Special Issue: Emerging Chemical Terrorism Threats

Chemical exposure emergencies posing a serious threat to the health and survival of civilians can be caused by terrorism events or industrial accidents. The National Institutes of Health (NIH) developed a comprehensive research program named the Countermeasures Against Chemical Threats (CounterACT) in 2006 with a goal to integrate cutting-edge research with the latest technological advances in science and medicine for a more rapid and effective response during a chemical emergency. CounterACT changed the previous paradigm for medical countermeasure (MCM) research from one focused on the U.S. military to one focused on treatments for first responders and civilians (Jett 2016; Jett and Yeung 2010). The basis for this change was to address the terrorist threat to our homeland and provide MCMs to those who would not have the prophylactic treatments and protective personal equipment typically available for the U.S. military. CounterACT also broadened the base of academic researchers and laboratories across the nation to include those who are actively engaged in translational research, and applying ideas, insights, and discoveries generated through basic scientific study. In the first decade of the 21st century, CounterACT supported laboratories working on a various chemical threat agents including nerve (e.g., sarin) and blister (e.g., sulfur mustard) agents as the primary focus of the original CounterACT Research Centers of Excellence (Jett and Spriggs 2018). Progress in understanding the molecular biology of these agents and the development of MCMs has been well documented through several review articles and publications (Businaro et al. 2016; Gray et al. 2015; Richardson et al. 2019; Weinberger et al. 2016).

The goal of this special issue, “Emerging Chemical Terrorism Threats,” is to highlight current CounterACT research on the molecular biology and MCM development landscape for chemical agents that pose a real future threat and not widely covered in the peer reviewed literature. Other chemical threats that might be used in terrorism or cause natural disasters/large scale accidents include a range of Toxic Industrial Chemicals (TICs) and Toxic Industrial Materials (TIMs) that are used widely in industry (Bennett 2003). While chemicals have been used in warfare for centuries, the availability or access to TICs/TIMs makes their use in terrorist activities more likely because they are not tightly controlled or secured like conventional chemical warfare agents (and precursors) which are monitored globally by The Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons (United Nations 1992). Furthermore, TICs/TIMs may also be released in industrial accidents or natural disasters. Table 1 identifies Chemical Terrorism Threat agents that lack definitive FDA licensed MCMs, require improved MCMs, or have limited understanding of the mechanism of action and pathophysiology.

Table 1. Chemicals with potential for industrial accidents or use in terrorism.

Second tier chemical threats have lower toxicity compared with traditional chemical weapons but can be easily synthesized or are readily available due to their use in industry or medicine. These chemicals might be subverted for terrorism or released in a natural disaster, impacting civilian populations.

Chemical name	Industrial usage/Ease of synthesis	Mechanism(s) of action	CounterACT Support
Halogens (chlorine, bromine)*	Significant industrial usage	Pulmonary toxicity (Achanta and Jordt 2019; Govier and Coulson 2018; Milanez 2015)	U01, R21
Hydrogen sulfide	Significant industrial usage produced in petroleum refineries	Inhibits cellular respiration, neurotoxic (Ng et al. 2019)	U01, R21
Cyanide	Significant industrial usage	Inhibits cellular respiration (Bhattacharya and Flora 2015; Cope 2020)	U01
Phosgene*	Significant industrial usage	Irritant, delayed onset non-cardiogenic pulmonary edema (Hobson et al. 2019)	R21
Phosgene oxime*	Ease of synthesis and limited understanding of the mechanism of action and pathophysiology	Urticant (Goswami et al. 2018; Tewari-Singh 2020)	U01, R21
Convulsants (such as tetramethylenedisulfotetramine)	Rodenticide	Seizures (Laukova et al. 2019)	U54 Center of Excellence
Arsenicals	Chemical weapon, cancer drugs	Rapid, severe hemolysis, DNA alkylation, inhibition of glutathione phase 2 metabolism (Srivastava and Flora 2020)	U54 Center of Excellence, U01
Hydrochloric acid	Significant industrial usage	Respiratory inhalational damage	U01

^*These agents are covered in this special issue.

The CounterACT program is the first step in MCM development. Progression to pharmaceutical lead generation first requires target validation and basic understanding of the molecular biology of chemical agents. CounterACT supports the development of adequate translational model systems including a widely accepted in vitro model system and at least one sufficiently well-characterized animal model for predicting the response in humans. The Animal Rule states that the FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of a drug only when certain criteria are met. The FDA will make this determination based on the adequacy of the data from the human disease or condition and the corresponding data from the pivotal animal model studies. Advanced development for lead MCMs produced by the CounterACT program can then be subsequently supported by the Biomedical Advanced Research and Development Authority (BARDA). Following BARDA support and (typically) FDA approval, MCMs are considered for inclusion in the Strategic National Stockpile (SNS), at which point the focus shifts from preparedness to response. The Centers for Disease Control has prepared a list of public-facing preparation and planning resources related specifically to chemical emergencies (Centers for Disease Control 2021). Additionally, HHS’s Chemical Hazards Emergency Medical Management provides specific guidance for exposure to ammonia, chlorine, hydrogen cyanide, mustard agents, nerve agents, and phosgene (U.S. Department of Health and Human Services 2021).

This special issue provides readers with insights into the toxicity, molecular biology and development of MCMs for the next generation of chemical threats. A brief discussion of the CounterACT and BARDA programs authored by CounterACT Director Dr. David Jett of NINDS and Dr. Judith Wolfe Laney, Chief, Chemical Medical Countermeasures, Division of CBRN Countermeasures of BARDA is included in the this special issue and highlights the role of these programs in supporting the development of MCMs for chemical threats (Jett and Laney 2019). Subsequent in-depth reviews cover chlorine, halogens, phosgene oxime, and phosgene. Finally, this Special Issue includes an in-depth review of the Strategic National Stockpile and the future acquisition of MCMs to protect the homeland from chemical agents.