RESUMEN
Smoke inhalation from a structure fire is a common route of cyanide poisoning in the U.S. Cyanide inhibits cellular respiration, often leading to death. Its rapid distribution throughout the body can result in injuries to multiple organs, and cyanide victims were reported to experience myocardial infarction and other cardiac complications. However, molecular mechanisms of such complications are yet to be elucidated. While FDA-approved CN antidotes such as sodium thiosulfate and hydroxocobalamin are clinically used, they have foreseeable limitations during mass casualty situations because they require intravenous administration. To facilitate the development of better antidotes and therapeutic treatments, a global view of molecular changes induced by cyanide exposure is necessary. As an exploratory pursuit, we performed oligonucleotide microarrays to establish cardiac transcriptomes of an animal model of nose-only inhalation exposure to hydrogen cyanide (HCN), which is relevant to smoke inhalation. We also profiled cardiac transcriptomes after subcutaneous injection of potassium cyanide (KCN). Although the KCN injection model has often been used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 h after exposure. Pathway analysis identified that HCN-induced transcriptomes were enriched with genes encoding mediators of pathways critical in modulation of cardiac complications and that a large number of such genes were significantly decreased in expression. We utilized the upstream regulatory analysis to propose drugs that can be potentially employed to treat cyanide-induced cardiac complications.
Asunto(s)
Lesiones Cardíacas/complicaciones , Cianuro de Hidrógeno/envenenamiento , Cianuro de Potasio/envenenamiento , Animales , Cianuro de Hidrógeno/administración & dosificación , Exposición por Inhalación , Inyecciones Subcutáneas , Masculino , Ratones , Cianuro de Potasio/administración & dosificaciónRESUMEN
Toxic industrial chemicals and chemical warfare agents present an acute inhalation hazard to exposed populations. The hazardous materials consequence assessment modeling community requires toxicity models to estimate these hazards. One popular phenomenological toxicity model is the toxic load model. Although this model is only well-defined for constant-concentration exposures, several generalizations have been proposed for the case of time-varying exposures. None of them, however, were validated by experimental evidence at the time they were proposed. Accordingly, the Defense Threat Reduction Agency (DTRA) sponsored experiments to explore the effects of time-varying inhalation exposures of hydrogen cyanide (HCN) and carbon monoxide (CO) gas on rats. The experiments were designed and executed by the U.S. Army's Edgewood Chemical and Biological Center (ECBC) and the Naval Medical Research Unit Dayton (NAMRU-D) between 2012 and 2015. We conducted an independent analysis of the toxic load model's ability to predict the ECBC/NAMRU-D experimental data using an analytical methodology oriented toward hazard prediction model users. We found that although some of the proposed extensions of the toxic load model perform better than others, all of them have difficulty reproducing the experimental data. The toxic load model also has difficulty reproducing even the constant-concentration data for HCN exposures under 10â¯min.
Asunto(s)
Monóxido de Carbono/análisis , Monóxido de Carbono/toxicidad , Cianuro de Hidrógeno/análisis , Cianuro de Hidrógeno/toxicidad , Exposición por Inhalación/análisis , Modelos Biológicos , Animales , Monóxido de Carbono/administración & dosificación , Modelos Animales de Enfermedad , Cianuro de Hidrógeno/administración & dosificación , Ratas , Factores de TiempoRESUMEN
OBJECTIVE: Cyanide is a highly toxic chemical, and acute exposure depletes cells and tissue of oxygen, depressing the respiratory, cardiovascular and neurological systems and potentially leading to death. Cyanide has been used as a weapon since ancient Rome and continues to pose a potential threat today. A well-characterized animal model is necessary for the development of novel methods of rapid detection and treatment. This manuscript describes the development of an inhalation exposure system designed to evaluate the lethality of acute cyanide inhalation in the porcine model. MATERIALS AND METHODS: A custom designed hydrogen cyanide (HCN) inhalation exposure system provided stable cyanide concentrations to un-anesthetized swine while monitoring respiratory parameters. Real-time respiratory monitoring, cyanide concentration and body weight were used to calculate inhaled doses. RESULTS: The inhalation exposure system generated controlled HCN ranging from 260 to 986 ppm to achieve inhaled doses between 1.78 and 3.97 mg/kg. Based on survival outcomes, the median lethal dose was determined to be 2.21 mg/kg, and the median lethal exposure level was 5893 mg min/m3. DISCUSSION: The ability of the HCN inhalation exposure system to deliver target inhaled doses and the determination of the inhaled median lethal dose in swine support the use of the exposure system and animal model for the evaluation of medical countermeasures of acute inhaled HCN toxicity.
Asunto(s)
Cianuro de Hidrógeno/toxicidad , Exposición por Inhalación , Pruebas de Toxicidad/métodos , Animales , Femenino , Cianuro de Hidrógeno/administración & dosificación , Dosificación Letal Mediana , Modelos Animales , Sus scrofa , Factores de Tiempo , Pruebas de Toxicidad/instrumentaciónRESUMEN
Cyanides are highly toxic compounds that have been used as weapons of terrorism throughout history. Cyanide (CN) is acutely toxic by all routes of administration; however, inhalation is the main exposure route. To adequately test effective countermeasures against inhalational CN threats, robust and well-characterized animal models are needed. This paper describes the initial development of a hydrogen cyanide (HCN) exposure swine model for documenting the physiological effects and toxicological profile during and after HCN inhalation exposure. Animals were implanted with telemetry transmitters for heart rate (HR), blood pressure, and electrocardiogram monitoring, and vascular access ports for serial blood collections. Nine female swine were exposed to HCN concentrations of 500 ± 6 ppm while breathing parameters were monitored real-time. Inhaled HCN doses ranged from 2.02 to 2.83 mg/kg. Clinical signs included vocalization, agitation, salivation, respiratory distress and apnea. After HCN exposure initiation, systemic arterial pressure fell dramatically with a concomitant increase in HR. Blood samples were collected to determine CN blood levels using LC-MS/MS and blood gas analysis. In summary, the developed HCN inhalation swine model permitted documentation of the physiological effects associated with CN poisoning. This model could be used to evaluate potential CN medical countermeasures in the event of a public health emergency stemming from inhalational CN threats.
Asunto(s)
Modelos Animales de Enfermedad , Cianuro de Hidrógeno/administración & dosificación , Cianuro de Hidrógeno/envenenamiento , Administración por Inhalación , Animales , Presión Sanguínea/efectos de los fármacos , Electrocardiografía , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Cianuro de Hidrógeno/sangre , Porcinos , TelemetríaRESUMEN
The ten Berge model (or "toxic load" model) is often used to estimate the acute toxicity for varying combinations of inhaled concentration and duration. Expressed as C(n) × t = toxic load (TL), TLs are assumed constant for various combinations of concentration (C) and time (t). Experimental data in a recent acute inhalation study of rats exposed to time-varying concentrations of hydrogen cyanide (HCN) supported the validity of the toxic load model except under very brief, discontinuous, high concentration exposures. In the present investigation, experiments were conducted to extend the evaluation of the applicable domain of the model for acute lethality of HCN in the rat (cumulative exposure range of 2900-11,000 ppm min). The lethality of HCN over very short (< 5 min) durations of high concentrations did not conform to the toxic load model. A value of n=1.57 was determined for uninterrupted exposures ⩾ 5 min. For 30-min exposures, the presence or absence of a gap between two exposure pulses of different concentrations, the relative duration, relative height, and the ordering of the pulses (low then high, vs. high then low) did not appear to have a meaningful impact on the toxic load required for median lethality.
Asunto(s)
Cianuro de Hidrógeno/toxicidad , Exposición por Inhalación , Modelos Teóricos , Pruebas de Toxicidad/métodos , Animales , Simulación por Computador , Relación Dosis-Respuesta a Droga , Gases , Cianuro de Hidrógeno/administración & dosificación , Dosificación Letal Mediana , Masculino , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
CONTEXT: Bamboo shoots contain cyanogenic glycosides named taxiphyllin. Cyanide poisoning from cyanogenic glycosides commonly occurs following ingestion. However, toxicity caused by inhalation of hydrogen cyanide gas (HCN) produced from pickled shoots has never been reported. OBJECTIVE: To describe cyanide poisoning in eight victims who were exposed to HCN produced in a well containing pickling bamboo shoots. MATERIALS AND METHODS: Due to a series of botched rescue attempts, a total of eight patients entered into a 27 m(3) well containing pickled bamboo shoots and immediately lost consciousness. After rescue, two patients developed cardiac arrest, metabolic acidosis and died. Four other patients suffered metabolic acidosis, but recovered after supportive care. The remaining two regained consciousness and recovered soon after the event. Ambient air study and cyanide content of bamboo shoots helped confirm the diagnosis. RESULTS: All patients had high anion gap metabolic acidosis with normal oxygenation. Blood cyanide levels ranged from 2.66 to 3.30 mcg/ml (taken after about 18 h of incident). Ambient air study (21 h after incident) revealed oxygen 20.9%, and sulfur dioxide 19.4 ppm. The instrument was unfortunately not equipped to detect HCN. A simulation study revealed HCN and sulfur dioxide in the ambient air at 10 ppm and 7.5 ppm, respectively. Cyanide content in the bamboo shoots ranged from 39 to 434 mg/kg in the wet shoots. DISCUSSION: This series of patients developed sudden onset of alteration of consciousness and metabolic acidosis upon exposure, and cyanide was confirmed in all victims. The simulation study confirmed the presence of HCN in the ambient air of the well containing bamboo shoots. CONCLUSION: We have reported mass acute cyanide poisoning with two fatalities. The source of HCN was unusual as it was produced from pickling bamboo shoot.
Asunto(s)
Bambusa/toxicidad , Cianuro de Hidrógeno/envenenamiento , Intoxicación por Plantas/complicaciones , Brotes de la Planta/envenenamiento , Acidosis/etiología , Administración por Inhalación , Adulto , Cianuros/sangre , Manipulación de Alimentos/métodos , Paro Cardíaco/etiología , Humanos , Cianuro de Hidrógeno/administración & dosificación , Masculino , Persona de Mediana Edad , Intoxicación por Plantas/sangre , Brotes de la Planta/química , Dióxido de Azufre/análisis , Tailandia , Adulto JovenRESUMEN
Cyanide poisoning is an important source of morbidity and mortality from smoke exposure in structural fires. This case involved administration of a cyanide antidote to a prisoner (male, 23 years) in France, discovered in cardiorespiratory arrest after about 30 minutes exposure to smoke from a burning mattress during an apparent suicide attempt. Smoke exposure, circulatory failure during initial resuscitation, and elevated blood cyanide and lactate led to the diagnosis of cyanide poisoning. Hydroxocobalamin (Cyanokit®), 5 g intravenous) was given immediately and on arrival at the hospital. Cardiopulmonary resuscitation restored cardiovascular function after 33 minutes. There were no neurological or other sequelae. Timely hydroxocobalamin administration contributed to full recovery from cardiorespiratory arrest secondary to cyanide poisoning from smoke inhalation. Hydroxocobalamin should be available to emergency medical teams attending fire scenes.
Asunto(s)
Cianuro de Hidrógeno/envenenamiento , Inhalación , Prisioneros , Cuidados Críticos/métodos , Electrocardiografía , Francia , Paro Cardíaco/inducido químicamente , Paro Cardíaco/diagnóstico , Paro Cardíaco/tratamiento farmacológico , Humanos , Cianuro de Hidrógeno/administración & dosificación , Cianuro de Hidrógeno/sangre , Hidroxocobalamina/administración & dosificación , Hidroxocobalamina/uso terapéutico , Masculino , Humo/efectos adversos , Adulto JovenRESUMEN
Tobacco cell death induced by palmitoleic acid (16:1), ceramide, and KCN was found to possess features associated with program cell death (PCD), including cell volume decrease, loss of membrane integrity, DNA damage, nuclear and plastid disorganization, and chromatin condensation. Cell volume decrease was found to be caused by loss of intracellular K(+). Ba(2+) was able to prevent the K(+) loss and it also protected the cells from death induced by 16:1 and ceramide but not KCN. The results suggest that K(+) loss is a critical step in plant PCD. The inability of Ba(2+) to prevent cell death was most likely due to its other effects of KCN, i.e., inhibition of cytochrome oxidase in the respiratory chain and generation of reactive oxygen species.
Asunto(s)
Apoptosis/fisiología , Ceramidas/administración & dosificación , Ácidos Grasos Monoinsaturados/administración & dosificación , Cianuro de Hidrógeno/administración & dosificación , Nicotiana/citología , Nicotiana/metabolismo , Apoptosis/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Nicotiana/efectos de los fármacosRESUMEN
Carbon monoxide (CO) and hydrogen cyanide (HCN) are generated during aircraft interior fires in sufficient amounts to incapacitate cabin occupants. For typical post-crash and in-flight fires, minimum protection periods of 5 and 35 min, respectively, have been suggested for breathing devices to protect the occupants from smoke. Relationships of blood carboxyhemoglobin (COHb) and cyanide (CN-) levels to incapacitation have not been well defined for these gases. Therefore, time to incapacitation (ti) and blood COHb and CN- at incapacitation were examined in rats exposed to CO (5706 ppm for 5-min ti; 1902 ppm for 35-min ti), HCN (184 ppm for 5-min ti; 64 ppm for 35-min ti) and their mixtures (equipotent concentrations of each gas that produced 5- and 35-min ti). Blood CO and HCN uptakes were evaluated at the two concentrations of each gas. With either gas, variation in ti was higher for the 35-min ti than the 5-min ti The COHb level reached a plateau prior to incapacitation at both CO concentrations, and COHb levels at the 5- and 35-min ti were different from each other. Blood CN- increased as a function of both HCN concentration and exposure time, but CN- at the 5-min ti was half of the 35-min ti CN- level. The HCN uptake at the high concentration was about three times that at the low concentration. In the high concentration CO-HCN mixture, ti was shortened from 5 to 2.6 min; COHb dropped from 81 to 55% and blood CN- from 2.3 to 1.1 microgram ml(-1). At the low-concentration CO-HCN mixture, where ti was reduced from 35 to 11.1 min, COHb decreased from 71 to 61% and blood CN- from 4.2 to 1.1 microgram ml(-1). Any alteration in the uptake of either gas by the presence of the other was minimal. Our findings suggest that specific levels of blood COHb and CN- cannot be correlated directly with the incapacitation onset and that postmortem blood COHb and CN- levels should be evaluated carefully in fire victims.
Asunto(s)
Intoxicación por Monóxido de Carbono , Monóxido de Carbono/toxicidad , Carboxihemoglobina/efectos de los fármacos , Cianuros/sangre , Cianuro de Hidrógeno/toxicidad , Aeronaves , Animales , Monóxido de Carbono/administración & dosificación , Monóxido de Carbono/metabolismo , Carboxihemoglobina/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Incendios , Cianuro de Hidrógeno/administración & dosificación , Cianuro de Hidrógeno/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Análisis de RegresiónRESUMEN
Critical levels of selected cigarette smoke constituents have been expressed in terms of maximum numbers of pre-1960 cigarettes that a smoker may consume daily without increasing his mortality risk substantially above that of a nonsmoker. This could still imply an important risk, although it may be difficult to detect. We relate these levels to the yields of 27 current low tar and nicotine commercial cigarettes, as measured at the Oak Ridge National Laboratory. In addition, the yields of these selected constituents concomitant with the yield of 1 mg of nicotine are provided as a guide for the smoker who titrates or adjusts his smoking pattern to accommodate a fixed daily intake of nicotine.