LUNG METABOLISM & TOXICITY OF ENVIRONMENTAL ARSENICALS

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Arsenic (As) is an important environmental toxin which is toxic to the lung after inhalation exposure, however, the interaction between inorganic arsenic and the lung has not been examined in any detail. In addition, assessments of the risk from arsenic-induced lung cancer generally ignore any toxic differences between AS(III) and As(V) despite the fact that these arsenic species are assumed to act by different toxic mechanisms. This is important since estimates of the carcinogenic potential are based on smelter exposures to AS(III) compounds whereas As levels in the air are primarily composed of As(V). Our specific objective is to determine if arsenical compounds which differ in oxidation state and physical state also differ in their toxicity toward the lung and toward specific lung cell populations. This includes an investigation of how the lung cells protect themselves from the toxic effects of arsenicals, particularly in their ability to bind and/or metabolize arsenical compounds to modulate cellular toxicity. Recent information suggests that reduction by thiols, particularly glutathione, is important in the metabolism and binding of arsenical compounds and that reduction may be an important bioactivation step in the toxicity of the arsenicals. Specific aims include a study of the lung action on soluble sodium arsenate (V) and sodium arsenite (III). The metabolic actions including oxidation, reduction and methylation will be quantified. In addition, a study of the toxicity of As(III), As(V) and its methylated metabolites (monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) on whole lung and specific lung cell populations will be determined. This will include changes in pyruvate dehydrogenase, glutathione levels and metabolism, collagen synthesis and degradation, DNA strand breaks and repair and alterations of lung tissue and cellular structure. Finally, the effect of slightly soluble forms of AS(III) and As(V) on the metabolism and toxicity in the lung will be determined to assess the involvement of phagocytic cells in the pulmonary toxicity of arsenic.