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Toxicity of Arsenic compounds; analytical toxicology; toxicokinetics
Research Activities
Metabolism and Toxicity of Arsenic Compounds in the Lung and Blood
Toxic arsenic compounds are widespread in our environment due to both natural and
industrial processes but their toxicity is not well understood. We do not understand
why humans are about 100 times more sensitive to the toxic effects of arsenic as compared
to animals or how arsenic causes cancer. Part of the answers may relate to arsenic
metabolism but, despite knowing the products of metabolism, the routes and responsible
enzymes have not been identified. Arsenic metabolism is a combination of
oxidation-reduction and methylation reactions. Inorganic arsenic which is released
to the environment is in two oxidation states: arsenite (As(III)) and arsenate
(As(V)). When exposure occurs to either form, the arsenic is converted partially to
the other oxidation state and is also metabolized partially to methylated compounds
(monomethylarsonic acid and dimethylarsinic acid). Our hypothesis is that arsenic
toxicity in a given species or at a given dose depends on the rate of metabolism in the
target tissue. Related to this is the hypothesis that the rate of metabolism also
depends on the extent of uptake of the various arsenic species into the target
tissue. We have chosen to study two target tissues: the lung and the blood.
Our studies examine the metabolism and uptake of arsenic in the lung and in the red blood
cell. Recent experiments have shown chemical evidence that the reduction reactions
are mediated by glutathione and currently we are testing the idea that GSH is responsible
for these reactions in vivo. It is also possible that GSH influences uptake through
the formation of complexes with arsenic; our laboratory has isolated some of these
complexes. This work will be followed by an investigation of species differences in
this metabolism.
Mechanism of Arsine-induced Hemolysis and Its Possible Treatment
Arsine, the hydride of arsenic (AsH3), is used extensively in the electronics industry as
a dopant and in the synthesis of gallium arsenide devices. It is very toxic and
attacks the erythrocyte to cause massive hemolysis. If death does not occur
immediately, it often occurs from renal failure when the fragments of the red cell
accumulate in the kidney. Arsine is a gas at room temperature and this causes
problems in designing quantitative experiments. Arsine is slightly soluble in water
but reaches concentrations which can rapidly cause hemolysis. We have developed
procedures to prepare reproducible solution concentrations and to allow arsine to be
incubated with red blood cells. Arsine was found to be taken up by the red cell in
less than one minute and glutathione was somewhat depleted. However, the amount of
depletion was relatively small and hemolysis started before GSH depletion was
significant. Our current hypothesis is that the arsine is interacting with the iron
in hemoglobin and this interaction forms the reactive species which cause hemolysis.
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