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Toxicology Mechanisms and Methods May 2021Highly toxic industrial chemicals that are widely accessible, and hazardous chemicals like phosgene oxime (CX) that can be easily synthesized, pose a serious threat as... (Review)
Review
Highly toxic industrial chemicals that are widely accessible, and hazardous chemicals like phosgene oxime (CX) that can be easily synthesized, pose a serious threat as potential chemical weapons. In addition, their accidental release can lead to chemical emergencies and mass casualties. CX, an urticant, or nettle agent, grouped with vesicating agents, causes instant pain, injury and systemic effects, which can lead to mortality. With faster cutaneous penetration, corrosive properties, and more potent toxicity compared to other vesicating agents, CX causes instantaneous and severe tissue damage. CX, a potential chemical terrorism threat agent, could therefore be weaponized with other chemical warfare agents to enhance their harmful effects. CX is the least studied vesicant and its acute and long-term toxic effects as well as its mechanism of action are largely unknown. This has hampered the identification of therapeutic targets and the development of effective medical countermeasures. There are only protective measures, decontamination, and supportive treatments available for reducing the toxic effects from CX exposure. This review summarizes CX toxicity, its known mechanism of action, and our current studies exploring the role of mast cell activation and associated signaling pathways in CX cutaneous exposure under the National Institutes of Health Countermeasures Against Chemical Threats program. Potential treatment options and the development of effective targeted countermeasures against CX-induced morbidity and mortality is also discussed.
Topics: Chemical Warfare Agents; Irritants; Oximes; Phosgene; Skin
PubMed: 33297803
DOI: 10.1080/15376516.2020.1861670 -
Toxicology Letters Sep 2018Phosgene Oxime (CX, ClCNOH), a halogenated oxime, is a potent chemical weapon that causes immediate acute injury and systemic effects. CX, grouped together with... (Review)
Review
Phosgene Oxime (CX, ClCNOH), a halogenated oxime, is a potent chemical weapon that causes immediate acute injury and systemic effects. CX, grouped together with vesicating agents, is an urticant or nettle agent with highly volatile, reactive, corrosive, and irritating vapor, and has considerably different chemical properties and toxicity compared to other vesicants. CX is absorbed quickly through clothing with faster cutaneous penetration compared to other vesicating agents causing instantaneous and severe damage. For this reason, it could be produced as a weaponized mixture with other chemical warfare agents to enhance their deleterious effects. The immediate devastating effects of CX and easy synthesis makes it a dangerous chemical with both military and terrorist potentials. Although CX is the most potent vesicating agent, it is one of the least studied chemical warfare agents and the pathophysiology as well as long term effects are largely unknown. CX exposure results in immediate pain and inflammation, and it mainly affects skin, eye and respiratory system. There are no antidotes available against CX-induced injury and the treatment is only supportive. This review summarizes existing knowledge regarding exposure, toxicity and the probable underlying mechanisms of CX compared to other important vesicants' exposure.
Topics: Animals; Antidotes; Arsenic Poisoning; Arsenicals; Blister; Chemical Warfare Agents; Humans; Irritants; Mustard Gas; Phosgene; Poisoning; Skin Diseases
PubMed: 29141200
DOI: 10.1016/j.toxlet.2017.11.011 -
Supporting discovery and development of medical countermeasures for chemical injury to eye and skin.Experimental Eye Research Aug 2022Vesicants, from vesica (Latin for blister), can cause local and systemic toxicity. They include the chemotherapy drug nitrogen mustard and chemical warfare agents sulfur...
Vesicants, from vesica (Latin for blister), can cause local and systemic toxicity. They include the chemotherapy drug nitrogen mustard and chemical warfare agents sulfur mustard, Lewisite, and phosgene oxime. These agents are commonly released in vapor form and consequently, eyes and skin are the most vulnerable. The ocular and cutaneous injuries can be acute, subacute, or chronic, and can predispose casualties to secondary deleterious effects. Underlying these broad organ responses are shared and tissue-specific cellular and molecular biological cascades that attempt to counteract such chemical injuries. Depending on the severity of the chemical insult, biological responses often lead to inadequate wound healing and result in long-term pathology instead. Exposure to other toxic industrial chemicals such as acrolein, chloropicrin, and hydrogen fluoride, can also cause prominent eye and skin damage. There are currently no FDA-approved drugs to counteract these injuries. Hence, the possibility of a mass casualty emergency involving these chemicals is a major public health concern. Recognizing this critical challenge, the United States Department of Health and Human Services (HHS) is committed to the development of medical countermeasures to advance national health and medical preparedness against these highly toxic chemicals. Here, we provide an overview of various HHS funding and scientific opportunities available in this space, emphasizing parallels between eye and skin response to chemical injury. We also discuss a main limitation of existing data and suggest ways to overcome it.
Topics: Burns, Chemical; Chemical Warfare Agents; Humans; Mechlorethamine; Medical Countermeasures; Mustard Gas; Skin; United States
PubMed: 35716762
DOI: 10.1016/j.exer.2022.109156 -
Chemico-biological Interactions Apr 2024The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine,... (Review)
Review
The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.
PubMed: 38574837
DOI: 10.1016/j.cbi.2024.110973