Most studies of occupationally relevant chemical hazards have involved use of single contaminants, so the biological and safety implications from inhalation of realistic mixtures have commonly been ignored in evaluations related to worker health and safety. In this regard, chromium (Cr) is released with ozone (O3) during welding, and a major health hazard from inhalation exposure to Cr-containing materials is lung cancer; this is likely due largely to the insoluble Cr species in the fumes. However, the contribution from other co-inhalants in modulating Cr-initiated responses is not clear. Co-contaminants may change the pulmonary environment producing conditions which could enhance the formation and survival of Cr- initiated tumors. For example, it has been demonstrated that simultaneously-inhaled O3 increases the pulmonary retention of inhaled insoluble Cr particles; this could be part of a scenario which would ultimately give rise to conditions within the lungs conductive to the formation and survival of Cr-initiated neoplasia. This proposal investigates other mechanisms underlying the elevated lung cancer incidence in welders exposed welding fumes containing both Cr and O3. It is hypothesized that the carcinogenic potential of insoluble Cr(VI) in the lungs of hosts inhaling the Cr/O3 mixture is greater than that in hosts inhaling the Cr alone due to O3-mediated increases in the lung tissue burdens of Cr(VI) and/or augmentation of one or more of the documented genetic/epigenetic mechanisms associated with Cr-induced conversion of normal cells to transformed types (i.e., an enhancement in level of DNA damage, chromosomal aberrations, and/or induced increases in the activity of cell kinases known to regulate the expression of nascent oncogenes) arising from the effects of O3 upon mechanisms utilized for the intracellular of insoluble Cf(VI) particles. The project involves exposure of rats to atmospheres containing carcinogenic Cr(VI), namely calcium chromate, alone and in combination with O3. This study will improve our understanding of the mechanisms underlying the interaction between Cr and O3 in the lungs and the role which mixtures of air contaminants may play in pulmonary disease pathogenesis following exposure to realistic mixed atmospheres of occupational relevance.
