Annetta P. Watson

Organophosphate Nerve Agents

Publisher Summary The chemical warfare (CW) nerve agents primarily addressed in this chapter include the anticholinesterase nerve agents tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, all of which are, or have been, part of the US domestic munitions inventories. These agents are potent anticholinesterase compounds deliberately formulated to induce debilitating effects or death during wartime hostilities, and have been used by military authorities of several nations to develop munitions. All of the nerve agents under consideration are anticholinesterase compounds and induce accumulation of the neurotransmitter acetylcholine (ACh) at neural synapses and neuromuscular junctions by phosphorylating acetylcholinesterase (AChE). Depending on the route of exposure and amount absorbed, the PNS and/or CNS can be affected and muscarinic and/or nicotinic receptors may be stimulated. Interaction with other esterases may also occur, and direct effects to the nervous system have been observed. Exposure to acutely toxic concentrations of nerve agents can result in excessive bronchial, salivary, ocular, and intestinal secretions, sweating, miosis, bronchospasm, intestinal hypermotility, bradycardia, muscle fasciculations, twitching, weakness, paralysis, loss of consciousness, convulsions, depression of the central respiratory drive, and death. More recent global events have focused attention on the potential threat of chemical terrorism, especially at transportation hubs. For example, the deliberate release of nerve agent sarin at lethal concentrations in the Japanese cities of Matsumoto (1994) and Tokyo (1995) by a Japanese domestic terrorist group has illustrated that such attacks can be a reality and require advance emergency preparedness planning.

Sulfur mustard as a carcinogen: Application of relative potency analysis to the chemical warfare agents H, HD, and HT

A relative potency method for assessing potential human health effects from exposures to relatively untested chemicals is presented and documented. The need for such a method in evaluating the carcinogenic potential of the chemical warfare agent sulfur mustard (agent HD) from a limited data base is specifically addressed. The best-estimate potency factor for sulfur mustard relative to benzo[a]pyrene is 1.3, with an interquartile range of 0.6 to 2.9. The method is applied to (1) the estimated fence-boundary air concentrations of mustard during operation of a proposed agent incinerator at Aberdeen Proving Ground (APG), Maryland, and (2) the current approved general population exposure level of 1 X 10(-4) mg HD/m3 and the occupational exposure level of 3 X 10(-3) mg HD/m3. Maximum estimates of excess lifetime cancer risk for individuals at sites along the APG boundary range between 3 X 10(-8) and 1 X 10(-7). Lifetime cancer risk estimates less than or equal to 10(-6) are not now regulated by the U.S. Environmental Protection Agency or the Food and Drug Administration. Maximum estimates of excess lifetime cancer risk assuming daily exposure to the approved standards during the proposed 5 years of incinerator operation are on the order of 10(-5) for the general public and 10(-4) for the worker population. These values are considered upper limit estimates.

Development and Application of Acute Exposure Guideline Levels (AEGLs) for Chemical Warfare Nerve and Sulfur Mustard Agents

Acute exposure guideline levels (AEGLs) have been developed for the chemical warfare agents GB, GA, GD, GF, VX, and sulfur mustard. These AEGLs were approved by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances after Federal Register publication and comment, and judged as scientifically valid by the National Research Council Committee on Toxicology Subcommittee on AEGLs. AEGLs represent general public exposure limits for durations ranging from 10 min to 8 h, and for three levels of severity (AEGL-1, AEGL-2, AEGL-3). Mild effects are possible at concentrations greater than AEGL-1, while life-threatening effects are expected at concentrations greater than AEGL-3. AEGLs can be applied to various civilian and national defense purposes, including evacuation and shelter-in-place protocols, reentry levels, protective clothing specifications, and analytical monitoring requirements. This report documents development and derivation of AEGL values for six key chemical warfare agents, and makes recommendations for their application to various potential exposure scenarios. This submission was sponsored by a contractor of the U.S. government under contract DE-AC05-00OR22725. Accordingly, the U.S. government retains a nonexclusive, royalty-free license to publish or reproduce these documents, or to allow others to do so, for U.S. government purposes. These documents may be freely distributed and used for noncommercial, scientific and educational purposes.

Deriving Toxicity Values for Organophosphate Nerve Agents: A Position Paper in Support of the Procedures and Rationale for Deriving Oral RfDs for Chemical Warfare Nerve Agents

During the process of deriving oral Reference Dose (RfDs) values for chemical warfare agents, several issues arose regarding the identification of adverse effect levels and the application of uncertainty factors. For those agents that function as cholinesterase inhibitors (e.g., agents VX, GA, GB, and GD), these issues included the following: (1) Is the endpoint of blood cholinesterase inhibition an indicator of toxicity or a biomarker of exposure? (2) Can an experimental animal species be more sensitive than humans, thereby eliminating the need for an animal-to-human uncertainty factor? (3) Can the uncertainty factor that is used to extrapolate from a lowest-observed adverse-effect-level (LOAEL) to a no-observed-adverse-effect-level (NOAEL) be less than the default value of 10? (4) Can an oral RfD be derived from non-oral toxicity data? (5) Can an uncertainty factor of less than 10 be used to extrapolate from subchronic to chronic exposure (e.g., is the critical effect adequately described by the subchro...

Cholinesterase Inhibitors as Chemical Warfare Agents: Community Preparedness Guidelines

Publisher Summary Chemical warfare nerve agents are potent anticholinesterase compounds deliberately formulated to induce debilitating effects or death during wartime hostilities. Because of their steep dose response, these agents have been used by military authorities of several nations to develop munitions, and have been deployed by certain domestic terrorists. A key need for both community emergency preparedness and installation restoration is the availability of health-based exposure guidelines derived in a transparent manner by contemporary methods of data analysis. The chapter summarizes guidelines for acute vapor and chronic ingestion exposure to the nerve agents, GA (tabun), GB (satin), GD (soman), GF (cyclosarin), and VX. The toxicological analysis and logic incorporated into the estimation of reference dose (RfDe), and AEGL values for these nerve agents employ standard protocols to govern management of Superfund sites, and extremely hazardous substances unintentionally released during industrial accidents or chemical spills. In addition, both parameters are considered critical to maintaining compliance with international treaty obligations governing the stockpile and destruction of chemical weapons. The nerve agent RfDe and AEGL values, are now available for application to civilian and military defense purposes, such as shelter-in-place and evacuation protocols, recovery and remediation levels, analytical monitoring requirements, and protective clothing specifications. These guidelines are intended to preserve public health by not only characterizing potentially harmful exposure levels, but also identifying levels at which minimal or no toxic effects are expected. The toxicological analyses, protocol, and logic incorporated into nerve agent chronic RfDe and AEGL guideline development are documented, and their recent use by civilian and military authorities is summarized.Publisher Summary Chemical warfare nerve agents are potent anticholinesterase compounds deliberately formulated to induce debilitating effects or death during wartime hostilities. Because of their steep dose response, these agents have been used by military authorities of several nations to develop munitions, and have been deployed by certain domestic terrorists. A key need for both community emergency preparedness and installation restoration is the availability of health-based exposure guidelines derived in a transparent manner by contemporary methods of data analysis. The chapter summarizes guidelines for acute vapor and chronic ingestion exposure to the nerve agents, GA (tabun), GB (satin), GD (soman), GF (cyclosarin), and VX. The toxicological analysis and logic incorporated into the estimation of reference dose (RfDe), and AEGL values for these nerve agents employ standard protocols to govern management of Superfund sites, and extremely hazardous substances unintentionally released during industrial accidents or chemical spills. In addition, both parameters are considered critical to maintaining compliance with international treaty obligations governing the stockpile and destruction of chemical weapons. The nerve agent RfDe and AEGL values, are now available for application to civilian and military defense purposes, such as shelter-in-place and evacuation protocols, recovery and remediation levels, analytical monitoring requirements, and protective clothing specifications. These guidelines are intended to preserve public health by not only characterizing potentially harmful exposure levels, but also identifying levels at which minimal or no toxic effects are expected. The toxicological analyses, protocol, and logic incorporated into nerve agent chronic RfDe and AEGL guideline development are documented, and their recent use by civilian and military authorities is summarized.

Chemical Warfare Agents: Current Status of Oral Reference Doses

A 1998 paper published in Reviews in Environmental Contamination and Toxicology (Opresko et al. 1998) documented the development of oral reference doses (RfDs) for several groups of chemical warfare agents; i.e., sulfur mustard agents, nitrogen mustard agents, organophosphate nerve agents, the arsenical lewisite, and cyanogen chloride. The development of these reference doses was initiated by the U.S. Army Environmental Center (USAEC) to support its continuing task of remediating sites potentially contaminated by past releases of hazardous substances. This action was taken under general provisions of the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). The USAEC, which functions as the program manager for the Army’s Installation Restoration Program (IRP), determined that responsible and efficient cleanup of both active installations and formerly used defense sites (FUDS) contaminated with chemical warfare agent residues required key toxicological parameters for performing IRP site health risk assessments.

Currently available permeability and breakthrough data characterizing chemical warfare agents and their simulants in civilian protective clothing mater

Abstract The current analysis characterizes chemical protective clothing (CPC) that would be available to civilian emergency personnel responding to possible ne

Low level detection of chemical agent simulants in meat and milk by ion trap mass spectrometry

Abstract Analytical methods for the detection of two chemical warfare agent simulants, diisopropyl methylphosphonate and chloroethylethylsulfide, in beef tissue and milk have been demonstrated to be effective to levels as low as 50–100 parts-per-billion. These methods are based upon thermal desorption into an ion trap mass spectrometer. Selective detection of the target compounds is achieved by isobutane chemical ionization in combination with collision-induced dissociation, which yields characteristic fragment ions. Rapid sample clean-up steps were also devised to reduce interferences from the sample matrix. The low detection limits achieved with this method suggest that it may be possible to take small tissue samples from livestock by needle biopsy, without requiring animal sacrifice for the analysis. In addition, because the new methods may be performed more quickly than conventional methods requiring substantial sample preparation and analysis time, more samples could be analyzed.

Movement of chemical warfare agent simulants through porous media

Abstract A measurement protocol is documented and data presented to characterize the permeation of chemical warfare agent simulants through the porous con- struction materials brick, cinder block, gypsum wall board, and wood. These data will be used to develop guidelines for access (‘reentry’) to potentially contaminated properties if nerve or vesicant agents are released during any phase of the US Department of the Armys Chemical Stock- pile Disposal Program. A novel permeation cell design allowed sampling of air volumes adjacent to the spiked face, breakthrough face and lateral face of each test medium at two temperatures. Simulant movement through wood is nearly always in the direction of the wood grain. Two-dimensional breakthrough was observed in brick and gypsum wall board. The sulfur mustard simulant broke through all test media in less than 60 min; nerve agent simulant breakthrough required several hours. Surface decontamination of wood with high test hypochlorite is 95% effective.

Chapter 9 – Organophosphate Nerve Agents

Chemical warfare nerve agents are potent anticholinesterase compounds deliberately formulated to induce debilitating effects or death during wartime hostilities. A key need for both community emergency preparedness, and restoration of military installations where agents have been processed and/or stored, is access to concise and timely information on agent characteristics and treatment, as well as health-based exposure guidelines derived in a clear manner by contemporary methods of data analysis. These parameters are summarized for the nerve agents GA (tabun), GB (sarin), GD (soman), GF (cyclosarin), and VX, as well as for agent GE. Toxicological analysis and logic incorporated into estimation of vapor exposure and ingestion guidelines for these agents is also summarized. Recent experimental data characterizing low-level nerve agent vapor exposures for multiple agents and species have placed existing guidelines in context and further substantiates their protective nature.