Measures of genotoxicity in Gulf war I veterans exposed to depleted uranium

Exposure to depleted uranium (DU), an alpha‐emitting heavy metal, has prompted the inclusion of markers of genotoxicity in the long‐term medical surveillance of a cohort of DU‐exposed Gulf War veterans followed since 1994. Using urine U (uU) concentration as the measure of U body burden, the cohort has been stratified into low‐u (<0.10 μg U/g creatinine) and high‐u groups (≥0.10 μg U/g creatinine). Surveillance outcomes for this cohort have historically included markers of mutagenicity and clastogenicity, with past results showing generally nonsignificant differences between low‐ vs. high‐U groups. However, mean hypoxanthine‐guanine phosphoribosyl transferase (HPRT) mutant frequencies (MFs) have been almost 50% higher in the high‐U group. We report here results of a more comprehensive protocol performed in a 2009 evaluation of a subgroup (N = 35) of this cohort. Four biomarkers of genotoxicity [micronuclei (MN), chromosome aberrations, and MFs of HPRT and PIGA] were examined. There were no statistically significant differences in any outcome measure when results were compared between the low‐ vs. high‐U groups. However, modeling of the HPRT MF results suggests a possible threshold effect for MFs occurring in the highest U exposed cohort members. Mutational spectral analysis of HPRT mutations is underway to clarify a potential clonal vs. a threshold uU effect to explain this observation. This study provides a comprehensive evaluation of a human population chronically exposed to DU and demonstrates a relatively weak genotoxic effect of the DU exposure. These results may explain the lack of clear epidemiologic evidence for U carcinogenicity in humans. Environ. Mol. Mutagen., 2011. © 2011 Wiley‐Liss, Inc.