Toxic blister agents: Chemistry, mode of their action and effective treatment strategies.

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.

Supramolecular Sensing of Chemical Warfare Agents.

Chemical warfare agents are a class of organic molecules used as chemical weapons due to their high toxicity and lethal effects. For this reason, the fast detection of these compounds in the environment is crucial. Traditional detection methods are based on instrumental techniques, such as mass spectrometry or HPLC, however the use of molecular sensors able to change a detectable property (e. g., luminescence, color, electrical resistance) can be cheaper and faster. Today, molecular sensing of chemical warfare agents is mainly based on the "covalent approach", in which the sensor reacts with the analyte, or on the "supramolecular approach", which involves the formation of non-covalent interactions between the sensor and the analyte. This Review is focused on the recent developments of supramolecular sensors of organophosphorus chemical warfare agents (from 2013). In particular, supramolecular sensors are classified by function of the sensing mechanism: i) Lewis Acids, ii) hydrogen bonds, iii) macrocyclic hosts, iv) multi-topic sensors, v) nanosensors. It is shown how the supramolecular non-covalent approach leads to a reversible sensing and higher selectivity towards the selected analyte respect to other interfering molecules.

Skin sensitizing effects of sulfur mustard and other alkylating agents in accordance to OECD guidelines.

Vesicants cause a multitude of cutaneous reactions like erythema, blisters and ulcerations. After exposure to sulfur mustard (SM) and related compounds, patients present dermal symptoms typically known for chemicals categorized as skin sensitizer (e.g. hypersensitivity and flare-up phenomena). However, although some case reports led to the assumption that SM and other alkylating compounds represent sensitizers, a comprehensive investigation of SM-triggered immunological responses has not been conducted so far. Based on a well-structured system of in chemico and in vitro test methods, the Organization for Economic Co-operation and Development (OECD) established procedures to categorize agents on their skin sensitizing abilities. In this study, the skin sensitizing potential of SM and three related alkylating agents (AAs) was assessed following the OECD test guidelines. Besides SM, investigated AAs were chlorambucil (CHL), nitrogen mustard (HN3) and 2-chloroethyl ethyl sulfide (CEES). The methods are described in detail in the EURL ECVAM DataBase service on ALternative Methods to animal experimentation (DB-ALM). In accordance to OECD recommendations, skin sensitization is a pathophysiological process starting with a molecular initiating step and ending with the in vivo outcome of an allergic contact dermatitis. This concept is called adverse outcome pathway (AOP). An AOP links an adverse outcome to various key events which can be assayed by established in chemico and in vitro test methods. Positive outcome in two out of three key events indicates that the chemical can be categorized as a skin sensitizer. In this study, key event 1 "haptenation" (covalent modification of epidermal proteins), key event 2 "activation of epidermal keratinocytes" and key event 3 "activation of dendritic cells" were investigated. Covalent modification of epidermal proteins measured by using the DPRA-assay provided distinct positive results for all tested substances. Same outcome was seen in the KeratinoSens assay, investigating the activation of epidermal keratinocytes. The h-CLAT assay performed to determine the activation of dendritic cells provided positive results for SM and CEES but not for CHL and HN3. Altogether, following OECD requirements, our results suggest the classification of all investigated substances as skin sensitizers. Finally, a tentative AOP for SM-induced skin sensitization is suggested.

Chemical warfare agents. Classes and targets.

Synthetic toxic chemicals (toxicants) and biological poisons (toxins) have been developed as chemical warfare agents in the last century. At the time of their initial consideration as chemical weapon, only restricted knowledge existed about their mechanisms of action. There exist two different types of acute toxic action: nonspecific cytotoxic mechanisms with multiple chemo-biological interactions versus specific mechanisms that tend to have just a single or a few target biomolecules. TRPV1- and TRPA-receptors are often involved as chemosensors that induce neurogenic inflammation. The present work briefly surveys classes and toxicologically relevant features of chemical warfare agents and describes mechanisms of toxic action.

Exposure levels for chemical threat compounds: information to facilitate chemical incident response.

Although not widely known, a robust set of peer-reviewed public health and occupational exposure levels presently exist for key chemical warfare agents (CWAs) and certain acutely toxic industrial chemicals (TICs) identified as terrorist attack threats. Familiarity with these CWA and TIC exposure levels and their historic applications has facilitated emergency management decision-making by public and environmental health decision-makers. Specifically, multiple air, soil, and water exposure levels for CWAs and TICs summarized here have been extensively peer-reviewed and published; many have been recognized and are in use by federal and state health agencies as criteria for hazard zone prediction and assessment, occupational safety, and "how clean is clean enough" decisions. The key, however, is to know which criteria are most appropriate for specific decisions. While public safety is critical, high levels of concern often associated with perceived or actual proximity to extremely toxic chemical agents could result in overly cautious decisions that generate excessive delays, expenditure of scarce resources, and technological difficulties. Rapid selection of the most appropriate chemical exposure criteria is recommended to avoid such problems and expedite all phases of chemical incident response and recovery.

Human paraoxonase double mutants hydrolyze V and G class organophosphorus nerve agents.

Variants of human paraoxonase 1 (PON1) are being developed as catalytic bioscavengers for the organophosphorus chemical warfare agents (OP). It is preferable that the new PON1 variants have broad spectrum hydrolase activities to hydrolyze both G- and V-class OPs. H115W PON1 has shown improvements over wild type PON1 in its capacity to hydrolyze some OP compounds. We improved upon these activities either by substituting a tryptophan (F347W) near the putative active site residues for enhanced substrate binding or by reducing a bulky group (Y71A) at the periphery of the putative enzyme active site. When compared to H115W alone, we found that H115W/Y71A and H115W/F347W maintained VX catalytic efficiency but showed mixed results for the capacity to hydrolyze paraoxon. Testing our double mutants against racemic sarin, we observed reduced values of K(M) for H115W/F347W that modestly improved catalytic efficiency over wild type and H115W. Contrary to previous reports, we show that H115W can hydrolyze soman, and the double mutant H115W/Y71A is nearly 4-fold more efficient than H115W for paraoxon hydrolysis. We also observed modest stereoselectivity for hydrolysis of the P(-) stereoisomer of tabun by H115W/F347W. These data demonstrate enhancements made in PON1 for the purpose of developing an improved catalytic bioscavenger to protect cholinesterase against chemical warfare agents.

Mass casualty chemical exposure and implications for respiratory failure.

Exposure to chemical agents, both deliberate and accidental, over the past 100 years has resulted in the deaths of thousands and a significant number of casualties requiring hospitalization. The respiratory system is an important portal of entry into the human body for many of these agents, and pulmonary symptoms are a hallmark of many chemical exposures. The 4 major chemical warfare agents are: lung-damaging, blood, blister, and nerve compounds. The review will cover historical exposures, signs and symptoms, treatment, and long-term consequences. There are numerous examples of deliberate (as well as accidental) exposure to harmful chemicals, and each incident requires the provider to understand the signs and symptoms of the particular chemical so that the correct treatment is provided. The respiratory implications of these agents appear to be dose and timing dependent, with full recovery often seen if supportive measures and appropriate antidotes are administered in a timely fashion.

[Strategic preparedness of selected hospitals to act during massive chemical disasters]. / Strategiczne przygotowanie wybranych szpitali do dzialan w warunkach masowych skaien chemicznych.

The aim of our study was the evaluation of strategic preparedness of twelve hospitals in Kraków, Warsaw and the Triple City to give aid during massive chemical accidents. The study was carried on 146 persons, including 9 managers, 31 ward heads, 75 assistants, and 31 ward nurses. In statistical analysis the generalized linear model extended by random factors, particularly the Poisson's regression has been used. In any of the investigated hospitals, there were no plans regarding of action in case of chemical accidents. The knowledge about sources of possible contamination as well as environment threats were insufficient. The majority of the medical staff did not know their role as well as the role of their hospitals in case of a chemical accident. There is an urgent need for courses about the procedures which should be used during chemical accidents. The lack of hospital preparedness to act during chemical disasters in the big cities suggests that a similar situation is common in other such medical units all over the country. Further investigations, especially in the hospitals which are placed near the potentially dangerous factories, should be carried on in the near future.

Nonconventional terror--the anesthesiologist's role in a nerve agent event.

The structure and biologic action of nerve agents is similar to organophosphates, commonly used as insecticides. Acetylcholine accumulation and binding to the cholinergic receptor site stimulates the affected organs producing a predictable set of clinical symptoms. Treatment of the affected patients will include decontamination, respiratory and hemodynamic support, as well as specific antidotes. The multiple casualties that may be expected present additional logistical and organizational problems. The specific skills of anesthesiologists will make them invaluable members of the care team in such a chemical mass casualty event.

Fuzzy classification by fuzzy labeled neural gas.

We extend the neural gas for supervised fuzzy classification. In this way we are able to learn crisp as well as fuzzy clustering, given labeled data. Based on the neural gas cost function, we propose three different ways to incorporate the additional class information into the learning algorithm. We demonstrate the effect on the location of the prototypes and the classification accuracy. Further, we show that relevance learning can be easily included.

History of chemical and biological warfare agents.

Chemical and biological warfare agents constitute a low-probability, but high-impact risk both to the military and to the civilian population. The use of hazardous materials of chemical or biological origin as weapons and for homicide has been documented since ancient times. The first use of chemicals in terms of weapons of mass destruction goes back to World War I, when on April 22, 1915 large amounts of chlorine were released by German military forces at Ypres, Belgium. Until around the 1970s of the 20th century, the awareness of the threat by chemical and biological agents had been mainly confined to the military sector. In the following time, the development of increasing range delivery systems by chemical and biological agents possessors sensitised public attention to the threat emanating from these agents. Their proliferation to the terrorists field during the 1990s with the expanding scale and globalisation of terrorist attacks suggested that these agents are becoming an increasing threat to the whole world community. The following article gives a condensed overview on the history of use and development of the more prominent chemical and biological warfare agents.

Toxicological aspects of preparedness and aftercare for chemical-incidents.

The threat of using chemical warfare agents still exists despite the 1993 Chemical Weapons Convention. Preparedness for attacks with chemical agents has become an important issue of national security programs. It can be anticipated that toxicologists will be increasingly involved in preparedness programs of their institutions and of the government, no matter whether they work in agencies, industry or universities. Toxicologists must get prepared to give fast and reliable advice in the case of an attack, a sabotage or an accident with release of toxic chemicals. They should be familiar with the principles of hazard management and with incident command structures and cooperate with first responders of other organizations involved such as fire department and medical emergency teams already in the planning phase. In the emergency planning phase, toxicologists are expected to help identifying possible hazards. Moreover, they consult public health services with regard to toxicosurveillance and advice hospitals regarding antidotes, decontamination procedures and shelters. They may be involved in the procurement of antidotes and of protective equipment and will support qualified analytical laboratories. In the response phase, toxicologists must be ready to gain and to interpret analytical data, to support the medical care of poisoned victims and to provide repeated risk assessment reports. This requires an on-scene access to databases and registries. The aftercare phase includes the identification of exposed persons, mapping of contaminated areas, organization of decontamination measures and the release of areas. A medical study may be initiated to observe long-term health effects. Good cooperation between regulatory and clinical toxicologists, specific education of toxicologist in the field of chemical emergencies and regular trainings are essential elements of good preparedness.

A review of multi-threat medical countermeasures against chemical warfare and terrorism.

The Multi-Threat Medical Countermeasure (MTMC) hypothesis has been proposed with the aim of developing a single countermeasure drug with efficacy against different pathologies caused by multiple classes of chemical warfare agents. Although sites and mechanisms of action and the pathologies caused by different chemical insults vary, common biochemical signaling pathways, molecular mediators, and cellular processes provide targets for MTMC drugs. This article will review the MTMC hypothesis for blister and nerve agents and will expand the scope of the concept to include other chemicals as well as briefly consider biological agents. The article will also consider how common biochemical signaling pathways, molecular mediators, and cellular processes that contribute to clinical pathologies and syndromes may relate to the toxicity of threat agents. Discovery of MTMC provides the opportunity for the integration of diverse researchers and clinicians, and for the exploitation of cutting-edge technologies and drug discovery. The broad-spectrum nature of MTMC can augment military and civil defense to combat chemical warfare and chemical terrorism.

Chemical warfare agents: their past and continuing threat and evolving therapies. Part I of II.

Chemical warfare agents are potentially accessible to even underdeveloped nations because they are easily and inexpensively produced. This means that they are ideal for use by terrorists and in military operations against civilian populations and troops. In terms of cutaneous injury, vesicants-mainly sulfur mustard-are the most significant chemical warfare agents. Advances in understanding the pathophysiology of the lesions produced by sulfur mustard have led to the research and development of barrier creams as well as pre- and post-exposure therapies to moderate the damage and accelerate healing. Part I of this paper will discuss the history and classification of chemical agents; Part II, which will appear in the September/October 2003 issue of SKINmed, will discuss characteristic manifestations of exposure to chemical agents, as well as prevention and therapy.