Benzene is an airborne pollutant that is known to have carcinogenic effects: exposure to this compound alters gene expression in peripheral blood cells and induces chromosomal damage. Human exposure to benzene occurs mainly through inhalation in both environmental and occupational settings. The US Occupational Safety and Health Administration has set an 8-hour time-weighted-average exposure limit of 1 ppm, but workers exposed to air concentrations of benzene below this level have shown evidence of hematotoxicity. Occupational exposures as low as 0.3 ppm have been shown to increase the risk of leukemia and myelodysplastic syndrome. Current exposure limits therefore may be insufficient to protect against the damaging effects of benzene exposure.

Benzene metabolism and clearance varies in the human population, likely owing to the effect of genetic variation on toxicity responses. This effect remains poorly understood, however, because toxicity is typically evaluated using genetically identical animal models. For example, toxicology assessments at the National Toxicology Program are done in B6C3F1 mice, which are derived from crossing two inbred strains, C57BL/6J and C3H/HeJ.

Diversity outbred (DO) mice are a recently developed population derived from eight inbred founder strains and have a level of genetic diversity that is similar to that of humans. As such, they may more accurately reflect the range of toxicity responses observed in human populations. Furthermore, because of their genetic diversity, genetic associations can be localized in these mice with high precision. John French and other researchers used DO mice to study how genetic variability influences toxicity responses as well as to provide more insight into benzene-induced genotoxicity.

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The researchers exposed male DO mice to various doses of benzene (75 mice per group) via inhalation for 28 days (6 hours per day for 5 days per week). The study was repeated using two independent cohorts of 300 animals each. Toxicity response to benzene exposure varied among individuals of the genetically diverse DO population (Env. Health. Perspect. doi:10.1289/ehp.1408202; published online 6 November 2014). A dose-dependent increase in benzene-induced chromosomal damage was observed, and a locus was identified that encoded a pair of over-expressed sulfotransferases that were inversely correlated with genotoxicity.

Using the results in the DO mice, the scientists estimated a benchmark exposure limit of 0.205 ppm benzene, an order of magnitude below the value estimated using B6C3F1 mice. The DO-based estimate is consistent with observed exposure toxicity in human subjects and may provide a more appropriate estimate of exposure thresholds that would protect the most sensitive human subpopulations.