IRIS Toxicological Review of Benzene (Noncancer Effects) (External Review Draft)
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Benzene is a widely used as an industrial solvent, an intermediate in chemical synthesis of commercial products, and a component of gasoline. The potential for human exposure via inhalation, dermal, and oral routes is great under environmental and occupational situations. The U.S. EPA conducted a comprehensive review of the published literature on noncancer health effects (e.g., acute chronic, reproductive, developmental, neurotoxicity, immunotoxicity, hematotoxicity, etc.) of benzene to derive an inhalation reference concentration (RfC) and an oral reference dose (RfD) in support of its regulatory authority under the Clean Air Act Amendments of 1990 for hazardous air pollutants. It was concluded that benzene exposure results in adverse noncancer health effects by all routes of exposure to test animal species. Hematotoxicity and immunotoxicity have been consistently reported to be the most critical noncancer effects both in limited studies in humans and experimental animals. The bone marrow is the most sensitive target organ for the expression of benzene hematotoxicity and immunotoxicity. Benzene has been shown to have neurotoxic effects in test animals and humans after short-term exposure to relatively high concentrations; however chronic neurotoxicity studies are lacking. There is some evidence of reproductive and developmental effects due to benzene exposure to humans, but data are inconclusive. The human occupational exposure epidemiologic study of Rothman et al. (Am J Ind Med 29:236-246, 1996) and the 28-day drinking water exposure study of Hsieh et al. (Arch Environ Toxicol 17:157-158, 1988) were considered to be the co-principal critical studies for derivation of the RfC and RfD. The Rothman et al. (1996) showed significant reductions in absolute lymphocyte counts in Chinese factory workers exposed to a median 8-hr TWA concentration of 7.6 ppm (24 mg/m3) and was identified as a lowest observed effect level (LOAEL).
A LOAEL (HEC) was adjusted to 8.6 mg/m3 for the occupational ventilation rate and for an intermittent work week schedule of 24 hr exposure, 7 days/week. The adjusted LOAEL (HEC) and 1000-fold uncertainty factors (for lack of NOAEL, subchronic to chronic extrapolation and data deficiencies) were used to derive an RfC of 9 E-3 mg/m3. The human chronic dose of ingested benzene considered to be without any appreciable risk (RfD) is 1 E-3 mg/kg-day, and it is supported by an RfD value of 8 E-4 mg/kg-day, which is 1/10,000 of the LOAEL identified for hematological effects in subchronic drinking water study of Hseih et al. (1988). The overall confidence in the RfC/RfD is medium because there are few human studies with reliable estimates of exposure to benzene and few long-term low-dose studies in test animals to establish reliable NOAELs.
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