[Show abstract][Hide abstract] ABSTRACT: 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 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.
[Show abstract][Hide abstract] ABSTRACT: Dose-lethality response curves were characterized in non-sedated, atropinized Dunkin-Hartley male guinea pigs for the nerve agents tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), VX, the pesticides aldicarb and methomyl, and the oxon metabolites paraoxon, phorate oxon (PHO), and chlorpyrifos oxon (CPO) administered by subcutaneous (SC) injection in guinea pigs that subsequently received atropine free base at 0.4 mg/kg, the guinea pig human-equivalent dose of atropine after administration of three Atropen® or DuoDote® autoinjectors. Lethality rates were obtained at 24 hr after challenge by percutaneous challenge. Probit analysis was used to calculate the median lethal dose (LD50). Protective ratios (PR) for atropine were calculated as the LD50 for a challenge material (CM) in atropinized guinea pigs divided by the LD50 for the same CM in no-therapy guinea pigs using data from either the literature or concurrent experiments. Statistically significant (p < 0.05) therapy in terms of survival was attributed to atropine therapy against a SC challenge of GA, aldicarb, and methomyl. Atropine alone at 0.4 mg/kg did not improve survivability against any other CM exposure by SC injection. These data suggest that the recommended dose of atropine alone administered in the pre-hospital setting may not be a sufficient medical countermeasure for most OP nerve agents and some important pesticides.
[Show abstract][Hide abstract] ABSTRACT: The Chemical Events Working Group of the Global Health Security Initiative has developed a flexible screening tool for chemicals that present a risk when accidentally or deliberately released into the atmosphere. The tool is generic, semi-quantitative, independent of site, situation and scenario, encompasses all chemical hazards (toxicity, flammability and reactivity), and can be easily and quickly implemented by non-subject matter experts using freely available, authoritative information. Public health practitioners and planners can use the screening tool to assist them in directing their activities in each of the five stages of the disaster management cycle.
BMC Public Health 03/2013; 13(1):253. DOI:10.1186/1471-2458-13-253 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Seizurogenic chemicals include a variety of toxic agents, including chemical warfare agents, toxic industrial chemicals, and natural toxins. Chemical weapons such as sarin and VX, and pesticides such as parathion and carbaryl cause hyperstimulation of cholinergic receptors and an increase in excitatory neurotransmission. Glutamatergic hyperstimulation can occur after exposure to excitatory amino acid toxins such as the marine toxin domoic acid. Other pesticides such as lindane and strychnine do not affect excitatory neurotransmission directly, but rather, they block the inhibitory regulation of neurotransmission by antagonism of inhibitory GABA and glycine synapses. In this article is a discussion of chemicals that cause seizures by a variety of molecular mechanisms and pathways.
[Show abstract][Hide abstract] ABSTRACT: Pesticides represent one of the largest classes of toxic chemicals produced, stored, and used in the United States and abroad. These chemicals are designed to be toxic and many, besides being toxic to the pests they are intended to control, are also toxic to nontarget species including humans. The article gives a brief review of their toxicity to humans with emphasis on their effects on the nervous system. Examples of case studies are included to illustrate their toxicity. A discussion of the possible contribution of occupational and other pesticide exposures to neurologic diseases and disorders is also included.
[Show abstract][Hide abstract] ABSTRACT: The National Institutes of Health has developed a comprehensive research program that includes research centers of excellence, individual research projects, small business projects, contracts, and interagency agreements to conduct basic, translational, and clinical research aimed at the discovery and/or identification of better medical countermeasures against chemical threat agents. Chemical threats include chemical warfare agents, toxic industrial and agricultural chemicals, and toxins and other chemicals that could be used intentionally as an act of terror or by large-scale accidents or natural disasters. The overarching goal of this research program is to enhance our medical response capabilities during an emergency. The program is named Countermeasures Against Chemical Threats (CounterACT). It supports translational research, applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of mortality and morbidity caused by chemical threat agents. The categories of research supported under this program include creation and development of screening assays and animal models for therapy development, identification of candidate therapeutics, obtaining preliminary proof-of-principle data on the efficacy of candidate therapeutics, advanced efficacy and preclinical safety studies with appropriate animal models using Good Laboratory Practices (GLP), and clinical studies, including clinical trials with new drugs. Special consideration is given to research relevant to people who are particularly vulnerable, including the young, the elderly, and individuals with pre-existing medical conditions.
Proceedings of the American Thoracic Society 07/2010; 7(4):254-6. DOI:10.1513/pats.201001-003SM
[Show abstract][Hide abstract] ABSTRACT: The National Institutes of Health (NIH) supports research about and the development of better therapies for treating exposure to toxic chemicals that could be used in a terrorist attack or released during an industrial accident. A review of recent research published by NIH investigators working in this field indicates that scientific advances in this area also have implications for reducing the burden of other neurological diseases and disorders. Some key examples discussed include studies on the development of therapeutic drugs to treat seizures and the neuropathology caused by chemical nerve agents, which may help find better cures for epilepsy, stroke, and neurodegenerative diseases.
Science translational medicine 03/2010; 2(23):23ps12. DOI:10.1126/scitranslmed.3000752 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The use of chemical warfare agents (CWAs) has historically been a primary concern of military personnel due to their devastating physical and psychological effects when employed on the battlefield. As a result of these new threats, agencies within the Department of Health and Human Services (DHHS) and other federal agencies have sustained a highly focused effort to assess and, if necessary, improve upon current emergency response capabilities in the event of an actual terrorist event. These efforts include both nonmedical countermeasures such as personal protective equipment for first responders who must enter a contaminated site, and medical capabilities such as safe and effective antidotes and diagnostic tools to reduce mortality and morbidity after a chemical attack or accident. In 2006, the US Congress appropriated funds to the National Institutes of Health (NIH) to implement the National Strategic Plan and Research Agenda for Medical Chemical Countermeasures. The goal of the CounterACT program is to develop safer and more effective therapeutics to treat victims exposed during a chemical incident. Complementing this goal, the CounterACT program also supports the research and development of novel diagnostic technologies, which could be utilized after a chemical incident to determine the proper course of medical intervention.
Handbook of Toxicology of Chemical Warfare Agents, 1st edited by Ramesh C. Gupta, 03/2009: chapter 59: pages 889-895; Academic Press., ISBN: 978-0-12-374484-5
[Show abstract][Hide abstract] ABSTRACT: Presented below is a brief description of research supported by the National Institutes of Health (NIH) on cholinesterases that was discussed at the IXth International Meeting on Cholinesterases in Suzhou, China. It is a partial description of the research conducted by researchers at academic and other institutions supported by the NIH, and by some of the researchers in NIH intramural laboratories. It does not represent a comprehensive survey of all research supported by the NIH related to cholinesterases, but rather a brief discussion of some of the studies discussed at the IXth International Meeting on Cholinesterases. The article describes exciting basic, translational and clinical research on therapies for neurological and other diseases. In addition, cholinesterases that may treat substance abuse are discussed, and pesticide and chemical warfare agents that inhibit cholinesterases are highlighted as part of the NIH portfolio. It is the intent of this article to share with the international community some of the research being supported by the NIH on cholinesterases that complements many of the studies being conducted elsewhere. The information was obtained only from published articles or from abstracts available to the public within the NIH CRISP database (http://crisp.cit.nih.gov/).
[Show abstract][Hide abstract] ABSTRACT: he Centers for Disease Control and Prevention urge physicians to become familiar with chemical and biological weapons. Preparedness among neurologists is especially im- portant because several of these agents affect the nervous system. This article reviews 4 agents that have a history of military or terrorist use: cyanide poisons, organophos- phate poisons, botulinum toxin, and anthrax. Cyanide and organophosphate poisons are charac- terized by dose-dependent impairment of neurological function with nonspecific symptoms such as headache or dizziness at one end of the spectrum and convulsions and coma at the other. Neu- rological examinations help clinicians to differentiate these agents from other intoxications. Botu- linum toxin has a delayed onset of action and results in descending paralysis and prominent cra- nialnervepalsies.Anthraxfrequentlycausesfulminatinghemorrhagicmeningitis.Earlyrecognition of these chemical and biological weapons is key to instituting specific therapy and preventing ca- sualties within the health care team and the community at large. Arch Neurol. 2003;60:21-25 Several chemical and biological weapons affect the nervous system, increasing the likelihood of a neurological consulta- tion.Ofthemanyagentsthatmightbeem- ployed,thisarticlefocusesoncyanide,cho- linesteraseinhibitors,botulinumtoxin,and anthraxbecausetheyhaveprominentneu- rological manifestations. This article re- views the weapon applications, clinical manifestations, and treatments of these agents.
Annals of Neurology 01/2007; 61(1):9-13. DOI:10.1002/ana.21072 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The chapter discusses the role of acetylcholinesterase (AChE) inhibition in the toxicity of organophosphorus (OP) and carbamate (CM) pesticides, with particular emphasis on lower doses that are sublethal, but induce changes in cholinergic receptors, either by indirect modulation of ACh levels via AChE inhibition or by direct interaction with the receptor. Case studies are presented that suggest that some of the toxicities associated with OP insecticides may not involve AChE or cholinergic receptors. Inhibition of AChE and subsequent cholinergic dysfunction represent a common mechanism of toxicity after acute exposure to high levels of OP and CM pesticides. However, the range of toxicities among different compounds is broad, and the potency of a compound for the inhibition of AChE is not a good predictor of its toxicity. Furthermore, toxicities associated with repeated exposures to lower levels of OPs do not correlate well with AChE inhibition. These observations suggest that significant interaction of OPs and CMs with other critical molecules within the cell may be important in explaining some of the toxicity of these compounds not attributable to AChE inhibition. Examples are presented with AChE null mice, direct interactions with muscarinic receptors and other molecules, impairment of cognitive development in weaning rats, OP-induced airway hyperreactivity mediated by M2 receptors, and direct effects on axonal growth in cell culture. The case studies provide strong evidence that noncholinesterase mechanisms are involved in the toxicity of OPs, and they have identified important gaps in the understanding of the mechanism of action of these important classes of insecticides.
[Show abstract][Hide abstract] ABSTRACT: Evidence that children are widely exposed to organophosphorus pesticides (OPs) and that OPs cause developmental neurotoxicity in animal models raises significant concerns about the risks these compounds pose to the developing human nervous system. Critical to assessing this risk is identifying specific neurodevelopmental events targeted by OPs. Observations that OPs alter brain morphometry in developing rodents and inhibit neurite outgrowth in neural cell lines suggest that OPs perturb neuronal morphogenesis. However, an important question yet to be answered is whether the dysmorphogenic effect of OPs reflects perturbation of axonal or dendritic growth. We addressed this question by quantifying axonal and dendritic growth in primary cultures of embryonic rat sympathetic neurons derived from superior cervical ganglia (SCG) following in vitro exposure to chlorpyrifos (CPF) or its metabolites CPF-oxon (CPFO) and trichloropyridinol (TCP). Axon outgrowth was significantly inhibited by CPF or CPFO, but not TCP, at concentrations > or =0.001 microM or 0.001 nM, respectively. In contrast, all three compounds enhanced BMP-induced dendritic growth. Acetylcholinesterase was inhibited only by the highest concentrations of CPF (> or =1 microM) and CPFO (> or =1 nM); TCP had no effect on this parameter. In summary, these compounds perturb neuronal morphogenesis via opposing effects on axonal and dendritic growth, and both effects are independent of acetylcholinesterase inhibition. These findings have important implications for current risk assessment practices of using acetylcholinesterase inhibition as a biomarker of OP neurotoxicity and suggest that OPs may disrupt normal patterns of neuronal connectivity in the developing nervous system.
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that pesticide exposure may be a contributing factor underlying the increased incidence of asthma in the United States and other industrialized nations. To test this hypothesis, airway hyperreactivity was measured in guinea pigs exposed to chlorpyrifos, a widely used organophosphate pesticide. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals 24 h or 7 days after a single subcutaneous injection of either 390 mg/kg or 70 mg/kg of chlorpyrifos, respectively. Mechanisms by which chlorpyrifos may cause airway hyperreactivity include inhibition of acetylcholinesterase (AChE) or dysfunction of M3 muscarinic receptors on airway smooth muscle or of autoinhibitory M2 muscarinic receptors on parasympathetic nerves in the lung. AChE activity in the lung was significantly inhibited 24 h after treatment with 390 mg/kg of chlorpyrifos, but not 7 days after injection of 70 mg/kg of chlorpyrifos. Acute exposure to eserine (250 microg/ml) also significantly inhibited lung AChE but did not potentiate vagally induced bronchoconstriction. Neuronal M2 receptor function was tested using the M2 agonist pilocarpine, which inhibits vagally induced bronchoconstriction in control animals. In chlorpyrifos-treated animals, pilocarpine dose-response curves were shifted significantly to the right, demonstrating decreased responsiveness of neuronal M2 receptors. In contrast, chlorpyrifos treatment did not alter methacholine-induced bronchoconstriction, suggesting that chlorpyrifos does not alter M3 muscarinic receptor function on airway smooth muscle. These data demonstrate that organophosphate insecticides can cause airway hyperreactivity in the absence of AChE inhibition by decreasing neuronal M2 receptor function.
[Show abstract][Hide abstract] ABSTRACT: Receptor autoradiography and membrane radioligand-binding assays were used to determine the expression of nicotinic cholinergic receptors in the brains of weanling rats exposed to low-levels of lead (Pb) during development. Nicotinic receptors were identified with the frog toxin epibatidine (EB) that binds with high affinity to a variety of receptors containing alpha and beta subunits. Rat pups were exposed to Pb from their mothers given 750-ppm Pb in the diet beginning on gestational day 0 through postnatal day (PN) 21. Blood Pb levels ranged from 36.5 to 46.5 microg/dl in the PN21 pups, and this exposure did not alter their body weight when compared to control rats. Several brain regions identified by autoradiographic studies as having significant binding of EB were dissected from control and Pb-treated pups and used in saturation-binding experiments with membrane preparations to determine the affinity constant (K(d)) and maximal-binding capacity (B(max)) of [3H]EB. Results indicate that the B(max) of [3H]EB was increased in several brain regions in Pb-treated rat pups, without a significant effect on K(d) estimates. [3H]EB-binding to membranes from untreated rats was not affected by in vitro exposure to 20-microM Pb, indicating that the effect of Pb on [3H]EB-binding in vivo was not likely due to direct influence of free Pb remaining in the tissue at the time of assay. The data therefore suggest that expression of nicotinic receptors that bind [3H]EB were increased by developmental exposure to Pb. Several possible mechanisms for these effects and the potential toxicological significance are discussed.
Neurotoxicology and Teratology 11/2002; 24(6):805-11. DOI:10.1016/S0892-0362(02)00314-8 · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies suggest that low doses of the organophosphate insecticide chlorpyrifos (CPF) disrupt brain development and cognitive function by mechanisms that do not involve the inhibition of acetylcholinesterase (AChE). In the present study we tested the hypothesis that CPF and its metabolites alter the Ca2+/cAMP response element binding protein (CREB), a critical molecule in brain development and cognitive function. We further tested the hypothesis that changes in CREB occur independent of AChE inhibition. Western blot analysis of lysates from primary cultures of cortical neurons exposed to CPF, CPF-oxon, or trichloropyridinol (TCP) for 1 h and cultures exposed to trichloropyridinol (TCP) for 7 days indicated that all exposures increased the level of the phosphorylated (activated) form of CREB (pCREB), without significant changes in total CREB or alpha-tubulin. Remarkably, pCREB in cortical neurons was elevated by 300-400% of control levels with estimated EC50s of 60 pM, <30 fM, and <30 pM for CPF, CPF-oxon, and TCP, respectively. AChE activity and cell viability were not affected by organophosphate concentrations that caused significant increases in pCREB (up to 100 nM, 100 pM, and 10 microM of CPF, CPF-oxon, and TCP, respectively). The level of pCREB in hippocampal neurons was also elevated after exposure to CPF, but pCREB in cultured astrocytes was not affected. Inclusion of the cytochrome P-450 inhibitor SKF-525A did not inhibit the effects of CPF on pCREB levels, indicating that metabolism of CPF to CPF-oxon was not necessary to cause the increase in pCREB. The increases in neuronal pCREB observed in this study provide biochemical evidence that CPF and its metabolites are active at critical sites within the nervous system at levels far below those required to inhibit AChE, which could explain many of the reported neurodevelopmental and behavioral changes attributed to CPF toxicity.
Toxicology and Applied Pharmacology 07/2002; 182(2):176-85. · 3.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have shown that moderate to high levels of chlorpyrifos (CPF) alter cognitive function in adult and immature rats. In the present study, we tested the hypothesis that lower-level exposure to CPF before or immediately after weaning causes deficits in cognitive function. A total of 78 Long-Evans rats were injected subcutaneously with 0, 0.3 or 7.0 mg/kg CPF every 4 days before or after weaning and were tested with the Morris swim task from postnatal day 24 through 28. Exposure to CPF before weaning did not cause signs of overt cholinergic intoxication or impaired growth nor did the exposures cause significant inhibition of regional brain cholinesterase (ChE) activity or reduction in muscarinic receptors 24 h after the last injection. However, spatial learning was impaired after 5 days of training in the group of weanling rats administered 7.0 mg/kg CPF. Rats administered 0.3 or 7.0 mg/kg CPF after weaning were also impaired in the task, without significant changes in brain ChE activity. These data indicate that low-level exposure to CPF caused deficits in cognitive function in weanling rats, and these effects did not appear to be mediated by the inhibition of brain ChE. It is suggested that the alteration of cognitive function in juvenile rats is an important functional correlate of the cellular and molecular effects of CPF in the immature brain. The mechanisms for CPF-induced cognitive dysfunction are unknown.
[Show abstract][Hide abstract] ABSTRACT: Preliminary findings of a study on the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos (CPF) indicates that in vitro exposure to 1-100 microM CPF or 1-100 nM CPF-oxon had no effect on the activity of glutathione peroxidase (GSHpx) in brain homogenates from postnatal day (PN) 21 rats, or on the activity of purified GSHpx. A single high-dose acute injection of 45 mg/kg CPF to PN19 rats also did not significantly alter GSHpx activity at PN21, in spite of extensive (72%) brain acetylcholinesterase (AChE) inhibition. However, catalase activity was significantly reduced by 28%. PN21 pups exposed maternally to a lower effective dose of CPF throughout development (dams injected with 50 mg/kg every 3 days) also had normal GSHpx activity, but a 30% increase in H2O2-independent NADPH consumption. Brain catalase activity in these rats was significantly increased by 24%. These preliminary data suggest that specific GSHpx activity is not altered by in vitro or in vivo exposures to CPF-oxon or CPF, but catalase and an unknown H2O2-independent NADPH-consuming factor were affected differentially depending on the type and timing of exposure.