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', • • I , i~ ential ultraviolet irradiation (Kelada 1989); differ- ential pulse polarography (Westly 1988); and modified spectrophotometric (Blago 1989; Ohno 1989), colorometric (Lundquist and Sorbo 1989), and ion chromatographic determinations (Nono- mura and Hobo 1989). Analysis of cyanide and cytochrome oxidase is usually conducted with sam- ples of whole blood, serum, plasma, brain, or ven- tricular myocardium tissues. Samples should be obtained as soon as possible after cyanide exposure and analyzed immediately, otherwise erroneous analytical values will result (Tow•ill et a1. 1978; Ballantyne 1983). Brain and liver are recom- mended for cyanide analysis if removed and ana- lyzed within a week (Ballantyne et al. 1974). Cyanide measurements are further confounded by the presence of various antidotal agents (Ballan- tyne 19831; by v;;rious tissue presen•atives, such as formaldoxime (Knocke 1981) and sodium fluo- ride (Curry et al. 1967); and by the spontan- eous postmortem production of cyanide in various tissues (e.g., sterile blood, brain, liver, kidney, uterus, intestines) over time in cases of noncyani de death (Curry et al. 1967; Ballantyne et al. 1974). Mode of Action Cyanide is a potent and rapid-acting asphyxi- ant. At lethal doses, inhalation or ingestion of cya- nide produces reactions within seconds and death within minutes. Cyanide's toxic effect is due to its affinity for the ferric heme form of cytochrome aa, also known as cytochrome c oxidase, the terminal oxidase of the mitochondria] respiratory chain (Towill et al. 1978; Egekeze and Oehme 1980; Solomonson 1981; Way 1981, 1984; Leduc et al. 1982; Biehl 1984; Ballantyne 1987a; Marrs and Ballantyne 1987; Yamamoto 1989). Inhibition of the enzyme c}~tochrome c oxidase is thought Co in- volve atwo-step reaction-initial penetration of cyanide into s protein crevice followed by binding to heme iron. Formation of a stable cvtochrome c oxidase-CN complex in the mitochondria produces a blockage of electron transfer from c}~tochrome oxidase to molecular oxygen and cessation of cellu- 3ar respiration, causing cytotoxic h}•poxia in the presence of normal hemoglobin oxygenation. Tis- sueanoxia induced by the activation of cvtochrome oxidase causes a shift from aerobic to anaerobic metabolism, resulting in the depletion of energ}- rich compounds such as glycogen, phosphocrea- tine,and adenosine triphosphate, and the accumu- CYANIDE lation of lactate with decreased blood pH. The com- bination of cytotoxic hypoxia with lactate acidosis depresses the central nervous system-the most sensitive site of anoxia-resulting in respiratory arrest and death. If the absorption rate is signifi- cantly greater than the detoxification rate, there will be a rapid accumulation of free cyanide in tis- sues and body fluids, resulting in the prompt onset of signs of acute cyanide poisoning. Acute cyanide poisoning is frequently encountered as a relatively massive overdose, where the amqunt of cyanide greatly exceeds the minima] conceptration neces- sary toinhibit cytochrome coxidase. Insuch cases, many enzymes and biological systems are dis- rupted. includingvarious metalloegzymes,nitrate reductase, nitrite reductase, myo~lobin, various peroxidases, catalase, and ribulose diphosphate carboxylase, resulting in severe signs of toxicity and rapid death. The great majority of the absorbed cyanide re- acts with thiosultate in the presence of enzymes to produce thiocyanate, which is excreted in the urine over a period of several days. Owing to this rapid detoxification, animals can ingest high sublethal doses of cyanide over extended periods without harm (Towil] et al. 1978; Egekeze and Oehme 1980; EPA 1980; Davis 1981; Solorttonson 1981; Leduc 1989; Ballantyne 1987a; Oh et al. 1987; Marrs and Ballantyne 1987; Westley 1988; Mengel et al. 1989). Authorities are also in general agree- ment on several points: thiosultate iS usually low in the body, and higher levels can sigrzoficantly pro- tectagainstcyanidetoxicity;species v&ryconsider- ably in both the extent to which thiocyanate is formed and the rate at which it is elitriinated from the body; thiocyanate metabolites resulting from the transulfuration process are about 120 times less toxic than the parent cyanide compound; thiocyanate may accumulate in tissues and has been associated with developmental abnormalities and other adverse effects; the two enzyme sys- tems responsible for the transulfuratlion process are thiosultate-cyanide sulfurtransfkrase-also known as rhodanese-and beta-mercaptopvru- vate cyanide sulfurtransCerase. Rhpdanese is widely distributed in the body, but acflivity levels in mammals are highest in the mitochondria] frac- tion of liver. Rhodanese activity levels in catalyz- ing the transformation of thiosultate to thio- cyanate are limited by the availability aCsulfur. Minor detoxification pathways for cyanide in- clude exhalation in breath as HCN and as CO: from oxidative metabolism of formic acid; conjuga- tion with cystine to form 2-iminothiazolidene-