Toxic Inhalation Hazard Research Articles

Transient receptor potential channels in pulmonary chemical injuries and as countermeasure targets.

The lung is highly sensitive to chemical injuries caused by exposure to threat agents in industrial or transportation accidents, occupational exposures, or deliberate use as weapons of mass destruction (WMD). There are no antidotes for the majority of the chemical threat agents and toxic inhalation hazards despite their use as WMDs for more than a century. Among several putative targets, evidence for transient receptor potential (TRP) ion channels as mediators of injury by various inhalational chemical threat agents is emerging. TRP channels are expressed in the respiratory system and are essential for homeostasis. Among TRP channels, the body of literature supporting essential roles for TRPA1, TRPV1, and TRPV4 in pulmonary chemical injuries is abundant. TRP channels mediate their function through sensory neuronal and nonneuronal pathways. TRP channels play a crucial role in complex pulmonary pathophysiologic events including, but not limited to, increased intracellular calcium levels, signal transduction, recruitment of proinflammatory cells, neurogenic inflammatory pathways, cough reflex, hampered mucus clearance, disruption of the integrity of the epithelia, pulmonary edema, and fibrosis. In this review, we summarize the role of TRP channels in chemical threat agents-induced pulmonary injuries and how these channels may serve as medical countermeasure targets for broader indications.

Unexpected association between increased levels of ambient carbon monoxide and reduced daily outpatient visits for vaginitis: A hospital-based study

Carbon monoxide (CO) is a well-known “toxic gas”. It represents a toxic inhalation hazard at high concentration and is commonly found in polluted air. However, a series of recent studies have suggested that low concentration of CO can also produce protective functions. This study was performed to investigate the association between ambient CO exposure and vaginitis outpatient visits. Daily baseline outpatient data of vaginitis from January 1, 2013 to December 31, 2015 were obtained from Xi'an, a heavily-polluted metropolis in China. The over-dispersed Poisson generalized additive model was applied to discover the relations between short-term ambient CO exposure and the number of vaginitis outpatient visits by adjusting day of the week and weather conditions. A total of 16,825 outpatient hospital visits for vaginitis were recorded. The mean daily concentration of carbon monoxide (CO) was well below Chinese and WHO guidelines. During the study period, increased levels of ambient CO was associated with reduced outpatient-visits through concurrent to lag 5 days, and the most significant association was evidenced at lag 05. A 0.1 mg/m3 increase in daily average CO at lag 05 corresponded to −1.25% (95%CI: −1.85%, −0.65%) change in outpatient-visits for vaginitis. Moreover, the association was more significant in those women aged 20–29 years. After adjustment for PM10, PM2.5, SO2, and NO2, and O3, the negative associations of CO with vaginitis kept significant, suggesting relative stability of effect estimates. In summary, this is the first evidence that increased ambient CO exposure can be related to reduced daily outpatient visits for vaginitis. The results of our study may not only help to establish more comprehensive understanding of the health effects of ambient air on vaginitis and other gynecological diseases, but also provide a clue to new potential interventions.

Analysis of TRPA1 antagonist, A-967079, in plasma using high-performance liquid chromatography tandem mass-spectrometry

The noxious effects from exposure to toxic inhalation hazards (TIHs, such as isocyanates, chlorine, etc.) are known to be triggered by the activation of transient receptor potential ankyrin 1 (TRPA1) ion channel. Antagonists of TRPA1 have shown near complete attenuation of the noxious effects from TIH exposure. One of the TRPA1 antagonists, (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-pentene-3-one oxime (A-967079), has shown impressive efficacy, high selectivity, high potency, and oral bioavailability. Although a validated method to quantify A-967079 in biological matrices is vital for the further development of A-967079 as a therapeutic agent, no method for its analysis from any matrix is currently available. Hence, a rapid and simple HPLC-MS/MS method was developed and validated to quantify A-967079 in rabbit plasma. The method presented here features an excellent LOD of 25 nM and a wide linear range (0.05–200 μM), with good accuracy and precision (100 ± 10.5% and <14.2% relative standard deviation, respectively). The stability of A-967079 in plasma was excellent for most of the storage conditions evaluated. The method was successfully applied to determine A-967079 from treated animals and it may facilitate the development of this TRPA1 antagonist as a therapeutic agent against the noxious effects of TIH exposure.

Transient receptor potential (TRP) channels as a therapeutic target for intervention of respiratory effects and lethality from phosgene.

Phosgene (CG), a toxic inhalation and industrial hazard, causes bronchoconstriction, vasoconstriction and associated pathological effects that could be life threatening. Ion channels of the transient receptor potential (TRP) family have been identified to act as specific chemosensory molecules in the respiratory tract in the detection, control of adaptive responses and initiation of detrimental signaling cascades upon exposure to various toxic inhalation hazards (TIH); their activation due to TIH exposure may result in broncho- and vasoconstriction. We studied changes in the regulation of intracellular free Ca(2+) concentration ([Ca(2+)]i) in cultures of human bronchial smooth muscle cells (BSMC) and human pulmonary microvascular endothelial cells (HPMEC) exposed to CG (16ppm, 8min), using an air/liquid interface exposure system. CG increased [Ca(2+)]i (p<0.05) in both cell types, The CG-induced [Ca(2+)]i was blocked (p<0.05) by two types of TRP channel blockers, SKF-96365, a general TRP channel blocker, and RR, a general TRPV (vanilloid type) blocker, in both BSMC and HPMEC. These effects correlate with the in vivo efficacies of these compounds to protect against lung injury and 24h lethality from whole body CG inhalation exposure in mice (8-10ppm×20min). Thus the TRP channel mechanism appears to be a potential target for intervention in CG toxicity.

Carbon monoxide in the treatment of sepsis.

Carbon monoxide (CO), a low-molecular-weight gas, is endogenously produced in the body as a product of heme degradation catalyzed by heme oxygenase (HO) enzymes. As the beneficial roles of HO system have been elucidated in vitro and in vivo, CO itself has also been reported as a potent cytoprotective molecule. Whereas CO represents a toxic inhalation hazard at high concentration, low-dose exogenous CO treatment (~250-500 parts per million) demonstrates protective functions including but not limited to the anti-inflammatory and antiapoptotic effects in preclinical models of human diseases. Of note, CO exposure confers protection in animal models of sepsis by inhibiting inflammatory responses and also enhancing bacterial phagocytosis in leukocytes. These unique functions of CO including both dampening inflammation and promoting host defense mechanism are mediated by multiple pathways such as autophagy induction or biosynthesis of specialized proresolving lipid mediators. We suggest that CO gas may represent a novel therapy for patients with sepsis.

Rail Transportation of Toxic Inhalation Hazards: Policy Responses to the Safety and Security Externality

Toxic inhalation hazard (TIH) chemicals such as chlorine gas and anhydrous ammonia are among the most dangerous of hazardous materials. Rail transportation of TIH creates risk that is not adequately reflected in the costs, creating a TIH safety and security externality. This paper describes and evaluates policy alternatives that might effectively mitigate the dangers of TIH transportation by rail. After describing the nature of TIH risk and defining the TIH externality, general policy approaches to externalities from other arenas are examined. Potential risk reduction strategies and approaches for each segment of the supply chain are reviewed. The paper concludes by summarizing policy options and assessing some of the most promising means to reduce the risks of transportation of toxic inhalation hazards. Four policy approaches are recommended: internalizing external costs through creation of a fund for liability and claims, improving supply chain operations, enhancing emergency response and focusing regulatory authority. It is further suggested that the Department of Transportation convene a discussion among stakeholder representatives to evaluate policy alternatives.

Carbon monoxide: present and future indications for a medical gas

Gaseous molecules continue to hold new promise in molecular medicine as experimental and clinical therapeutics. The low molecular weight gas carbon monoxide (CO), and similar gaseous molecules (e.g., H2S, nitric oxide) have been implicated as potential inhalation therapies in inflammatory diseases. At high concentration, CO represents a toxic inhalation hazard, and is a common component of air pollution. CO is also produced endogenously as a product of heme degradation catalyzed by heme oxygenase enzymes. CO binds avidly to hemoglobin, causing hypoxemia and decreased oxygen delivery to tissues at high concentrations. At physiological concentrations, CO may have endogenous roles as a signal transduction molecule in the regulation of neural and vascular function and cellular homeostasis. CO has been demonstrated to act as an effective anti-inflammatory agent in preclinical animal models of inflammation, acute lung injury, sepsis, ischemia/reperfusion injury, and organ transplantation. Additional experimental indications for this gas include pulmonary fibrosis, pulmonary hypertension, metabolic diseases, and preeclampsia. The development of chemical CO releasing compounds constitutes a novel pharmaceutical approach to CO delivery with demonstrated effectiveness in sepsis models. Current and pending clinical evaluation will determine the usefulness of this gas as a therapeutic in human disease.

Marine Highway Transport of Toxic Inhalation Hazard Materials

This paper presents highlights of research conducted under Phase 2 of the Transportation Research Board's National Cooperative Freight Research Program 17 and reported in North American Marine Highways. The possibility of transporting greater volumes of chlorine and anhydrous ammonia via the marine highway system was investigated. Currently, there is no coast-to-coast (and only limited inland waterway) activity related to transportation of either chemical. The researchers identified major obstacles to development and expansion and corresponding potential courses of action. Geographical dispersion of producers and consumers works against greater waterborne volumes. Chlorine and anhydrous ammonia are characterized by mature, low-growth markets. Expansion of marine services will require significant capital costs and time to set up new terminals. There is great concern over the current condition of the system of locks and dams. Marine carriers face the same economic ramifications from risk of catastrophic accidents as rail carriers, necessitating the establishment of a new risk paradigm. The federal government could provide initial funds and expedite the permit process to allow new marine highway ventures to develop more rapidly and could also identify and assist potential new import points for both chemicals into the United States. Finally, the federal government must indicate its commitment to maintain the current inland waterway system. However, with no measures that can overcome the geographical dispersion of producers and users, the lack of density in any given corridor, and the already mature markets, significant expansion of the transport of toxic inhalation hazard materials via marine highways is not anticipated.

Between Safety and Security: The Policy Challenges of Transporting Toxic Inhalation Hazards

Abstract The transportation of hazardous materials is vital to the U.S. economy and inherently dangerous. In the decade since the terrorist attacks of September 11th, 2001, policymakers have struggled to confront the distinct safety and security challenges associated with hazardous materials transportation. Reducing the risks of “toxic inhalation hazards,” a dangerous subset of hazardous materials, from both accidents and intentional disruptions is an ongoing source of controversy. In this paper, we examine proposed risk mitigation measures and outline a policy program designed to reduce the risks associated with hazardous materials transportation. The analysis highlights the limitations and counterproductive nature of narrowly-targeted strategies exclusively designed to confront either safety or security, and emphasizes the importance of comprehensive risk-mitigation strategies.

Effective Monitoring and Protection of Workers and the Community during Waterway Chemical Spills

ABSTRACT Waterway spills can consist of many compounds ranging from chemicals classified as Toxic Inhalation Hazards (TIH) to petroleum products. Any particular product may comprise hundreds of ind...

Effects of Route Rationalization on Hazardous Materials Transportation Risk

Hazardous materials traffic originates and terminates at numerous locations throughout the North American railroad network. Rerouting of this traffic, especially toxic inhalation hazard materials, away from populated areas has received considerable attention in recent years as a means of reducing risk. However, rerouting on a route-specific basis is neither simple nor necessarily effective at reducing risk because of physical constraints in the configuration of the rail network and the possible need to increase the miles traveled by hazardous materials so as to avoid populated areas. A more comprehensive approach is rationalization of the transportation route structure for these materials. This does not simply involve trying to reroute traffic between the current set of origins and destinations to avoid population centers en route. Instead, route rationalization encompasses analysis of the entire route structure for a particular material. The objective is to identify opportunities to reduce risk by considering critical factors associated with each possible route, while simultaneously taking into account the production and consumption levels at each location in the network. This paper presents a risk analysis model combined with an optimization technique to formally consider risk reduction by means of rationalization of the hazardous materials transportation rail route structure. The model is flexible and enables optimization of the route structure based on a variety of possible objective functions, including minimization of miles traveled, accident (derailment) probability, likelihood of release, population exposure, and risk.