EFFECT OF TETRAETHYLTHIURAMDISULPHIDE AND DIETHYLDITHIOCARBAMATE ON NICKEL TOXICOKINETICS IN MICE

A new experimental pharmacokinetic model using the gamma-emitting isotope Ni-57 for studying nickel toxicokinetics was employed in a recent investigation (Nielsen et al. 1993) in order to quantitatively study, for the first time, the effect of tetraethylthiuram disulphide (disulfiram, Antabuse (R), TTD) and sodium diethyldithiocarbamate (DDC) on whole-body retention and organ distribution of nickel in mice. TTD or its decomposition product DDC given orally by stomach tube shortly after oral administration of a low dose of nickel chloride labelled with Ni-57 resulted in an approximately ten times higher whole-body retention of nickel compared to the retention in a control group exposed to nickel only. These chelators increased the whole-body retention of nickel also when given by intraperitoneal injection shortly after oral or intraperitoneal administration of nickel. Oral administration of a single dose of TTD or DDC rapidly after an oral dose of nickel chloride also resulted in extensive changes in the organ distribution of nickel, thus the nickel content in the brain was at least 700 times higher than in a control group given the same dose of nickel only. If DDC was given intraperitoneally after nickel given orally, the relative organ distribution of nickel to most organs was the same as if the chelator was given orally, though the contents of the liver and lungs were lower. That TTD and DDC resulted in a transport of nickel to the brain, is underlined by the fact that after 20 hr, approximately 15% and after 45-50 hr, 30% of the total body burden of Ni was found in the brain. Stating the nickel content as concentrations, we found after 19 hr to 23 hr the highest nickel concentration in the brain, kidneys, lungs and liver, in order of decreasing concentration. From 68 hr to 122 hr the order was brain, lungs, kidneys and liver. TTD and DDC are widely used clinically. These results indicate, that long-term simultaneous administration of nickel and TTD or DDC to humans should be avoided, as enhanced body-burden and extensive brain deposition of nickel may occur, possibly leading to toxicity.