The Toxicokinetic Behavior of Cyanide, Thiocyanate and 2-Amino-2-Thiazoline-4-Carboxylic Acid Following Cyanide Exposure in Multiple Animal Models Utilizing Novel Methods of Detection

<p>Humans may be exposed to cyanide (CN-), a highly toxic chemical, by a number of means, such as consumption of cyanogenic plants (e.g., cassava, sorghum, lima beans, etc.), vehicle exhaust, cigarette smoke, or accidental exposure during industrial operations, such as plastic and paint processing, gold mining, and pesticide production. Once cyanide is absorbed, it blocks terminal electron transfer by inhibiting cytochrome c oxidase, resulting in cellular hypoxia, cytotoxic anoxia, and, eventually, death. Confirmation of cyanide exposure via direct analysis is difficult, as it has a half-life of less than one hour in mammals (e.g., humans, rats, pigs). Considering the major limitations to the direct analysis of cyanide exposure, analysis of other cyanide markers (such as thiocyanate (SCN-) and 2-amino-2-thiazoline-4-carboxylic acid (ATCA)) has been proposed. Novel methods of simultaneous detection of cyanide and thiocyanate were developed utilizing chemical-ionization gas-chromatography mass-spectrometry (CI-GC-MS) and high-performance liquid chromatography tandem mass-spectrometry (HPLC-MS-MS). The CI-GC-MS method produced limits of detection (LOD) of 1 μM and 50 nM with linear dynamic ranges of 10 μM-20 mM and 500 nM-200 μM for cyanide and thiocyanate, respectively. For both cyanide and thiocyanate, the precision, as measured by %RSD, was below 9% and the accuracy was within 15% of the nominal concentration. The HPLC-MS-MS method produced a LOD of 10 and 50 nM for cyanide and thiocyanate respectively, with a linear dynamic range of 0.1-50 μM for cyanide and 0.2-50 μM for thiocyanate. The %RSD was below 8% and the accuracy was within 10% of the nominal concentration. The toxicokinetic behavior of CN- and its metabolites, SCN- and ATCA were evaluated in three animal models: 1) rats, 2) rabbits, and 3) swine. Cyanide concentrations reached a maximum and declined rapidly in all the animal models as it was absorbed, distributed, metabolized, and eliminated. Thiocyanate rose more slowly as CN- was enzymatically converted to SCN- and the ATCA concentrations did not rise significantly above the baseline in the rat model, but rose quickly in rabbits and swine, and then fell rapidly, generally following the behavior of cyanide. In rats, rabbits, and swine, the half-life (t1/2) of cyanide was approximately 1506, 177 and 27 minutes, respectively. The t1/2 of SCN- in rats was 3013 minutes, while it was not calculated in rabbits and swine because SCN- concentrations did not reach a maximum. The t1/2 of ATCA was approximately 41 and 14 minutes in rabbits and swine respectively, while it could not be determined in rats due to large inter-animal variability. The results of this study show that cyanide exposure may be verified shortly after encounter by analyzing significantly elevated plasma CN- and SCN-, and when the ATCA detoxification pathway is significant, ATCA may also be used to confirm cyanide exposure.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation - University Access Only

Discipline thesis:degree_discipline

Chemistry and Biochemistry

Year dc:date.available

2013

Author dc:creator

• Bhandari, Raj K.

Contributors dc:contributor

• Brian A. Logue

• Chemistry

Statement dc:rights

• <p>In Copyright - Educational Use Permitted<br /><a href="http://rightsstatements.org/vocab/InC-EDU/1.0/">http://rightsstatements.org/vocab/InC-EDU/1.0/</a></p>

Language dc:language

en

Repository record dc:identifier

https://openprairie.sdstate.edu/etd/1365

OAI identifier oai:identifier

oai:openprairie.sdstate.edu:etd-2377