-
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 -
The Journal of Pharmacology and... Jan 2024Phosgene oxime (CX), categorized as a vesicating chemical threat agent, causes effects that resemble an urticant or nettle agent. CX is an emerging potential threat...
Phosgene oxime (CX), categorized as a vesicating chemical threat agent, causes effects that resemble an urticant or nettle agent. CX is an emerging potential threat agent that can be deployed alone or with other chemical threat agents to enhance their toxic effects. Studies on CX-induced skin toxicity, injury progression, and related biomarkers are largely unknown. To study the physiologic changes, skin clinical lesions and their progression, skin exposure of SKH-1 and C57BL/6 mice was carried out with vapor from 10 l CX for 0.5-minute or 1.0-minute durations using a designed exposure system for consistent CX vapor exposure. One-minute exposure caused sharp (SKH-1) or sustained (C57BL/6) decrease in respiratory and heart rate, leading to mortality in both mouse strains. Both exposures caused immediate blanching, erythema with erythematous ring (wheel) and edema, and an increase in skin bifold thickness. Necrosis was also observed in the 0.5-minute CX exposure group. Both mouse strains showed comparative skin clinical lesions upon CX exposure; however, skin bifold thickness and erythema remained elevated up to 14 days postexposure in SKH-1 mice but not in C57BL/6 mice. Our data suggest that CX causes immediate changes in the physiologic parameters and gross skin lesions resembling urticaria, which could involve mast cell activation and intense systemic toxicity. This novel study recorded and compared the progression of skin injury to establish clinical biomarkers of CX dermal exposure in both the sexes of two murine strains relevant for skin and systemic injury studies and therapeutic target identification. SIGNIFICANCE STATEMENT: Phosgene oxime (CX), categorized as a vesicating agent, is considered as a potent chemical weapon and is of high military and terrorist threat interest since it produces rapid onset of severe injury as an urticant. However, biomarkers of clinical relevance related to its toxicity and injury progression are not studied. Data from this study provide useful clinical markers of CX skin toxicity in mouse models using a reliable CX exposure system for future mechanistic and efficacy studies.
Topics: Animals; Mice; Phosgene; Disease Models, Animal; Mustard Gas; Mice, Inbred C57BL; Skin; Irritants; Erythema; Biomarkers; Oximes; Chemical Warfare Agents
PubMed: 37652710
DOI: 10.1124/jpet.123.001718 -
Chemical Communications (Cambridge,... Apr 2022Herein, an aggregation-induced emission (AIE)-based sensor, 4-(1,2,2-triphenylvinyl)benzoxime (TPE-phos), has been rationally designed for phosgene detection. The sensor...
Herein, an aggregation-induced emission (AIE)-based sensor, 4-(1,2,2-triphenylvinyl)benzoxime (TPE-phos), has been rationally designed for phosgene detection. The sensor has a tetraphenylethylene unit combined with an oxime moiety. TPE-phos undergoes nitrile formation after the oxime group reacts with phosgene, which will give a significant "light-up" fluorescence due to the AIE effect within seconds.
Topics: Coloring Agents; Oximes; Phosgene; Spectrometry, Fluorescence
PubMed: 35403642
DOI: 10.1039/d2cc00745b -
Chemico-biological Interactions Dec 2021Since their use during the First World War, Blister agents have posed a major threat to the individuals and have caused around two million casualties. Major incidents... (Review)
Review
Since their use during the First World War, Blister agents have posed a major threat to the individuals and have caused around two million casualties. Major incidents occurred not only due to their use as chemical warfare agents but also because of occupational hazards. Therefore, a clear understanding of these agents and their mode of action is essential to develop effective decontamination and therapeutic strategies. The blister agents have been categorised on the basis of their chemistry and the biological interactions that entail post contamination. These compounds have been known to majorly cause blisters/bullae along with alkylation of the contaminated DNA. However, due to the high toxicity and restricted use, very little research has been conducted and a lot remains to be clearly understood about these compounds. Various decontamination solutions and detection technologies have been developed, which have proven to be effective for their timely mitigation. But a major hurdle seems to be the lack of proper understanding of the toxicological mechanism of action of these compounds. Current review is about the detailed and updated information on physical, chemical and biological aspects of various blister agents. It also illustrates the mechanism of their action, toxicological effects, detection technologies and possible decontamination strategies.
Topics: Alkylating Agents; Arsenicals; Blister; Chemical Warfare Agents; Decontamination; Eye; Humans; Lung; Models, Biological; Mustard Compounds; Oximes; Phosgene; Skin
PubMed: 34634268
DOI: 10.1016/j.cbi.2021.109654 -
Environmental Science. Processes &... Jul 2023Sensing of gaseous environment pollutants and health hazards is in demand these days and in this regard, lethal phosgene has emerged as a leading entrant. In this...
Sensing of gaseous environment pollutants and health hazards is in demand these days and in this regard, lethal phosgene has emerged as a leading entrant. In this contribution, we have successfully developed a facile chemodosimeter (ANO) based on an anthracene fluorophore and oxime recognition site with an interesting mechanism to sense lethal phosgene evolved from bleaching powder, a very popular disinfectant and sanitizer. The ANO probe is highly competent in recognizing deadly phosgene in solution and in the gaseous phase with a detection limit in the nanomolar range (1.52 nM). The sensing mechanism is confirmed by UV-vis, emission spectroscopy, mass spectrometry, and computational studies.
Topics: Phosgene; Cost-Benefit Analysis; Spectrometry, Fluorescence; Gases; Fluorescent Dyes
PubMed: 37345355
DOI: 10.1039/d3em00171g -
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 May 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.
Topics: Humans; Nerve Agents; Organophosphorus Compounds; Animals; Cholinesterase Reactivators; Medical Countermeasures; Acetylcholinesterase; Cholinesterase Inhibitors; Chemical Warfare Agents; Antidotes; Oximes
PubMed: 38574837
DOI: 10.1016/j.cbi.2024.110973