caused mild intoxication and elevated plasma alanine aminotransferase activity. Cold intensified methyl parathion toxicity, but did not affect that of fenvalerate. Thus, it would appear that organophosphorus insecticides pose far greater hazard than pyrethroids to raptorial birds.

Validation of GC-IRMS techniques for δ13C and δ2H CSIA of organophosphorus compounds and their potential for studying the mode of hydrolysis in the environment.

PubMed

Wu, Langping; Kümmel, Steffen; Richnow, Hans H

2017-04-01

Compound-specific stable isotope analysis (CSIA) is among the most promising tools for studying the fate of organic pollutants in the environment. However, the feasibility of multidimensional CSIA was limited by the availability of a robust method for precise isotope analysis of heteroatom-bearing organic compounds. We developed a method for δ 13 C and δ 2 H analysis of eight organophosphorus compounds (OPs) with different chemical properties. In particular, we aimed to compare high-temperature conversion (HTC) and chromium-based HTC (Cr/HTC) units to explore the limitations of hydrogen isotope analysis of heteroatom-bearing compounds. Analysis of the amount dependency of the isotope values (linearity analysis) of OPs indicated that the formation of HCl was a significant isotope fractionation process leading to inaccurate δ 2 H analysis in HTC. In the case of nonchlorinated OPs, by-product formation of HCN, H 2 S, or PH 3 in HTC was observed but did not affect the dynamic range of reproducible isotope values above the limit of detection. No hydrogen-containing by-products were found in the Cr/HTC process by use of ion trap mass spectrometry analysis. The accuracy of gas chromatography - isotope ratio mass spectrometry was validated in comparison with elemental analyzer - isotope ratio mass spectrometry. Dual-isotope fractionation yielded Λ values of 0 ± 0 at pH 7, 7 ± 1 at pH 9, and 30 ± 6 at pH 12, indicating the potential of 2D CSIA to characterize the hydrolysis mechanisms of OPs. This is the first report on the combination of δ 2 H and δ 13 C isotope analysis of OPs, and this is the first study providing a systematic evaluation of HTC and Cr/HTC for hydrogen isotope analysis using OPs as target compounds. Graphical Abstract Comparison of δ 2 H measurement of non-chlorinated and chlorinated OPs via GC-Cr/HTC-IRMS and GC-HTC-IRMS system.

Micellar catalyzed degradation of fenitrothion, an organophosphorus pesticide, in solution and soils.

PubMed

Balakrishnan, Vimal K; Buncel, Erwin; Vanloon, Gary W

2005-08-01

We report on a study of the decomposition of fenitrothion (an organophosphorus pesticide that is a persistent contaminant in soils and groundwater) as catalyzed by cetyltrimethylammonium (CTA+) micelles. The CTA micelles were associated with two types of counterions: (1) inert counterions (e.g. CTABr) and (2) reactive counterions (e.g. CTAOH). The reactive counterion surfactants used were hydroxide anion (HO-) as a normal nucleophile and hydroperoxide anion (HOO-) and the anion of pyruvaldehyde oxime (MINA-) as two alpha-nucleophiles. The reactivity order followed: CTABr < CTAOH < CTAMINA < CTAOOH. Treatment of the rate data using the Pseudo-Phase Ion Exchange (PPIE) model of micellar catalysis showed the ratio k2M/k2w to be less than unity for all the surfactants employed. Rather than arising from a "true catalysis", we attributed the observed rate enhancements to a "concentration effect", where both pesticide and nucleophile were incorporated into the small micellar phase volume. Furthermore, the CTAOOH/CTAOH pair gave an alpha-effect of 57, showing that the alpha-effect can play an important role in micellar systems. We further investigated the effectiveness of reactive counterion surfactants in decontaminating selected environmental solids that were spiked with 27 ppb fenitrothion. The solids were as follows: the clay mineral montmorillonite and SO-1 and S0-2 soils (obtained from the Canadian Certified Reference Materials Project). The reactive counterion surfactant solutions significantly enhanced the rate of fenitrothion degradation in the spiked solids over that obtained when the spiked solid was placed in contact with either 0.02 M KOH or water. The rate enhancements followed the order CTAOOH > CTAMINA approximately CTAOH > KOH > water. We conclude that reactive counterion surfactants, especially with alpha-nucleophiles, hold great potential in terms of remediating soils contaminated by toxic organophosphorus esters.

A Characterization of Carboxylesterases in Rat and Guinea Pig - Their Heterogeneity and Role in Detoxication of Organophosphorus Compounds

DTIC Science & Technology

1993-09-01

those of plasma, are resistant to mol) from Amersham International (Amersham, inhibition by these very active anticholinesterases . U.K.); paraoxon...Subcutaneous and intraperitonal administration of paraoxon and DFP rapidly inhibited the CarbE activity in guinea pig plasma, much higher doses were...necessary to obtain a marked inhibition in lung and liver, and about 25% of (arbE activity in lung was resistant to inhibition. Gel filtration of lung homo

Development of Novel Decontamination Techniques for Chemical Agents (GB, VX, HD) Contaminated Facilities. Phase I. Identification and Evaluation of Novel Decontamination Concepts. Volume 1

DTIC Science & Technology

1983-02-01

ACTIVITY . . . . . . 4 3.0 PHASE I RESULTS . . . . . . . . . . . . . . . . . . . . . . 5 3.1 RESOURCE REVIEW . . . . . . . . . . . . . 5 ŗ.1.1 Surveys...commonly known as mustard, is a vesicant while VX and GB are organophosphorus compounds which act as anticholinesterases . HD Cl-( CH)-S-(CH- );cI 0...order to satisfy the task objective, work during this phase . consisted of three principal interrelated activities . The goal of the first activity was

α-Ketophosphonic Acid Esters — Synthesis, Structure, and Reactions

NASA Astrophysics Data System (ADS)

Zhdanov, Yu A.; Uzlova, L. A.; Glebova, Z. I.

1980-09-01

Studies on the synthesis and properties of α-ketophosphonic acid esters (KPE) — a class of highly reactive organophosphorus compounds — are surveyed. Data are presented concerning instances of the anomalous course of the process in the synthesis of KPE by the Arbuzov reaction. The reactions of KPE with nucleophiles, including those which lead to the rupture of the phosphorus-carbon bond, are examined in detail. The problems of the stereochemistry of KPE are dealt with briefly. The bibliography includes 162 references.

Third International Meeting on Esterases Reacting with Organophosphorus Compounds

DTIC Science & Technology

1998-01-01

cassette for negative selection, 884 bp of ACHE including exon 1, 1.6 kb of a Neor gene cassette for positive selection, 5.2 kb of the ACHE Bam HI...fragment including exon 6, and 3 kb of Bluescript. Deletion of exons 2-5 removed 80% of the ACHE coding sequence. The gene targeting vector was...expression due to environmental influences on CYP3A4 and the presence or absence of CYP3A5 which may be under genetic control in man. Plasma

Modeling receptor kinetics in the analysis of survival data for organophosphorus pesticides.

PubMed

Jager, Tjalling; Kooijman, Sebastiaan A L M

2005-11-01

Acute ecotoxicological tests usually focus on survival at a standardized exposure time. However, LC50's decrease in time in a manner that depends both on the chemical and on the organism. DEBtox is an existing approach to analyze toxicity data in time, based on hazard modeling (the internal concentration increases the probability to die). However, certain chemicals elicit their response through (irreversible) interaction with a specific receptor, such as inhibition of acetylcholinesterase (AChE). Effects therefore do not solely depend on the actual internal concentration, but also on its (recent) past. In this paper, the DEBtox method is extended with a simple mechanistic model to deal with receptor interactions. We analyzed data from the literature for organophosphorus pesticides in guppies, fathead minnows, and springtails. Overall, the observed survival patterns do not clearly differ from those of chemicals with a less-specific mode of action. However, using the receptor model, resulting parameter estimates are easier to interpret in terms of underlying mechanisms and reveal similarities between the various pesticides. We observed thatthe no-effect concentration estimated from the receptor model is basically identical to the value from standard DEBtox, illustrating the robustness of this summary statistic.

Catalytic degradation of organophosphorous nerve agent simulants by polymer beads@graphene oxide with organophosphorus hydrolase-like activity based on rational design of functional bimetallic nuclear ligand.

PubMed

Ma, Xuejuan; Zhang, Lin; Xia, Mengfan; Zhang, Xiaohong; Zhang, Yaodong

2018-05-15

The degradation of organophosphorous nerve agents is of primary concern due to the severe toxicity of these agents. Based on the active center of organophosphorus hydrolase (OPH), a bimetallic nuclear ligand, (5-vinyl-1,3-phenylene)bis(di(1H-imidazol-2-yl) methanol) (VPIM), was designed and synthesized, which contains four imidazole groups to mimic the four histidines at OPH active center. By grafting VPIM on graphene oxide (GO) surface via polymerization, the VPIM-polymer beads@GO was produced. The obtained OPH mimics has an impressive activity in dephosphorylation reactions (turnover frequency (TOF) towards paraoxon: 2.3 s -1 ). The synergistic catalytic effect of the bimetallic Zn 2+ nuclear center and carboxyl groups on surface of GO possibly contributes to the high hydrolysis on organophosphate substrate. Thus, a biomimetic catalyst for efficient degradation of some organophosphorous nerve agent simulants, such as paraoxon and chlorpyrifos, was prepared by constructing catalytic active sites. The proposed mechanism and general synthetic strategy open new avenues for the engineering of functional GOs for biomimetic catalysts. Copyright © 2018 Elsevier B.V. All rights reserved.

A study of the degradation of organophosphorus pesticides in river waters and the identification of their degradation products by chromatography coupled with mass spectrometry.

PubMed

Zhao, Xueheng; Hwang, Huey-Min

2009-05-01

The degradation of selected organophosphorus pesticides (OPs), i.e., malathion and parathion, in river water, has been studied with solar simulator irradiation. The degradation of OPs and formation of degradation products were determined by chromatography coupled with mass spectrometry analysis. The effect of a photosensitizer, i.e., riboflavin, on the photolysis of OPs in a river-water environment was examined. There was no significant increase in the degradation rate in the presence of the photosensitizer. Degradation products of the OPs were identified with gas chromatography coupled with mass spectrometry (GC-MS) after derivatization by pentafluorobenzyl bromide (PFBB) and with high-performance liquid chromatography-mass spectrometry (HPLC-MS) with electrospray (ESI) or atomospheric pressure chemical ionization (APCI). Malaoxon, paraoxon, 4-nitrophenol, aminoparathion, O,O-dimethylthiophosphoric acid, and O,O-dimethyldithiophosphoric acid, have been separated and identified as the degradation products of malathion and parathion after photolysis in river water. Based on the identified transformation products, a rational degradation pathway in river water for both OPs is proposed. The identities of these products can be used to evaluate the toxic effects of the OPs and their transformation products on natural environments.

Enzyme-mediated Nutrient Regeneration Following Lysis of Synechococcus WH7803

NASA Astrophysics Data System (ADS)

Mine, A. H.; Coleman, M.; Colman, A. S.

2016-02-01

Phosphate availability plays a pivotal role in limiting primary production in large regions of the oceans. In order to meet their metabolic needs, microbes use a variety of strategies to overcome phosphate stress. Expression of enzymes such as alkaline phosphatase (APase) allows cells to hydrolyze and use certain ambient dissolved organic phosphorus (DOP) compounds to meet their P demand. Cell lysis releases a range of nutrient forms and enzymes into the ambient environment and is an essential component of the microbial loop. Yet very few studies have attempted to characterize both the immediate and sustained nutrient remineralization linked to the milieu of organophosphorus compounds and enzymatic activity in lysate. We conducted experiments using Synechococcus WH7803 grown under nutrient replete and starved conditions to quantify the release of phosphate during viral lysis and lysis by lysozyme treatment. Dissolved inorganic and organic phosphorus concentrations and APase activity were monitored over time following lysis. We observed a significant initial release of orthophosphate that accompanies lysis. Following lysis, phosphate concentrations continue to rise for a period of hours to days as organophosphorus compounds continue to hydrolyze. Our observations suggest this is due to a combination of direct hydrolysis of DOP released during lysis, solubilization of POP followed by hydrolysis, and possibly polyphosphate decomposition. Size fractionated enzymatic assays suggest cellular debris associated enzymes and dissolved fractions are both important in DOP hydrolysis in the viral lysate, whereas particle associated APase activity dominates in the lysozyme treatments. Moreover, nutrient status prior to lysis has important controls on the initial nutrient release and subsequent regenerative flux. These findings underscore the significance of lysis and subsequent enzyme-mediated hydrolysis in nutrient regeneration and biogeochemical dynamics in marine ecosystems.

Solid-Phase Microextraction Coupled to Capillary Atmospheric Pressure Photoionization-Mass Spectrometry for Direct Analysis of Polar and Nonpolar Compounds.

PubMed

Mirabelli, Mario F; Zenobi, Renato

2018-04-17

A novel capillary ionization source based on atmospheric pressure photoionization (cAPPI) was developed and used for the direct interfacing between solid-phase microextraction (SPME) and mass spectrometry (MS). The efficiency of the source was evaluated for direct and dopant-assisted photoionization, analyzing both polar (e.g., triazines and organophosphorus pesticides) and nonpolar (polycyclic aromatic hydrocarbons, PAHs) compounds. The results show that the range of compound polarity, which can be addressed by direct SPME-MS can be substantially extended by using cAPPI, compared to other sensitive techniques like direct analysis in real time (DART) and dielectric barrier discharge ionization (DBDI). The new source delivers a very high sensitivity, down to sub parts-per-trillion (ppt), making it a viable alternative when compared to previously reported and less comprehensive direct approaches.

Acetylcholine-hydrolyzing activities in soluble brain fraction: Characterization with reversible and irreversible inhibitors.

PubMed

Estévez, Jorge; Selva, Verónica; Benabent, Mónica; Mangas, Iris; Sogorb, Miguel Ángel; Vilanova, Eugenio

2016-11-25

Some effects of organophosphorus compounds (OPs) esters cannot be explained through actions on currently recognized targets acetylcholinesterase or neuropathy target esterase (NTE). In soluble chicken brain fraction, three components (Eα, Eβ and Eγ) of pheny lvalerate esterase activity (PVase) were kinetically discriminated and their relationship with acetylcholine-hydrolyzing activity (cholinesterase activity) were studied in previous works. In this work, four enzymatic components (CS1, CS2, CS3 and CS4) of cholinesterase activity have been discriminated in soluble fraction, according to their sensitivity to irreversible inhibitors mipafox, paraoxon, PMSF and iso-OMPA and to reversible inhibitors ethopropazine and BW284C51. Cholinesterase component CS1 can be related to the Eα component of PVase activity and identified as butyrylcholinesterase (BuChE). No association and similarities can be stablished among the other PVase component (Eβ and Eγ) with the other cholinesterase components (CS2, CS3, CS4). The kinetic analysis has allowed us to stablish a method for discriminating the enzymatic component based on a simple test with two inhibitors. It can be used as biomarker in toxicological studies and for monitoring these cholinesterase components during isolation and molecular identification processes, which will allow OP toxicity to be understood by a multi-target approach. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Analysis of organophosphate-Zn metalloporphyrin interactions via UV-vis spectroscopy and molecular modeling.

PubMed

Rompoti, A; Dalal, N; Athanasopoulos, D; Rutan, S; Helburn, R

2015-01-25

UV-vis absorption spectra of zinc tetraphenylporphine (ZnTPP) on interaction with six organophosphorus (OP) compounds in cyclohexane were compared using ab initio methods and the molecular and solvation ligand descriptors π(*), Vx, and σ. OPs with polarizable hydrocarbon substituents in the homologous series tri-ethyl, -pentyl, -octyl, and -phenyl phosphates and the toxicologically relevant methyl paraoxon (1a-e) each gave a red shift in the Soret band (λsor) of ZnTPP in the range of 8-10 nm. Sensitivity as ΔAsor-b/Δug OP for the spectral band of the ligand bound ZnTPP (λsor-b) decreased with increasing extent of alkyl and aromatic substitution. Calculated and combined energies for OP and ZnTPP examined as a function of distance (Å) between ligand and porphyrin center suggest increased steric crowding with increasing Vx, and aromatic content of the OP. Spectrally fitted K1:1 and ΔAsor-b/ug OP each vary exponentially with Vx/σ. Lack of a red shift in λsor-b where ZnTPP was titrated with the toxic diethyl chlorophosphate (1g) is consistent with a model in which the magnitude of ΔEsor is proportional to the donor capacity of the phosphoryl-O ligand. Copyright © 2014 Elsevier B.V. All rights reserved.

Gastric Lavage in Acute Organophosphorus Pesticide poisoning (GLAOP) – a randomised controlled trial of multiple vs. single gastric lavage in unselected acute organophosphorus pesticide poisoning

PubMed Central

Li, Yi; Yu, XueZhong; Wang, Zhong; Wang, HouLi; Zhao, XiangHuai; Cao, YuPing; Wang, WeiZhan; Eddleston, Michael

2006-01-01

Background Organophosphorus (OP) pesticide poisoning is the most common form of pesticide poisoning in many Asian countries. Guidelines in western countries for management of poisoning indicate that gastric lavage should be performed only if two criteria are met: within one hour of poison ingestion and substantial ingested amount. But the evidence on which these guidelines are based is from medicine overdoses in developed countries and may be irrelevant to OP poisoning in Asia. Chinese clinical experience suggests that OP remains in the stomach for several hours or even days after ingestion. Thus, there may be reasons for doing single or multiple gastric lavages for OP poisoning. There have been no randomised controlled trials (RCTs) to assess this practice of multiple lavages. Since it is currently standard therapy in China, we cannot perform a RCT of no lavage vs. a single lavage vs. multiple lavages. We will compare a single gastric lavage with three gastric lavages as the first stage to assess the role of gastric lavage in OP poisoning. Methods/Design We have designed an RCT assessing the effectiveness of multiple gastric lavages in adult OP self-poisoning patients admitted to three Chinese hospitals within 12 hrs of ingestion. Patients will be randomised to standard treatment plus either a single gastric lavage on admission or three gastric lavages at four hour intervals. The primary outcome is in-hospital mortality. Analysis will be on an intention-to-treat basis. On the basis of the historical incidence of OP at the study sites, we expect to enroll 908 patients over three years. This projected sample size provides sufficient power to evaluate the death rate; and a variety of other exposure and outcome variables, including particular OPs and ingestion time. Changes of OP level will be analyzed in order to provide some toxic kinetic data. Discussion the GLAOP study is a novel, prospective cohort study that will explore to the toxic kinetics of OP and effects of gastric lavage on it. Given the poor information about the impact of gastric lavage on clinical outcomes for OP patients, this study can provide important information to inform clinical practice. PMID:17049100

Poisoning of raptors with organophosphorus and carbamate pesticides with emphasis on Canada, U.S. and U.K.

USGS Publications Warehouse

Mineau, P.; Fletcher, M.R.; Glaser, L.C.; Thomas, N.J.; Brassard, C.; Wilson, L.K.; Elliott, J.E.; Lyon, L.A.; Henny, C.J.; Bollinger, T.; Porter, S.L.

1999-01-01

We reviewed cases of raptor mortality resulting from cholinesterase-inhibiting pesticides. We compiled records from the U.S., U.K. and Canada for the period 1985-95 (520 incidents) and surveyed the relevant literature to identify the main routes of exposure and those products that led to the greatest number of poisoning cases. A high proportion of cases in the U.K. resulted from abusive uses of pesticides (willful poisoning). The proportion was smaller in North America where problems with labeled uses of pesticides were as frequent as abuse cases. Poisoning resulting from labeled use was possible with a large number of granular pesticides and some seed treatments through secondary poisoning or through the ingestion of contaminated invertebrates, notably earthworms. With the more toxic products, residue levels in freshly-sprayed insects were high enough to cause mortality. The use of organophosphorus products as avicides and for the topical treatment of livestock appeared to be common routes of intoxication. The use of insecticides in dormant oils also gave rise to exposure that can be lethal or which can debilitate birds and increase their vulnerability. A few pesticides of high toxicity were responsible for the bulk of poisoning cases. Based on limited information, raptors appeared to be more sensitive than other bird species to organophosphorus and carbamate pesticides. Some of the more significant risk factors that resulted in raptor poisonings were: insectivory and vermivory; opportunistic taking of debilitated prey; scavenging, especially if the gastrointestinal tracts are consumed; presence in agricultural areas; perceived status as pest species; and flocking or other gregarious behavior at some part of their life cycle. Lethal or sublethal poisoning should always be considered in the diagnosis of dead or debilitated raptors even when another diagnosis (e.g., electrocution, car or building strike) is apparent. Many cases of poisoning are not currently diagnosed as such and, even when diagnosed, the information is often not made available to regulatory authorities. The importance of pesticide intoxications relative to other sources of mortality is highly variable in time and place; on a regional level, the increased mortality of raptors resulting from cholinesterase-inhibiting pesticides can be significant, especially in the case of rare species.

Development of a sensitive, generic and easy to use organophosphate skin disclosure kit.

PubMed

Worek, Franz; Wosar, Andreas; Baumann, Madlen; Thiermann, Horst; Wille, Timo

2017-10-05

Various organophosphorus compounds (OP), primarily the nerve agent VX and other V-agents, are highly toxic to humans after skin exposure. Percutaneous exposure by such OP results in a delayed onset of toxic signs which enables the initiation of specific countermeasures if contamination is detected rapidly. Presently available mobile detection systems can hardly detect skin exposure by low volatile OP. In order to fill this gap an OP skin disclosure kit was developed which should fulfill different requirements, i.e. a high sensitivity, coverage of human toxic OP, easy handling, rapid results, small dimension and weight. The kit includes a cotton swab to sample skin, human AChE as target and chemicals for a color reaction based on the Ellman assay which is recorded by visual inspection. OP is dissolved from the sampler in a test tube filled with phosphate buffer (0.1M, pH 7.4) and incubated with lyophilized human AChE for 1min. The reaction with acetylthiocholine and 5,5'-dithio-bis-2-nitrobenzoic acid (1min) results in a rich yellow color in the absence of OP and in contrast, in transparent or pale yellow buffer in the presence of OP. At the recommended conditions, the limit of detection is 100ng VX and Russian VX and 50ng Chinese VX on plain surface and 200ng VX on rat skin. With activated pesticides, paraoxon and malaoxon, a concentration of ∼10μg can be detected on plain surface. The ready-to-use kit has a weight of 16g and a size of 10×12×1cm. In the end, this kit has the potential to fill a major gap and to enable timely detection of OP skin exposure and initiation of life-saving countermeasures. Copyright © 2017 Elsevier B.V. All rights reserved.

High-throughput immunomagnetic scavenging technique for quantitative analysis of live VX nerve agent in water, hamburger, and soil matrixes.

PubMed

Knaack, Jennifer S; Zhou, Yingtao; Abney, Carter W; Prezioso, Samantha M; Magnuson, Matthew; Evans, Ronald; Jakubowski, Edward M; Hardy, Katelyn; Johnson, Rudolph C

2012-11-20

We have developed a novel immunomagnetic scavenging technique for extracting cholinesterase inhibitors from aqueous matrixes using biological targeting and antibody-based extraction. The technique was characterized using the organophosphorus nerve agent VX. The limit of detection for VX in high-performance liquid chromatography (HPLC)-grade water, defined as the lowest calibrator concentration, was 25 pg/mL in a small, 500 μL sample. The method was characterized over the course of 22 sample sets containing calibrators, blanks, and quality control samples. Method precision, expressed as the mean relative standard deviation, was less than 9.2% for all calibrators. Quality control sample accuracy was 102% and 100% of the mean for VX spiked into HPLC-grade water at concentrations of 2.0 and 0.25 ng/mL, respectively. This method successfully was applied to aqueous extracts from soil, hamburger, and finished tap water spiked with VX. Recovery was 65%, 81%, and 100% from these matrixes, respectively. Biologically based extractions of organophosphorus compounds represent a new technique for sample extraction that provides an increase in extraction specificity and sensitivity.

Microchip-Based Organophosphorus Detection Using Bienzyme Bioelectrocatalysis

NASA Astrophysics Data System (ADS)

Han, Yong Duk; Jeong, Chi Yong; Lee, Jun Hee; Lee, Dae-Sik; Yoon, Hyun C.

2012-06-01

We have developed a microsystem for the detection of organophosphorus (OP) compounds using acetylcholine esterase (AchE) and choline oxidase (ChOx) bienzyme bioelectrocatalysis. Because AchE is irreversibly inhibited by OP pesticides, the change in AchE activity with OP treatment can be traced to determine OP concentration. Polymer-associated ChOx immobilization on the working electrode surface and magnetic microparticle (MP)-assisted AchE deposition methods were employed to create an AchE-ChOx bienzyme-modified biosensing system. ChOx was immobilized on the micropatterned electrodes using poly(L-lysine), glutaraldehyde, and amine-rich interfacial surface. AchE was immobilized on the MP surface via Schiff's base formation, and the enzyme-modified MPs were deposited on the working electrode using a magnet under the microfluidic channel. The bioelectrocatalytic reaction between AchE-ChOx bienzyme cascade and the ferrocenyl electron shuttle was successfully used to detect OP with the developed microchip. This provides a self-contained and relatively easy method for OP detection. It requires minimal time and a small sample size, and has potential analytic applications in pesticides and chemical warfare agents.

Studies of the acetylcholinesterase from houseflies (Musca domestica L.) resistant and susceptible to organophosphorus insecticides.

PubMed Central

Devonshire, A L

1975-01-01

Acetylcholinesterase from the heads of insecticide-resistant and -susceptible houseflies (Musca domestica L.) was studied in vitro. The enzymes could not be distinguished electrophoretically, and their behaviour on polyacrylamide-disc-gel electrophoresis was influenced by the presence of Triton X-100 in both the homogenate and the gels. In the absence of detergent, the acetylcholinesterase was heterogeneous, but behaved as a single enzyme when it was present. By analogy with studies of acetylcholinesterase from other sources, these observations were attributed to aggregation of the enzyme when not bound by membranes. The enzyme from resistant flies was more slowly inhibited than the susceptible enzyme, bimolecular rate constants (ki) differing by approx. 4-20-fold for a range of organophosphorus compounds. The kinetics of inhibition of acetylcholinesterase were consistent with the results of electrophoresis, i.e. they corresponded to those of a single enzyme in the presence of Triton X-100, but a mixture of enzymes in its absence. The susceptibility of the more sensitive components in these mixtures was determined. Images PLATE 1 PMID:1180906

Computational Enzymology and Organophosphorus Degrading Enzymes: Promising Approaches Toward Remediation Technologies of Warfare Agents and Pesticides.

PubMed

Ramalho, Teodorico C; de Castro, Alexandre A; Silva, Daniela R; Silva, Maria Cristina; Franca, Tanos C C; Bennion, Brian J; Kuca, Kamil

2016-01-01

The re-emergence of chemical weapons as a global threat in hands of terrorist groups, together with an increasing number of pesticides intoxications and environmental contaminations worldwide, has called the attention of the scientific community for the need of improvement in the technologies for detoxification of organophosphorus (OP) compounds. A compelling strategy is the use of bioremediation by enzymes that are able to hydrolyze these molecules to harmless chemical species. Several enzymes have been studied and engineered for this purpose. However, their mechanisms of action are not well understood. Theoretical investigations may help elucidate important aspects of these mechanisms and help in the development of more efficient bio-remediators. In this review, we point out the major contributions of computational methodologies applied to enzyme based detoxification of OPs. Furthermore, we highlight the use of PTE, PON, DFP, and BuChE as enzymes used in OP detoxification process and how computational tools such as molecular docking, molecular dynamics simulations and combined quantum mechanical/molecular mechanics have and will continue to contribute to this very important area of research.

Development and validation of a multiresidue method for the analysis of polybrominated diphenyl ethers, new brominated and organophosphorus flame retardants in sediment, sludge and dust.

PubMed

Cristale, Joyce; Lacorte, Silvia

2013-08-30

This study presents a multiresidue method for simultaneous extraction, clean-up and analysis of priority and emerging flame retardants in sediment, sewage sludge and dust. Studied compounds included eight polybrominated diphenyl ethers congeners, nine new brominated flame retardants and ten organophosphorus flame retardants. The analytical method was based on ultrasound-assisted extraction with ethyl acetate/cyclohexane (5:2, v/v), clean-up with Florisil cartridges and analysis by gas chromatography coupled to tandem mass spectrometry (GC-EI-MS/MS). Method development and validation protocol included spiked samples, certified reference material (for dust), and participation in an interlaboratory calibration. The method proved to be efficient and robust for extraction and determination of three families of flame retardants families in the studied solid matrices. The method was applied to river sediment, sewage sludge and dust samples, and allowed detection of 24 among the 27 studied flame retardants. Organophosphate esters, BDE-209 and decabromodiphenyl ethane were the most ubiquitous contaminants detected. Copyright © 2013 Elsevier B.V. All rights reserved.

Removal of atrazine and four organophosphorus pesticides from environmental waters by diatomaceous earth-remediation method.

PubMed

Agdi, K; Bouaid, A; Esteban, A M; Hernando, P F; Azmani, A; Camara, C

2000-10-01

A new viable remediation technique based on the use of diatomaceous earth is proposed to improve the ecological system. Its ability to remove atrazine and the four organophosphorus pesticides parathion-methyl, chlorpyriphos, fenamiphos and methidathion from river and waste waters has been proven. A series of experiments including variable conditions, such as temperature, pH, contact time, pesticide concentration and adsorbent quantity, were performed to demonstrate the efficiency of pesticide removal from three different water samples. The batch experiments showed that diatomaceous earth was able to remove 95% of chlorpyriphos, 75% of methidathion and parathion-methyl and 55% of atrazine and fenamiphos from all types of waters tested. The individual adsorption of each pesticide on diatomaceous earth could be described by the Freundlich isotherm and a tentative adsorption mechanism was proposed. The Freundlich coefficient (Kf) and Freundlich constant (1/n) appeared to be closely related to the physicochemical properties (Kow, solubility) of the compounds. The actual results support the conclusion that diatomaceous earth has the potential to serve as an extractant in remediation techniques.

[Acute risk assessment of cumulative dietary exposure to organophosphorus pesticide among people in Jiangsu province].

PubMed

Zhao, Minxian; Wang, Cannan; Li, Tingting; Yi, Nannan; He, Xiansong; Wu, Hui; Yao, Xinya

2013-09-01

To understand the cumulative dietary exposure of Jiangsu residents to organophosphorus (OPs) pesticide and make acute risk assessment. Integrated the data of the nutrition and health status of residents in Jiangsu and the data of monitoring of OPs pesticide in agricultural products. Chlorpyrifos was selected as index compound (index chemical, IC), then use relative potency factor (RPF) approach which commended by EPA and simple distribution evaluation. Caloulated the dietary cumulative exposure of OPs pesticide among Jiangsu residents and compared with acute reference dose (ARfD), then made risk assessment. The exposure of rural group of age 3-6 and 7-11 were 133.84 microg/kg BW and 154.32 microg/kg BW, exceeded ARfD. The exposure level of kids and elder was higher than adults. The exposure level of rural residents were higher than urban residents. The highest contribution to the food of each age group was greengrocery and leek. The average level of exposure was safety in Jiangsu, high exposure children were at acute poisoning risk. High contribution food such as greengrocery and leek should be strengthen monitoring.

Demonstration of in vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents.

PubMed

Zhuang, Qinggeng; Franjesevic, Andrew J; Corrigan, Thomas S; Coldren, William H; Dicken, Rachel; Sillart, Sydney; DeYong, Ashley; Yoshino, Nathan; Smith, Justin; Fabry, Stephanie; Fitzpatrick, Keegan; Blanton, Travis G; Joseph, Jojo; Yoder, Ryan J; McElroy, Craig A; Dogan Ekici, Ozlem; Callam, Christopher S; Hadad, Christopher M

2018-06-05

After inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction, referred to as aging, of the phosphylated serine can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reverse aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screening, successfully resurrected 32.7% and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE.

[Rapid simultaneous determination of organophosphorus pesticides in human serum and urine by liquid chromatography-mass spectrometry].

PubMed

Zlatković, Milica; Jovanović, Miodrag; Djordjević, Dragana; Vucinić, Slavica

2010-09-01

Analysis of organophosphosphorus compounds and their metabolites in a biological material includes the use of numerous methods, covering both preparation of samples for analysis and their identification that is considered to be very complex. Low concentrations monitoring requires implementation of highly sensitive analytical techniques. The aim of this study was to develop and validate an original and sensitive method for the detection and quantitation of organophosphorus pesticides (dimethoate, diazinon, malathion and malaoxon) in human biological matrices (serum, urine). This method was based on a solid-phase extraction procedure, a chromatographic separation using an ACQUITY UPLC HSST3 column and mass spectrometric detection in the positive ion mode. Mobile phase: was consited of Solvent A (5 mM ammonium formate pH 3.0) and Solvent B (0.1% acetic formate in methanol), in a linear gradient (constant flow-rate 0.3 mL/min). The standard curve was linear in the range of 0.05-5.00 mg/L for malathion and malaoxon, 0.10-5.00 mg/L for dimethoate and 0.05-2.50 mg/L for diazinon. The correlation coefficient was r > or = 0.99. Extraction recoveries were satisfactory and ranged between 90-99%. The limits of detection (LOD) was between 0.007-0.07 mg/L and the limits of quantitation (LOQ) ranged between 0.022-0.085 mg/L. Intra- and interassay precision and accuracy were satisfactory for all of the pesticides analyzed. The method of liquid chromatography-mass spectrometry is simple, accurate, and useful for the determination of organophosphorus pesticides in both clinical and forensic toxicology.

A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilhelm, Christina M., E-mail: wilhelmc@battelle.org; Snider, Thomas H., E-mail: snidert@battelle.org; Babin, Michael C., E-mail: babinm@battelle.org

The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection atmore » the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl{sub 2}, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. - Highlights: • First comprehensive evaluation of leading AChE oxime reactivators • All oximes are compared against current U.S. therapy 2-PAM Cl. • Relative therapeutic oxime efficacies against OP CWNA and pesticides • Contribution to more effective antidotes for civilian and military populations.« less

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for detection and identification of albumin phosphylation by organophosphorus pesticides and G- and V-type nerve agents.

PubMed

John, Harald; Breyer, Felicitas; Thumfart, Jörg Oliver; Höchstetter, Hans; Thiermann, Horst

2010-11-01

Toxic organophosphorus compounds (OPC), e.g., pesticides and nerve agents (NA), are known to phosphylate distinct endogenous proteins in vivo and in vitro. OPC adducts of butyrylcholinesterase and albumin are considered to be valuable biomarkers for retrospective verification of OPC exposure. Therefore, we have detected and identified novel adducts of human serum albumin (HSA) by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Pure albumin and plasma were incubated with numerous pesticides and NA of the V- and G-type in different molar ratios. Samples were prepared either by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by in-gel enzymatic cleavage using endoproteinase Glu-C (Glu-C) or by combining highly albumin-selective affinity extraction with ultrafiltration followed by reduction, carbamidomethylation, and enzymatic cleavage (Glu-C) prior to MALDI-TOF MS analysis. Characteristic mass shifts for phosphylation revealed tyrosine adducts at Y(411) (Y(401)KFQNALLVRY(411)TKKVPQVSTPTLVE(425)), Y(148) and Y(150) (I(142)ARRHPY(148)FY(150)APE(153), single and double labeled), and Y(161) (L(154)LFFAKRY(161)KAAFTE(167)) produced by original NA (tabun, sarin, soman, cyclosarin, VX, Chinese VX, and Russian VX) as well as by chlorpyrifos-oxon, diisopropyl fluorophosphate (DFP), paraoxon-ethyl (POE), and profenofos. MALDI-MS/MS of the single-labeled I(142)-E(153) peptide demonstrated that Y(150) was phosphylated with preference to Y(148). Aged albumin adducts were not detected. The procedure described was reproducible and feasible for detection of adducts at the most reactive Y(411)-residue (S/N ≥ 3) when at least 1% of total albumin was labeled. This was achieved by incubating plasma with molar HSA/OPC ratios ranging from approximately 1:0.03 (all G-type NA, DFP, and POE) to 1:3 (V-type NA, profenofos). Relative signal intensity of the Y(411) adduct correlated well with the spotted relative molar amount underlining the usefulness for quantitative adduct determination. In conclusion, the current analytical design exhibits potential as a verification tool for high-dose exposure.

Organophosphorus pesticides enhance the genotoxicity of benzo(a)pyrene by modulating its metabolism.

PubMed

Hreljac, Irena; Filipic, Metka

2009-12-01

Organophosphorus compounds (OPs) are widely used as pesticides. They act primarily as neurotoxins, but there is increasing evidence for secondary mechanisms of their toxicity. We have shown that the model OPs, methyl parathion (PT) and methyl paraoxon (PO), are genotoxic. Benzo(a)pyrene (BaP) is a widespread environmental genotoxin found in cigarette smoke, polluted air and grilled food. As people are constantly exposed to low concentrations of BaP and also to OPs, the aim of this study was to determine possible synergistic effects of PT and PO on BaP-induced genotoxicity. In the bacterial reverse mutation assay, PT and PO increased the number of BaP-induced mutations. The comet assay with human hepatoma HepG2 cells showed that BaP-induced DNA strand breaks were increased by PT but slightly decreased by PO. Using the acellular comet assay with UVC-induced DNA strand breaks, we observed a decrease in DNA migration, indicating that OPs cause cross-linking, thus interfering with comet assay results. In HepG2 cells the two OPs induced micronuclei formation at very low doses (0.01 microg/ml) and together with BaP, a more than additive increase of micronuclei was observed, confirming their co-genotoxic effect. We demonstrated for the first time that PT and PO modulate the metabolic activation of BaP. Addition of PT or PO increased aldo-keto reductase (AKR1C1/2) levels in the presence of BaP, while cytochrome 1A (CYP1A) mRNA expression and activity were decreased. Further, specific inhibition of CYP1A had no effect on BaP or OP+BaP-induced micronuclei, whereas inhibition of AKR1C dramatically decreased the number of micronuclei induced by BaP or OP+BaP. Based on these results we propose that co-genotoxicity results from OPs mediated modulation of BaP metabolism, favouring the induction of AKR1C enzymes known to catalyse the formation of DNA reactive BaP o-quinones and the production of reactive oxygen species.

Activity Based Protein Profiling Leads to Identification of Novel Protein Targets for Nerve Agent VX.

PubMed

Carmany, Dan; Walz, Andrew J; Hsu, Fu-Lian; Benton, Bernard; Burnett, David; Gibbons, Jennifer; Noort, Daan; Glaros, Trevor; Sekowski, Jennifer W

2017-04-17

Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways. While much is known about the primary toxicity mechanisms of nerve agents, there remains a paucity of information regarding impacts on other pathways and systemic effects. These are important for establishing a comprehensive understanding of the toxic mechanisms of OP nerve agents. To identify novel proteins that interact with VX, and that may give insight into these other mechanisms, we used activity-based protein profiling (ABPP) employing a novel VX-probe on lysates from rat heart, liver, kidney, diaphragm, and brain tissue. By making use of a biotin linked VX-probe, proteins covalently bound by the probe were isolated and enriched using streptavidin beads. The proteins were then digested, labeled with isobarically distinct tandem mass tag (TMT) labels, and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative analysis identified 132 bound proteins, with many proteins found in multiple tissues. As with previously published ABPP OP work, monoacylglycerol lipase associated proteins and fatty acid amide hydrolase (FAAH) were shown to be targets of VX. In addition to these two and other predicted neurotransmitter-related proteins, a number of proteins involved with energy metabolism were identified. Four of these enzymes, mitochondrial isocitrate dehydrogenase 2 (IDH2), isocitrate dehydrogenase 3 (IDH3), malate dehydrogenase (MDH), and succinyl CoA (SCS) ligase, were assayed for VX inhibition. Only IDH2 NADP+ activity was shown to be inhibited directly. This result is consistent with other work reporting animals exposed to OP compounds exhibit reduced IDH activity. Though clearly a secondary mechanism for toxicity, this is the first time VX has been shown to directly interfere with energy metabolism. Taken together, the ABPP work described here suggests the discovery of novel protein-agent interactions, which could be useful for the development of novel diagnostics or potential adjuvant therapeutics.

Bioscavengers for the protection of humans against organophosphate toxicity.

PubMed

Doctor, Bhupendra P; Saxena, Ashima

2005-12-15

Current antidotes for organophosphorus compounds (OP) poisoning consist of a combination of pretreatment with carbamates (pyridostigmine bromide), to protect acetylcholinesterase (AChE) from irreversible inhibition by OP compounds, and post-exposure therapy with anti-cholinergic drugs (atropine sulfate) to counteract the effects of excess acetylcholine and oximes (e.g., 2-PAM chloride) to reactivate OP-inhibited AChE. These antidotes are effective in preventing lethality from OP poisoning, but they do not prevent post-exposure incapacitation, convulsions, seizures, performance decrements, or in many cases permanent brain damage. These symptoms are commonly observed in experimental animals and are likely to occur in humans. The problems intrinsic to these antidotes stimulated attempts to develop a single protective drug, itself devoid of pharmacological effects, which would provide protection against the lethality of OP compounds and prevent post-exposure incapacitation. One approach is the use of enzymes such as cholinesterases (ChEs), beta-esterases in general, as single pretreatment drugs to sequester highly toxic OP anti-ChEs before they reach their physiological targets. This approach turns the irreversible nature of the OP: ChE interaction from disadvantage to an advantage; instead of focusing on OP as an anti-ChE, one can use ChE as an anti-OP. Using this approach, it was shown that administration of fetal bovine serum AChE (FBSAChE) or equine serum butyrylcholinesterase (EqBChE) or human serum BChE (HuBChE) protected the animals from multiple LD50s of a variety of highly toxic OPs without any toxic effects or performance decrements. The bioscavengers that have been explored to date for the detoxification of OPs fall into three categories: (A) those that can catalytically hydrolyze OPs and thus render them non-toxic, such as OP hydrolase and OP anhydrase; (B) those that stoichiometrically bind to OPs, that is, 1 mol of enzyme neutralizes one or 2 mol of OP inactivating both, such as ChEs and related enzymes; and (C) and those generally termed as "pseudo catalytic", e.g., a combination of ChE and an oxime pre-treatment such that the catalytic activity of OP-inhibited ChE can rapidly and continuously be restored in the presence of an oxime. Since the biochemical mechanism underlying prophylaxis by exogenous esterases such as ChEs is established and tested in several animal species, including non-human primates, this concept should allow a reliable extrapolation of results from animal experiments to human application. Having being extensively investigated by several groups, plasma derived HuBChE is judged to be the most suitable bioscavenger for its advancement for human use. The program is being developed at the present time for conducting a safety clinical trial in human volunteers. Several other candidate bioscavengers will follow; e.g., recombinant HuBChE expressed in the milk of transgenic goats, pseudo catalytic scavenger(s), e.g., a combination of ChE and oxime, and possibly PON 1 as a catalytic scavenger in the future.

PROTEIN ADDUCTS AS BIOMAKERS OF EXPOSURE TO ORGANOPHOSPHORUS COMPOUNDS

PubMed Central

Marsillach, Judit; Costa, Lucio G.; Furlong, Clement E.

2013-01-01

Exposure to organophosphorus (OP) compounds can lead to serious neurological damage or death. Following bioactivation by the liver cytochromes P450, the OP metabolites produced are potent inhibitors of serine active-site enzymes including esterases, proteases and lipases. OPs may form adducts on other cellular proteins. Blood cholinesterases (ChEs) have long served as biomarkers of OP exposure in humans. However, the enzymatic assays used for biomonitoring OP exposures have several drawbacks. A more useful approach will focus on multiple biomarkers and avoid problems with the enzymatic activity assays. OP inhibitory effects result from a covalent bond with the active-site serine of the target enzymes. The serine OP adducts become irreversible following a process referred to as aging where one alkyl group dissociates over variable lengths of time depending on the OP adduct. The OP-adducted enzyme then remains in circulation until it is degraded, allowing for a longer window of detection compared with direct analysis of OPs or their metabolites. Mass spectrometry (MS) provides a very sensitive method for identification of post-translational protein modifications. MS analyses of the percentage adduction of the active-site serine of biomarker proteins such as ChEs will eliminate the need for basal activity levels of the individual and will provide for a more accurate determination of OP exposure. MS analysis of biomarker proteins also provides information about the OP that has caused inhibition. Other useful biomarker proteins include other serine hydrolases, albumin, tubulin and transferrin. PMID:23261756

Occurrence and sources of brominated and organophosphorus flame retardants in dust from different indoor environments in Barcelona, Spain.

PubMed

Cristale, Joyce; Hurtado, Alba; Gómez-Canela, Cristian; Lacorte, Silvia

2016-08-01

In this study, the simultaneous presence of eight polybrominated diphenyl ethers (PBDEs), nine new brominated flame retardants (NBFRs) and ten organophosphorus flame retardants (OPFRs) was investigated in dust samples collected from different indoor environments (homes, schools, theatres, a university and a Research Institute) in Barcelona, Spain. OPFRs were detected at the highest concentrations followed by PBDEs. ∑OPFRs ranged from 2053 to 72,090ngg(-1) and tris(2-chloroisopropyl) phosphate (TCIPP) was the most abundant compound. BDE-209 was the main PBDE congener detected (up to 14,990ngg(-1)), while other PBDEs ranged from 2.6 to 118ngg(-1). Among the studied NBFRs, decabromodiphenyl ethane (DBDPE - up to 4432ngg(-1)) followed by bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP - up to 508ngg(-1)) were detected at the highest concentration, whereas a lower detection frequency was observed for 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), pentabromotoluene (PBT) and hexabromobenzene (HBB). The levels and profile of flame retardants (FRs) were characteristic of each environment, where theatres followed by homes presented the highest concentrations and schools had the lowest levels. Principal Component Analysis permitted to identify the main sources and distribution of all FRs, according to specific uses in each environment. The simultaneous presence of all FR families in indoor dust points to the need to monitor these compounds to minimize human exposure. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of moisture on the field dependence of mobility for gas-phase ions of organophosphorus compounds at atmospheric pressure with field asymmetric ion mobility spectrometry.

PubMed

Krylova, N; Krylov, E; Eiceman, G A; Stone, J A

2003-05-15

The electric field dependence of the mobilities of gas-phase protonated monomers [(MH+(H2O)n] and proton-bound dimers [M2H+(H2O)n] of organophosphorus compounds was determined at E/N values between 0 and 140 Td at ambient pressure in air with moisture between 0.1 and 15 000 ppm. Field dependence was described as alpha (E/N) and was obtained from the measurements of compensation voltage versus field amplitude in a planar high-field asymmetric waveform ion mobility spectrometer. The alpha function for protonated monomers to 140 Td was constant from 0.1 to 10 ppm moisture in air with onset of effect at approximately 50 ppm. The value of alpha increased 2-fold from 100 to 1000 ppm at all E/N values. At moisture values between 1000 and 10 000 ppm, a 2-fold or more increase in alpha (E/N) was observed. In a model proposed here, field dependence for mobility through changes in collision cross sections is governed by the degree of solvation of the protonated molecule by neutral molecules. The process of ion declustering at high E/N values was consistent with the kinetics of ion-neutral collisional periods, and the duty cycle of the waveform applied to the drift tube. Water was the principal neutral above 50 ppm moisture in air, and nitrogen was proposed as the principal neutral below 50 ppm.

Levels of organophosphorus pesticides in medicinal plants commonly consumed in Iran

PubMed Central

2012-01-01

The frequent occurrence of pesticide residues in herbal materials was indicated by previous studies. In this study, the concentration of some of the organophosphorus pesticides including parathion, malathion, diazinon and pirimiphos methyl in different kinds of medicinal plants were determined. The samples were collected randomly from ten local markets of different areas of Iran. At the detection limit of 0.5 ng g-1, parathion and pirimiphos methyl were not detected in any of the samples. Some amounts of malathion and diazinon were found in Zataria, Matricaria chamomile, Spearmint and Cumin Seed samples while, the concentrations of target organophosphorus pesticides in Borage samples were below the detection limits of the methods which could be a result of intensive transformation of organophosphorus pesticides by Borage. In addition the organophosphorus pesticides were detected in all of the samples below the maximum residue levels (MRLs) proposed by the international organizations. PMID:23351610

Ground-water, surface-water, and bottom-sediment contamination in the O-field area, Aberdeen Proving Ground, Maryland, and the possible effects of selected remedial actions on ground water

USGS Publications Warehouse

Vroblesky, Don A.; Lorah, Michelle M.; Oliveros, James P.

1995-01-01

Disposal of munitions and chemical-warfare substances has introduced inorganic and organic contaminants to the ground water, surface water, and bottom sediment at O-Field, in the Edgewood area of Aberdeen Proving Ground, Maryland. Contaminants include chloride, arsenic, transition metals, chlorinated aliphatic hydrocarbons, aromatic compounds, and organosulfur and organophosphorus compounds. The hydrologic effects of several remedial actions were estimated by use of a ground-water-flow model. The remedial actions examined were an impermeable covering, encapsulation, subsurface barriers, a ground-water drain, pumping of wells to manage water levels or to remove contaminated ground water for treatment, and no action.

Synthetic routes to 3(5)-phosphonylated pyrazoles

NASA Astrophysics Data System (ADS)

Goulioukina, N. S.; Makukhin, N. N.; Beletskaya, I. P.

2016-07-01

This review comprehensively covers the currently available synthetic routes to 3(5)-phosphonylated pyrazoles. There are demonstrated significant advances in this field over the last 10-15 years caused by the use of the Bestmann-Ohira reagent [as well as (diazomethyl)phosphonates and phosphonylated hydrazonoyl halides] in reactions with diverse dipolarophiles. 1,3-Dipolar cycloaddition of diazo compounds to α,β-unsaturated phosphonates as well as intramolecular heterocyclization of (1-diazoallyl)phosphonates and (3--diazo-1-propenyl)phosphonates are discussed. Synthetic potential of cyclocondensation of organophosphorus 1,3-dielectrophilic compounds with hydrazines is shown. Ways to introduce a phosphonate group into the pyrazole ring are considered. Examples of chemical transformations of 3(5)-phosphonylated pyrazoles are reported. The bibliography includes 88 references.

Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi

The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P{submore » R} and P{sub S} stereoisomers at the P-chiral center. The tabun complex displayed only the P{sub R} stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.« less

Ecological risk estimation of organophosphorus pesticides in riverine ecosystems.

PubMed

Wee, Sze Yee; Aris, Ahmad Zaharin

2017-12-01

Pesticides are of great concern because of their existence in ecosystems at trace concentrations. Worldwide pesticide use and its ecological impacts (i.e., altered environmental distribution and toxicity of pesticides) have increased over time. Exposure and toxicity studies are vital for reducing the extent of pesticide exposure and risk to the environment and humans. Regional regulatory actions may be less relevant in some regions because the contamination and distribution of pesticides vary across regions and countries. The risk quotient (RQ) method was applied to assess the potential risk of organophosphorus pesticides (OPPs), primarily focusing on riverine ecosystems. Using the available ecotoxicity data, aquatic risks from OPPs (diazinon and chlorpyrifos) in the surface water of the Langat River, Selangor, Malaysia were evaluated based on general (RQ m ) and worst-case (RQ ex ) scenarios. Since the ecotoxicity of quinalphos has not been well established, quinalphos was excluded from the risk assessment. The calculated RQs indicate medium risk (RQ m  = 0.17 and RQ ex  = 0.66; 0.1 ≤ RQ < 1) of overall diazinon. The overall chlorpyrifos exposure was observed at high risk (RQ ≥ 1) based on RQ m and RQ ex at 1.44 and 4.83, respectively. A contradictory trend of RQs > 1 (high risk) was observed for both the general and worst cases of chlorpyrifos, but only for the worst cases of diazinon at all sites from downstream to upstream regions. Thus, chlorpyrifos posed a higher risk than diazinon along the Langat River, suggesting that organisms and humans could be exposed to potentially high levels of OPPs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes.

PubMed

Samanta, Uttamkumar; Kirby, Stephen D; Srinivasan, Prabhavathi; Cerasoli, Douglas M; Bahnson, Brian J

2009-08-15

The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(R) stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

Review of the Toxicity of the Metallic Compounds Proposed for Use in the New Green Missile Formulation

NASA Technical Reports Server (NTRS)

Major, Michael A.

2000-01-01

In an effort to modernize and minimize hazards posed by the toxic components of missile propellant, the USACHPPM has been tasked to provide a comparison of the toxicity of compounds currently in use as missile propellants and the suite of compounds proposed to replace them. This report deals with the portion of this work concerning the toxicity of the organometallic compounds used in these formulations. Toxicity assessments of the organic compounds used in these formulations are published elsewhere. In general, toxicity data were available for all the metal compounds of concern or for closely related compounds that can serve as surrogates for the assessment of toxicity. We have high confidence in the reliability of these comparisons. This report is organized by element to provide the reader with an in-depth assessment with a minimum of redundancy. The narrative will first describe general concepts about the toxicity of each metal and then provide a summary of the toxicological information available for the specific compound.

Reactive skin decontamination lotion (RSDL) for the decontamination of chemical warfare agent (CWA) dermal exposure.

PubMed

Schwartz, M D; Hurst, C G; Kirk, M A; Reedy, S J D; Braue, E H

2012-08-01

Rapid decontamination of the skin is the single most important action to prevent dermal absorption of chemical contaminants in persons exposed to chemical warfare agents (CWA) and toxic industrial chemicals (TICs) as a result of accidental or intentional release. Chemicals on the skin may be removed by mechanical means through the use of dry sorbents or water. Recent interest in decontamination systems which both partition contaminants away from the skin and actively neutralize the chemical has led to the development of several reactive decontamination solutions. This article will review the recently FDA-approved Reactive Skin Decontamination Lotion (RSDL) and will summarize the toxicity and efficacy studies conducted to date. Evidence of RSDL's superior performance against vesicant and organophosphorus chemical warfare agents compared to water, bleach, and dry sorbents, suggests that RSDL may have a role in mass human exposure chemical decontamination in both the military and civilian arenas.

Toxic effects of triazophos on rare minnow (Gobiocypris rarus) embryos and larvae.

PubMed

Zhu, Bin; Gong, Yu-Xin; Liu, Lei; Li, Dong-Liang; Wang, Yuan; Ling, Fei; Wang, Gao-Xue

2014-08-01

Triazophos (TAP) has been widely used in agriculture for controlling insect pests and is a known organophosphorus pesticide. Due to TAP characteristics, such as high chemical and photochemical stability, its potential toxicity to aquatic organisms has gained great interest. To explore the potential developmental toxicity of TAP, Gobiocypris rarus embryos and larvae were exposed to various concentrations of TAP (0.1-15 mg L(-1)) until 72 h. Results showed that values of 72 h LC50 and EC50 were 7.44 and 5.60 mg L(-1) for embryos, 2.52 and 1.37 mg L(-1) for larvae. Increased malformation, decreased heart rate and body length provide a gradual concentration-dependent pattern. Enzyme activities and mRNA levels were significantly changed even at low concentration (0.05 mg L(-1) for embryos and 0.01 mg L(-(1) for larvae). Overall, the present study points out that TAP is likely a risk to the early development of G. rarus. The information presented in this study will be helpful in better understanding the toxicity induced by TAP in fish embryos and larvae. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fish embryo toxicity test: identification of compounds with weak toxicity and analysis of behavioral effects to improve prediction of acute toxicity for neurotoxic compounds.

PubMed

Klüver, Nils; König, Maria; Ortmann, Julia; Massei, Riccardo; Paschke, Albrecht; Kühne, Ralph; Scholz, Stefan

2015-06-02

The fish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute toxicity in the fish embryo. In order to better define the applicability domain and improve the predictive capacity of the fish embryo test, we performed a systematic analysis of existing fish embryo and acute fish toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no toxicity in the fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating fish embryo toxicity. Published fish embryo LC50 values were confirmed by experimental analysis of zebrafish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute fish toxicity LC50. Our data provided the first evidence that the applicability domain of the fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute fish toxicity LC50 using behavioral assays in fish embryos may not yet be possible, the identification of neurotoxicity could trigger the conduction of a conventional fish acute toxicity test or application of assessment factors while considering the very good fish embryo-acute fish toxicity correlation for other compounds.

Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shih, T.M.

1993-12-31

The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 ttg/kg. SC; equivalent to 0.9 x LDs0 dose) and treated 1 min later with one of these oximes (100 or 200 ttmo1/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93 - 96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (rangingmore » from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. in contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than Hl-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximesreactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. 111-6 reactivated soman-inhibited ChE in all tis- sues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in Intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman.« less

Oximes in organophosphate poisoning: 60 years of hope and despair.

PubMed

Worek, Franz; Thiermann, Horst; Wille, Timo

2016-11-25

The high number of annual fatalities following suicidal poisoning by organophosphorus (OP) pesticides and the recent homicidal use of the chemical warfare nerve agent sarin against civilian population in Syria underlines the continuous threat by these highly toxic agents. The need for an effective treatment of OP poisoning resulted in the implementation of a combination therapy with the muscarinic receptor antagonist atropine and an oxime for the reactivation of OP-inhibited acetylcholinesterase (AChE). Since the invention of the first clinically used oxime pralidoxime (2-PAM) in the 1950s ongoing research attempted to identify more effective oximes. In fact, several thousand oximes were synthesized in the past six decades. These include charged and non-charged compounds, mono- and bispyridinium oximes, asymmetric oximes, oximes with different substitutes and more recently non-oxime reactivators. Multiple in vitro and in vivo studies investigated the potential of oximes to reactivate OP-inhibited AChE and to reverse OP-induced cholinergic signs. Depending on the experimental model, the investigated species and the tested OP largely variable results were obtained by different laboratories. These findings and the inconsistent effectiveness of oximes in the treatment of OP-pesticide poisoned patients led to a continuous discussion on the value of oximes. In order to provide a forward-looking evaluation of the significance of oximes in OP poisoning multiple aspects, including intrinsic toxicity, in vitro reactivation potency, efficacy and pharmacokinetics, as well as the impact of the causative OP have to be considered. The different influencing factors in order to define the benefit and limitations of oximes in OP poisoning will be discussed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Response of Bioluminescent Bacteria to Alkyltin Compounds.

DTIC Science & Technology

1987-12-01

found in the butyltiri series of compounds; tributyltin was (’Stimes more toxic than dibutyltin and (- 50 times more toxic than (mono)butyltin. When...correlations between compounds, tributyltin was -35 tine more Kicrotxit and fish bLoessays for pure toxic than dibutyltin end -750 times More compounds and...the compounds as a decrease in toxicity (5) tributyltin compounds ea -150 tines more and a method to study synergistic andtoxic than trinethyltia

Neonicotinoid insecticides: highlights of a symposium on strategic molecular designs.

PubMed

Tomizawa, Motohiro; Casida, John E

2011-04-13

Neonicotinoids are the newest of the five major classes of insecticides (the others are chlorinated hydrocarbons, organophosphorus compounds, methylcarbamates, and pyrethroids), and they make up approximately one-fourth of the world insecticide market. Nithiazine was the lead compound from Shell Development Co. in California later optimized by Shinzo Kagabu of Nihon Tokushu Noyaku Seizo to increase the potency and photostability, resulting in imidacloprid and thiacloprid. These discoveries are the basis for the International Award for Research in Agrochemicals of the American Chemical Society presented in 2010 to Professor Shinzo Kagabu. Five other neonicotinoids were added by others for the current set of seven commercial compounds. This symposium considers the progress in discovery and development of novel chemotype nicotinic insecticides with enhanced effectiveness, unique biological properties, and maximal safety. Chemorational approaches considered include physicochemical properties, metabolic activation and detoxification, and chemical and structural biology aspects potentially facilitating receptor structure-guided insecticide design.

The taste of toxicity: A quantitative analysis of bitter and toxic molecules.

PubMed

Nissim, Ido; Dagan-Wiener, Ayana; Niv, Masha Y

2017-12-01

The role of bitter taste-one of the few basic taste modalities-is commonly assumed to signal toxicity and alert animals against consuming harmful compounds. However, it is known that some toxic compounds are not bitter and that many bitter compounds have negligible toxicity while having important health benefits. Here we apply a quantitative analysis of the chemical space to shed light on the bitterness-toxicity relationship. Using the BitterDB dataset of bitter molecules, The BitterPredict prediction tool, and datasets of toxic compounds, we quantify the identity and similarity between bitter and toxic compounds. About 60% of the bitter compounds have documented toxicity and only 56% of the toxic compounds are known or predicted to be bitter. The LD 50 value distributions suggest that most of the bitter compounds are not very toxic, but there is a somewhat higher chance of toxicity for known bitter compounds compared to known nonbitter ones. Flavonoids and alpha acids are more common in the bitter dataset compared with the toxic dataset. In contrast, alkaloids are more common in the toxic datasets compared to the bitter dataset. Interestingly, no trend linking LD 50 values with the number of activated bitter taste receptors (TAS2Rs) subtypes is apparent in the currently available data. This is in accord with the newly discovered expression of TAS2Rs in several extra-oral tissues, in which they might be activated by yet unknown endogenous ligands and play non-gustatory physiological roles. These results suggest that bitter taste is not a very reliable marker for toxicity, and is likely to have other physiological roles. © 2017 IUBMB Life, 69(12):938-946, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Discrimination of excess toxicity from baseline level for ionizable compounds: Effect of pH.

PubMed

Li, Jin J; Zhang, Xu J; Wang, Xiao H; Wang, Shuo; Yu, Yang; Qin, Wei C; Su, Li M; Zhao, Yuan H

2016-03-01

The toxic effect can be affected by pH in water through affecting the degree of ionization of ionizable compounds. Wrong classification of mode of action can be made from the apparent toxicities. In this paper, the toxicity data of 61 compounds to Daphnia magna determined at three pH values were used to investigate the effect of pH on the discrimination of excess toxicity. The results show that the apparent toxicities are significantly less than the baseline level. Analysis on the effect of pH on bioconcentration factor (BCF) shows that the log BCF values are significantly over-estimated for the strongly ionizable compounds, leading to the apparent toxicities greatly less than the baseline toxicities and the toxic ratios greatly less than zero. A theoretical equation between the apparent toxicities and pH has been developed basing on the critical body residue (CBR). The apparent toxicities are non-linearly related to pH, but linearly to fraction of unionized form. The determined apparent toxicities are well fitted with the toxicities predicted by the equation. The toxicities in the unionized form calculated from the equation are close to, or greater than the baseline level for almost all the strongly ionizable compounds, which are very different from the apparent toxicities. The studied ionizable compounds can be either classified as baseline, less inert or reactive compounds in D. magna toxicity. Some ionizable compounds do not exhibit excess toxicity at a certain pH, due not to their poor reactivity with target molecules, but because of the ionization in water. Copyright © 2015 Elsevier Ltd. All rights reserved.

Enzyme system comprising an enzyme bonded in a porous matrix

DOEpatents

Ackerman, Eric [Richland, WA; Liu, Jun [West Richland, WA

2010-12-07

A protein system is described in which a protein is bound within a matrix material that has pores that are sized to achieve excellent properties such as: activity, protein density, and stability. In a preferred embodiment, the pore sizes range from 50 to 400 .ANG.. One protein that has demonstrated surprisingly good results in this system is OPH. This protein is known to degrade organophosphorus compounds such as are found in chemical weapons and pesticides. Novel methods of forming the protein system and methods of making OPH are also described.

Dramatic Differences in Organophosphorus Hydrolase Activity between Human and Chimeric Recombinant Mammalian Paraoxonase-1 Enzymes

DTIC Science & Technology

2009-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Dramatic Differences in Organophosphorus Hydrolase Activity between Human and 5a... activity , V-agents, VX, bioscavenger, medical countermeasures 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES...Organophosphorus Hydrolase Activity between Human and Chimeric Recombinant Mammalian Paraoxonase-1 Enzymes† Tamara C. Otto,‡ Christina K. Harsch,§ David T

PHOS-Select Iron Affinity beads enrich peptides for detection of organophosphorus adducts on albumin

PubMed Central

Jiang, Wei; Dubrovskii, Yaroslav A; Podolskaya, Ekaterina P; Murashko, Ekaterina A; Babakov, Vladimir; Nachon, Florian; Masson, Patrick; Schopfer, Lawrence M; Lockridge, Oksana

2013-01-01

Albumin is covalently modified by organophosphorus toxicants (OP) on tyrosine 411, but less than 1% of albumin is modified in humans by lethal OP doses that inhibit 95% of plasma butyrylcholinesterase. A method that enriches OP-modified albumin peptides could aid analysis of low dose exposures. Soman or chlorpyrifos oxon treated human plasma was digested with pepsin. Albumin peptides were enriched by binding to Fe3+ beads at pH 11 and eluted with pH 2.6 buffer. Similarly, mouse and guinea pig albumin modified by chlorpyrifos oxon were digested with pepsin and enriched by binding to Fe3+ beads. Peptides were identified by MALDI-TOF/TOF mass spectrometry. PHOS-select Iron Affinity beads specifically enriched albumin peptides VRY411TKKVPQVST and LVRY411TKKVPQVST in a pepsin digest of human plasma. The unmodified as well as OP-modified peptides bound to the beads. The binding capacity of 500 μl beads was the pepsin digest of 2.1 μL human plasma. The limit of detection was 0.2% of OP-modified albumin peptide in 0.43 μL plasma. Enrichment of OP-modified albumin peptides by binding to Fe3+ beads is a method with potential application to diagnosis of OP pesticide and nerve agent exposure in humans, mice, and guinea pigs. PMID:24187955

Butyrylcholinesterase for protection from organophosphorus poisons; catalytic complexities and hysteretic behavior

PubMed Central

Masson, Patrick; Lockridge, Oksana

2009-01-01

Butyrylcholinesterase is a promiscuous enzyme that displays complex kinetic behavior. It is toxicologically important because it detoxifies organophosphorus poisons (OP) by making a covalent bond with the OP. The OP and the butyrylcholinesterase are both inactivated in the process. Inactivation of butyrylcholinesterase has no adverse effects. However inactivation of acetylcholinesterase in nerve synapses can be lethal. OP-inhibited butyrylcholinesterase and acetylcholinesterase can be reactivated with oximes provided the OP has not aged. Strategies for preventing the toxicity of OP include a) treatment with an OP scavenger, b) reaction of nonaged enzyme with oximes, c) reactivation of aged enzyme, d) slowing down aging with peripheral site ligands, and e) design of mutants that rapidly hydrolyze OP. Option (a) has progressed through phase I clinical trials with human butyrylcholinesterase. Option (b) is in routine clinical use. The others are at the basic research level. Butyrylcholinesterase displays complex kinetic behavior including activation by positively charged esters, ability to hydrolyze amides, and a lag time (hysteresis) preceding hydrolysis of benzoylcholine and N-methyl indoxyl acetate. Mass spectrometry has identified new OP binding motifs on tyrosine and lysine in proteins that have no active site serine. It is proposed, but not yet proven, that low dose exposure involves OP modification of proteins that have no active site serine. PMID:20004171

Acute effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate, on cardiovascular parameters in anaesthetized, artificially ventilated rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watanabe, Yoshimasa; Itoh, Takeo, E-mail: titoh@med.nagoya-cu.ac.jp; Shiraishi, Hiroaki

The organophosphorus compound sarin irreversibly inhibits acetylcholinesterase. We examined the acute cardiovascular effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate (BIMP), in anaesthetized, artificially ventilated rats. Intravenous administration of BIMP (0.8 mg/kg; the LD50 value) induced a long-lasting increase in blood pressure and tended to increase heart rate. In rats pretreated with the non-selective muscarinic-receptor antagonist atropine, BIMP significantly increased both heart rate and blood pressure. In atropine-treated rats, hexamethonium (antagonist of ganglionic nicotinic receptors) greatly attenuated the BIMP-induced increase in blood pressure without changing the BIMP-induced increase in heart rate. In rats treated with atropine plus hexamethonium, intravenous phentolaminemore » (non-selective α-adrenergic receptor antagonist) plus propranolol (non-selective β-adrenergic receptor antagonist) completely blocked the BIMP-induced increases in blood pressure and heart rate. In atropine-treated rats, the reversible acetylcholinesterase inhibitor neostigmine (1 mg/kg) induced a transient increase in blood pressure, but had no effect on heart rate. These results suggest that in anaesthetized rats, BIMP induces powerful stimulation of sympathetic as well as parasympathetic nerves and thereby modulates heart rate and blood pressure. They may also indicate that an action independent of acetylcholinesterase inhibition contributes to the acute cardiovascular responses induced by BIMP. - Highlights: • A sarin-like agent BIMP markedly increased blood pressure in anaesthetized rats. • Muscarinic receptor blockade enhanced the BIMP-induced increase in blood pressure. • Ganglionic nicotinic receptor blockade attenuated the BIMP-induced response. • Blockade of α- as well as β-receptors attenuated the BIMP-induced response.« less

Electrophysiologic changes following treatment with organophosphorus-induced delayed neuropathy-producing agents in the adult hen.

PubMed

Robertson, D G; Schwab, B W; Sills, R D; Richardson, R J; Anderson, R J

1987-03-15

Although clinical, pathological, and biochemical effects of organophosphorus-induced delayed neuropathy (OPIDN) have been intensively investigated in the adult hen, detailed electrophysiological studies are lacking. Adult white leghorn hens were treated with a single oral dose of either 30 mg/kg tri-2-cresyl phosphate (TOCP), 750 mg/kg TOCP, 4 mg/kg di-n-butyl-2,2-dichlorovinyl phosphate (DBCV), or 30 mg/kg di-n-butyl-2,2-dichlorovinyl phosphinate (DBCV-P). The 750 mg/kg TOCP and DBCV, but not the 30 mg/kg TOCP and DBCV-P, treatments resulted in clinical signs of OPIDN and mild to marked damage of the tibial nerve 21 days after dose. Twenty-four hr lymphocyte neurotoxic esterase (NTE) inhibition was used as an index of brain NTE inhibition for the various organophosphorus compound (OP) treatment. Twenty-four hr lymphocyte NTE inhibition for 30 mg/kg TOCP, 750 mg/kg TOCP, DBCV, and DBCV-P was 54.1, 87.1, 84.8, and 68.3%, respectively. Twenty-one days after dose, the TOCP-treated hens exhibited some abnormalities in conduction velocity and action potential duration in the tibial or sciatic nerves. No abnormalities were observed in action potential parameters of either the DBCV or DBCV-P treatments. Neurotoxic OP (TOCP and DBCV) treatment resulted in decreased refractoriness in the tibial nerve, increased refractoriness in the sciatic nerve, and elevated strength duration threshold for both nerves. These changes were not present in nerves from DBCV-P (a non-neurotoxic NTE inhibitor)-treated hens. These results suggest that refractory period and strength duration abnormalities in peripheral nerve correlate well with the production of OPIDN and are evident without coincident clinical signs or histopathology.

Suppressive effects of long-term exposure to P-nitrophenol on gonadal development, hormonal profile with disruption of tissue integrity, and activation of caspase-3 in male Japanese quail (Coturnix japonica).

PubMed

Ahmed, Eman; Nagaoka, Kentaro; Fayez, Mostafa; Abdel-Daim, Mohamed M; Samir, Haney; Watanabe, Gen

2015-07-01

P-Nitrophenol (PNP) is considered to be one of nitrophenol derivatives of diesel exhaust particles. PNP is a major metabolite of some organophosphorus compounds. PNP is a persistent organic pollutant as well as one of endocrine-disrupting compounds. Consequently, bioaccumulation of PNP potentiates toxicity. The objectives of the current study were to assess in vivo adverse effects of long-term low doses of PNP exposure on reproductive system during development stage. Twenty-eight-day-old male Japanese quails were orally administered different doses of PNP (0, 0.01, 0.1, 1 mg/kg body weight) daily for 2.5 months. Testicular histopathology, hormones, caspase-3 (CASP3), and claudin-1 (CLDN1) tight junction protein, as well as plasma hormones were analyzed. The results revealed that long-term PNP exposure caused testicular histopathological changes such as vacuolation of spermatogenic cell and spermatocyte with significant testicular and cloacal gland atrophy. PNP activated CASP3 enzyme that is an apoptosis-related cysteine peptidase. Besides, it disrupted the expression of CLDN1. Furthermore, a substantial decrease in plasma concentrations of luteinizing hormone (LH) and testosterone was observed after 2 and 2.5 months in the PNP-treated groups. Meanwhile, the pituitary LH did not significantly change. Site of action of PNP may be peripheral on testicular development and/or centrally on the hypothalamic-pituitary-gonadal axis through reduction of pulsatile secretion of gonadotrophin-releasing hormone. Consequently, it may reduce the sensitivity of the anterior pituitary gland to secrete LH. In conclusion, PNP induced profound endocrine disruption in the form of hormonal imbalance, induction of CASP3, and disruption of CLDN1 expression in the testis. Hence, it may hinder the reproductive processes.

Aging pathways for organophosphate-inhibited human butyrylcholinesterase, including novel pathways for isomalathion, resolved by mass spectrometry.

PubMed

Li, He; Schopfer, Lawrence M; Nachon, Florian; Froment, Marie-Thérèse; Masson, Patrick; Lockridge, Oksana

2007-11-01

Some organophosphorus compounds are toxic because they inhibit acetylcholinesterase (AChE) by phosphylation of the active site serine, forming a stable conjugate: Ser-O-P(O)-(Y)-(XR) (where X can be O, N, or S and Y can be methyl, OR, or SR). The inhibited enzyme can undergo an aging process, during which the X-R moiety is dealkylated by breaking either the P-X or the X-R bond depending on the specific compound, leading to a nonreactivatable enzyme. Aging mechanisms have been studied primarily using AChE. However, some recent studies have indicated that organophosphate-inhibited butyrylcholinesterase (BChE) may age through an alternative pathway. Our work utilized matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to study the aging mechanism of human BChE inhibited by dichlorvos, echothiophate, diisopropylfluorophosphate (DFP), isomalathion, soman, sarin, cyclohexyl sarin, VX, and VR. Inhibited BChE was aged in the presence of H2O18 to allow incorporation of (18)O, if cleavage was at the P-X bond. Tryptic-peptide organophosphate conjugates were identified through peptide mass mapping. Our results showed no aging of VX- and VR-treated BChE at 25 degrees C, pH 7.0. However, BChE inhibited by dichlorvos, echothiophate, DFP, soman, sarin, and cyclohexyl sarin aged exclusively through O-C bond cleavage, i.e., the classical X-R scission pathway. In contrast, isomalathion aged through both X-R and P-X pathways; the main aged product resulted from P-S bond cleavage and a minor product resulted from O-C and/or S-C bond cleavage.

Comparison of toxicity of class-based organic chemicals to algae and fish based on discrimination of excess toxicity from baseline level.

PubMed

Li, Jin J; Tai, Hong W; Yu, Yang; Wen, Yang; Wang, Xiao H; Zhao, Yuan H

2015-07-01

Toxicity data to fish and algae were used to investigate excess toxicity between species. Results show that chemicals exhibiting excess toxicity to fish also show excess toxicity to algae for most of the compounds. This indicates that they share the same mode of action between species. Similar relationships between logKOW and toxicities to fish and algae for baseline and less inert compounds suggest that they have similar critical body residues in the two species. Differences in excess toxicity for some compounds suggest that there is a difference of physiological structure and metabolism between fish and algae. Some reactive compounds (e.g. polyamines) exhibit greater toxic effects for algae than those for fish because of relatively low bio-uptake potential of these hydrophilic compounds in fish as compared with that in algae. Esters exhibiting greater toxicity in fish than that in algae indicate that metabolism can affect the discrimination of excess toxicity from baseline level. Algae growth inhibition is a very good surrogate for fish lethality. This is not only because overall toxicity sensitivity to algae is greater than that to fish, but also the excess toxicity calculated from algal toxicity can better reflect reactivity of compounds with target molecules than fish toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Biological monitoring of chlorinated pesticides among exposed workers of mango orchards: A case study in tropical climate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chandra, H.; Pangtey, B.S.; Modak, D.P.

1992-02-01

Organochlorine, organophosphorus and carbamate compounds are widely used pesticides in India for controlling disease carrying vectors and agricultural pests. Organochlorine compounds being persistent and lipophilic in nature, accumulate in the human body through food chain and environmental exposure. Accumulation of DDT, BHC and endosulfan has been implicated in the pathogenesis of cardiovascular disorders, hypertension and other health related problems. Earlier, the authors have observed respiratory impairment (36.5%) among workers engaged in spraying of organochlorine pesticides on mango trees at Malihabad. In the present investigation, the levels of chlorinated present investigation, the levels of chlorinated pesticides among exposed workers have beenmore » monitored to study the distribution pattern in blood and their excretion in urine of human subjects.« less

Modulation of Immune Response by Organophosphorus Pesticides: Fishes as a Potential Model in Immunotoxicology

PubMed Central

Díaz-Resendiz, K. J. G.; Toledo-Ibarra, G. A.; Girón-Pérez, M. I.

2015-01-01

Immune response is modulated by different substances that are present in the environment. Nevertheless, some of these may cause an immunotoxic effect. In this paper, the effect of organophosphorus pesticides (frequent substances spilled in aquatic ecosystems) on the immune system of fishes and in immunotoxicology is reviewed. Furthermore, some cellular and molecular mechanisms that might be involved in immunoregulation mechanisms of organophosphorus pesticides are discussed. PMID:25973431

Detection and determination of organophosphorus insecticides in tissues by thin-layer chromatography.

PubMed

Tewari, S N; Harpalani, S P

1977-01-11

The toxicological analysis of 12 common organophosphorus insecticides is described. Suitable methods for the extraction of organophosphorus insecticides from tissues are proposed. The detection, identification and estimation of these insecticides by thin-layer chromatography is described for 25 solvent systems and a series of chromogenic reagents. The distribution of insecticides in human body tissues in five cases of poisoning by ethyl parathion, malathion, dimethoate, sumithion and phosphamidon has also been studied.

Identification and characterization of chlorpyrifos-methyl and 3,5,6-trichloro-2-pyridinol degrading Burkholderia sp. strain KR100.

PubMed

Kim, Jun-Ran; Ahn, Young-Joon

2009-07-01

A chlorpyrifos-methyl (CM) degrading bacterium (designated strain KR100) was isolated from a Korean rice paddy soil and was further tested for its sensitivity against eight commercial antibiotics. Based on morphological, biochemical, and molecular characteristics, this bacterium showed greatest similarity to members of the order Burkholderiales and was shown to be most closely related to members of the Burkholderia cepacia group. Strain KR100 hydrolyzed CM to 3,5,6-trichloro-2-pyridinol (TCP) and utilized TCP as the sole source of carbon for its growth. The isolate was also able to degrade chlorpyrifos, dimethoate, fenitrothion, malathion, and monocrotophos at 300 microg/ml but diazinon, dicrotophos, parathion, and parathion-methyl at 100 microg/ml. The ability to degrade CM was found to be encoded on a single plasmid of approximately 50 kb, pKR1. Genes encoding resistance to amphotericin B, polymixin B sulfate, and tetracycline were also located on the plasmid. This bacterium merits further study as a potential biological agent for the remediation of soil, water, or crop contaminated with organophosphorus compounds because of its greater biodegradation activity and its broad specificity against a range of organophosphorus insecticides.

In vitro kinetic interactions of DEET, pyridostigmine and organophosphorus pesticides with human cholinesterases.

PubMed

Wille, Timo; Thiermann, Horst; Worek, Franz

2011-04-25

The simultaneous use of the repellent DEET, pyridostigmine, and organophosphorus pesticides has been assumed as a potential cause for the Gulf War Illness and combinations have been tested in different animal models. However, human in vitro data on interactions of DEET with other compounds are scarce and provoked the present in vitro study scrutinizing the interactions of DEET, pyridostigmine and pesticides with human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE). DEET showed to be a weak and reversible inhibitor of hAChE and hBChE. The IC(50) of DEET was calculated to be 21.7mM DEET for hAChE and 3.2mM DEET for hBChE. The determination of the inhibition kinetics of pyridostigmine, malaoxon and chlorpyrifos oxon with hAChE in the presence of 5mM DEET resulted in a moderate reduction of the inhibition rate constant k(i). The decarbamoylation velocity of pyridostigmine-inhibited hAChE was not affected by DEET. In conclusion, the in vitro investigation of interactions between human cholinesterases, DEET, pyridostigmine, malaoxon and chlorpyrifos oxon showed a weak inhibition of hAChE and hBChE by DEET. The inhibitory potency of the tested cholinesterase inhibitors was not enhanced by DEET and it did not affect the regeneration velocity of pyridostigmine-inhibited AChE. Hence, this in vitro study does not give any evidence of a synergistic effect of the tested compounds on human cholinesterases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A sensitive LC-MS/MS method for measurement of organophosphorus pesticides and their oxygen analogs in air sampling matrices

PubMed Central

ARMSTRONG, JENNA L.; DILLS, RUSSELL L.; YU, JIANBO; YOST, MICHAEL G.; FENSKE, RICHARD A.

2018-01-01

A rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed for determination of levels of the organophosphorus (OP) pesticides chlorpyrifos (CPF), azinphos methyl (AZM), and their oxygen analogs chlorpyrifos-oxon (CPF-O) and azinphos methyl-oxon (AZM-O) on common active air sampling matrices. XAD-2 resin and polyurethane foam (PUF) matrices were extracted with acetonitrile containing stable-isotope labeled internal standards (ISTD). Analysis was accomplished in Multiple Reaction Monitoring (MRM) mode, and analytes in unknown samples were identified by retention time (±0.1 min) and qualifier ratio (±30% absolute) as compared to the mean of calibrants. For all compounds, calibration linearity correlation coefficients were ≥0.996. Limits of detection (LOD) ranged from 0.15–1.1 ng/sample for CPF, CPF-O, AZM, and AZM-O on active sampling matrices. Spiked fortification recoveries were 78–113% from XAD-2 active air sampling tubes and 71–108% from PUF active air sampling tubes. Storage stability tests also yielded recoveries ranging from 74–94% after time periods ranging from 2–10 months. The results demonstrate that LC-MS/MS is a sensitive method for determining these compounds from two different matrices at the low concentrations that can result from spray drift and long range transport in non-target areas following agricultural applications. In an inter-laboratory comparison, the limit of quantification (LOQ) for LC-MS/MS was 100 times lower than a typical gas chromatography-mass spectrometry (GC-MS) method. PMID:24328542

A sensitive LC-MS/MS method for measurement of organophosphorus pesticides and their oxygen analogs in air sampling matrices.

PubMed

Armstrong, Jenna L; Dills, Russell L; Yu, Jianbo; Yost, Michael G; Fenske, Richard A

2014-01-01

A rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed for determination of levels of the organophosphorus (OP) pesticides chlorpyrifos (CPF), azinphos methyl (AZM), and their oxygen analogs chlorpyrifos-oxon (CPF-O) and azinphos methyl-oxon (AZM-O) on common active air sampling matrices. XAD-2 resin and polyurethane foam (PUF) matrices were extracted with acetonitrile containing stable-isotope labeled internal standards (ISTD). Analysis was accomplished in Multiple Reaction Monitoring (MRM) mode, and analytes in unknown samples were identified by retention time (±0.1 min) and qualifier ratio (±30% absolute) as compared to the mean of calibrants. For all compounds, calibration linearity correlation coefficients were ≥0.996. Limits of detection (LOD) ranged from 0.15-1.1 ng/sample for CPF, CPF-O, AZM, and AZM-O on active sampling matrices. Spiked fortification recoveries were 78-113% from XAD-2 active air sampling tubes and 71-108% from PUF active air sampling tubes. Storage stability tests also yielded recoveries ranging from 74-94% after time periods ranging from 2-10 months. The results demonstrate that LC-MS/MS is a sensitive method for determining these compounds from two different matrices at the low concentrations that can result from spray drift and long range transport in non-target areas following agricultural applications. In an inter-laboratory comparison, the limit of quantification (LOQ) for LC-MS/MS was 100 times lower than a typical gas chromatography-mass spectrometry (GC-MS) method.

Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by Soman. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sparenborg, S.; Brennecke, L.H.; Jaax, N.K.

1992-12-31

The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a post treatment (30, 100 or 300 micron g/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions andmore » electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Post treatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity....Seizure-related brain damage, Organophosphorus compound, Nerve agent, Cholinesterase inhibition, Excitotoxicity, Guinea pig.« less

Downregulation of human paraoxonase 1 (PON1) by organophosphate pesticides in HepG2 cells.

PubMed

Medina-Díaz, Irma Martha; Ponce-Ruiz, Néstor; Ramírez-Chávez, Bryana; Rojas-García, Aurora Elizabeth; Barrón-Vivanco, Briscia S; Elizondo, Guillermo; Bernal-Hernández, Yael Y

2017-02-01

Paraoxonase 1 (PON1) is a calcium-dependent esterase synthesized primarily in the liver and secreted into the plasma where it is associated with high-density lipoproteins (HDL). PON1 hydrolyzes and detoxifies some toxic metabolites of organophosphorus compounds (OPs) such as methyl parathion and chlorpyrifos. Thus, PON1 activity and expression levels are important for determining susceptibility against OPs poisoning. Some studies have demonstrated that OPs can modulate gene expression through interactions with nuclear receptors. In this study, we evaluated the effects of methyl parathion and chlorpyrifos on the modulation of PON1 in Human Hepatocellular Carcinoma (HepG2) cells by real-time PCR, PON1 activity assay, and western blot. The results showed that the treatments with methyl parathion and chlorpyrifos decreased PON1 mRNA and immunoreactive protein and increased inflammatory cytokines in HepG2 cells. The effects of methyl parathion and chlorpyrifos on the downregulation of PON1 gene expression in HepG2 cells may provide evidence of OPs cytotoxicity related to oxidative stress and an inflammatory response. A decrease in the expression of the PON1 gene may increase the susceptibility to OPs intoxication and the risk of diseases related to inflammation and oxidative stress. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 490-500, 2017. © 2016 Wiley Periodicals, Inc.

Electrophysiological investigation of the effect of structurally different bispyridinium non-oxime compounds on human α7-nicotinic acetylcholine receptor activity-An in vitro structure-activity analysis.

PubMed

Scheffel, Corinna; Niessen, Karin V; Rappenglück, Sebastian; Wanner, Klaus T; Thiermann, Horst; Worek, Franz; Seeger, Thomas

2018-09-01

Organophosphorus compounds, including nerve agents and pesticides, exert their toxicity through irreversible inhibition of acetylcholinesterase (AChE) resulting in an accumulation of acetylcholine and functional impairment of muscarinic and nicotinic acetylcholine receptors. Current therapy comprises oximes to reactivate AChE and atropine to antagonize effects induced by muscarinic acetylcholine receptors. Nicotinic malfunction leading to depression of the central and peripheral respiratory system is not directly treated calling for alternative therapeutic interventions. In the present study, we investigated the electrophysiological properties of the human nAChR subtype α7 (hα7-nAChR) and the functional effect of the 4-tert-butyl bispyridinium (BP) compound MB327 and of a series of novel substituted bispyridinium compounds on the receptors by an automated patch clamp technique. Activation of hα7-nAChRs was induced by nicotine and acetylcholine demonstrating rapid cationic influx up to 100μM. Agonist-induced currents decayed within a few milliseconds revealing fast desensitization of the receptors. Application of higher agonist concentrations led to a decline of current amplitudes which seemed to be due to increasing receptor desensitization. When 100μM of agonist was coapplied with low concentrations of the well characterized α7-specific positive allosteric modulator PNU-120596 (1μM-10μM), the maximum response and duration of nAChR activation were markedly augmented indicating an elongated mean open-time of receptors and prevention of receptor desensitization. However, co-application of increasing PNU-120596 concentrations (>10μM) with agonist induced a decline of potentiated current responses. Although less pronounced than PNU-120596, six of the twenty tested substituted BP compounds, in particular those with a substituent at 3-position and 4-position at the pyridinium moieties, were found to potentiate current responses of hα7-nAChRs, most pronounced MB327.This effect was clearly depended on the presence of the agonist indicating a positive allosteric mechanism of these compounds. Besides potentiation at low concentrations, these compounds seem to interact at different binding sites on hα7-nAChRs since enhancement decreased at high concentrations. The residual fourteen BP compounds, possessing either an isopropyl-group or more than one group at the pyridinium moiety, antagonized nicotinic currents exhibiting IC 50 of low up to high micromolar concentrations (∼1μM-300μM). Copyright © 2017 Elsevier B.V. All rights reserved.

Manmade organic compounds in the surface waters of the United States: a review of current understanding

USGS Publications Warehouse

Smith, James A.; Witkowski, Patrick J.; Fusillo, Thomas V.

1987-01-01

This report reviews the occurrence and distribution of manmade organic compounds in the surface waters of the United States. On the basis of their aqueous solubilities, nonionic organic compounds partition themselves between water, dissolved organic matter, particulate organic matter, and the lipid reservoirs of aquatic organisms. Ionized organic compounds can be absorbed to sediments, thereby reducing their aqueous concentrations. Transformation processes of photolysis, hydrolysis, biodegradation, and volatilization can attenuate organic compounds, and attenuation rate commonly follow a first-order kinetic process. Eight groups of manmade organic compounds are discussed: 1. Polychlorinated biphenyls and organochlorine insecticides, 2. Carbamate and organophosphorus insecticides, 3. Herbicides, 4. Phenols, 5. Halogenated aliphatic and monocyclic aromatic hydrocarbons, 6. Phthalate esters, 7. Polychlorinated dibenzo-p-dioxins, and 8. Polycyclic aromatic hydrocarbons. For each compound group, data pertaining to use, production, and properties are presented and discussed. Processes that influence that the environmental fate of each group, as determined primarily through laboratory studies, are reviewed, and important fate processes are identified. Environmental concentrations of compounds from each group in water, biota, and sediment are given to demonstrate representative values for comparison to concentrations determined during ongoing research. Finally, where sufficient data exist, regional and temporal contamination trends in the United States are discussed.

Manmade organic compounds in the surface waters of the United States; a review of current understanding

USGS Publications Warehouse

Smith, James A.; Witkowski, P.J.; Fusillo, Thomas V.

1988-01-01

This report reviews the occurrence and distribution of manmade organic compounds in the surface waters of the United States. On the basis of their aqueous solubilities, nonionic organic compounds partition themselves among water, dissolved organic matter, particulate organic matter, and the lipid reservoirs of aquatic organisms. Ionized organic compounds can be adsorbed to sediments, thereby reducing their aqueous concentrations. Transformation processes of photolysis, hydrolysis, biodegradation, and volatilization can attenuate organic compounds, and attenuation rates commonly follow a first-order kinetic process. Eight groups of manmade organic compounds are discussed: 1. Polychlorinated biphenyls and organochlorine insecticides, 2. Carbamate and organophosphorus insecticides, 3. Herbicides, 4. Phenols, 5. Halogenated aliphatic and monocyclic aromatic hydrocarbons, 6. Phthalate esters, 7. Polychlorinated dibenzo-p-dioxins, and 8. Polycyclic aromatic hydrocarbons. For each compound group, data pertaining to use, production, and properties are presented and discussed. Processes that influence the environmental fate of each group, as determined primarily through laboratory studies, are reviewed, and important fate processes are identified. Environmental concentrations of compounds from each group in water, biota, and sediment are given to demonstrate representative values for comparison with concentrations determined during ongoing research. Finally, where data are sufficient, regional and temporal contamination trends in the United States are discussed.

Acute lethal toxicity of environmental pollutants to aquatic organisms.

PubMed

Yen, Jui-Hung; Lin, Kuo-Hsiung; Wang, Yei-Shung

2002-06-01

The acute lethal toxicity of environment pollutants including chlorophenol, haloalkane, quinone, and substituted nitrobenzene (i.e., nitrophenol, nitrobenzene, nitrotoluene, and aniline) compounds to aquatic organisms was determined. Determination of toxicity of chemicals was performed with chlorella, daphnia, carp, and tilapia. The toxicity of chlorophenols had no relation to the number of chlorine atoms on the benzene ring, but monochlorophenol had lower activity than more chlorine-substituted compounds. The tolerance levels of daphnia and carp to haloalkanes was found to be higher than that of chlorella; toxicity to chlorella was several hundred times higher than to daphnia. The toxicity of naphthoquinone compounds to chlorella and carp was higher than that of anthraquinone. A compound with a monochloride substitution on anthraquinone ring was less toxic to carp than those substituted with amine, hydroxyl, and dichlorine groups. Nitrobenzene compounds with an additional substitution group on the p position were extremely toxic to daphnia and carp. (c) 2002 Elsevier Science (USA).

Profiling Animal Toxicants by Automatically Mining Public Bioassay Data: A Big Data Approach for Computational Toxicology

PubMed Central

Zhang, Jun; Hsieh, Jui-Hua; Zhu, Hao

2014-01-01

In vitro bioassays have been developed and are currently being evaluated as potential alternatives to traditional animal toxicity models. Already, the progress of high throughput screening techniques has resulted in an enormous amount of publicly available bioassay data having been generated for a large collection of compounds. When a compound is tested using a collection of various bioassays, all the testing results can be considered as providing a unique bio-profile for this compound, which records the responses induced when the compound interacts with different cellular systems or biological targets. Profiling compounds of environmental or pharmaceutical interest using useful toxicity bioassay data is a promising method to study complex animal toxicity. In this study, we developed an automatic virtual profiling tool to evaluate potential animal toxicants. First, we automatically acquired all PubChem bioassay data for a set of 4,841 compounds with publicly available rat acute toxicity results. Next, we developed a scoring system to evaluate the relevance between these extracted bioassays and animal acute toxicity. Finally, the top ranked bioassays were selected to profile the compounds of interest. The resulting response profiles proved to be useful to prioritize untested compounds for their animal toxicity potentials and form a potential in vitro toxicity testing panel. The protocol developed in this study could be combined with structure-activity approaches and used to explore additional publicly available bioassay datasets for modeling a broader range of animal toxicities. PMID:24950175

Profiling animal toxicants by automatically mining public bioassay data: a big data approach for computational toxicology.

PubMed

Zhang, Jun; Hsieh, Jui-Hua; Zhu, Hao

2014-01-01

In vitro bioassays have been developed and are currently being evaluated as potential alternatives to traditional animal toxicity models. Already, the progress of high throughput screening techniques has resulted in an enormous amount of publicly available bioassay data having been generated for a large collection of compounds. When a compound is tested using a collection of various bioassays, all the testing results can be considered as providing a unique bio-profile for this compound, which records the responses induced when the compound interacts with different cellular systems or biological targets. Profiling compounds of environmental or pharmaceutical interest using useful toxicity bioassay data is a promising method to study complex animal toxicity. In this study, we developed an automatic virtual profiling tool to evaluate potential animal toxicants. First, we automatically acquired all PubChem bioassay data for a set of 4,841 compounds with publicly available rat acute toxicity results. Next, we developed a scoring system to evaluate the relevance between these extracted bioassays and animal acute toxicity. Finally, the top ranked bioassays were selected to profile the compounds of interest. The resulting response profiles proved to be useful to prioritize untested compounds for their animal toxicity potentials and form a potential in vitro toxicity testing panel. The protocol developed in this study could be combined with structure-activity approaches and used to explore additional publicly available bioassay datasets for modeling a broader range of animal toxicities.

Comparison of Toxicities to Vibrio fischeri and Fish Based on Discrimination of Excess Toxicity from Baseline Level

PubMed Central

Wang, Xiao H.; Yu, Yang; Huang, Tao; Qin, Wei C.; Su, Li M.; Zhao, Yuan H.

2016-01-01

Investigations on the relationship of toxicities between species play an important role in the understanding of toxic mechanisms to environmental organisms. In this paper, the toxicity data of 949 chemicals to fish and 1470 chemicals to V. fischeri were used to investigate the modes of action (MOAs) between species. The results show that although there is a positive interspecies correlation, the relationship is poor. Analysis on the excess toxicity calculated from toxic ratios (TR) shows that many chemicals have close toxicities and share the same MOAs between the two species. Linear relationships between the toxicities and octanol/water partition coefficient (log KOW) for baseline and less inert compounds indicate that the internal critical concentrations (CBRs) approach a constant both to fish and V. fischeri for neutral hydrophobic compounds. These compounds share the same toxic mechanisms and bio-uptake processes between species. On the other hand, some hydrophilic compounds exhibit different toxic effects with greatly different log TR values between V. fischeri and fish species. These hydrophilic compounds were identified as reactive MOAs to V. fischeri, but not to fish. The interspecies correlation is improved by adding a hydrophobic descriptor into the correlation equation. This indicates that the differences in the toxic ratios between fish and V. fischeri for these hydrophilic compounds can be partly attributed to the differences of bioconcentration between the two species, rather than the differences of reactivity with the target macromolecules. These hydrophilic compounds may more easily pass through the cell membrane of V. fischeri than the gill and skin of fish, react with the target macromolecules and exhibit excess toxicity. The compounds with log KOW > 7 exhibiting very low toxicity (log TR < –1) to both species indicate that the bioconcentration potential of a chemical plays a very important role in the identification of excess toxicity and MOAs. PMID:26901437

Computational Enzymology and Organophosphorus Degrading Enzymes: Promising Approaches Toward Remediation Technologies of Warfare Agents and Pesticides

DOE PAGES

Ramalho, Teodorico C.; DeCastro, Alexandre A.; Silva, Daniela R.; ...

2015-08-26

The re-emergence of chemical weapons as a global threat in hands of terrorist groups, together with an increasing number of pesticides intoxications and environmental contaminations worldwide, has called the attention of the scientific community for the need of improvement in the technologies for detoxification of organophosphorus (OP) compounds. A compelling strategy is the use of bioremediation by enzymes that are able to hydrolyze these molecules to harmless chemical species. Several enzymes have been studied and engineered for this purpose. However, their mechanisms of action are not well understood. Theoretical investigations may help elucidate important aspects of these mechanisms and helpmore » in the development of more efficient bio-remediators. In this review, we point out the major contributions of computational methodologies applied to enzyme based detoxification of OPs. Furthermore, we highlight the use of PTE, PON, DFP, and BuChE as enzymes used in OP detoxification process and how computational tools such as molecular docking, molecular dynamics simulations and combined quantum mechanical/molecular mechanics have and will continue to contribute to this very important area of research.The re-emergence of chemical weapons as a global threat in hands of terrorist groups, together with an increasing number of pesticides intoxications and environmental contaminations worldwide, has called the attention of the scientific community for the need of improvement in the technologies for detoxification of organophosphorus (OP) compounds. A compelling strategy is the use of bioremediation by enzymes that are able to hydrolyze these molecules to harmless chemical species. Several enzymes have been studied and engineered for this purpose. However, their mechanisms of action are not well understood. Theoretical investigations may help elucidate important aspects of these mechanisms and help in the development of more efficient bio-remediators. In this review, we point out the major contributions of computational methodologies applied to enzyme based detoxification of OPs. Furthermore, we highlight the use of PTE, PON, DFP, and BuChE as enzymes used in OP detoxification process and how computational tools such as molecular docking, molecular dynamics simulations and combined quantum mechanical/molecular mechanics have and will continue to contribute to this very important area of research.« less

Computational Enzymology and Organophosphorus Degrading Enzymes: Promising Approaches Toward Remediation Technologies of Warfare Agents and Pesticides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramalho, Teodorico C.; DeCastro, Alexandre A.; Silva, Daniela R.

The re-emergence of chemical weapons as a global threat in hands of terrorist groups, together with an increasing number of pesticides intoxications and environmental contaminations worldwide, has called the attention of the scientific community for the need of improvement in the technologies for detoxification of organophosphorus (OP) compounds. A compelling strategy is the use of bioremediation by enzymes that are able to hydrolyze these molecules to harmless chemical species. Several enzymes have been studied and engineered for this purpose. However, their mechanisms of action are not well understood. Theoretical investigations may help elucidate important aspects of these mechanisms and helpmore » in the development of more efficient bio-remediators. In this review, we point out the major contributions of computational methodologies applied to enzyme based detoxification of OPs. Furthermore, we highlight the use of PTE, PON, DFP, and BuChE as enzymes used in OP detoxification process and how computational tools such as molecular docking, molecular dynamics simulations and combined quantum mechanical/molecular mechanics have and will continue to contribute to this very important area of research.The re-emergence of chemical weapons as a global threat in hands of terrorist groups, together with an increasing number of pesticides intoxications and environmental contaminations worldwide, has called the attention of the scientific community for the need of improvement in the technologies for detoxification of organophosphorus (OP) compounds. A compelling strategy is the use of bioremediation by enzymes that are able to hydrolyze these molecules to harmless chemical species. Several enzymes have been studied and engineered for this purpose. However, their mechanisms of action are not well understood. Theoretical investigations may help elucidate important aspects of these mechanisms and help in the development of more efficient bio-remediators. In this review, we point out the major contributions of computational methodologies applied to enzyme based detoxification of OPs. Furthermore, we highlight the use of PTE, PON, DFP, and BuChE as enzymes used in OP detoxification process and how computational tools such as molecular docking, molecular dynamics simulations and combined quantum mechanical/molecular mechanics have and will continue to contribute to this very important area of research.« less

A mechanistic approach for modulation of chlorpyrifos-induced toxicity in human lymphocytes by melatonin, coenzyme Q10, and vinpocetine.

PubMed

Ghayomi, F; Navaei-Nigjeh, M; Baeeri, M; Rezvanfar, M A; Abdollahi, M

2016-08-01

Chlorpyrifos (CP) is an organophosphorus pesticide that induces oxidative stress through the production of free radicals and depletes intracellular antioxidant reserves. In this study, the efficacy of three antioxidants (melatonin, coenzyme Q10 (CoQ10), and vinpocetine) on alleviation of toxic effects of CP was evaluated. Cytotoxicity of CP, in the presence or absence of effective doses of melatonin, CoQ10, and vinpocetine, was determined in human peripheral blood lymphocytes after 72-h exposure. The levels of acetylcholinesterase (AChE) activity along with tumor necrosis factor α (TNF-α), as inflammatory index, were measured. Further, the viability and oxidative stress markers including cellular mitochondrial activity, cell death modes (apoptosis vs. necrosis), total antioxidant power (TAP), total thiol molecules (TTM), lipid peroxidation (LPO), and myeloperoxidase (MPO) activity were measured. CoQ10 and also the combination of the three antioxidants were the most notable in opposing toxicity of CP and led to increasing TAP and TTM; improvement of AChE activity; and lowering LPO, MPO, TNF-α, and apoptosis compared to CP alone. CP toxicity overwhelms the intracellular antioxidant defense mechanisms. Exogenous supplementation with antioxidants, such as the ones we have investigated, seems to be effective in the prevention of cytotoxicity of CP. © The Author(s) 2015.

Synergistic ameliorative effects of sesame oil and alpha-lipoic acid against subacute diazinon toxicity in rats: hematological, biochemical, and antioxidant studies.

PubMed

Abdel-Daim, Mohamed M; Taha, Ramadan; Ghazy, Emad W; El-Sayed, Yasser S

2016-01-01

Diazinon (DZN) is a common organophosphorus insecticide extensively used for agriculture and veterinary purposes. DZN toxicity is not limited to insects; it also induces harmful effects in mammals and birds. Our experiment evaluated the protective and antioxidant potential of sesame oil (SO) and (or) alpha-lipoic acid (ALA) against DZN toxicity in male Wistar albino rats. DZN-treated animals exhibited macrocytic hypochromic anemia and significant increases in serum biochemical parameters related to liver injury, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (γGT), cholesterol, and triglycerides. They also had elevated levels of markers related to cardiac injury, such as lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), and increased biomarkers of renal injury, urea and creatinine. DZN also increased hepatic, renal, and cardiac lipid peroxidation and decreased antioxidant biomarker levels. SO and (or) ALA supplementation ameliorated the deleterious effects of DZN intoxication. Treatment improved hematology and serum parameters, enhanced endogenous antioxidant status, and reduced lipid peroxidation. Importantly, they exerted synergistic hepatoprotective, nephroprotective, and cardioprotective effects. Our findings demonstrate that SO and (or) ALA supplementation can alleviate the toxic effects of DZN via their potent antioxidant and free radical-scavenging activities.

Organophosphorus pesticide poisonings in humans: determination of residues and metabolites in tissues and urine.

PubMed

Lores, E M; Bradway, D E; Moseman, R F

1978-01-01

The analyses of four organophosphorus pesticide poisoning cases, three of which resulted in death, are reported. The case histories of the subjects, along with the analysis of tissues, urine, and blood for the levels of pesticides and metabolites are given. The pesticides involved include dicrotophos, chlorpyrifos, malathion, and parathion. The methods of analysis were adapted from previously published methods that provide a very rapid means of identification of organophosphorus pesticides in the tissues or in the blood of poisoned patients.

Pesticide concentrations in water and sediment and associated invertebrate toxicity in Del Puerto and Orestimba Creeks, California, 2007-2008.

PubMed

Ensminger, Michael; Bergin, Rick; Spurlock, Frank; Goh, Kean S

2011-04-01

The California's San Joaquin River and its tributaries including Orestimba (ORC) and Del Puerto (DPC) Creeks are listed on the 2006 US EPA Clean Water Act §303(d) list for pesticide impairment. From December 2007 through June 2008, water and sediment samples were collected from both creeks in Stanislaus County to determine concentrations of organophosphorus (OP) and pyrethroid insecticides and to identify toxicity to Ceriodaphnia dubia and Hyalella azteca. OPs were detected in almost half (10 of 21) of the water samples, at concentrations from 0.005 to 0.912 μg L(-1). Diazinon was the most frequently detected OP, followed by chlorpyrifos and dimethoate. Two water samples were toxic to C. dubia; based on median lethal concentrations (LC50), chlorpyrifos was likely the cause of this toxicity. Pyrethroids were detected more frequently in sediment samples (18 detections) than in water samples (three detections). Pyrethroid concentrations in water samples ranged from 0.005 to 0.021 μg L(-1). These concentrations were well below reported C. dubia LC50s, and toxicity was not observed in laboratory bioassays. Cyfluthrin, bifenthrin, esfenvalerate, and λ-cyhalothrin were detected in sediment samples at concentrations ranging from 1.0 to 74.4 ng g(-1), dry weight. At DPC, all but one sediment sample caused 100% toxicity to H. azteca. Based on estimated toxicity units (TUs), bifenthrin was likely responsible for this toxicity and λ-cyhalothrin also contributed. At ORC, survival of H. azteca was significantly reduced in four of the 11 sediment samples. However, pyrethroids were detected in only two of these samples. Based on TUs, bifenthrin and λ-cyhalothrin likely contributed to the toxicity.

Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells.

PubMed

Huang, Tao; Yan, Lichen; Zheng, Shanshan; Wang, Yue; Wang, Xiaohong; Fan, Lingyun; Li, Chao; Zhao, Yuanhui; Martyniuk, Christopher J

2017-12-01

The objective of this study was to determine whether toxicity in mouse fibroblast cells (3T3 cells) could predict toxicity in mice. Synthesized data on toxicity was subjected to regression analysis and it was observed that relationship of toxicities between mice and 3T3 cells was not strong (R 2  = 0.41). Inclusion of molecular descriptors (e.g. ionization, pKa) improved the regression to R 2  = 0.56, indicating that this relationship is influenced by kinetic processes of chemicals or specific toxic mechanisms associated to the compounds. However, to determine if we were able to discriminate modes of action (MOAs) in mice using the toxicities generated from 3T3 cells, compounds were first classified into "baseline" and "reactive" guided by the toxic ratio (TR) for each compound in mice. Sequence, binomial and recursive partitioning analyses provided strong predictions of MOAs in mice based upon toxicities in 3T3 cells. The correct classification of MOAs based on these methods was 86%. Nearly all the baseline compounds predicted from toxicities in 3T3 cells were identified as baseline compounds from the TR in mice. The incorrect assignment of MOAs for some compounds is hypothesized to be due to experimental uncertainty that exists in toxicity assays for both mice and 3T3 cells. Conversely, lack of assignment can also arise because some reactive compounds have MOAs that are different in mice compared to 3T3 cells. The methods developed here are novel and contribute to efforts to reduce animal numbers in toxicity tests that are used to evaluate risks associated with organic pollutants in the environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Determination and identification of malathion, ethion and dichlorovos using ion mobility spectrometry.

PubMed

Jafari, Mohammad T

2006-07-15

Positive ion mobility spectra of different organophosphorus pesticides such as malathion (s-(1,2-dicarb-ethoxyethyl) o,o-dimethyl dithiophosphate), ethion (o,o,o',o'-tetraethyl s,s'-methylene bis(phosphorodithioate)) and dichlorovos (2,2-dichlorovinyl dimethyl phosphate) have been studied in air at ambient pressure using ion mobility spectrometry method with (63)Ni ionization source. The limits of quantification (LOQs) were 1.0 x 10(-9), 1.0 x 10(-9) and 5.0 x 10(-9)g for malathion, ethion and dichlorovos, respectively. The working range of these compounds was about three orders of magnitude and the relative standard deviation (R.S.D.) of repeatability at the 5 microg ml(-1) level were all below 15%. Furthermore, in this study, the influences of IMS cell temperature on the ion mobility spectra of these compounds were investigated.

Fumigant toxicity of basil oil compounds and related compounds to Thrips palmi and Orius strigicollis.

PubMed

Kim, Kwang-Ho; Yi, Chang-Geun; Ahn, Young-Joon; Kim, Soon Il; Lee, Sang-Guei; Kim, Jun-Ran

2015-09-01

This study was aimed at assessing the fumigant toxicity to adult Thrips palmi (a serious insect pest) and Orius strigicollis (a beneficial predator insect) of basil (Ocimum basilicum) essential oil compounds and structurally related compounds using vapour-phase toxicity bioassays. Against adult T. palmi, linalool (LD50 0.0055 mg cm(-3) ) was the most toxic fumigant and was 15.2-fold more effective than dichlorvos (0.0837 mg cm(-3) ). Strong fumigant toxicity was also observed in pulegone (0.0095 mg cm(-3) ), (±)-camphor (0.0097 mg cm(-3) ) and 1,8-cineole (0.0167 mg cm(-3) ). Moderate toxicity was produced by camphene, 3-carene, (-)-menthone, (+)-α-pinene, (+)-β-pinene, α-terpineol and (-)-α-thujone (0.0215-0.0388 mg cm(-3) ). Against adult O. strigicollis, dichlorvos (LD50 9.0 × 10(-10) mg cm(-3) ) was the most toxic fumigant, whereas the LD50 values of these compounds ranged from 0.0127 to >0.23 mg cm(-3) . Based upon the selective toxicity ratio, the compounds described are more selective than dichlorvos. The basil oil compounds described merit further study as potential insecticides for control of T. palmi in greenhouses because of their generally lower toxicity to O. strigicollis and their greater activity as a fumigant than dichlorvos. © 2014 Society of Chemical Industry.

Organoelement chemistry: promising growth areas and challenges

NASA Astrophysics Data System (ADS)

Abakumov, G. A.; Piskunov, A. V.; Cherkasov, V. K.; Fedushkin, I. L.; Ananikov, V. P.; Eremin, D. B.; Gordeev, E. G.; Beletskaya, I. P.; Averin, A. D.; Bochkarev, M. N.; Trifonov, A. A.; Dzhemilev, U. M.; D'yakonov, V. A.; Egorov, M. P.; Vereshchagin, A. N.; Syroeshkin, M. A.; Jouikov, V. V.; Muzafarov, A. M.; Anisimov, A. A.; Arzumanyan, A. V.; Kononevich, Yu N.; Temnikov, M. N.; Sinyashin, O. G.; Budnikova, Yu H.; Burilov, A. R.; Karasik, A. A.; Mironov, V. F.; Storozhenko, P. A.; Shcherbakova, G. I.; Trofimov, B. A.; Amosova, S. V.; Gusarova, N. K.; Potapov, V. A.; Shur, V. B.; Burlakov, V. V.; Bogdanov, V. S.; Andreev, M. V.

2018-05-01

The chemistry of organoelement compounds is now one of the most rapidly developing fields of research, regarding both fundamental science and solution of applied problems. This review covers a variety of classes of organoelement compounds, ranging from molecules with highly labile carbon–element bonds to compounds with stable bonds that form the basis of novel structural materials and demonstrates their role in scientific research and industrial production. The use of Grignard reagents in modern organic synthesis and application of catalytic cyclomagnesiation and cycloalumination reactions for the preparation of difficult-to-access metallacycles are considered. The electron transfer processes in redox-active derivatives of Group 14 elements and the role of radical ions in these processes are discussed. Considerable attention is paid to organometallic compounds, first of all, as catalysts; the dynamic nature of catalysis with these compounds is noted. Unusual strained metallacycles of high thermal stability, zirconacyclocumulenes, which also exhibit catalytic activity, are described. Complexes with redox-active ligands that substantially affect the reactivity of the metal centre and directly participate in reactions with various substrates as well as organometallic compounds of lanthanides are considered. Modern environmentally benign methods for the synthesis of organosilicon compounds and production of unique materials based on them are discussed. Particular Sections are devoted to organophosphorus compounds, including those exhibiting therapeutic properties and possessing unusual optical characteristics, and organic chalcogen compounds, which find use as ligands and biologically active molecules. The bibliography includes 1045 references.

Experimental strategy for translational studies of organophosphorus pesticide neurotoxicity based on real-world occupational exposures to chlorpyrifos.

PubMed

Lein, Pamela J; Bonner, Matthew R; Farahat, Fayssal M; Olson, James R; Rohlman, Diane S; Fenske, Richard A; Lattal, K Matthew; Lasarev, Michael R; Galvin, Kit; Farahat, Taghreed M; Anger, W Kent

2012-08-01

Translational research is needed to understand and predict the neurotoxic consequences associated with repeated occupational exposures to organophosphorus pesticides (OPs). In this report, we describe a research strategy for identifying biomarkers of OP neurotoxicity, and we characterize pesticide application workers in Egypt's Menoufia Governorate who serve as our anchor human population for developing a parallel animal model with similar exposures and behavioral deficits and for examining the influence of human polymorphisms in cytochrome P450 (CYP) and paraoxonase 1 (PON1) enzymes on OP metabolism and toxicity. This population has previously been shown to have high occupational exposures and to exhibit a broad range of neurobehavioral deficits. In addition to observational studies of work practices in the field, questionnaires on demographics, lifestyle and work practices were administered to 146 Egyptian pesticide application workers applying pesticides to the cotton crop. Survey results indicated that the application workforce uses standard operating procedures and standardized equipment provided by Egypt's Ministry of Agriculture, which provides a workforce with a stable work history. We also found that few workers report using personal protective equipment (PPE), which likely contributes to the relatively high exposures reported in these application workers. In summary, this population provides a unique opportunity for identifying biomarkers of OP-induced neurotoxicity associated with occupational exposure. Copyright © 2012 Elsevier Inc. All rights reserved.

Experimental strategy for translational studies of organophosphorus pesticide neurotoxicity based on real-world occupational exposures to chlorpyrifos

PubMed Central

Lein, Pamela J.; Bonner, Matthew R.; Farahat, Fayssal M.; Olson, James R.; Rohlman, Diane S.; Fenske, Richard A.; Lattal, K. Matthew; Lasarev, Michael R.; Galvin, Kit; Farahat, Taghreed M.; Anger, W. Kent

2012-01-01

Translational research is needed to understand and predict the neurotoxic consequences associated with repeated occupational exposures to organophosphorus pesticides (OPs). In this report, we describe a research strategy for identifying biomarkers of OP neurotoxicity, and we characterize pesticide application workers in Egypt’s Menoufia Governorate who serve as our anchor human population for developing a parallel animal model with similar exposures and behavioral deficits and for examining the influence of human polymorphisms in cytochrome P450 (CYP) and paraoxonase 1 (PON1) enzymes on OP metabolism and toxicity. This population has previously been shown to have high occupational exposures and to exhibit a broad range of neurobehavioral deficits. In addition to observational studies of work practices in the field, questionnaires on demographics, lifestyle and work practices were administered to 146 Egyptian pesticide application workers applying pesticides to the cotton crop. Survey results indicated that the application workforce uses standard operating procedures and standardized equipment provided by Egypt’s Ministry of Agriculture, which provides a workforce with a stable work history. We also found that few workers report using personal protective equipment (PPE), which likely contributes to the relatively high exposures reported in these application workers. In summary, this population provides a unique opportunity for identifying biomarkers of OP-induced neurotoxicity associated with occupational exposure. PMID:22240005

Reactivation of Plasma Butyrylcholinesterase by Pralidoxime Chloride in Patients Poisoned by WHO Class II Toxicity Organophosphorus Insecticides

PubMed Central

Eddleston, Michael

2013-01-01

Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide, and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) class II OP insecticide poisoning. Patient data were derived from 2 studies, a cohort study (using a bolus treatment of 1g pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2g pralidoxime over 20min, followed by an infusion of 0.5g/h, with placebo). Two grams of pralidoxime variably reactivated BuChE in patients poisoned by 2 diethyl OP insecticides, chlorpyrifos and quinalphos; however, unlike acetylcholinesterase reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1-g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO class II OP-poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful. PMID:24052565

Non-muscarinic therapeutic targets for acute organophosphorus poisoning.

PubMed

Rosenbaum, Christopher; Bird, Steven B

2010-12-01

Organophosphorus (OP) pesticides are a broad class of acetylcholinesterase inhibitors that are responsible for tremendous morbidity and mortality worldwide, contributing to an estimated 300,000 deaths annually. Current pharmacotherapy for acute OP poisoning includes the use of atropine, an oxime, and benzodiazepines. However, even with such therapy, the mortality from these agents is as high as 40%. It is increasingly recognized that not all OPs are the same. Significant differences exist in their toxicity, lipophilicity, and response to oxime therapy. Other non-muscarinic effects of OP pesticides exist, such as acute and chronic neuromuscular junction failure and central respiratory failure. In part because most of the mortality from these chemicals takes place in the developing world, little National Institutes of Health (NIH) research has been directed towards these agents. However, the similar mechanism of action of OP pesticides and the military nerve agents, along with increasing concerns about chemical terrorism has lead to the formation of the NIH Countermeasures Against Chemical Threats (CounterACT) Program. As part of the CounterACT Program, the NIH has recently designated six OP pesticides as "threat agents". This concept paper describes some of the knowledge gaps related to non-muscarinic effects of OP pesticides and highlights needed areas of further research. Leveraging the current NIH interest in these chemicals to medical necessities in the developing world offers the possibility of delivering new therapeutics where they are needed on a daily basis.

Effects of organophosphorus flame retardant TDCPP on normal human corneal epithelial cells: Implications for human health.

PubMed

Xiang, Ping; Liu, Rong-Yan; Li, Chao; Gao, Peng; Cui, Xin-Yi; Ma, Lena Q

2017-11-01

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is one of the most detected organophosphorus flame retardants (OPFRs) in the environment, especially in indoor dust. Continuous daily exposure to TDCPP-containing dust may adversely impact human cornea. However, its detrimental effects on human corneal epithelium are largely unknown. In this study, we investigated the cell apoptosis in normal human corneal epithelial cells (HCECs) after TDCPP exposure and elucidated the underlying molecular mechanisms. Our data indicated a dose-dependent decrease of cell viability after TDCPP exposure with LC 50 at 202 μg/mL. A concentration-dependent apoptotic sign was observed in HCECs after exposing to ≥2 μg/mL TDCPP. Endoplasmic reticulum stress induction was evidenced by up-regulation of its biomarker genes (ATF-4, CHOP, BiP, and XBP1). Furthermore, alternation of Bcl-2/Bax expression, mitochondrial membrane potential loss, cellular ATP content decrease, and caspase-3 and -9 activity increase were observed after exposing to 2 or 20 μg/mL TDCPP. Taken together, the data implicated the involvement of endoplasmic reticulum stress in TDCPP-induced HCEC apoptosis, probably mediated by mitochondrial apoptotic pathway. Our findings showed TDCPP exposure induced toxicity to human cornea. Due to TDCPP's presence at high levels in indoor dust, further study is warranted to evaluate its health risk on human corneas. Published by Elsevier Ltd.

Determination of organophosphorus pesticides in environmental water samples by dispersive liquid-liquid microextraction with solidification of floating organic droplet followed by high-performance liquid chromatography.

PubMed

Wu, Chunxia; Liu, Huimin; Liu, Weihua; Wu, Qiuhua; Wang, Chun; Wang, Zhi

2010-07-01

A simple dispersive liquid-liquid microextraction based on solidification of floating organic droplet coupled with high-performance liquid chromatography-diode array detection was developed for the determination of five organophosphorus pesticides (OPs) in water samples. In this method, the extraction solvent used is of low density, low toxicity, and proper melting point near room temperature. The extractant droplet could be collected easily by solidifying it in the lower temperature. Some important experimental parameters that affect the extraction efficiencies were optimized. Under the optimum conditions, the calibration curve was linear in the concentration range from 1 to 200 ng mL(-1) for the five OPs (triazophos, parathion, diazinon, phoxim, and parathion-methyl), with the correlation coefficients (r) varying from 0.9991 to 0.9998. High enrichment factors were achieved ranging from 215 to 557. The limits of detection were in the range between 0.1 and 0.3 ng mL(-1). The recoveries of the target analytes from water samples at spiking levels of 5.0 and 50.0 ng mL(-1) were 82.2-98.8% and 83.6-104.0%, respectively. The relative standard deviations fell in the range of 4.4% to 6.3%. The method was suitable for the determination of the OPs in real water samples.

DETECTION OF TOXICANT(S) ON BUILDING SURFACES FOLLOWING CHEMICAL ATTACK

EPA Science Inventory

A critical step prior to reoccupation of any facility following a chemical attack is monitoring for toxic compounds on surfaces within that facility. Low level detection of toxicant(s) is necessary to ensure that these compounds have been eliminated after building decontaminatio...

Sorption of Organophosphorus Flame Retardants on Settled Dust

EPA Science Inventory

Organophosphorus flame retardants (OPFRs) are widely used as additives in industrial and consumer products such as electrical and electronic products, furniture, plastics, textiles, and building/construction materials. Due to human exposure and potential health effects, OPFRs inc...

Chloramination of Organophosphorus Pesticides Found in Drinking Water Sources

EPA Science Inventory

The degradation of commonly detected organophosphorus (OP) pesticides, in drinking water sources, was investigated under simulated chloramination conditions. Due to monochloramine autodecomposition, it is difficult to observe the direct reaction of monochloramine with each OP pe...

Decontamination Technologies for Emerging CBRNE Agents: Scoping Study

DTIC Science & Technology

2014-05-01

organophosphorus pesticides ( chlorpyrifos , diazinon, malathion) which are neurotoxins, and other pesticides (captan, folpet, tralkoxydim, chlorthalonil, 1,3...organophosphorus pesticides (OPPs), gamma radiolysis for chlorpyrifos , and bio-detoxification of pesticides such as diazinon and chlorpyrifos . For instance

Clinical analysis of penehyclidine hydrochloride combined with hemoperfusion in the treatment of acute severe organophosphorus pesticide poisoning.

PubMed

Liang, M J; Zhang, Y

2015-05-11

This study aimed to observe the clinical curative effect of penehyclidine hydrochloride (PHC) combined with hemoperfusion in treating acute severe organophosphorus pesticide poisoning. We randomly divided 61 patients with severe organophosphorus pesticide poisoning into an experimental group (N = 31) and a control group (N = 30), and we compared the coma-recovery time, mechanical ventilation time, healing time, hospital expenses, and mortality between the two groups. The coma-recovery time, mechanical ventilation time, and healing time were lower in the experimental group than in the control group (P < 0.05), while the hospitalization expenses were higher in the experimental group than in the control group (P < 0.01); moreover, no significant difference was observed in the mortality rate between the two groups. Thus, PHC combined with hemoperfusion exerts a better therapeutic effect in acute severe organophosphorus pesticide poisoning than PHC alone.

Organophosphorus and carbamate pesticides. Chapter 12 in Handbook of Ecotoxicology

USGS Publications Warehouse

Hill, Elwood F.; Hoffman, David J.; Rattner, Barnett A.; Burton, G. Allen; Cairns, John

1995-01-01

Organophosphorus and carbamate pesticides are used throughout the world to control a large variety of insects and other invertebrates, fungi, birds, mammals, and herbaceous plants. Over 100 different organophosphorus and carbamate chemicals are registered in the U.S. alone for use in thousands of products applied to widely diverse habitats including agricultural crops, forests, rangelands, wetlands, towns, and cities. These applications are estimated to be nearly 200 million acre-treatments (i.e., number of acres treated corrected for number of treatments) per year to control nuisance, depradating, and disease-bearing invertebrates and vertebrates, and to maintain landscape aesthetics. Except for mosquito control, most applications target terrestrial habitat. Due to drift or run-off, pesticide and degrades are inevitably detected in soils and water that are fundamental to the primary productivity of ecosystems. Thus, critical life-giving systems are frequently contaminated with organophosphorus and carbamate pesticides, however briefly, each year.

QSAR for cholinesterase inhibition by organophosphorus esters and CNDO/2 calculations for organophosphorus ester hydrolysis

NASA Technical Reports Server (NTRS)

Johnson, H.; Kenley, R. A.; Rynard, C.; Golub, M. A.

1985-01-01

Quantitative structure-activity relationships were derived for acetyl- and butyrylcholinesterase inhibition by various organophosphorus esters. Bimolecular inhibition rate constants correlate well with hydrophobic substituent constants, and with the presence or absence of catonic groups on the inhibitor, but not with steric substituent constants. CNDO/2 calculations were performed on a separate set of organophosphorus esters, RR'P(O)X, where R and R' are alkyl and/or alkoxy groups and X is fluorine, chlorine or a phenoxy group. For each subset with the same X, the CNDO-derived net atomic charge at the central phosphorus atom in the ester correlates well with the alkaline hydrolysis rate constant. For the whole set of esters with different X, two equations were derived that relate either charge and leaving group steric bulk, or orbital energy and bond order to the hydrogen hydrolysis rate constant.

QSAR for cholinesterase inhibition by organophosphorus esters and CNDO/2 calculations for organophosphorus ester hydrolysis. [quantitative structure-activity relationship, complete neglect of differential overlap

NASA Technical Reports Server (NTRS)

Johnson, H.; Kenley, R. A.; Rynard, C.; Golub, M. A.

1985-01-01

Quantitative structure-activity relationships were derived for acetyl- and butyrylcholinesterase inhibition by various organophosphorus esters. Bimolecular inhibition rate constants correlate well with hydrophobic substituent constants, and with the presence or absence of cationic groups on the inhibitor, but not with steric substituent constants. CNDO/2 calculations were performed on a separate set of organophosphorus esters, RR-primeP(O)X, where R and R-prime are alkyl and/or alkoxy groups and X is fluorine, chlorine or a phenoxy group. For each subset with the same X, the CNDO-derived net atomic charge at the central phosphorus atom in the ester correlates well with the alkaline hydrolysis rate constant. For the whole set of esters with different X, two equations were derived that relate either charge and leaving group steric bulk, or orbital energy and bond order to the hydrolysis rate constant.

Liquid chromatography-tandem mass spectrometry direct injection analysis of organophosphorus flame retardants in Ontario surface water and wastewater effluent.

PubMed

Hao, Chunyan; Helm, Paul A; Morse, David; Reiner, Eric J

2018-01-01

Organophosphorus flame retardants (OPFRs) started to be used in plastics, electronics and furnishings back in the 1960s and became popular again last decade. They are now widely present in the environment and regarded as "new" emerging organic pollutants. An effective liquid chromatography-tandem mass spectrometry (LC-MS/MS) direct injection analysis (DIA) method was developed to monitor OPFR levels in aquatic environment. The removal of sample extraction and concentration steps not only improved operation efficiency, but also reduced the potential contamination commonly observed during the sample preparation process before. Positive background signals from the analytical instrument were eliminated by employing a "trap" column in front of the sample injector while an ACE C18 and an ACE C18-PFP column were compared for the separation of OPFRs. Nineteen OPFR related compounds were evaluated and rapid signal drops were observed for seven of them including TOTP, TMTP, TPTP, TEHP, T35DMPP, T2iPPP and EHDP, due to their low water solubility. The other twelve compounds, TMP, TEP, TPrP, TiPP, TBP, TCEP, TCPP, TDCPP, TPP, TBEP, BDCP and BEHP, were included for the measurement of OPFRs in drinking water, surface water, ground water and wastewater effluent samples. The instrumental detection limits of these twelve OPFRs at signal-to-noise ≥3 were in the 1.5-30 ng/L range. The method was applied for the determination of OPFRs in surface water and wastewater samples in Ontario, Canada, and BEHP, TBEP, TBP, TCEP, TCPP, TDCPP, and TEP were commonly detected. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

N-acetylcysteine in Acute Organophosphorus Pesticide Poisoning: A Randomized, Clinical Trial.

PubMed

El-Ebiary, Ahmad A; Elsharkawy, Rasha E; Soliman, Nema A; Soliman, Mohammed A; Hashem, Ahmed A

2016-08-01

Organophosphorus poisoning is a major global health problem with hundreds of thousands of deaths each year. Research interest in N-acetylcysteine has grown among increasing evidence of the role of oxidative stress in organophosphorus poisoning. We aimed to assess the safety and efficacy of N-acetylcysteine as an adjuvant treatment in patients with acute organophosphorus poisoning. This was a randomized, controlled, parallel-group trial on 30 patients suffering from acute organophosphorus poisoning, who were admitted to the Poison Control Center of Tanta University Emergency Hospital, Tanta, Egypt, between April and September 2014. Interventions included oral N-acetylcysteine (600 mg three times daily for 3 days) as an added treatment to the conventional measures versus only the conventional treatment. Outcome measures included mortality, total dose of atropine administered, duration of hospitalization and the need for ICU admission and/or mechanical ventilation. A total of 46 patients were screened and 30 were randomized. No significant difference was found between both groups regarding demographic characteristics and the nature or severity of baseline clinical manifestations. No major adverse effects to N-acetylcysteine therapy were reported. Malondialdehyde significantly decreased and reduced glutathione significantly increased only in the NAC-treated patients. The patients on NAC therapy required less atropine doses than those who received only the conventional treatment; however, the length of hospital stay showed no significant difference between both groups. The study concluded that the use of N-acetylcysteine as an added treatment was apparently safe, and it reduced atropine requirements in patients with acute organophosphorus pesticide poisoning. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Tandem screening of toxic compounds on GFP-labeled bacteria and cancer cells in microtiter plates.

PubMed

Montoya, Jessica; Varela-Ramirez, Armando; Shanmugasundram, Muthian; Martinez, Luis E; Primm, Todd P; Aguilera, Renato J

2005-09-23

A 96-well fluorescence-based assay has been developed for the rapid screening of potential cytotoxic and bacteriocidal compounds. The assay is based on detection of green fluorescent protein (GFP) in HeLa human carcinoma cells as well as gram negative (Escherichia coli) and gram positive bacteria (Mycobacterium avium). Addition of a toxic compound to the GFP marked cells resulted in the loss of the GFP fluorescence which was readily detected by fluorometry. Thirty-nine distinct naphthoquinone derivatives were screened and several of these compounds were found to be toxic to all cell types. Apart from differences in overall toxicity, two general types of toxic compounds were detected, those that exhibited toxicity to two or all three of the cell types and those that were primarily toxic to the HeLa cells. Our results demonstrate that the parallel screening of both eukaryotic and prokaryotic cells is not only feasible and reproducible but also cost effective.

HPLC SEPARATION OF CHIRAL ORGANOPHOSPHORUS PESTICIDES ON POLYSACCHARIDE CHIRAL STATIONARY PHASES

EPA Science Inventory

High-performance liquid chromatographic separation of the individual enantiomers of 12 organophosphorus pesticides (OPs) were obtained on polysaccharide chiral HPLC columns using an alkane-alcohol mobile phase. The OP pesticides were crotoxyphos, dialifor, dyfonate, fenamiphos, ...

UPTAKE AND PHYTOTRANSFORMATION OF ORGANOPHOSPHORUS PESTICIDES BY AXENICALLY CULTIVATED AQUATIC PLANTS

EPA Science Inventory

The uptake and phytotransformation of organophosphorus (OP) pesticides (malathion, demeton-S-methyl, and crufomate) was investigated in vitro using the axenically aquatic cultivated plants parrot feather (Myriophyllum aquaticum), duckweed (Spirodela oligorrhiza L.), and elodea (E...

Sorption of Organophosphorus Flame-Retardants on Settled Dust

EPA Science Inventory

Dust is an important sink for indoor air pollutants, such as organophosphorus flame-retardants (OPFRs) that are used as additives in industrial and consumer products including electrical and electronic products, furniture, plastics, textile, and building/construction materials. T...

Sorption of Organophosphorus Flame Retardants (OPFRs) on Settled Dust

EPA Science Inventory

Organophosphorus flame retardants (OPFRs) are widely used as additives in industrial and consumer products such as electrical and electronic products, furniture, plastics, textiles, and building/construction materials. Due to human exposure and potential health effects, OPFRs inc...

ORGANOPHOSPHORUS PESTICIDE DEGRADATION PATHWAYS DURING DRINKING WATER TREATMENT

EPA Science Inventory

The objective of this work was to investigate organophosphorus (OP) pesticide transformation pathways as a class in the presence of aqueous chlorine. Seven priority OP pesticides were examined for their reactivity with aqueous chlorine: chlorpyrifos (CP), parathion (PA), diazino...

Evaluation of organic compounds and trace elements in Amazon Creek Basin, Oregon, September 1990

USGS Publications Warehouse

Rinella, F.A.

1993-01-01

Water and bottom sediment were collected from Amazon Creek, Oregon during a summer low-flow condition and analyzed for different classes of organic compounds, including many from the U.S. Environmental Protection Agency's priority pollutant list. Bottom sediment also was analyzed for trace elements typically associated with urban runoff. Trace-element concentrations in the less than 63 micrometer fraction of Amazon Creek bottom-sediment samples were compared with baseline concentrations (expected 95 percent confidence range) for soils from the Western United States and with concen- trations found in bottom sediment from the Willamette River Basin. Total-digestion concentrations of antimony, arsenic, cadmium, chromium, cobalt, copper, lead, manganese, mercury, nickel, silver, titanium, and zinc were enriched at some or all sites sampled. Whole-water samples from some sites contained concentrations of several chlorophenoxy-acid herbicides, the organophosphorus insecticide diazinon, and several semivolatile priority pollutants. Classes of compounds not detected in whole-water samples included carbamate insecticides, triazine and other nitrogen-containing herbicides, and purgeable organic compounds. Bottom-sediment samples contained many organochlorine compounds, including chlordane, DDT plus metabolites, dieldrin, endrin, heptachlor epoxide (a metabolite of heptachlor), and PCBs at some or all sites sampled. Twenty-four of 54 semivolatile compounds were detected in bottom- sediment samples at some or all sites sampled.

Potential Uses of Biomonitoring Data: A Case Study Using the Organophosphorus Pesticides Chlorpyrifos and Malathion

PubMed Central

Barr, Dana B.; Angerer, Jürgen

2006-01-01

Background Organophosphorus pesticides such as chlorpyrifos and malathion are widely used insecticides. They do not bioaccumulate appreciably in humans and are rapidly metabolized and excreted in the urine. In nonoccupational settings, exposures to these pesticides are typically sporadic and short-lived because the pesticides tend to degrade in the environment over time; however, dietary exposures may be more chronic. Biologic monitoring has been widely used to assess exposures, susceptibility, and effects of chlorpyrifos and malathion; thus, the information base on these compounds is data rich. For biomonitoring of exposure, chlorpyrifos and malathion have been measured in blood, but most typically their urinary metabolites have been measured. For assessing early effects and susceptibility, cholinesterase and microsomal esterase activities, respectively, have been measured. Objectives Although many biologic monitoring data have been generated and published on these chemicals, their interpretation is not straightforward. For example, exposure to environmental degradates of chlorpyrifos and malathion may potentially increase f urinary metabolite levels, thus leading to overestimation of exposure. Also, the temporal nature of the exposures makes the evaluation of both exposure and effects difficult. We present an overview of the current biomonitoring and other relevant data available on exposure to chlorpyrifos and malathion and the use of these data in various environmental public health applications. PMID:17107865

Plant-Associated Bacterial Degradation of Toxic Organic Compounds in Soil

PubMed Central

McGuinness, Martina; Dowling, David

2009-01-01

A number of toxic synthetic organic compounds can contaminate environmental soil through either local (e.g., industrial) or diffuse (e.g., agricultural) contamination. Increased levels of these toxic organic compounds in the environment have been associated with human health risks including cancer. Plant-associated bacteria, such as endophytic bacteria (non-pathogenic bacteria that occur naturally in plants) and rhizospheric bacteria (bacteria that live on and near the roots of plants), have been shown to contribute to biodegradation of toxic organic compounds in contaminated soil and could have potential for improving phytoremediation. Endophytic and rhizospheric bacterial degradation of toxic organic compounds (either naturally occurring or genetically enhanced) in contaminated soil in the environment could have positive implications for human health worldwide and is the subject of this review. PMID:19742157

Acute oral toxicity test of chemical compounds in silkworms.

PubMed

Usui, Kimihito; Nishida, Satoshi; Sugita, Takuya; Ueki, Takuro; Matsumoto, Yasuhiko; Okumura, Hidenobu; Sekimizu, Kazuhisa

2016-02-01

This study performed an acute oral toxicity test of 59 compounds in silkworms. These compounds are listed in OECD guidelines as standard substances for a cytotoxicity test, and median lethal dose (LD(50)) werecalculated for each compound. Acute oral LD(50) values in mammals are listed in OECD guidelines and acute oral LD(50) values in silkworms were determined in this study. R(2) for the correlation between LD(50) values in mammals and LD(50) values in silkworms was 0.66. In addition, the acute oral toxicity test in silkworms was performed by two different facilities, and test results from the facilities were highly reproducible. These findings suggest that an acute oral toxicity test in silkworms is a useful way to evaluate the toxicity of compounds in mammals.

NMR-based urine analysis in rats: prediction of proximal tubule kidney toxicity and phospholipidosis.

PubMed

Lienemann, Kai; Plötz, Thomas; Pestel, Sabine

2008-01-01

The aim of safety pharmacology is early detection of compound-induced side-effects. NMR-based urine analysis followed by multivariate data analysis (metabonomics) identifies efficiently differences between toxic and non-toxic compounds; but in most cases multiple administrations of the test compound are necessary. We tested the feasibility of detecting proximal tubule kidney toxicity and phospholipidosis with metabonomics techniques after single compound administration as an early safety pharmacology approach. Rats were treated orally, intravenously, inhalatively or intraperitoneally with different test compounds. Urine was collected at 0-8 h and 8-24 h after compound administration, and (1)H NMR-patterns were recorded from the samples. Variation of post-processing and feature extraction methods led to different views on the data. Support Vector Machines were trained on these different data sets and then aggregated as experts in an Ensemble. Finally, validity was monitored with a cross-validation study using a training, validation, and test data set. Proximal tubule kidney toxicity could be predicted with reasonable total classification accuracy (85%), specificity (88%) and sensitivity (78%). In comparison to alternative histological studies, results were obtained quicker, compound need was reduced, and very importantly fewer animals were needed. In contrast, the induction of phospholipidosis by the test compounds could not be predicted using NMR-based urine analysis or the previously published biomarker PAG. NMR-based urine analysis was shown to effectively predict proximal tubule kidney toxicity after single compound administration in rats. Thus, this experimental design allows early detection of toxicity risks with relatively low amounts of compound in a reasonably short period of time.

Development of marine toxicity data for ordnance compounds

USGS Publications Warehouse

Nipper, M.; Carr, R.S.; Biedenbach, J.M.; Hooten, R.L.; Miller, K.; Saepoff, S.

2001-01-01

A toxicity database for ordnance compounds was generated using eight compounds of concern and marine toxicity tests with five species from different phyla. Toxicity tests and endpoints included fertilization success and embryological development with the sea urchin Arbacia punctulata; zoospore germination, germling length, and cell number with the green macroalga Ulva fasciata; survival and reproductive success of the polychaete Dinophilus gyrociliatus; larvae hatching and survival with the redfish Sciaenops ocellatus; and survival of juveniles of the opossum shrimp Americamysis bahia (formerly Mysidopsis bahia). The studied ordnance compounds were 2,4- and 2,6-dinitrotoluene, 2,4,6-trinitrotoluene, 1,3-dinitrobenzene, 1,3,5-trinitrobenzene, 2,4,6-trinitrophenylmethylnitramine (tetryl), 2,4,6-trinitrophenol (picric acid), and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). The most sensitive toxicity test endpoints overall were the macroalga zoospore germination and the polychaete reproduction tests. The most toxic ordnance compounds overall were tetryl and 1,3,5-trinitrobenzene. These were also the most degradable compounds, often being reduced to very low or below-detection levels at the end of the test exposure. Among the dinitro- and trinitrotoluenes and benzenes, toxicity tended to increase with the level of nitrogenation. Picric acid and RDX were the least toxic chemicals tested overall.

Characterization of organophosphorus flame retardants' sorption on building materials and consumer products

EPA Science Inventory

Better understanding the transport mechanisms of organophosphorus flame-retardants (OPFRs) in the residential environment is important to more accurately estimate their indoor exposure and develop risk management strategies that protect human health. This study describes an impro...

Organophosphorus poisoning (acute).

PubMed

2007-03-01

Acute organophosphorus poisoning occurs after dermal, respiratory, or oral exposure to either low-volatility pesticides (e.g. chlorpyrifos, dimethoate) or high-volatility nerve gases (e.g. sarin, tabun). Most cases occur in resource-poor countries as a result of occupational or deliberate exposure to organophosphorus pesticides. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute organophosphorus poisoning? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: activated charcoal, alpha2 adrenergic receptor agonists, atropine, benzodiazepines, butyrylcholinesterase replacement therapy, cathartics, extracorporeal clearance, gastric lavage, glycopyrronium bromide, ipecacuanha, magnesium sulphate, milk or other home remedies, N-methyl-D-aspartate receptor antagonists, organophosphorus hydrolases, oximes, sodium bicarbonate, washing the poisoned person and removing contaminated clothing.

Environmental impact of pesticides after sewage treatment plants removal in four Spanish Mediterranean rivers

NASA Astrophysics Data System (ADS)

Campo, Julian; Masiá, Ana; Blasco, Cristina; Picó, Yolanda; Andreu, Vicente

2013-04-01

The re-use of sewage treatment plant (STP) effluents is currently one of the most employed strategies in several countries to deal with the water shortage problem. Some pesticides are bio-accumulative and due to their toxicity they can affect non-target organisms, especially in the aquatic ecosystems, threating their ecological status. Despite these facts, and to our knowledge, there are few peer-reviewed articles that report concentrations of pesticides in Spanish STPs. This work presents the results of an extensive survey that was carried out in October of 2010 in 15 of the STPs of Ebro, Guadalquivir, Jucar and Llobregat rivers in Spain. Forty-three currently used pesticides, belonging to anilide, neonicotinoid, thiocarbamate, acaricide, juvenile hormone mimic, insect growth regulator, urea, azole, carbamate, chloroacetanilide, triazine and organophosphorus, have been monitored. Integrated samples of influent and effluent, and dehydrated, lyophilized sludge from 15 STPs located along the rivers were analyzed for pesticide residues. With these data, removal efficiencies are also calculated. Extraction of water samples was performed through Solid Phase Extraction (SPE) and sludge samples were extracted using the QuEchERS method. Pesticide determination was carried out using Liquid Chromatograph - tandem Mass Spectrometry (LC-MS/MS). Recoveries ranged from 48% to 70%, in water samples, and from 40 to 105 %, in sludge samples. The limits of quantification were 0.01-5 ng L-1 for the former, and 0.1-5.0 ng g-1 for the latter. In terms of frequency of detection, 31 analytes were detected in influent, 29 in effluent and 11 in sludge samples. Organophosphorus pesticides were the most frequently detected in all wastewater samples, but azole, urea, triazine, neonicotinoid and the insect growth regulator were also commonly found. Imazalil revealed the maximum concentration in wastewater samples from all rivers except the Guadalquivir, in which diuron presented the maximum one. Eleven pesticides including five organophosphorus, two azoles, one triazine, one chloroacetanilide, one juvenile hormone mimic and one acaricide were detected in the sludge samples. Accordingly, organophosphorus were the most frequently detected pesticides in the sludge samples, but the highest concentration was observed for imazalil. The higher concentration of this azole in the influent and their possible stronger adsorption may be the reason for their higher concentration in the sludge samples. The removal efficiency of pesticides was calculated from the analyte concentration in influent (Cin) and effluent (Cef): [(Cin-Cef)/Cin] x 100%. The removal of organophosporus ranged from -810,47 to 93,11%, meanwhile azoles and ureas were not removed in the STPs. The poor elimination of pesticides by sewage treatment plants presented in this study could be related to the treatment process used, hydraulic and solid retention times, besides the dilution and temperature of the raw sewage and the plant's configuration. These poor efficiencies are responsible of the high pesticides concentration (e.g.diuron) found in some effluents, which may endanger water quality of the ecosystem when they are re-used or directly discharged into the river. In fact, with respect to the Maximum Allowable Concentrations (MAC) stipulated by the Directive 2008/105/EC for pesticides in inland and other surface waters (Council of the European Communities, 2008), diuron exceeded these limits. Nevertheless, it is important to emphasize that, even though, the pesticides concentrations measured were relatively low (according to directives); this study analysed just some of them. A wide variety of other compounds, including other pesticides and pesticides transformation products, may contribute to the bad quality of the water ecosystems. Acknowledgements: This work has been supported by by the Spanish Ministry of Science and Innovation through the project Consolider-Ingenio 2010 (CSD2009), as well as by this Ministry and the European Regional Development Funds (ERDF) (projects CGL2011-29703-C02-00, CGL2011-29703-C02-01, CGL2011-29703-C02-02).

The chemical nature of phenolic compounds determines their toxicity and induces distinct physiological responses in Saccharomyces cerevisiae in lignocellulose hydrolysates

PubMed Central

2014-01-01

We investigated the severity of the inhibitory effects of 13 phenolic compounds usually found in spruce hydrolysates (4-hydroxy-3-methoxycinnamaldehyde, homovanilyl alcohol, vanillin, syringic acid, vanillic acid, gallic acid, dihydroferulic acid, p-coumaric acid, hydroquinone, ferulic acid, homovanillic acid, 4-hydroxybenzoic acid and vanillylidenacetone). The effects of the selected compounds on cell growth, biomass yield and ethanol yield were studied and the toxic concentration threshold was defined for each compound. Using Ethanol Red, the popular industrial strain of Saccharomyces cerevisiae, we found the most toxic compound to be 4-hydroxy-3-methoxycinnamaldehyde which inhibited growth at a concentration of 1.8 mM. We also observed that toxicity did not generally follow a trend based on the aldehyde, acid, ketone or alcohol classification of phenolic compounds, but rather that other structural properties such as additional functional groups attached to the compound may determine its toxicity. Three distinctive growth patterns that effectively clustered all the compounds involved in the screening into three categories. We suggest that the compounds have different cellular targets, and that. We suggest that the compounds have different cellular targets and inhibitory mechanisms in the cells, also compounds who share similar pattern on cell growth may have similar inhibitory effect and mechanisms of inhibition. PMID:24949277

Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.

PubMed

Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A; Mishin, Vladimir; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

2016-08-01

Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity. © 2016 New York Academy of Sciences.

Novel approaches to mitigating parathion toxicity: targeting cytochrome P450–mediated metabolism with menadione

PubMed Central

Jan, Yi-Hua; Richardson, Jason R.; Baker, Angela A.; Mishin, Vladimir; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

2016-01-01

Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase (AChE). We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH–cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the FDA for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity. PMID:27441453

[Comparison of the effects of BI-6, a new asymmetric bipyridine oxime, with HI-6 oxime and obidoxime in combination with atropine on soman and fosdrine toxicity in mice].

PubMed

Kassa, J

1999-01-01

The therapeutic efficacy of the new asymmetric bispyridinium oxime BI-6 against acute toxicity of the highly toxic organophosphate soman and the organophosphorus insecticide fosdrin by means of affecting the LD50 values of these noxiores substances was compared with the effect of the hitherto most perspective oxime HI-6 and the classic obidoxime always in combination with the identical dose of atropine. At the equimolar level the effect of oxime BI-6 against fosdrin completely equals the effects of both oximes HI-6 and obidoxime. The effect of oxime BI-6 against soman is even more marked than the effect of HI-6 but this difference is not statistically significant. On the other hand, at the equi-effective level, the effect of oxime BI-6 against soman is statistically significantly lower than the effect of HI-6, and against fosdrin it is even lower than the effect of both remaining oximes. The effects of the new oxime BI-6 equal, or slightly exceed the therapeutic effect of HI-6 but at the equimolar level only. At the equi-effective level which respects the toxicity of the oxime and is therefore more important for practical use, it is a therapeutically weaker reactivator of acetylcholinesterase than HI-6.

Occurrence and transport of pesticides and alkylphenols in water samples along the Ebro River Basin

NASA Astrophysics Data System (ADS)

Navarro, Alícia; Tauler, Romà; Lacorte, Sílvia; Barceló, Damià

2010-03-01

SummaryWe report the temporal and geographical variations of a set of 30 pesticides (including triazines, organophosphorus and acetanilides) and industrial compounds in surface waters along the Ebro River during the period 2004-2006. Using descriptive statistics we found that the compounds with industrial origin (tributylphosphate, octylphenol and nonylphenol) appeared in over 60% of the samples analyzed and at very high concentrations, while pesticides had a point source origin in the Ebro delta area and overall low-levels, between 0.005 and 2.575 μg L -1. Correlations among pollutants and their distributions were studied using Principal Component Analysis (PCA), a multivariate exploratory data analysis technique which permitted us to discern between agricultural and industrial source contamination. Over a 3 years period a seasonal trend revealed highest concentrations of pesticides over the spring-summer period following pesticide application.

Head lice. Dimeticone is the pediculicide of choice.

PubMed

2014-07-01

Infestation of the scalp by head lice, or pediculosis, is a common, unpleasant but harmless parasitosis. For patients with pediculosis, which topical treatment eradicates the parasites effectively while causing the least harm? We reviewed the available evidence using the standard Prescrire methodology. Lice can be eradicated by shaving the head or combing the hair several times a day for several weeks with a fine-toothed lice comb, although combing is only completely effective in about 50% of cases. Pyrethroids (permethrin, phenothrin and bioallethrin), often combined with piperonyl butoxide, are insecticides that are neurotoxic to lice. The lice eradication rates achieved in trials of these agents are highly variable, ranging from 13% to 75% depending on the country, probably due to the development of resistance. In five randomised trials, the organophosphorus insecticide malathion was more effective than permethrin or phenothrin, achieving eradication rates of 80% to 98%. Topical application of the insecticides ivermectin or spinosad was effective in 75% to 85% of patients in randomised trials. Insecticides have mainly local adverse effects: pruritus and irritation of the scalp. Cases of malathion poisoning have been reported following topical application or ingestion. The long-term toxicity of insecticides is unclear; it therefore appears preferable to minimise their use. Agents that kill lice through physical mechanisms have few known adverse effects. It seems unlikely that lice will develop resistance to them. Dimeticone, a silicone compound, is not absorbed through the skin and provokes very few adverse effects. It is one of the better evaluated agents: in three randomised trials, 70% to 97% of patients were lice-free after two weeks. Other agents with a physical action on lice have been evaluated, each in one randomised trial including a few dozen patients. One of these, 1,2-octanediol, applied in an alcoholic solution, seemed to eradicate lice effectively with no notable adverse effects. It is advisable to avoid aerosol formulations due to the risk of bronchospasm, products containing terpenes as these compounds can cause seizures in infants and young children, and products that lack a child-proof cap. In practice, as of early 2014, pyrethroids are no longer the first-choice treatment for head lice: they are losing effectiveness and may be toxic in the long-term. Dimeticone is a better choice, because it has few known adverse effects and proven efficacy.

Flame retardant treatments of PBI fabric.

NASA Technical Reports Server (NTRS)

Temin, S. C.

1972-01-01

Fabrics knitted or woven from polybenzimidazole (PBI) fibers were treated to reduce flammability in oxygen atmospheres, particularly that of 5 psia oxygen. Bromination to approximately 15% weight gain of such fabrics led to markedly lower burning rates; samples brominated to over 80% weight gain were self-extinguishing in 5 psia oxygen. The loss in tensile strength of fabrics due to bromination was negligible although shrinkage was observed. Free fibers showed negligible losses on bromination. Treatment of PBI fabric with organophosphorus compounds also achieved self-extinguishing character in 5 psia oxygen but the enhanced flameproofing was largely lost on leaching. Reaction with POCl3 in pyridine led to a permanent reduction in flammability.

ORGANOPHOSPHORUS HYDROLASE-BASED AMPEROMETRIC SENSOR: MODULATION OF SENSITIVITY AND SUBSTRATE SELECTIVITY

EPA Science Inventory

The detection of organophosphate (OP) insecticides with nitrophenyl substituents is reported using an enzyme electrode composed of Organophosphorus Hydrolase (OPH) and albumin co-immobilized to a nylon net and attached to a carbon paste electrode. The mechanism for this biosen...

ORGANOPHOSPHORUS HYDROLASE-BASED ASSAY FOR ORGANOPHOSPHATE PESTICIDES

EPA Science Inventory

We report a rapid and versatile Organophosphorus hydrolase (OPH)-based method for measurement of organophosphates. This assay is based on a substrate-dependent change in pH at the local vicinity of the enzyme. The pH change is monitored using fluorescein isothiocyanate (FITC), ...

HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC SEPARATION OF THE ENANTIOMERS OF ORGANOPHOSPHORUS PESTICIDES ON POLYSACCHARIDE CHIRAL STATIONARY PHASES

EPA Science Inventory

High-performance liquid chromatographic separation of the individual enantiomers of 12 organophosphorus pesticides (OPs) was obtained on polysaccharide enantioselective HPLC columns using alkane-alcohol mobile phase. The OP pesticides were crotoxyphos, dialifor, fonofos, fenamiph...

CUMULATIVE RISK ANALYSIS FOR ORGANOPHOSPHORUS PESTICIDES

EPA Science Inventory

Cumulative Risk Analysis for Organophosphorus Pesticides
R. Woodrow Setzer, Jr. NHEERL MD-74, USEPA, RTP, NC 27711

The US EPA has recently completed a risk assessment of the effects of exposure to 33 organophosphorous pesticides (OPs) through the diet, water, and resi...

Sorption of triazine and organophosphorus pesticides on soil and biochar

USDA-ARS?s Scientific Manuscript database

Although a large number of reports are available on sorption and degradation of triazine and organophosphorus pesticides in soils, systematic studies are lacking to directly compare and predict the fate of agrochemicals having different susceptibilities for hydrolysis and other degradation pathways....

Declining ring-necked pheasants in the Klamath Basin, California: I. Insecticide exposure

USGS Publications Warehouse

Grove, Robert A.; Buhler, D.R.; Henny, Charles J.; Drew, A.D.

1998-01-01

A study of organophosphorus (OP) insecticide exposure was conducted on a declining population of ring-necked pheasants (Phasianus colchicus) associated with agricultural lands at Tule Lake National Wildlife Refuge (TLNWR) during the summers of 1990a??92. Findings at TLNWR were compared with a nearby pheasant population at Lower Klamath National Wildlife Refuge (LKNWR) not subjected to intensive farming or OP insecticide applications. Direct toxicity of anticholinesterase (antiChE) compounds (in this case methamidophos) killed 2 young pheasants (91 and 92% brain acetylcholinesterase [AChE] inhibition), but no deaths of adult radio-equipped hens were ascribed to direct insecticide intoxication. However, within 20 days postspray of OP insecticides, 68% (28 of 41) of the adult pheasants collected at TLNWR were exposed to antiChE insecticides, and exhibited brain AChE inhibition of 19a??62%, with 15% (6 of 41) showing >55% brain AChE inhibition. The lack of radio-equipped hens dying was unexpected because >50% brain AChE inhibition has been frequently used as a diagnostic tool for evaluating cause of death from antiChE insecticides. No young were radio-equipped, so the extent of the effects of insecticide exposure on the survivorship of young was unknown. It is concluded that insecticide exposure was not the major factor impacting the pheasant population (see Grove et al., in press), although some young were acutely intoxicated. However, the loss of insects killed by insecticide use may have contributed to food shortages of young pheasants, indirectly influencing survival.

DETECTION OF TOXICANTS ON BUILDING SURFACES FOLLOWING CHEMICAL ATTACK

EPA Science Inventory

A critical step prior to reoccupation of any facility following a chemical attack will be the monitoring of toxic compounds on surfaces within that facility. Low level detection of toxicant(s) is necessary to ensure that these compounds have been eliminated after decontamination...

Optimal choice of pH for toxicity and bioaccumulation studies of ionizing organic chemicals.

PubMed

Rendal, Cecilie; Kusk, Kresten Ole; Trapp, Stefan

2011-11-01

It is recognized that the pH of exposure solutions can influence the toxicity and bioaccumulation of ionizing compounds. The present study investigates whether it can be considered a general rule that an ionizable compound is more toxic and more bioaccumulative when in the neutral state. Three processes were identified to explain the behavior of ionizing compounds with changing pH: the change in lipophilicity when a neutral compound becomes ionized, electrical attraction, and the ion trap. The literature was screened for bioaccumulation and toxicity tests of ionizing organic compounds performed at multiple pH levels. Toxicity and bioconcentration factors (BCFs) were higher for acids at lower pH values, whereas the opposite was true for bases. The effect of pH was most pronounced when pH - pK(a) was in the range of -1 to 3 for acids, and -3 to 1 for bases. The factor by which toxicity and BCF changed with pH was correlated with the lipophilicity of the compound (log K(OW) of the neutral compound). For both acids and bases, the correlation was positive, but it was significant only for acids. Because experimental data in the literature were limited, results were supplemented with model simulations using a dynamic flux model based on the Fick-Nernst-Planck diffusion equation known as the cell model. The cell model predicts that bases with delocalized charges may in some cases show declining bioaccumulation with increasing pH. Little information is available for amphoteric and zwitterionic compounds; however, based on simulations with the cell model, it is expected that the highest toxicity and bioaccumulation of these compounds will be found where the compounds are most neutral, at the isoelectric point. Copyright © 2011 SETAC.

Compounds with species and cell type specific toxicity identified in a 2000 compound drug screen of neural stem cells and rat mixed cortical neurons.

PubMed

Malik, Nasir; Efthymiou, Anastasia G; Mather, Karly; Chester, Nathaniel; Wang, Xiantao; Nath, Avindra; Rao, Mahendra S; Steiner, Joseph P

2014-12-01

Human primary neural tissue is a vital component for the quick and simple determination of chemical compound neurotoxicity in vitro. In particular, such tissue would be ideal for high-throughput screens that can be used to identify novel neurotoxic or neurotherapeutic compounds. We have previously established a high-throughput screening platform using human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) and neurons. In this study, we conducted a 2000 compound screen with human NSCs and rat cortical cells to identify compounds that are selectively toxic to each group. Approximately 100 of the tested compounds showed specific toxicity to human NSCs. A secondary screen of a small subset of compounds from the primary screen on human iPSCs, NSC-derived neurons, and fetal astrocytes validated the results from >80% of these compounds with some showing cell specific toxicity. Amongst those compounds were several cardiac glycosides, all of which were selectively toxic to the human cells. As the screen was able to reliably identify neurotoxicants, many with species and cell-type specificity, this study demonstrates the feasibility of this NSC-driven platform for higher-throughput neurotoxicity screens. Published by Elsevier B.V.

DETOXIFICATION OF ORGANOPHOSPHATE PESTICIDES BY IMMOBILIZED ESCHERICHIA COLI EXPRESSING ORGANOPHOSPHORUS HYDROLASE ON CELL SURFACE. (R823663)

EPA Science Inventory

An improved whole-cell technology for detoxifying organophosphate nerve agents was recently developed based on genetically engineered Escherichia coli with organophosphorus hydrolase anchored on the surface. This article reports the immobilization of these novel biocatalys...

Furthering the Enzymatic Destruction of Nerve Agents

DTIC Science & Technology

2002-01-01

properties of an organophosphorus acid anhydrase from a halophilic bacterial isolate. J. Bacteriol. 173, 1938-1943. DeFrank, J.J.; Beaudry, W.T...Cheng, T.-c.; Harvey, S.P.; Stroup, A.N. and Szafraniec, L.L. (1993) Screening of halophilic bacteria and Alteromonas species for organophosphorus

Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay

EPA Science Inventory

Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphor...

[Determination of 44 organophosphorus pesticides in food by SPE disk extraction-capillary gas chromatography with pulsed flame photometric detection].

PubMed

Luo, Xiao-Fei; Yang, Yuan; Sun, Cheng-Jun

2012-01-01

To develop a method for the simultaneous determination of 44 organophosphorus pesticides in food by SPE disk extraction-capillary gas chromatography with pulsed flame photometric detection. Organophosphorus pesticides in food were extracted ultrasonically with water. Then the extract was cleaned-up with SPE disk and eluted with ethyl acetate. Finally the eluent was condensed to 1mL under N2 at 55 degrees C. Gas chromatography was applied for quantitative detection of the organophosphorus pesticides in the sample. The linear range of the method for all the pesticides were in the range of 0.01-0.5 mg/kg with correlation coefficients of 0.992-1.000. The detection limits of the method were in the range of 0.0005-0.01 mg/kg. The recoveries for most pesticides were 60%-120% with relative standard deviations of less than 15%. The method is simple, sensitive, environmentally friendly and suitable for the determination of organophosphorous pesticides in food.

Organotin compounds and aquatic bacteria: A review

NASA Astrophysics Data System (ADS)

Cooney, J. J.

1995-03-01

Organotins are toxic to microorganisms. Trisubstituted organotins (R3SnX) are considered more toxic than disubstituted (R2SnX2) or monosubstituted (RSnX3) compounds, and tetrasubstituted compounds (R4Sn) are not considered toxic. In the R3Sn series propyl-, butyl-, pentyl-, phenyl- and cyclohexyltins are the most toxic to microorganisms. Toxicity towards aerobes in the R3Sn series is related to total molecular surface area and to the octanol: water partition coefficient, Kow, which is a measure of hydrophobicity. Care must be taken when testing the toxicity of tin compounds in the laboratory, for a number of biological, chemical and physical factors can influence the apparent toxicity. Although TBT is generally the most toxic of the butyltins, there are instances where monobutyltin (MBT) is as toxic, or more toxic, than TBT to microorganisms. Thus, debutylation in the sequence TBT→DBT→MBT→Sn does not detoxity TBT for all microorganisms. Some microorganisms can methylate inorganic or organic tins under aerobic or anaerobic conditions. Methylation can also occur by chemical means and the relative contributions of biotic and abiotic mechanisms are not clear. It is difficult to isolate a pure culture which can methylate tin compounds aerobically, and it is difficult to isolate a pure culture which degrades TBT, suggesting that microbial consortiums may be involved in transformations of organotins in the aquatic environment. Methylation and debutylation alter the adsorbtivity and solubility of tin compounds; thus microorganisms can influence the environmental mobility of tin. TBT-resistant microorganisms can be isolated, and in some of them resistance to TBT can be plasmid-mediated.

Space Toxicology

NASA Technical Reports Server (NTRS)

James, John T.

2011-01-01

Safe breathing air for space faring crews is essential whether they are inside an Extravehicular Mobility Suit (EMU), a small capsule such as Soyuz, or the expansive International Space Station (ISS). Sources of air pollution can include entry of propellants, excess offgassing from polymeric materials, leakage of systems compounds, escape of payload compounds, over-use of utility compounds, microbial metabolism, and human metabolism. The toxicological risk posed by a compound is comprised of the probability of escaping to cause air pollution and the magnitude of adverse effects on human health if escape occurs. The risk from highly toxic compounds is controlled by requiring multiple levels of containment to greatly reduce the probability of escape; whereas compounds that are virtually non-toxic may require little or no containment. The potential for toxicity is determined by the inherent toxicity of the compound and the amount that could potentially escape into the breathing air.

A Review of the Toxicity of Compounds Found in Herbal Dietary Supplements.

PubMed

Hudson, Amy; Lopez, Elizabeth; Almalki, Ahmad J; Roe, Amy L; Calderón, Angela I

2018-07-01

Use of herbal dietary supplements by the public is common and has been happening for centuries. In the United States, the Food and Drug Administration has a limited scope of regulation over marketed herbal dietary supplements, which may contain toxic botanical compounds that pose a public health risk. While the Food and Drug Administration has made efforts to prohibit the sale of unsafe herbal dietary supplements, numerous reports have proliferated of adverse events due to these supplements. This literature review investigates bioactive plant compounds commonly used in herbal dietary supplements and their relative toxicities. Using primarily the National Library of Medicine journal database and SciFinder for current reports, 47 toxic compounds in 55 species from 46 plant families were found to demonstrate harmful effects due to hepatic, cardiovascular, central nervous system, and digestive system toxicity. This review further contributes a novel and comprehensive view of toxicity across the botanical dietary market, and investigates the toxicity of the top ten botanical dietary supplements purchased in the United States of America to gauge the exposure risk of toxicity to the public. The criteria of measuring toxicity in this review (plant compound, family, quantity, and toxicity effects) across the entire market in the United States, with special attention to those supplements whose exposure to the consumer is maximal, provides a unique contribution to the investigation of botanical supplements. Georg Thieme Verlag KG Stuttgart · New York.

Synthesis, Properties and Stereochemistry of 2-Halo-1,2λ⁵-oxaphosphetanes.

PubMed

Kolodiazhna, Anastasy O; Kolodiazhnyi, Oleg I

2016-10-17

Results of research into four-membered 2-halo-1,2λ⁵-oxaphosphetane phosphorus(V)-heterocycles are presented. The preparation of 2-halo-1,2λ⁵-oxaphosphetanes by reaction of P- haloylides with carbonyl compounds is described. The mechanism of asynchronous [2+2]-сycloaddition of ylides to aldehydes was proposed on the base of low-temperature NMR investigations. 2-Halo-1,2λ⁵-oxaphosphetanes were isolated as individual compounds and their structures were confirmed by ¹Н-, 13 C-, 19 F- and 31 Р-NMR spectra. These compounds are convenient reagents for preparing of various organic and organophosphorus compounds hardly available by other methods. Chemical and physical properties of the 2-halo-1,2λ⁵-oxaphosphetanes are reviewed. The 2-chloro-1,2λ⁵-oxaphosphetanes, rearrange with formation of 2-chloroalkyl-phosphonates or convert into trans -phosphorylated alkenes depending on the substituents at the α-carbon atom. Prospective synthetic applications of 2-halo-1,2λ⁵-oxaphosphetanes are analyzed. The 2-halo-1,2λ⁵-oxaphosphetanes may be easily converted to various alkenylphosphonates: allyl- or vinylphosphonates, phosphorus ketenes, thioketenes, ketenimines.

Continental bottled water assessment by stir bar sorptive extraction followed by gas chromatography-tandem mass spectrometry (SBSE-GC-MS/MS).

PubMed

Guart, Albert; Calabuig, Ignacio; Lacorte, Silvia; Borrell, Antonio

2014-02-01

This study was aimed to determine the presence of 69 organic contaminants in 77 representative bottled waters collected from 27 countries all over the world. All water samples were contained in polyethylene terephthalate bottles. Target compounds were (1) environmental contaminants (including 13 polycyclic aromatic hydrocarbons (PAHs), 31 pesticides including organochlorine (OCPs), organophosphorus, and pyrethroids; 7 polychlorinated biphenyls (PCBs); and 7 triazines) and (2) plasticizers (including 6 phthalates and 5 other compounds). Samples were analyzed by stir bar sorptive extraction followed by gas chromatography-tandem mass spectrometry. PAHs, OCPs, PCBs, and triazines, which are indicators of groundwater pollution, were not detected in most of the samples, except for naphthalene (0.005-0.202 μg/L, n = 16). On the other hand, plastic components were detected in 77 % of the samples. Most frequently detected compounds were dimethyl phthalate and benzophenone at concentrations of 0.005-0.125 (n = 41) and 0.014-0.921 (n = 32), respectively. Levels detected are discussed in terms of contamination origin and geographical distribution. Target compounds were detected at low concentrations. Results obtained showed the high quality of bottled water in the different countries around the world.

MOVEMENT AND DEPOSITION OF TWO ORGANOPHOSPHORUS PESTICIDES WITHIN A RESIDENCE AFTER INTERIOR AND EXTERIOR APPLICATIONS

EPA Science Inventory

Post-application temporal and spatial distributions of two organophosphorus pesticides, diazinon and chlorpyrifos, were monitored after homeowner applications for indoor and outdoor insect control. Samples were taken before and up to 12 days after treatments in the family room...

Water quality in Reedy Fork and Buffalo Creek basins in the Greensboro area, North Carolina, 1986-87

USGS Publications Warehouse

Davenport, M.S.

1989-01-01

Water and bottom-sediment samples were collected from April 1986 through September 1987 at 19 sites in Guilford County and the City of Greensboro, North Carolina. Sampling locations included 13 stream sites, two lakes that supply the City of Greensboro with drinking water, two City of Greensboro finished drinking-water filtration plants, and effluent from the two municipal wastewater plants prior to outfall into receiving streams. Water sampling consisted of six surveys during various stages of steady ground-water flow at all sites and high-flow-event sampling during two storms at six sites. Bottom-sediment samples were collected at three sites during two routine sampling surveys. A summary of nearly 22, 000 separate chemical or physical analyses of water samples or bottom sediment is presented and discussed as individual values, ranges of values, or median values with respect to the locations of sampling sites, streamflow conditions, or other information bearing on water-quality conditions under discussion. The results include discussions of general water-quality indicators; major ion, nutrient, and trace-element concentrations; acid and base/neutral extractable organic compounds; volatile organic compounds; and organochlorine and organophosphorus pesticides detected at each sampling site. Loadings of selected constituents are also estimated on a yearly and daily basis. The quality of the raw and finished water, municipal effluents, and streams in the Greensboro area are characterized by using State and Federal water-quality standards. Inorganic constituents most commonly found in excess of standards were iron, copper, zinc, arsenic, phosphorus, manganese, cyanide, and mercury. Relatively few organic compounds were detected; however, those consistently reported were phthalate, thihalomethane, organophosphorus pesticide, benzol, and phenolic compounds. Selected inorganic, physical, and total organic carbon data are used in a Wilcoxon test for two independent variables to statistically compare water-quality characteristics in selected rural, semideveloped and urban basins. During low-flow sampling, the constituents that differed significantly among all sites were calcium, magnesium, and chloride. During low flows, concentrations of orthophosphate, fluoride, sulfate, and TOC differed at the urban site from the rural and semideveloped and urban sites. There were no significant differences among sites in concentrations of sodium, suspended sediment, nickel, zinc, copper, and mercury during low flows. The Wilcoxon test performed on high-flow data indicated that concentrations of TOC, chloride, sulfate, suspended sediment, and nickel were not significantly different among the sites.

Literature-based compound profiling: application to toxicogenomics.

PubMed

Frijters, Raoul; Verhoeven, Stefan; Alkema, Wynand; van Schaik, René; Polman, Jan

2007-11-01

To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action.

Mono-oxime bisquaternary acetylcholinesterase reactivators with prop-1,3-diyl linkage-Preparation, in vitro screening and molecular docking.

PubMed

Musilek, Kamil; Komloova, Marketa; Holas, Ondrej; Horova, Anna; Pohanka, Miroslav; Gunn-Moore, Frank; Dohnal, Vlastimil; Dolezal, Martin; Kuca, Kamil

2011-01-15

The treatment of organophosphorus (OP) poisoning consists of the administration of a parasympatholytic agent (e.g., atropine), an anticonvulsant (e.g., diazepam) and an acetylcholinesterase (AChE) reactivator (e.g., obidoxime). The AChE reactivator is the causal treatment of OP exposure, because it cleaves the OP moiety covalently bound to the AChE active site. In this paper, fourteen novel AChE reactivators are described. Their design originated from a former promising compound K027. These compounds were synthesized, evaluated in vitro on human AChE (hAChE) inhibited by tabun, paraoxon, methylparaoxon and DFP and then compared to commercial hAChE reactivators (pralidoxime, HI-6, trimedoxime, obidoxime, methoxime) or previously prepared compounds (K027, K203). Three of these novel compounds showed a promising ability to reactivate hAChE comparable or better than the used standards. Consequently, a molecular docking study was performed for three of these promising novel compounds. The docking results confirmed the apparent influence of π-π or cation-π interactions and hydrogen bonding for reactivator binding within the hAChE active site cleft. The SAR features concerning the non-oxime part of the reactivator molecule are also discussed. Copyright © 2010 Elsevier Ltd. All rights reserved.

A comparative assessment of the acute inhalation toxicity of vanadium compounds.

PubMed

Rajendran, N; Seagrave, J C; Plunkett, L M; MacGregor, J A

2016-11-01

Vanadium compounds have become important in industrial processes, resulting in workplace exposure potential and are present in ambient air as a result of fossil fuel combustion. A series of acute nose-only inhalation toxicity studies was conducted in both rats and mice in order to obtain comparative data on the acute toxicity potential of compounds used commercially. V 2 O 3 , V 2 O 4 , and V 2 O 5 , which have different oxidation states (+3, +4, +5, respectively), were delivered as micronized powders; the highly water-soluble and hygroscopic VOSO 4 (+4) could not be micronized and was instead delivered as a liquid aerosol from an aqueous solution. V 2 O 5 was the most acutely toxic micronized powder in both species. Despite its lower overall percentage vanadium content, a liquid aerosol of VOSO 4 was more toxic than the V 2 O 5 particles in mice, but not in rats. These data suggest that an interaction of characteristics, i.e., bioavailability, solubility and oxidation state, as well as species sensitivity, likely affect the toxicity potential of vanadium compounds. Based on clinical observations and gross necropsy findings, the lung appeared to be the target organ for all compounds. The level of hazard posed will depend on the specific chemical form of the vanadium. Future work to define the inhalation toxicity potential of vanadium compounds of various oxidation states after repeated exposures will be important in understanding how the physico-chemical and biological characteristics of specific vanadium compounds interact to affect toxicity potential and the potential risks posed to human health.

Identification of water soluble and particle bound compounds causing sublethal toxic effects. A field study on sediments affected by a chlor-alkali industry.

PubMed

Bosch, Carme; Olivares, Alba; Faria, Melissa; Navas, Jose M; del Olmo, Iván; Grimalt, Joan O; Piña, Benjamín; Barata, Carlos

2009-08-13

A combination of cost effective sublethal Daphnia magna feeding tests, yeast- and cell culture-based bioassays and Toxicity Identification Evaluation (TIE) procedures was used to characterize toxic compounds within sediments collected in a river area under the influence of the effluents from a chlor-alkali industry (Ebro River, NE Spain). Tests were designed to measure and identify toxic compounds in the particulate and filtered water fractions of sediment elutriates. The combined use of bioassays responding to elutriates and dioxin-like compounds evidenced the existence of three major groups of hazardous contaminants in the most contaminated site: (A) metals such as cadmium and mercury bound to sediment fine particles that could be easily resuspended and moved downstream, (B) soluble compounds (presumably, lye) able to alkalinize water to toxic levels, and (C) organochlorine compounds with high dioxin-like activity. These results provided evidence that elutriate D. magna feeding responses can be used as surrogate assays for more tedious chronic whole sediment tests, and that the incorporation of such tests in sediment TIE procedures may improve the ability to identify the toxicity of particle-bound and water-soluble contaminants in sediments.

Assessment of ToxCast Phase II for Mitochondrial Liabilities Using a High-Throughput Respirometric Assay

PubMed Central

Wills, Lauren P.; Beeson, Gyda C.; Hoover, Douglas B.; Schnellmann, Rick G.; Beeson, Craig C.

2015-01-01

Previous high-throughput screens to identify mitochondrial toxicants used immortalized cell lines and focused on changes in mitochondrial membrane potential, which may not be sufficient and do not identify different types of mitochondrial dysfunction. Primary cultures of renal proximal tubule cells (RPTC) were examined with the Seahorse Extracellular Flux Analyzer to screen 676 compounds (5 μM; 1 h) from the ToxCast Phase II library for mitochondrial toxicants. Of the 676 compounds, 19 were classified as cytotoxicants, 376 were electron transport chain (ETC) inhibitors, and 5 were uncouplers. The remaining 276 compounds were examined after a 5-h exposure to identify slower acting mitochondrial toxicants. This experiment identified 3 cytotoxicants, 110 ETC inhibitors, and 163 compounds with no effect. A subset of the ToxCast Phase II library was also examined in immortalized human renal cells (HK2) to determine differences in susceptibility to mitochondrial toxicity. Of the 131 RPTC ETC inhibitors tested, only 14 were ETC inhibitors in HK2 cells. Of the 5 RPTC uncouplers, 1 compound was an uncoupler in HK2 cells. These results demonstrate that 73% (491/676) of the compounds in the ToxCast Phase II library compounds exhibit RPTC mitochondrial toxicity, overwhelmingly ETC inhibition. In contrast, renal HK2 cells are markedly less sensitive and only identified 6% of the compounds as mitochondrial toxicants. We suggest caution is needed when studying mitochondrial toxicity in immortalized cell lines. This information will provide mechanisms and chemical-based criteria for assessing and predicting mitochondrial liabilities of new drugs, consumer products, and environmental agents. PMID:25926417

Transformation of Organophosphorus Pesticides in the Presence of Aqueous Chlorine: Kinetics, Pathways, and Structure-Activity Relationships

EPA Science Inventory

The fate of organophosphorus (OP) pesticides in the presence of aqueous chlorine was investigated under simulated drinking water treatment conditions. Intrinsic rate coefficients were found for the reaction of hypochlorous acid (kHOCl,OP) and hypochlorite ion (kOCl,OP) for eight...

Comparison of the Developmental and Acute Neurotoxicity of a Library of Organophosphorus Pesticides Using a Vertebrate Behavioral Assay

EPA Science Inventory

The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphorus pesticides for neurotoxicity using behavioral tests in an in vivo, vertebrate, medium-throughput model (zebrafish; Danio rerio). Our behavioral testing paradigm assesses the e...

AMPEROMETRIC THICK-FILM STRIP ELECTRODES FOR MONITORING ORGANOPHOSPHATE NERVE AGENTS BASED ON IMMOBILIZED ORGANOPHOSPHORUS HYDROLASE. (R823663)

EPA Science Inventory

An amperometric biosensor based on the immobilization of organophosphorus hydrolase
(OPH) onto screen-printed carbon electrodes is shown useful for the rapid, sensitive, and low-cost
detection of organophosphate (OP) nerve agents. The sensor relies upon the sensitive and ra...

Monoclonal antibody-based broad-specificity immunoassay for monitoring organophosphorus pesticides in environmental water samples

USDA-ARS?s Scientific Manuscript database

The extensive use of organophosphorus pesticides (OPs) in agriculture and domestic settings can result in widespread water contamination. The development of easy-to-use and rapid-screening immunoassay methods in a class-selective manner is a topic of considerable environmental interest. In this wo...

Effects of Organophosphorus Flame Retardants on Spontaneous Activity in Neuronal Networks Grown on Microelectrode Arrays

EPA Science Inventory

EFFECTS OF ORGANOPHOSPHORUS FLAME RETARDANTS ON SPONTANEOUS ACTIVITY IN NEURONAL NETWORKS GROWN ON MICROELECTRODE ARRAYS TJ Shafer1, K Wallace1, WR Mundy1, M Behl2,. 1Integrated Systems Toxicology Division, NHEERL, USEPA, RTP, NC, USA, 2National Toxicology Program, NIEHS, RTP, NC...

COMPARISON OF THE NON-ADDITIVE INTERACTIONS OF AN ORGANOPHOSPHORUS PESTICIDE MIXTURE IN ADULT AND PREWEANLING RATS.

EPA Science Inventory

Critical features of risk assessment include the evaluation of risk following exposure to pesticide mixtures as well as the potential for increased sensitivity of the young. This research tested for interaction(s) using a mixture of five organophosphorus (OP) pesticides (chlorp...

EFFECTS OF TEMPERATURE AND SOLVENT COMPOSITION ON THE CHIRALCEL OJ SEPARATION OF CHIRAL ORGANOPHOSPHORUS PESTICIDES

EPA Science Inventory

The separation of the enantiomers of twelve organophosphorus pesticides (OPs) was investigated on the CHIRALCEL?OJ column to determine whether the mobile phase composition, flow rate and column temperature could be optimized to yield at least partial separation of the enantiomers...

Relieving Mipafox Inhibition in Organophosphorus Acid Anhydrolase by Rational Design

DTIC Science & Technology

2013-03-01

acid anhydrolase (OPAA, EC 3.1.8.2) was purified from halophilic Alteromonas sp. bacteria. OPPA displayed hydrolysis activity against several highly...2010, 49, 547–559. 3. DeFrank, J.J.; Cheng, T.-C. Purification and Properties of Organophosphorus Acid Anhydrolase from a Halophilic Bacterial

Pharmacological treatment of organophosphorus insecticide poisoning: the old and the (possible) new.

PubMed

Eddleston, Michael; Chowdhury, Fazle Rabbi

2016-03-01

Despite being a major clinical and public health problem across the developing world, responsible for at least 5 million deaths over the last three decades, the clinical care of patients with organophosphorus (OP) insecticide poisoning has little improved over the last six decades. We are still using the same two antidotes - atropine and oximes - that first came into clinical use in the late 1950s. Clinical research in South Asia has shown how improved regimens of atropine can prevent deaths. However, we are still unsure about which patients are most likely to benefit from the use of oximes. Supplemental antidotes, such as magnesium, clonidine and sodium bicarbonate, have all been proposed and studied in small trials without production of definitive answers. Novel antidotes such as nicotinic receptor antagonists, beta-adrenergic agonists and lipid emulsions are being studied in large animal models and in pilot clinical trials. Hopefully, one or more of these affordable and already licensed antidotes will find their place in routine clinical care. However, the large number of chemically diverse OP insecticides, the varied poisoning they produce and their varied response to treatment might ultimately make it difficult to determine definitively whether these antidotes are truly effective. In addition, the toxicity of the varied solvents and surfactants formulated with the OP active ingredients complicates both treatment and studies. It is possible that the only effective way to reduce deaths from OP insecticide poisoning will be a steady reduction in their agricultural use worldwide. © 2015 The British Pharmacological Society.

Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms

PubMed Central

Burke, Richard D.; Todd, Spencer W.; Lumsden, Eric; Mullins, Roger J.; Mamczarz, Jacek; Fawcett, William P.; Gullapalli, Rao P.; Randall, William R.; Pereira, Edna F. R.; Albuquerque, Edson X.

2017-01-01

Organophosphorus (OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain. PMID:28791702

Predicting the aquatic risk of realistic pesticide mixtures to species assemblages in Portuguese river basins.

PubMed

Silva, Emília; Daam, Michiel A; Cerejeira, Maria José

2015-05-01

Although pesticide regulatory tools are mainly based on individual substances, aquatic ecosystems are usually exposed to multiple pesticides from their use on the variety of crops within the catchment of a river. This study estimated the impact of measured pesticide mixtures in surface waters from 2002 and 2008 within three important Portuguese river basins ('Mondego', 'Sado' and 'Tejo') on primary producers, arthropods and fish by toxic pressure calculation. Species sensitivity distributions (SSDs), in combination with mixture toxicity models, were applied. Considering the differences in the responses of the taxonomic groups as well as in the pesticide exposures that these organisms experience, variable acute multi-substance potentially affected fractions (msPAFs) were obtained. The median msPAF for primary producers and arthropods in surface waters of all river basins exceeded 5%, the cut-off value used in the prospective SSD approach for deriving individual environmental quality standards. A ranking procedure identified various photosystem II inhibiting herbicides, with oxadiazon having the relatively largest toxic effects on primary producers, while the organophosphorus insecticides, chlorfenvinphos and chlorpyrifos, and the organochloride endosulfan had the largest effects on arthropods and fish, respectively. These results ensure compliance with European legislation with regard to ecological risk assessment and management of pesticides in surface waters. Copyright © 2015. Published by Elsevier B.V.

Interactions of pesticides with membrane drug transporters: Implications for toxicokinetics and toxicity.

PubMed

Chedik, Lisa; Bruyere, Arnaud; Bacle, Astrid; Potin, Sophie; Le Vée, Marc; Fardel, Olivier

2018-06-10

Drug transporters are now recognized as major actors of pharmacokinetics. They are also likely implicated in toxicokinetics and toxicology of environmental pollutants, notably pesticides, to which humans are widely exposed and which are known to exert various deleterious effects towards health. Interactions of pesticides with drug transporters are therefore important to consider. Areas covered: This review provides an overview of the interactions of pesticides with membrane drug transporters, i.e., inhibition of their activity, regulation of their expression and handling of pesticides. Consequences for toxicokinetics and toxicity of pesticides are additionally summarized and discussed. Expert opinion: Some pesticides belonging to several chemical classes, such as organochlorine, pyrethroid and organophosphorus pesticides, have been demonstrated to interact with various uptake and efflux drug transporters, including the efflux pump P-glycoprotein and the uptake organic cation transporters (OCTs). This provides the proof of the concept that pesticide-transporter relationships merit attention. More extensive and systematic characterization of pesticide-transporter relationships, possibly through the use of in silico methods, is however likely required. In addition, consideration of transporter polymorphisms, pesticide mixture effects and realistic pesticide concentrations reached in humans, may help to better define the in vivo relevance of pesticide-transporter interactions in terms of toxicokinetics and toxicity.

Classifying environmental pollutants: Part 3. External validation of the classification system.

PubMed

Verhaar, H J; Solbé, J; Speksnijder, J; van Leeuwen, C J; Hermens, J L

2000-04-01

In order to validate a classification system for the prediction of the toxic effect concentrations of organic environmental pollutants to fish, all available fish acute toxicity data were retrieved from the ECETOC database, a database of quality-evaluated aquatic toxicity measurements created and maintained by the European Centre for the Ecotoxicology and Toxicology of Chemicals. The individual chemicals for which these data were available were classified according to the rulebase under consideration and predictions of effect concentrations or ranges of possible effect concentrations were generated. These predictions were compared to the actual toxicity data retrieved from the database. The results of this comparison show that generally, the classification system provides adequate predictions of either the aquatic toxicity (class 1) or the possible range of toxicity (other classes) of organic compounds. A slight underestimation of effect concentrations occurs for some highly water soluble, reactive chemicals with low log K(ow) values. On the other end of the scale, some compounds that are classified as belonging to a relatively toxic class appear to belong to the so-called baseline toxicity compounds. For some of these, additional classification rules are proposed. Furthermore, some groups of compounds cannot be classified, although they should be amenable to predictions. For these compounds additional research as to class membership and associated prediction rules is proposed.

Toxicities of emamectin benzoate homologues and photodegradates to Lepidoptera.

PubMed

Argentine, Joseph A; Jansson, Richard K; Starner, Van R; Halliday, W Ross

2002-12-01

The toxicity of a number of emamectin benzoate homologues and photodegradates to five species of Lepidoptera was investigated using diet and foliar bioassays. The emamectin benzoate homologues B1a and B1b were equally toxic in the diet and foliar assays to Spodoptera exigua (Hübner), Heliothis virescens (F.), Tricoplusia ni (Hübner), and Spodoptera frugiperda (J. E. Smith), within each of these species. Plutella xylostella (L.) was the most sensitive species to emamectin benzoate. The AB1a photodegradate of emamectin benzoate was as toxic as the parent compound in the diet assay. However, in the foliage assay AB1a was 4.4-fold less toxic to S. exigua than the parent compound. The MFB1a photodegradate of emamectin benzoate was as toxic as the parent compound to P. xylostella, and 3.1 to 6.2 times as toxic as the parent compound to the other species in the diet assay. The order of toxicity of the photodegradates were AB1a > MFB1a > FAB1a > 8,9-Z-MAB1a > PAB1a.

Toxicity prediction of compounds from turmeric (Curcuma longa L).

PubMed

Balaji, S; Chempakam, B

2010-10-01

Turmeric belongs to the ginger family Zingiberaceae. Currently, cheminformatics approaches are not employed in any of the spices to study the medicinal properties traditionally attributed to them. The aim of this study is to find the most efficacious molecule which does not have any toxic effects. In the present study, toxicity of 200 chemical compounds from turmeric were predicted (includes bacterial mutagenicity, rodent carcinogenicity and human hepatotoxicity). The study shows out of 200 compounds, 184 compounds were predicted as toxigenic, 136 compounds are mutagenic, 153 compounds are carcinogenic and 64 compounds are hepatotoxic. To cross validate our results, we have chosen the popular curcumin and found that curcumin and its derivatives may cause dose dependent hepatotoxicity. The results of these studies indicate that, in contrast to curcumin, few other compounds in turmeric which are non-mutagenic, non-carcinogenic, non-hepatotoxic, and do not have any side-effects. Hence, the cost-effective approach presented in this paper could be used to filter toxic compounds from the drug discovery lifecycle. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donlon, B.A.; Razo-Flores, E.; Field, J.A.

1995-11-01

N-substituted aromatics are important priority pollutants entering the environment primarily through anthropogenic activities associated associated with the industrial production of dyes, explosives, pestides, and pharmaceuticals. Anaerobic treatment of wastewaters discharged by these industries could potentially be problematical as a result of the high toxicity of N-substituted aromatics. The objective of this study was to examine the structure-toxicity relationship of N-substituted aromatic compounds to acetoclastic methanogenic bacteria. The toxicity was assayed to serum flasks by measuring methane production in granular sludge. Unacclimated cultures were used to minimize the biotransformation of the toxic organic chemicals during the test. The nature and themore » degree of the aromatic substitution were observed to have a profound effect on the toxicity of the test compound. Nitroaromatic compounds were, on the average, over 500-fold more toxic than their corresponding aromatic amines. Considering the facile reduction of nitro groups by anerobic microorganisms, a dramatic detoxification of nitroaromatics towards methanogens can be expected to occur during anaerobic wastewater treatment. While the toxicity exerted by the N-substituted aromatic compounds was closely correlated with compound apolarity (log P), it was observed that at any given log P, N-substituted phenols had a toxicity that was 2 orders of magnitude higher than that of chlorophenols and alkylphenols. This indicates that toxicity due to the chemical reactivity of nitroaromatics is much more important than partitioning effects in bacterial membranes. 41 refs., 3 figs., 1 tab.« less

ANTICHOLINESTERASE INSECTICIDE RETROSPECTIVE

PubMed Central

Casida, John E.; Durkin, Kathleen A.

2012-01-01

The anticholinesterase (antiChE) organophosphorus (OP) and methylcarbamate (MC) insecticides have been used very effectively as contact and systemic plant protectants for seven decades. About 90 of these compounds are still in use – the largest number for any insecticide chemotype or mode of action. In both insects and mammals, AChE inhibition and acetylcholine accumulation leads to excitation and death. The cholinergic system of insects is located centrally (where it is protected from ionized OPs and MCs) but not at the neuromuscular junction. Structural differences between insect and mammalian AChE are also evident in their genomics, amino acid sequences and active site conformations. Species selectivity is determined in part by inhibitor and target site specificity. Pest population selection with OPs and MCs has resulted in a multitude of modified AChEs of altered inhibitor specificity some conferring insecticide resistance and others enhancing sensitivity. Much of the success of antiChE insecticides results from a suitable balance of bioactivation and detoxification by families of CYP450 oxidases, hydrolases, glutathione S-transferases and others. Known inhibitors for these enzymes block detoxification and enhance potency which is particularly important in resistant strains. The current market for OPs and MCs of 19% of worldwide insecticide sales is only half of that of 10 years ago for several reasons: there have been no major new compounds for 30 years; resistance has eroded their effectiveness; human toxicity problems are still encountered; the patents have expired reducing the incentive to update registration packages; alternative chemotypes or control methods have been developed. Despite this decline, they still play a major role in pest control and the increasing knowledge on their target sites and metabolism may make it possible to redesign the inhibitors for insensitive AChEs and to target new sites in the cholinergic system. The OPs and MCs are down but not out. PMID:22926007

Anticholinesterase insecticide retrospective.

PubMed

Casida, John E; Durkin, Kathleen A

2013-03-25

The anticholinesterase (antiChE) organophosphorus (OP) and methylcarbamate (MC) insecticides have been used very effectively as contact and systemic plant protectants for seven decades. About 90 of these compounds are still in use - the largest number for any insecticide chemotype or mode of action. In both insects and mammals, AChE inhibition and acetylcholine accumulation leads to excitation and death. The cholinergic system of insects is located centrally (where it is protected from ionized OPs and MCs) but not at the neuromuscular junction. Structural differences between insect and mammalian AChE are also evident in their genomics, amino acid sequences and active site conformations. Species selectivity is determined in part by inhibitor and target site specificity. Pest population selection with OPs and MCs has resulted in a multitude of modified AChEs of altered inhibitor specificity some conferring insecticide resistance and others enhancing sensitivity. Much of the success of antiChE insecticides results from a suitable balance of bioactivation and detoxification by families of CYP450 oxidases, hydrolases, glutathione S-transferases and others. Known inhibitors for these enzymes block detoxification and enhance potency which is particularly important in resistant strains. The current market for OPs and MCs of 19% of worldwide insecticide sales is only half of that of 10 years ago for several reasons: there have been no major new compounds for 30 years; resistance has eroded their effectiveness; human toxicity problems are still encountered; the patents have expired reducing the incentive to update registration packages; alternative chemotypes or control methods have been developed. Despite this decline, they still play a major role in pest control and the increasing knowledge on their target sites and metabolism may make it possible to redesign the inhibitors for insensitive AChEs and to target new sites in the cholinergic system. The OPs and MCs are down but not out. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Indoor sorption of surrogates for sarin and related nerve agents.

PubMed

Singer, Brett C; Hodgson, Alfred T; Destaillats, Hugo; Hotchi, Toshifumi; Revzan, Kenneth L; Sextro, Richard G

2005-05-01

Sorption rate parameters were determined for three organophosphorus (OP) compounds [dimethyl methylphosphonate (DMMP), diethyl ethylphosphonate (DEEP), and triethyl phosphate (TEP)] as surrogates for the G-type nerve agents sarin (GB), soman (GD), and tabun (GA). OP surrogates were injected and vaporized with additional volatile organic compounds into a 50 m3 chamber finished with painted wallboard. Experiments were conducted at two furnishing levels: (i) chamber containing only hard surfaces including a desk, a bookcase, tables, and chairs and (ii) with the addition of plush materials including carpet with cushion, draperies, and upholstered furniture. Each furnishing level was studied with aged and new painted wallboard. Gas-phase concentrations were measured during sealed chamber adsorb and desorb phases and then fit to three mathematical variations of a previously proposed sorption model having a surface sink and allowing for an embedded sink. A four-parameter model allowing unequal transport rates between surface and embedded sinks provided excellent fits for all conditions. To evaluate the potential effect of sorption, this model was incorporated into an indoor air quality simulation model to predict indoor concentrations of a G-type agent and a nonsorbing agent for hypothetical outdoor releases with shelter-in-place (SIP) response. Sorption was simulated using a range of parameters obtained experimentally. Simulations considered outdoor Gaussian plumes of 1- and 5-h duration and infiltration rates of 0.1, 0.3, and 0.9 h(-1). Indoor toxic loads (TL) for a 10-h SIP were calculated as integral C2 dt for a G-type agent. For the 5-h plume, sheltering reduced TLs for the nonsorbing agent to approximately 10-65% of outdoor levels. Analogous TLs for a G-type agent were 2-31% or 0.3-12% of outdoor levels assuming slow or moderate sorption. The relative effect of sorption was more pronounced for the longer plume and higher infiltration rates.

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

PubMed Central

2016-01-01

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides. PMID:27551784

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.

PubMed

Lockridge, Oksana; Norgren, Robert B; Johnson, Rudolph C; Blake, Thomas A

2016-09-19

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides.

In vitro effect of fenthion on human lymphocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rani, M.V.U.; Rao, M.S.

1991-08-01

Fenthion is an organophosphorus insecticide which is extensively used in control of leaf hoppers, cutworms, mites on vegetable crops. It has been reported that organophosphorus pesticides cause a significant increase in sister chromatid exchanges in mammalian cell lines. A significant increase of chromosomal aberrations has been reported in rural population exposed to pesticides. Organosphosphorus pesticides malathion, diazinon, dimethoate, phosdrin and dursban induced sister chromatid exchanges in human lymphoid cells. Exchange type of aberration has been reported in fluoriculturist who were exposed to organophosphorus, organochlorine pesticides. In the present investigation an attempt has been made to evaluate the cytogenetic effect ofmore » fenthion in human lymphocyte cultures in vitro.« less

[Assessment of the relationship of properties of chemical compounds and their toxicity to a unified hygienic standardization for chemicals].

PubMed

Trushkov, V F; Perminov, K A; Sapozhnikova, V V; Ignatova, O L

2013-01-01

The connection of thermodynamic properties and parameters of toxicity of chemical substances was determined. Obtained data are used for the evaluation of toxicity and hygienic rate setting of chemical compounds. The relationship between enthalpy and toxicity of chemical compounds has been established. Orthogonal planning of the experiment was carried out in the course of the investigations. Equation of unified hygienic rate setting in combined, complex, conjunct influence on the organism is presented. Prospects of determination of toxicity and methodology of unified hygienic rate setting in combined, complex, conjunct influence on the organism are presented

Prediction of human population responses to toxic compounds by a collaborative competition.

PubMed

Eduati, Federica; Mangravite, Lara M; Wang, Tao; Tang, Hao; Bare, J Christopher; Huang, Ruili; Norman, Thea; Kellen, Mike; Menden, Michael P; Yang, Jichen; Zhan, Xiaowei; Zhong, Rui; Xiao, Guanghua; Xia, Menghang; Abdo, Nour; Kosyk, Oksana; Friend, Stephen; Dearry, Allen; Simeonov, Anton; Tice, Raymond R; Rusyn, Ivan; Wright, Fred A; Stolovitzky, Gustavo; Xie, Yang; Saez-Rodriguez, Julio

2015-09-01

The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson's r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.

In vitro screening of organotin compounds and sediment extracts for cytotoxicity to fish cells.

PubMed

Giltrap, Michelle; Macken, Ailbhe; McHugh, Brendan; McGovern, Evin; Foley, Barry; Davoren, Maria

2011-01-01

The present study reports an in vitro screening method for contaminants in sediment samples utilizing an RTG-2 cell line. This technique integrates cytotoxicity testing with analytical chemistry with the aim of achieving a toxicity evaluation of the sediment sample. The toxic effect of individual organotin (OT) compounds and their presence in the sediment sample is the focus of the present study; however, other contaminants are also discussed. The following OT compounds: tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), and a sediment solvent extract are exposed to the RTG-2 fish cell line. Both the alamar blue (AB) and neutral red (NR) assays are used to assess cytotoxicity after 24-h and 96-h exposure. Methodology for preparation of a sediment solvent extract suitable for biological testing and analytical determination is also described. With the RTG-2 cells, the AB and NR assays had comparable sensitivity for each individual OT compound exposure after 24 h, with TPT being the most toxic compound tested. The individual OT compound concentrations required to induce a 50% toxic effect on the cells (369 ng ml⁻¹ TBT, 1,905 ng ml⁻¹ DBT) did not equate to the concentrations of these contaminants present in the sediment extract that induced a 50% effect on the cells (294 ng ml⁻¹ TBT, 109 ng ml⁻¹ DBT). The solvent extract therefore exhibited a greater toxicity, and this suggests that the toxic effects observed were not due to OT compounds alone. The presence of other contaminants in the solvent extract is confirmed with chemical analysis, warranting further toxicity testing of contaminant mixtures and exposure to the cell line to further elucidate a complete toxicity evaluation. © 2010 SETAC.

Occurrences of organophosphorus esters and phthalates in the microplastics from the coastal beaches in north China.

PubMed

Zhang, Haibo; Zhou, Qian; Xie, Zhiyong; Zhou, Yang; Tu, Chen; Fu, Chuancheng; Mi, Wenying; Ebinghaus, Ralf; Christie, Peter; Luo, Yongming

2018-03-01

Chemical pollution in the microplastics has been concerned worldwide as pollutants might potentially transfer from the environment to living organisms via plastics. Here, we investigate organophosphorus esters (OPEs) and phthalic acid esters (PAEs) in the beached microplastics collected from 28 coastal beaches of the Bohai and Yellow Sea in north China. The analyzed microplastics included polyethylene (PE) pellets and fragments, polypropylene (PP) flakes and fragments and polystyrene (PS) foams. The tris-(2-chloroethyl)-phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCPP) and di-(2-ethylhexyl) phthalate (DEHP) were the three predominant compounds found overall. The maximum Σ4 OPEs concentration was 84,595.9ngg -1 , almost three orders of magnitude higher than the maximum Σ9 PAEs concentration. The PP flakes and PS foams contained the highest concentrations of the additives in contrast to the PE pellets which contained the lowest. The high concentration level of carcinogenic chlorinated OPEs and DEHP with endocrine disrupting effects implied the suggested potential hazards to coastal organisms. Spatial differences and compositional variation of the additives among the different microplastics suggests different origins and residence times in the coastal environment. This indicates that the characteristics of chemical additives might be a useful approach when tracing sources of microplastics in the environment. Copyright © 2017 Elsevier B.V. All rights reserved.

Poisoning severity score, APACHE II and GCS: effective clinical indices for estimating severity and predicting outcome of acute organophosphorus and carbamate poisoning.

PubMed

Sam, Kishore Gnana; Kondabolu, Krishnakanth; Pati, Dipanwita; Kamath, Asha; Pradeep Kumar, G; Rao, Padma G M

2009-07-01

Self-poisoning with organophosphorus (OP) compounds is a major cause of morbidity and mortality across South Asian countries. To develop uniform and effective management guidelines, the severity of acute OP poisoning should be assessed through scientific methods and a clinical database should be maintained. A prospective descriptive survey was carried out to assess the utility of severity scales in predicting the outcome of 71 organophosphate (OP) and carbamate poisoning patients admitted during a one year period at the Kasturba Hospital, Manipal, India. The Glasgow coma scale (GCS) scores, acute physiology and chronic health evaluation II (APACHE II) scores, predicted mortality rate (PMR) and Poisoning severity score (PSS) were estimated within 24h of admission. Significant correlation (P<0.05) between PSS and GCS and APACHE II and PMR scores were observed with the PSS scores predicting mortality significantly (P< or =0.001). A total of 84.5% patients improved after treatment while 8.5% of the patients were discharged with severe morbidity. The mortality rate was 7.0%. Suicidal poisoning was observed to be the major cause (80.2%), while other reasons attributed were occupational (9.1%), accidental (6.6%), homicidal (1.6%) and unknown (2.5%) reasons. This study highlights the application of clinical indices like GCS, APACHE, PMR and severity scores in predicting mortality and may be considered for planning standard treatment guidelines.

Mechanistic insights into the luminescent sensing of organophosphorus chemical warfare agents and simulants using trivalent lanthanide complexes.

PubMed

Dennison, Genevieve H; Johnston, Martin R

2015-04-20

Organophosphorus chemical warfare agents (OP CWAs) are potent acetylcholinesterase inhibitors that can cause incapacitation and death within minutes of exposure, and furthermore are largely undetectable by the human senses. Fast, efficient, sensitive and selective detection of these compounds is therefore critical to minimise exposure. Traditional molecular-based sensing approaches have exploited the chemical reactivity of the OP CWAs, whereas more recently supramolecular-based approaches using non-covalent interactions have gained momentum. This is due, in part, to the potential development of sensors with second-generation properties, such as reversibility and multifunction capabilities. Supramolecular sensors also offer opportunities for incorporation of metal ions allowing for the exploitation of their unique properties. In particular, trivalent lanthanide ions are being increasingly used in the OP CWA sensing event and their use in supramolecular sensors is discussed in this Minireview. We focus on the fundamental interactions of simple lanthanide systems with OP CWAs and simulants, along with the development of more elaborate and complex systems including those containing nanotubes, polymers and gold nanoparticles. Whilst literature investigations into lanthanide-based OP CWA detection systems are relatively scarce, their unique and versatile properties provide a promising platform for the development of more efficient and complex sensing systems into the future. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Detection of residual organochlorine and organophosphorus pesticides in agricultural soil in Rio Verde region of San Luis Potosi, Mexico.

PubMed

Velasco, Antonio; Hernández, Sergio; Ramírez, Martha; Ortíz, Irmene

2014-01-01

Organochlorine pesticides were intensively used in Mexico from 1950 until their ban and restriction in 1991. However, the presence of these compounds is commonly reported in many regions of the country. The aim of the present study was to identify and quantify residual organochlorine and organophosphorus pesticides in agricultural soil in Rio Verde region, San Luis Potosi state, which has been identified as possibly polluted by pesticides. Composed samples from 24 zones covering an area of approximately 5,440 ha were analyzed. The most frequently found pesticides were p,p'-DDT followed by ,p,p'-DDE, heptachlor, endosulfan and γ-HCH whose frequency rates were 100, 91, 83 and 54%, respectively. The concentration of p,p'-DDT in the crops grown in these soils was in the following order: chili > maize > tomato > alfalfa. The results obtained in this study show that p,p'-DDT values are lower or similar to those found in other agricultural regions of Mexico. Methyl and ethyl parathion were the most frequent organophosphate pesticide detected in 100% and 62.5% of the samples with average concentrations of 25.20 and 47.48 μg kg(-1), respectively. More research is needed to establish the background levels of pesticides in agricultural soils and their potential ecological and human health effects in this region.

Organophosphorus pesticide residues in milled rice (Oryza sativa) on the Chinese market and dietary risk assessment.

PubMed

Chen, Chen; Li, Yun; Chen, Mingxue; Chen, Zhijun; Qian, Yongzhong

2009-03-01

The present study investigates the occurrence of acetylcholinesterase (AChE)-inhibiting organophosphorus (OP) pesticide residues in milled rice samples obtained form local markets in China during the period 2004-2006 and estimates their cumulative exposure. Concentrations of OP pesticides were determined by gas chromatography with flame photometric detection (GC-FPD). The results showed that 9.3% of the samples contained detectable residues of at least one of the seven target OP pesticides (chlorpyrifos, dichlorvos, omethoate, methamidophos, parathion-methyl, parathion and triazophos) mainly used for agriculture in China, with concentrations ranging 0.011-1.756 mg kg(-1). Rice consumption data was obtained from an individual food consumption survey. Relative potency factors (RPFs) for each pesticide were calculated with methamidophos as the index compound (IC), using 1- or 2-year chronic non-observed adverse effect levels (NOAEL) for AChE inhibition, mostly in rat brain, obtained from international evaluations of pesticides. Exposure to AChE-inhibiting pesticides for the population above 7 years old at P99.9 represented 52-94.5% of the acceptable daily intake (ADI) expressed as methamidophos. Estimated exposure for children aged 2-4 and 4-7 years at P99.9 were 119 and 104.3% of the ADI level, respectively. This study suggests that a yearly monitoring program for OP pesticide residues and strict implementation of the national safety standard for milled rice is necessary.

Biomonitoring of Organophosphorus Agent Exposure by Reactivation of Cholinesterase Enzyme Based on Carbon Nanotube-Enhanced Flow-Injection Amperometric Detection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Dan; Wang, Jun; Smith, Jordan N.

2009-11-15

A portable, rapid, and sensitive assessment of sub-clinical organophosphorus (OPs) agent exposure based on reactivation of cholinesterase (ChE) from OP-inhibited ChE using rat saliva (in vitro) was developed using an electrochemical sensor coupled with a microflow-injection system. The sensor was based on a carbon nanotube (CNT)-modified screen printed carbon electrode (SPE), which was integrated into a flow cell. Due to the extent of inter-individual ChE activity variability, ChE biomonitoring often requires an initial base-line determination (non-inhibited) of enzyme activity which is then directly compared with activity after OP exposure. This manuscript described an alternative strategy where reactivation of the phosphorylatedmore » enzyme was exploited to enable measurement of both inhibited and baseline ChE activity (i.e. after reactivation) in the same sample. The use of CNT makes the electrochemical detection of the products from enzymatic reactions more feasible with extremely high sensitivity and at low potentials. Paraoxon was selected as a model OP compound for in vitro inhibition studies. Some experiment parameters, (e.g. inhibition and reactivation times), have been optimized such that, 92 - 95% ChE reactivation can be achieved over a broad range of ChE inhibition (5 - 94 %) with paraoxon. The extent of enzyme inhibition using this electrochemical sensor correlates well with conventional enzyme activity measurements.« less

Tolerance of ARPE 19 cells to organophosphorus pesticide chlorpyrifos is limited to concentration and time of exposure.

PubMed

Gomathy, Narayanan; Sumantran, Venil N; Shabna, A; Sulochana, K N

2015-01-01

Age related macular degeneration is a blinding disease common in elder adults. The prevalence of age related macular degeneration has been found to be 1.8% in the Indian population. Organophosphates are widely used insecticides with well documented neurological effects, and the persistent nature of these compounds in the body results in long term health effects. Farmers exposed to organophosphorus pesticides in USA had an earlier onset of age related macular degeneration when compared to unexposed controls. A recent study found significant levels of an organophosphate, termed chlorpyrifos, in the blood samples of Indian farmers. Therefore, in understanding the link between age related macular degeneration and chlorpyrifos, the need for investigation is important. Our data show that ARPE-19 (retinal pigment epithelial cells) exhibit a cytoprotective response to chlorpyrifos as measured by viability, mitochondrial membrane potential, superoxide dismutase activity, and increased levels of glutathione peroxidase and reduced glutathione, after 24 h exposure to chlorpyrifos. However, this cytoprotective response was absent in ARPE-19 cells exposed to the same range of concentrations of chlorpyrifos for 48 h. These results have physiological significance, since HPLC analysis showed that effects of chlorpyrifos were mediated through its entry into ARPE-19 cells. HPLC analysis also showed that chlorpyrifos remained stable, as we recovered up to 80% of the chlorpyrifos added to 6 different ocular tissues. Copyright © 2014. Published by Elsevier Inc.

Field monitoring of toxic organic pollution in the sediments of Pearl River estuary and its tributaries.

PubMed

Fu, J; Wang, Z; Mai, B; Kang, Y

2001-01-01

Field monitoring of the toxic organic compounds (PCBs, PAHs, organochlorine pesticides) in the top sediments of Pearl River Estuary and its up-streams were made. It was found that the highest concentrations of these toxic organic compounds occurred in the sediment sampled at Macau inner harbor (ZB013), which is a sink of suspended fine particles transported from the upstream waterways. Because of the affinity of the hydrophobic organic compounds (PAHs, PCBs) for the solid phase, these fine particle depositions led to accumulation of these compounds in the sediment of Macau. The atmospheric dry deposition may be another source of the toxic organic pollution in the sediment.

USE OF PBPK MODELS FOR ASSESSING ABSORBED DOSE AND CHE INHIBITION FROM AGGREGATE EXPOSURE OF INFANTS AND CHILDREN TO ORGANOPHOSPHORUS INSECTICIDES

EPA Science Inventory

A physiological pharmacokinetic (PBPK) modeling framework has been established to assess cumulative risk of dose and injury of infants and children to organophosphorus (OP) insecticides from aggregate sources and routes. Exposure inputs were drawn from all reasonable sources, pr...

Broad-specificity immunoassay for O,O-diethyl organophosphorus pesticides: Application of molecular modeling to improve assay sensitivity and study antibody recognition

USDA-ARS?s Scientific Manuscript database

A monoclonal antibody (MAb) against 4-(diethoxyphosphorothioyloxy)benzoic acid (hapten 1) was raised and used to develop a broad-specificity competitive indirect enzyme-linked immunosorbent assay (ciELISA) for 14 O,O-diethyl organophosphorus pesticides (OPs). Computer-assisted molecular modeling was...

Visual detection of organophosphorus pesticides represented by mathamidophos using Au nanoparticles as colorimetric probe.

PubMed

Li, Hongkun; Guo, Jiajia; Ping, Hong; Liu, Lurui; Zhang, Minwei; Guan, Fengrui; Sun, Chunyan; Zhang, Qian

2011-12-15

With citrate-coated Au nanoparticles as colorimetric probe, a novel visual method for rapid assay of organophosphorus pesticides has been developed. The assay principle is based on catalytic hydrolysis of acetylthiocholine into thiocholine by acetylcholinesterase, which induces the aggregation of Au nanoparticles and the color change from claret-red to purple or even grey. The original plasmon absorption of Au nanoparticles at 522 nm decreases, and simultaneously, a new absorption band appears at 675 nm. The irreversible inhibition of organophosphorus pesticides on acetylcholinesterase prevents aggregation of Au nanoparticles. Under optimum conditions, the absorbance at 522 nm of Au nanoparticles is related linearly to the concentration of mathamidophos in the range of 0.02-1.42 μg/mL with a detection limit of 1.40 ng/mL. This colorimetric method has been successfully utilized to detect mathamidophos in vegetables with satisfactory results. The proposed colorimetric assay exhibits good reproducibility and accuracy, providing a simple and rapid method for the analysis of organophosphorus pesticides. Copyright © 2011 Elsevier B.V. All rights reserved.

Bilayer Effects of Antimalarial Compounds

PubMed Central

Ramsey, Nicole B.; Andersen, Olaf S.

2015-01-01

Because of the perpetual development of resistance to current therapies for malaria, the Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process. We tested the 80 most potent compounds from the box for bilayer-mediated effects on membrane protein conformational changes (a measure of likely toxicity) in a gramicidin-based stopped flow fluorescence assay. Among the Malaria Box compounds tested, four compounds altered membrane properties (p< 0.05); MMV007384 stood out as a potent bilayer-perturbing compound that is toxic in many cell-based assays, suggesting that testing for membrane perturbation could help identify toxic compounds. In any case, MMV007384 should be approached with caution, if at all. PMID:26551613

Bilayer Effects of Antimalarial Compounds.

PubMed

Ramsey, Nicole B; Andersen, Olaf S

2015-01-01

Because of the perpetual development of resistance to current therapies for malaria, the Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process. We tested the 80 most potent compounds from the box for bilayer-mediated effects on membrane protein conformational changes (a measure of likely toxicity) in a gramicidin-based stopped flow fluorescence assay. Among the Malaria Box compounds tested, four compounds altered membrane properties (p< 0.05); MMV007384 stood out as a potent bilayer-perturbing compound that is toxic in many cell-based assays, suggesting that testing for membrane perturbation could help identify toxic compounds. In any case, MMV007384 should be approached with caution, if at all.

A BIOGENIC ROLE IN EXPOSURE TO TWO TOXIC COMPOUNDS

EPA Science Inventory

Biogenic sources play an important role in ozone and particulate concentrations through emissions of volatile organic compounds. The same emissions also contribute to chronic toxic exposures from formaldehyde and acetaldehyde because each compound arises through primary and se...

Infrared Spectroscopic Observations on the Fate of Organophosphorus Compounds Exposed to Atmospheric Moisture. Part 3

DTIC Science & Technology

2007-05-01

PF2), 740 cm’~ s (vy, PFA ) 682 cnf’ m (v~, P-N-C), 515, 481 and 408 cm74 vw (possible VY, and v. PCi2, impurity). 100 -N.N-OIETHYLPHOSPHORAMIOOUS...the last being at 212 days. After 212 days, some very weak ab- sorption due to the PN(CH3 )2 moiety is still visible at 1316, 1009 and 709 cm-1...cm-1 w (~C-H mono-substituted aromatic ring), 890 cniT’ s and 860 cm7’ mns (N and vy PFA ) 760 cmn’ s (P--S 1),- 744 cm-1 and 684 cn"’ ins (y C-H and

Hot cell purification of strontium-82, 85 and other isotopes from proton irradiated molybdenum

DOEpatents

Bentley, G.E.; Barnes, J.W.

1979-10-17

A process suitable for producing curie quantities of quite pure Sr-82,85 is given. After a Mo target is irradiated with energetic protons having energies greater than about 200 MeV, thus producing a large number of radioactive species, the particular species of Sr-82,85 are substantially separated from the other products by a 6-step process. The process comprises dissolution of the target in H/sub 2/O/sub 2/, followed by use of several ion exchange resins, extraction with an organophosphorus compound, and several adjustments of pH values. Other embodiments include processes for producing relatively pure long-lived Rb isotopes, Y-88, and Zr-88.

Carbon-hydrogen to carbon-phosphorus transformations.

PubMed

Montchamp, Jean-Luc

2015-01-01

Literature published between 2008 and 2013 concerning the functionalization of carbon-hydrogen into carbon-phosphorus bonds is surveyed. The chapter is organized by reaction mechanism. The majority of methods still proceed via deprotonation of C-H into C-M (M=Li, Na, etc.) followed by reaction with a phosphorus electrophile P-X, where X is usually chlorine. A few examples of electrophilic aromatic substitution and related processes have also been reported, although this approach has not yet been developed significantly. Over the past 5 years a rapidly growing family of reactions includes transition metal "C-H activation" and formally related radical-based processes has been developed. The latter processes offer exciting prospects for the synthesis of organophosphorus compounds.

REVIEW ARTICLE: Environmental applications of analytical biosensors

NASA Astrophysics Data System (ADS)

Marco, María-Pilar; Barceló, Damià

1996-11-01

A review of the fundamental aspects and environmental applications of biosensors is presented. The bases of different transducer principles such as electrochemical, optical and piezoelectric are discussed. Various examples are given of the applications of such principles to develop immunosensor devices to determine common environmental contaminants. Attention is also paid to catalytic biosensors, using enzymes as sensing elements. Biosensor devices based on the use of cholinesterase and various oxidase enzymes such as tyrosinase, laccase, peroxidase and aldehyde dehydrogenase are reported. Some examples are given of the applications of other biomolecules such as whole cells, DNA or proteins, to determine pollution. Validation studies are presented comparing biosensors with chromatographic techniques to determine organophosphorus pesticides and phenolic compounds in environmental samples.

Hot cell purification of strontium-82, 85 and other isotopes from proton irradiated molybdenum

DOEpatents

Bentley, Glenn E.; Barnes, John W.

1981-01-01

A process suitable for producing curie quantities of quite pure Sr-82,85 is given. After a Mo target is irradiated with energetic protons having energies greater than about 200 MeV, thus producing a large number of radioactive species, the particular species of Sr-82,85 are substantially separated from the other products by a 6-step process. The process comprises dissolution of the target in H.sub.2 O.sub.2, followed by use of several ion exchange resins, extraction with an organophosphorus compound, and several adjustments of pH values. Other embodiments include processes for producing relatively pure long-lived Rb isotopes, Y-88, and Zr-88.

Effects of Organoboron Antifoulants on Oyster and Sea Urchin Embryo Development

PubMed Central

Tsunemasa, Noritaka; Tsuboi, Ai; Okamura, Hideo

2013-01-01

Prohibition of Ot (organotin) compounds was introduced in Japan in 1997 and worldwide from September 2008. This meant that the production of paints containing TBT compounds was stopped and alternatives to the available Ot antifoulants had to be developed. It has been claimed that the degradation by-products of these alternative antifoulants were less toxic than those of Ot compounds. Since the introduction of the alternative antifoulants, the accumulation of these compounds has been reported in many countries. However, the toxicity of these compounds was still largely unreported. In this research, the toxicity of the alternative Ot antifoulants TPBP (triphenylborane pyridine) and TPBOA (triphenylborane octadecylamine) and their degradation products on Crassostea gigas and Hemicentrotus pulcherrimus were tested. The results showed that toxic effects in Crassostea gigas was higher for each antifouling biocide than that in Hemicentrotus pulcherrimus. Also, while the toxicity of the Organoboron antifoulants and the Ots were the same, the former’s degradation products were much less harmful. PMID:23263671

Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models

EPA Science Inventory

Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide...

Predictive ecotoxicity of MoA 1 of organic chemicals using in silico approaches.

PubMed

de Morais E Silva, Luana; Alves, Mateus Feitosa; Scotti, Luciana; Lopes, Wilton Silva; Scotti, Marcus Tullius

2018-05-30

Persistent organic products are compounds used for various purposes, such as personal care products, surfactants, colorants, industrial additives, food, pesticides and pharmaceuticals. These substances are constantly introduced into the environment and many of these pollutants are difficult to degrade. Toxic compounds classified as MoA 1 (Mode of Action 1) are low toxicity compounds that comprise nonreactive chemicals. In silico methods such as Quantitative Structure-Activity Relationships (QSARs) have been used to develop important models for prediction in several areas of science, as well as aquatic toxicity studies. The aim of the present study was to build a QSAR model-based set of theoretical Volsurf molecular descriptors using the fish acute toxicity values of compounds defined as MoA 1 to identify the molecular properties related to this mechanism. The selected Partial Least Squares (PLS) results based on the values of cross-validation coefficients of determination (Q cv 2 ) show the following values: Q cv 2 = 0.793, coefficient of determination (R 2 ) = 0.823, explained variance in external prediction (Q ext 2 ) = 0.87. From the selected descriptors, not only the hydrophobicity is related to the toxicity as already mentioned in previously published studies but other physicochemical properties combined contribute to the activity of these compounds. The symmetric distribution of the hydrophobic moieties in the structure of the compounds as well as the shape, as branched chains, are important features that are related to the toxicity. This information from the model can be useful in predicting so as to minimize the toxicity of organic compounds. Copyright © 2018. Published by Elsevier Inc.

Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: Implications for public protection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munro, N.B.; Ambrose, K.R.; Watson, A.P.

1994-01-01

The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is not evidence that itmore » causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxicity, the nerve agent exposure is the extraordinarily high acute toxicity of these substances. Futhermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent release, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. 187 refs., 3 figs., 7 tabs.« less

Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection.

PubMed Central

Munro, N

1994-01-01

The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is no evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxcity, the nerve agents are not likely to be carcinogens. The overreaching concern with regard to nerve agent exposure is the extraordinarily high acute toxicity of these substances. Furthermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent releaase, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. Images Figure 2. PMID:9719666

A comparative study on the relationship between various toxicological endpoints in Caenorhabditis elegans exposed to organophosphorus insecticides.

PubMed

Rajini, P S; Melstrom, Paul; Williams, Phillip L

2008-01-01

The toxicity of 10 organophophorus (OP) insecticides-acephate, dimethoate, dichlorvos, dicrotophos, monocrotophos, methamidophos, phosphamidon, omethoate, phosdrin, and trichlorfon-was evaluated in Caenorhabditis elegans using lethality, movement, and acetylcholinesterase (AChE) activity as the endpoints after a 4-hr- exposure period. The OP insecticides tested showed LC50 values ranging from 0.039 mM (for dichlorovs) to 472.8 mM (for methamidophos). The order of toxicity for lethality and movement was not significantly different when tested using the rank order correlation coefficient. AChE activity was markedly affected by all the OP insecticide exposures that caused significant inhibition in movement, indicating that the mechanism of toxicity of OP insecticides in C. elegans is the same as in higher animals. All OP insecticides induced greater than 50% inhibition of AChE at the lowest tested OP insecticide concentration resulting in inhibition in movement. While a significant correlation was evident between LC50 values in C. elegans and the LD50 values in rats for the 10 OP insecticides studied, a correlation was not evident between EC50 values in C. elegans and LD50 values in rats. Overall, the two endpoints, LC50 and movement, were more reliable and easier to perform than measurement of AChE activity in C. elegans for determining the toxicity of OP insecticides. Further, ranking of these endpoints with respect to the OP insecticides studied indicates that these parameters in C. elegans are predictive of OP insecticides mammalian neurotoxicity.

The use of high-throughput screening techniques to evaluate mitochondrial toxicity.

PubMed

Wills, Lauren P

2017-11-01

Toxicologists and chemical regulators depend on accurate and effective methods to evaluate and predict the toxicity of thousands of current and future compounds. Robust high-throughput screening (HTS) experiments have the potential to efficiently test large numbers of chemical compounds for effects on biological pathways. HTS assays can be utilized to examine chemical toxicity across multiple mechanisms of action, experimental models, concentrations, and lengths of exposure. Many agricultural, industrial, and pharmaceutical chemicals classified as harmful to human and environmental health exert their effects through the mechanism of mitochondrial toxicity. Mitochondrial toxicants are compounds that cause a decrease in the number of mitochondria within a cell, and/or decrease the ability of mitochondria to perform normal functions including producing adenosine triphosphate (ATP) and maintaining cellular homeostasis. Mitochondrial dysfunction can lead to apoptosis, necrosis, altered metabolism, muscle weakness, neurodegeneration, decreased organ function, and eventually disease or death of the whole organism. The development of HTS techniques to identify mitochondrial toxicants will provide extensive databases with essential connections between mechanistic mitochondrial toxicity and chemical structure. Computational and bioinformatics approaches can be used to evaluate compound databases for specific chemical structures associated with toxicity, with the goal of developing quantitative structure-activity relationship (QSAR) models and mitochondrial toxicophores. Ultimately these predictive models will facilitate the identification of mitochondrial liabilities in consumer products, industrial compounds, pharmaceuticals and environmental hazards. Copyright © 2017 Elsevier B.V. All rights reserved.

In Vitro Methods To Measure Toxicity Of Chemicals

DTIC Science & Technology

2004-12-01

industrial compounds for toxicity will require high-throughput in vitro assays with which to select candidate compounds for more intensive animal...for estimating the starting dose for the rat oral acute toxicity test, thus reducing and refining the use of animals in the toxicological

Comparison of the toxicity of fluoridation compounds in the nematode Caenorhabditis elegans.

PubMed

Rice, Julie R; Boyd, Windy A; Chandra, Dave; Smith, Marjolein V; Den Besten, Pamela K; Freedman, Jonathan H

2014-01-01

Fluorides are commonly added to drinking water in the United States to decrease the incidence of dental caries. Silicofluorides, such as sodium hexafluorosilicate (Na2 SiF6 ) and fluorosilicic acid (H2 SiF6 ), are mainly used for fluoridation, although fluoride salts such as sodium fluoride (NaF) are also used. Interestingly, only the toxicity of NaF has been examined and not that of the more often used silicofluorides. In the present study, the toxicities of NaF, Na2 SiF6 , and H2 SiF6 were compared. The toxicity of these fluorides on the growth, feeding, and reproduction in the alternative toxicological testing organism Caenorhabditis elegans was examined. Exposure to these compounds produced classic concentration-response toxicity profiles. Although the effects of the fluoride compounds varied among the 3 biological endpoints, no differences were found between the 3 compounds, relative to the fluoride ion concentration, in any of the assays. This suggests that silicofluorides have similar toxicity to NaF. © 2013 SETAC.

A32A-0126: A BIOGENIC ROLE IN EXPOSURE TO TWO TOXIC COMPOUNDS

EPA Science Inventory

Biogenic sources play an important role in ozone and particulate concentrations through emissions of volatile organic compounds. The same emissions also contribute to chronic toxic exposures from formaldehyde and acetaldehyde because each compound arises through primary and sec...

Optimization of Therapeutic Strategies for Organophosphate Poisoning

DTIC Science & Technology

2008-03-01

chemical (Szinicz, 2005:173). Researchers later created various forms of the organophosphate and applied the chemicals as insecticides (Szinicz, 2005:173...of organophosphorus insecticides and nerve agents (Cannard, 2006:87). Organophosphates poison an estimated 100,000 people each year throughout the...quantifiable result in order to facilitate comparison among different therapeutic strategies. Justification and Applicability Organophosphorus insecticides are

Determination of Organophosphate Pesticides at a Carbon Nanotube/Organophosphorus Hydrolase Electrochemical Biosensor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deo, R P.; Wang, Joseph; Block, I

2005-02-08

An amperometric biosensor for organophosphorus (OP) pesticides based on a carbon-nanotube (CNT) modified transducer and an organophosphorus hydrolase (OPH) biocatalyst is described. A bilayer approach with the OPH layer atop of the CNT film was used for preparing the CNT/OPH biosensor. The CNT layer leads to a greatly improved anodic detection of the enzymatically-generated p-nitrophenol product, including higher sensitivity and stability. The sensor performance was optimized with respect to the surface modification and operating conditions. Under the optimal conditions the biosensor was used to measure as low as 0.15 {micro}M paraoxon and 0.8 {micro}M methyl parathion with sensitivities of 25more » and 6 nA/{micro}M, respectively.« less

Divergent effects of postmortem ambient temperature on organophosphorus- and carbamate-inhibited brain cholinesterase activity in birds

USGS Publications Warehouse

Hill, E.F.

1989-01-01

Time- and temperature-dependent postmortem changes in inhibited brain cholinesterase (ChE) activity may confound diagnosis of field poisoning of wildlife by anticholinesterase pesticide. Carbamate-inhibited ChE activity may return to normal within 1 to 2 days of exposure of intact carcass to moderate ambient temperature (18-32C). Organophosphorus-inhibited ChE activity becomes more depressed over the same time. Uninhibited ChE activity was resilient to above freezing temperature to 32C for 1 day and 25C for 3 days. Carbamate- and organophosphorus-inhibited ChE can be separated by incubation of homogenate for 1 hour at physiological temperatures; carbamylated ChE can be readily reactivated while phosphorylated ChE cannot.

Chemical Compounds Toxic to Invertebrates Isolated from Marine Cyanobacteria of Potential Relevance to the Agricultural Industry

PubMed Central

Essack, Magbubah; Alzubaidy, Hanin S.; Bajic, Vladimir B.; Archer, John A. C.

2014-01-01

In spite of advances in invertebrate pest management, the agricultural industry is suffering from impeded pest control exacerbated by global climate changes that have altered rain patterns to favour opportunistic breeding. Thus, novel naturally derived chemical compounds toxic to both terrestrial and aquatic invertebrates are of interest, as potential pesticides. In this regard, marine cyanobacterium-derived metabolites that are toxic to both terrestrial and aquatic invertebrates continue to be a promising, but neglected, source of potential pesticides. A PubMed query combined with hand-curation of the information from retrieved articles allowed for the identification of 36 cyanobacteria-derived chemical compounds experimentally confirmed as being toxic to invertebrates. These compounds are discussed in this review. PMID:25356733

Chemical compounds toxic to invertebrates isolated from marine cyanobacteria of potential relevance to the agricultural industry.

PubMed

Essack, Magbubah; Alzubaidy, Hanin S; Bajic, Vladimir B; Archer, John A C

2014-10-29

In spite of advances in invertebrate pest management, the agricultural industry is suffering from impeded pest control exacerbated by global climate changes that have altered rain patterns to favour opportunistic breeding. Thus, novel naturally derived chemical compounds toxic to both terrestrial and aquatic invertebrates are of interest, as potential pesticides. In this regard, marine cyanobacterium-derived metabolites that are toxic to both terrestrial and aquatic invertebrates continue to be a promising, but neglected, source of potential pesticides. A PubMed query combined with hand-curation of the information from retrieved articles allowed for the identification of 36 cyanobacteria-derived chemical compounds experimentally confirmed as being toxic to invertebrates. These compounds are discussed in this review.

Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

PubMed Central

Hendriks, Delilah F. G.; Fredriksson Puigvert, Lisa; Messner, Simon; Mortiz, Wolfgang; Ingelman-Sundberg, Magnus

2016-01-01

Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound’s potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability. PMID:27759057

Weighted Feature Significance: A Simple, Interpretable Model of Compound Toxicity Based on the Statistical Enrichment of Structural Features

PubMed Central

Huang, Ruili; Southall, Noel; Xia, Menghang; Cho, Ming-Hsuang; Jadhav, Ajit; Nguyen, Dac-Trung; Inglese, James; Tice, Raymond R.; Austin, Christopher P.

2009-01-01

In support of the U.S. Tox21 program, we have developed a simple and chemically intuitive model we call weighted feature significance (WFS) to predict the toxicological activity of compounds, based on the statistical enrichment of structural features in toxic compounds. We trained and tested the model on the following: (1) data from quantitative high–throughput screening cytotoxicity and caspase activation assays conducted at the National Institutes of Health Chemical Genomics Center, (2) data from Salmonella typhimurium reverse mutagenicity assays conducted by the U.S. National Toxicology Program, and (3) hepatotoxicity data published in the Registry of Toxic Effects of Chemical Substances. Enrichments of structural features in toxic compounds are evaluated for their statistical significance and compiled into a simple additive model of toxicity and then used to score new compounds for potential toxicity. The predictive power of the model for cytotoxicity was validated using an independent set of compounds from the U.S. Environmental Protection Agency tested also at the National Institutes of Health Chemical Genomics Center. We compared the performance of our WFS approach with classical classification methods such as Naive Bayesian clustering and support vector machines. In most test cases, WFS showed similar or slightly better predictive power, especially in the prediction of hepatotoxic compounds, where WFS appeared to have the best performance among the three methods. The new algorithm has the important advantages of simplicity, power, interpretability, and ease of implementation. PMID:19805409

Compound toxicity screening and structure-activity relationship modeling in Escherichia coli.

PubMed

Planson, Anne-Gaëlle; Carbonell, Pablo; Paillard, Elodie; Pollet, Nicolas; Faulon, Jean-Loup

2012-03-01

Synthetic biology and metabolic engineering are used to develop new strategies for producing valuable compounds ranging from therapeutics to biofuels in engineered microorganisms. When developing methods for high-titer production cells, toxicity is an important element to consider. Indeed the production rate can be limited due to toxic intermediates or accumulation of byproducts of the heterologous biosynthetic pathway of interest. Conversely, highly toxic molecules are desired when designing antimicrobials. Compound toxicity in bacteria plays a major role in metabolic engineering as well as in the development of new antibacterial agents. Here, we screened a diversified chemical library of 166 compounds for toxicity in Escherichia coli. The dataset was built using a clustering algorithm maximizing the chemical diversity in the library. The resulting assay data was used to develop a toxicity predictor that we used to assess the toxicity of metabolites throughout the metabolome. This new tool for predicting toxicity can thus be used for fine-tuning heterologous expression and can be integrated in a computational-framework for metabolic pathway design. Many structure-activity relationship tools have been developed for toxicology studies in eukaryotes [Valerio (2009), Toxicol Appl Pharmacol, 241(3): 356-370], however, to the best of our knowledge we present here the first E. coli toxicity prediction web server based on QSAR models (EcoliTox server: http://www.issb.genopole.fr/∼faulon/EcoliTox.php). Copyright © 2011 Wiley Periodicals, Inc.