Benzene is a volatile liquid which has been widely used as an industrial solvent since its discovery in 1825. Today, 98% of benzene production is derived from the petrochemical and petroleum refining industries. Benzene is also produced during the combustion of gasoline, wood products, and tobacco. As a result, humans are exposed to a wide range of air levels of benzene, from parts per billion (ppb) levels in ambient air to parts per million (ppm) levels in certain workplaces.
Benzene is absorbed via ingestion, inhalation, and through the skin. Once in the body, benzene distributes to all organs including the brain and the fetus of a pregnant woman. Benzene is very quickly eliminated either unchanged in expired air or as metabolites in the urine. A small fraction of inhaled benzene also accumulates in body fat. Inhalation of benzene vapor concentrations of 20,000 ppm for 5-10 minutes can be fatal to humans; death results from central nervous system depression. However, even non-lethal doses of benzene can impact the nervous, hematological, and immunological systems.
Benzene is considered to be a reproductive and developmental toxin by the State of California. Subchronic and chronic daily exposures to benzene vapors can induce a progressive depletion of the bone marrow and dysfunction of the blood-forming system. Early symptoms of bone marrow depression include leukopenia, anemia or thrombocytopenia, or a combination of the three, called pancytopenia. Benzene may have long-term effects on the central nervous system, including atypical sleep activity and peripheral nerve damage. Benzene is carcinogenic in humans and animals by inhalation and in animals by the oral route of exposure. Occupational exposure to benzene has been associated mainly with increased incidences of acute myeloid leukemia and myelodysplastic syndromes, but also with chronic and acute lymphocytic leukemia and non-Hodgkin lymphoma. Benzene has been placed in the EPA weight-of-evidence classification A: human carcinogen.
In earlier studies, we showed that benzene exposure significantly affects leukemia-specific chromosomes, changes gene expression in blood cells, and causes toxicity in blood and bone marrow. We continue to employ new technologies to identify mechanisms for benzene-induced leukemogenesis and lymphomagenesis, to determine how key changes occur in critical progenitor or stem cells, to measure the effect of benzene on gene regulation, and to assess whether chromosomal abnormalities induced by benzene can cause other health effects, such as reproductive defects.
We have also used biomarkers of exposure in samples of blood and urine from benzene-exposed and unexposed workers to characterize human metabolism of benzene. This work has provided strong evidence that humans metabolize benzene at ambient (ppb) concentrations much more efficiently than at ppm levels encountered in some workplaces.
Our most recent findings in benzene research have allowed us to identify robust changes in gene expression in individuals occupationally exposed to benzene. We were able to cross-compare 2 microarray platforms, enabling us to identify a greater number of biomarkers than we ever have before.
We have also been able to gather additional evidence of the mechanism of benzene’s carcinogenicity in humans. After examining hydroquinone (HQ), a benzene metabolite, we found that HQ, along with etoposide, significantly induces endoreduplication (END), or DNA amplification without corresponding cell division, in TK6 cells in a dose-dependent manner. END plays a major role in inducing genomic instability and subsequent carcinogenesis.
We found two separate dose-dependent pathways for the metabolism of benzene in humans, suggesting that true leukemia risks from benzene could be substantially greater than currently thought at ambient levels of exposure. Thus, regulatory risk assessments need to be reevaluated in order to reflect this difference. We are currently investigating whether the enhanced metabolism of benzene at ambient exposure levels might result from the action of a hitherto unknown high-affinity enzyme.
Zhang L, Lan Q, Guo W, Hubbard AE, Li G, Rappaport SM, McHale CM, Shen M, Ji Z, Vermeulen R, Yin S, Rothman N, Smith MT (2011) Chromosome-wide aneuploidy study (CWAS) in workers exposed to an established leukemogen, benzene. Carcinogenesis. Apr;32(4):605-12. PMCID: PMC3066415. [PDF]
Hosgood HD 3rd, Zhang L, Shen M, Berndt SI, Vermeulen R, Li G, Yin S, Yeager M, Yuenger J, Rothman N, Chanock S, Smith M, Lan Q (2009) Association between genetic variants in VEGF, ERCC3 and occupational benzene hematotoxicity. Occup Environ Med. Dec;66(12):848-53. PMID: 19773279. [Abstract] [Full Text]
McHale CM, Zhang L, Lan Q, Li G, Hubbard AE, Forrest MS, Vermeulen R, Chen J, Shen M, Rappaport SM, Yin S, Smith MT, Rothman N (2009) Changes in the peripheral blood transcriptome associated with occupational benzene exposure identified by cross-comparison on two microarray platforms. Genomics. Apr;93(4):343-9. PMCID: 2693268. [Abstract] [Full Text]
Ji Z, Zhang L, Guo W, McHale CM, Smith MT (2009) The benzene metabolite, hydroquinone and etoposide both induce endoreduplication in human lymphoblastoid TK6 cells. Mutagenesis. Jul;24(4):367-72. PMCID: 2701990. [Abstract] [Full Text]
Rappaport SM, Kim S, Lan Q, Vermeulen R, Waidyanatha S, Zhang L, Li G, Yin S, Hayes RB, Rothman N, Smith MT (2009) Evidence That Humans Metabolize Benzene via Two Pathways. EHP. Jun 117(6):946-52. PMCID: 2702411. [Abstract] [Full Text]
Ren X, Lim S, Smith MT, Zhang L (2009) Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone. Toxicol Sci. Feb;107(2):367-75. PMCID: 2639759. [Abstract] [Full Text]
Kim S, Lan Q, Waidyanatha S, Chanock S, Johnson BA, Vermeulen R, Smith MT, Zhang L, Li G, Shen M, Yin S, Rothman N, Rappaport SM (2007) Genetic polymorphisms and benzene metabolism in humans exposed to a wide range of air concentrations. Pharmacogenet Genomics, 17:789-801. [abstract] [PDF]
Kim S, Vermeulen R, Waidyanatha S, Johnson BA, Lan Q, Smith MT, Zhang L, Li G, Shen M, Yin S, Rothman N, Rappaport SM (2006) Modeling human metabolism of benzene following occupational and environmental exposures. Cancer Epidemiol Biomarkers Prev, 15(11):2246-52. [abstract] [PDF]
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