Efficacy of orally-administered chelating agents for nickel carbonyl toxicity in rats

The oral efficacy of several chelating drugs, disulfiram, sodium diethyldithiocarbamate (dithiocarb), and D-penicillamine, was studied in relation to their ability to prevent lethality due to acute inhalation exposure to nickel carbonyl. Dithiocarb and, to a lesser degree, D-penicillamine were found to be especially effective as therapeutic agents. Since dithiocarb is chemically unstable (although it is an active metabolite of disulfiram), its practical usefulness outside the laboratory is limited. Therefore, further investigation was conducted to elucidate the pharmacokinetic differences between dithiocarb and disulfiram in order to explain their relative efficacies. Kinetic analysis indicated that oral dithiocarb provided moderately high but prolonged plasma levels of active chelating agent, while disulfiram resulted in a very high but transient level. These results suggested that small, repeated oral doses of disulfiram would be just as effective in nickel carbonyl poisoning as a single large dithiocarb dose. This was not borne out in subsequent experiments. Investigation into the tissue distribution of inhaled 63Ni-labeled nickel carbonyl 24 hours after exposure showed that all three chelating agents significantly reduced the amounts of nickel in heart and lung, and D-penicillamine further reduced the amounts in blood and kidney. Only disulfiram increased on average the nickel retained in brain tissue, possibly accounting for its limited efficacy. Our results suggest caution in the use of oral disulfiram in human nickel carbonyl intoxication.