Uptake and Mutagenicity of Moderately Soluble Hexavalent Chromium

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DESCRIPTION (provided by applicant): Hexavalent chromium (Cr(VI)) is a known human lung carcinogen. Millions of workers are exposed to Cr(VI) worldwide. The most recent paradigm proposes that the chromate compounds that are moderately water-soluble are more carcinogenic than the chromates that are either insoluble or water-soluble; however, it is not understood why this is so. Most of the data on how chromium damages DNA and causes DNA mutations has come from either the insoluble chromates or the water soluble chromates, not from the moderately soluble chromates that may be the most carcinogenic. The moderately soluble chromates are zinc chromate, strontium chromate and calcium chromate. Several crucial pieces of information are lacking regarding the activity of these moderately soluble chromates. No mutagenicity studies have been carried out with these compounds in human lung epithelial cells, which are the target cells for tumor formation. The types of mutations that these compounds cause have not been characterized in any cell line. The relative mutagenic potency of these chromates is not known. The extent to which these compounds dissolve outside of cells or enter cells as particulates is not known. The involvement of the zinc, strontium and calcium counterions in chromate toxicity is not known. The goals of the current proposal are to explain (1) how the moderately soluble Cr(VI) compounds enter cells and (2) if the mutations caused by the moderately soluble chromates differ from those caused by the soluble and insoluble chromates. The first aim of this proposal will apply the techniques of inductively coupled plasma mass spectrometry, laser scanning confocal microscopy, transmission electron microscopy, and scanning electron microscopy to determine how the moderately soluble chromates enter cells. The second aim of this proposal will measure and characterize mutations at the hypoxanthine (guanine) phosphoribosyl transferase (hprt) locus caused by the moderately soluble chromates in human lung epithelial cells and will compare mutation frequency and identity with mutations caused by the soluble and insoluble chromates. Data from these experiments will determine the relative mutagenic potency of these chromates, and will give insight into mechanisms of action, i.e., involvement of counterion and possible DNA lesions responsible for the mutations. Data from this proposal will provide mode of action information that will be necessary for thorough human risk assessment. The purpose of this work is to determine how chromium(VI) causes cancer. The goals of this proposal are to explain (1) how the moderately soluble chromium(VI) compounds enter cells and (2) if the mutations caused by the moderately soluble chromates differ from those caused by the less carcinogenic soluble and insoluble chromates. Understanding the mode of action of these chromates will provide a foundation for human risk assessment.