A Potential Antidote for Both Azide and Cyanide Poisonings.

There do not appear to be any established therapeutics for treating azide poisoning at this time, and presently available antidotes to cyanide poisoning are far from ideal, being particularly impractical for use if multiple victims present. The cobalt (II/III) complex of the Schiff-base ligand trans-[14]-diene (5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (CoN4[14]) is shown to act as an effective antidote to both azide and cyanide toxicity in mice. Groups of animals challenged with an LD40 dose of NaCN (100 µmol/kg i.p.) exhibited significantly faster recovery from knockdown and fewer (zero) deaths if given CoN4[14] (50 µmol/kg i.p.) 2 minutes after the toxicant. Groups of animals challenged with an essentially lethal dose of NaCN (1.5 x LD50 = 150 µmol/kg i.p.) all survived if given the CoN4[14] (75 µmol/kg i.p.) 5 minutes before the toxicant dose. These data represent improved antidotal capability over the Food and Drug Administration-approved cobalt-based cyanide antidote hydroxocobalamin. Recovery of animals challenged sublethally with NaN3 (415 µmol/kg i.p.) was assessed employing a modified pole-climbing test. Mice given the CoN4[14] antidote (70 µg/kg i.p.) 5 minutes after the toxicant dose recovered twice as fast as the controls given no antidote. The interactions of cyanide and azide with CoN4[14] in vitro (buffered aqueous solutions) have been further investigated by a combination of spectroscopic approaches. The Co(II) form of the complex is able to bind two CN- anions while only binding a single N3 -, providing a reasonable explanation for the difference between their therapeutic abilities. SIGNIFICANCE STATEMENT: The Schiff-base complex CoN4[14] is shown to be an effective antidote to cyanide in mice, with improved therapeutic capabilities compared to the Food and Drug Administration-approved cobalt-containing hydroxocobalamin. CoN4[14] is also antidotal in mice toward azide poisoning, for which there is seemingly no approved therapy currently available. The activity toward cyanide involves a "redox-switching" mechanism that could be a common, but largely unrecognized, feature of all cobalt-based cyanide antidotes in use and under development.

Presumptive Contamination: A New Approach to PFAS Contamination Based on Likely Sources.

While research and regulatory attention to per- and polyfluoroalkyl substances (PFAS) has increased exponentially in recent years, data are uneven and incomplete about the scale, scope, and severity of PFAS releases and resulting contamination in the United States. This paper argues that in the absence of high-quality testing data, PFAS contamination can be presumed around three types of facilities: (1) fluorinated aqueous film-forming foam (AFFF) discharge sites, (2) certain industrial facilities, and (3) sites related to PFAS-containing waste. While data are incomplete on all three types of presumptive PFAS contamination sites, we integrate available geocoded, nationwide data sets into a single map of presumptive contamination sites in the United States, identifying 57,412 sites of presumptive PFAS contamination: 49,145 industrial facilities, 4,255 wastewater treatment plants, 3,493 current or former military sites, and 519 major airports. This conceptual approach allows governments, industries, and communities to rapidly and systematically identify potential exposure sources.

A Cobalt Schiff-Base Complex as a Putative Therapeutic for Azide Poisoning.

There is presently no antidote available to treat azide poisoning. Here, the Schiff-base compound Co(II)-2,12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)2,11,13,15-pentaenyl dibromide (Co(II)N4[11.3.1]) is investigated to determine if it has the capability to antagonize azide toxicity through a decorporation mechanism. The stopped-flow kinetics of azide binding to Co(II)N4[11.3.1] in the absence of oxygen exhibited three experimentally observable phases: I (fast); II (intermediate); and III (slow). The intermediate phase II accounted for ∼70% of the overall absorbance changes, representing the major process observed, with second-order rate constants of 29 (±4) M-1 s-1 at 25 °C and 70 (±10) M-1 s-1 at 37 °C. The data demonstrated pH independence of the reaction around neutrality, suggesting the unprotonated azide anion to be the attacking species. The binding of azide to Co(II)N4[11.3.1] appears to have a complicated mechanism leading to less than ideal antidotal capability; nonetheless, this cobalt complex does protect against azide intoxication. Administration of Co(II)N4[11.3.1] at 5 min post sodium azide injection (ip) to mice resulted in a substantial decrease of righting-recovery times, 12 (±4) min, compared to controls, 40 (±8) min. In addition, only two out of seven mice "knocked down" when the antidote was administered compared to the controls given toxicant only (100% knockdown).

Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity.

Phosphine (PH3) poisoning continues to be a serious problem worldwide, for which there is no antidote currently available. An invertebrate model for examining potential toxicants and their putative antidotes has been used to determine if a strategy of using Au(I) complexes as phosphine-scavenging compounds may be antidotally beneficial. When Galleria mellonella larvae (or wax worms) were subjected to phosphine exposures of 4300 (±700) ppm·min over a 20 min time span, they became immobile (paralyzed) for ∼35 min. The administration of Au(I) complexes auro-sodium bisthiosulfate (AuTS), aurothioglucose (AuTG), and sodium aurothiomalate (AuTM) 5 min prior to phosphine exposure resulted in a drastic reduction in the recovery time (0-4 min). When the putative antidotes were given 10 min after the phosphine exposure, all the antidotes were therapeutic, resulting in mean recovery times of 14, 17, and 19 min for AuTS, AuTG, and AuTM, respectively. Since AuTS proved to be the best therapeutic agent in the G. mellonella model, it was subsequently tested in mice using a behavioral assessment (pole-climbing test). Mice given AuTS (50 mg/kg) 5 min prior to a 3200 (±500) ppm·min phosphine exposure exhibited behavior comparable to mice not exposed to phosphine. However, when mice were given a therapeutic dose of AuTS (50 mg/kg) 1 min after a similar phosphine exposure, only a very modest improvement in performance was observed.