Sodium nitrite alone is shown to ameliorate sub-lethal cyanide toxicity in mice when given from ~1 hour before until 20 minutes after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase; the effects of the two inhibitors being essentially additive under standard assay conditions, rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sub-lethal levels of cyanide intoxication.

Isoamyl nitrite has previously been considered acceptable as an inhaled cyanide antidote, so the antidotal utility of this organic nitrite compared with sodium nitrite was investigated. To facilitate a quantitative comparison, doses of both sodium nitrite and isoamyl nitrite were given intraperitoneally in equimolar amounts to sub-lethally cyanide-challenged mice. Righting recovery from the knockdown state was clearly compromised in the isoamyl nitrite-treated animals, the effect being attributable to the toxicity of the isoamyl alchol produced during hydrolysis of the isoamyl nitrite to release nitrite anion. Subsequently, inhaled aqueous sodium nitrite aerosol was demonstrated to ameliorate sub-lethal cyanide toxicity, when provided to mice after the toxic dose, by the more rapid recovery of righting ability compared to control animals given only the toxicant. Aerosolized sodium nitrite has thus been shown by these experiments to have promise as a better alternative to organic nitrites for development as an inhaled cyanide antidote. The inhaled sodium nitrite led to production of NO in the bloodstream as determined by the appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. The aerosol delivery was performed in an unmetered inhalation chamber and, in this study, no attempt was made to optimize the procedure. It is argued that administration of an effective inhaled aqueous sodium nitrite dose in humans is possible, though just beyond the capability of current individual metered-dose inhaler designs, such as those used for asthma. Finally, working at slightly greater than LD50 NaCN doses, it was fortuitously discovered that (i) anesthesia leads to significantly prolonged survival compared to unanesthetized animals and (ii) the antidotal activity of nitrite anion was completely abolished under anesthesia. Plausible explanations for these effects in mice and their practical consequences in relation to testing putative cyanide antidotes are discussed.

BackgroundCharacterizing intra-urban variation in air quality is important for epidemiological investigation of health outcomes and disparities. To date, however, few studies have been designed to capture spatial variation during select hours of the day, or to examine the roles of meteorology and complex terrain in shaping intra-urban exposure gradients.MethodsWe designed a spatial saturation monitoring study to target local air pollution sources, and to understand the role of topography and temperature inversions on fine-scale pollution variation by systematically allocating sampling locations across gradients in key local emissions sources (vehicle traffic, industrial facilities) and topography (elevation) in the Pittsburgh area. Street-level integrated samples of fine particulate matter (PM2.5), black carbon (BC), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3) were collected during morning rush and probable inversion hours (6-11 AM), during summer and winter. We hypothesized that pollution concentrations would be: 1) higher under inversion conditions, 2) exacerbated in lower-elevation areas, and 3) vary by season.ResultsDuring July - August 2011 and January - March 2012, we observed wide spatial and seasonal variability in pollution concentrations, exceeding the range measured at regulatory monitors. We identified elevated concentrations of multiple pollutants at lower-elevation sites, and a positive association between inversion frequency and NO2 concentration. We examined temporal adjustment methods for deriving seasonal concentration estimates, and found that the appropriate reference temporal trend differs between pollutants.ConclusionsOur time-stratified spatial saturation approach found some evidence for modification of inversion-concentration relationships by topography, and provided useful insights for refining and interpreting GIS-based pollution source indicators for Land Use Regression modeling.

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