Genotoxicity of benzene and its metabolites
The potential role of genotoxicity in human leukemias associated with benzene (BZ) exposures was investigated by a systematic review of over 1400 genotoxicity test results for BZ and its metabolites. Studies of rodents exposed to radiolabeled BZ found a low level of radiolabel in isolated DNA with no preferential binding in target tissues of neoplasia. Adducts were not identified by 32P-postlabeling (equivalent to a covalent binding index <0.002) under the dosage conditions producing neoplasia in the rodent bioassays, and this method would have detected adducts at 1/10,000th the levels reported in the DNA-binding studies. Adducts were detected by 32P-postlabeling in vitro and following high acute BZ doses in vivo, but levels were about 100-fold less than those found by DNA binding. These findings suggest that DNA-adduct formation may not be a significant mechanism for BZ-induced neoplasia in rodents. The evaluation of other genotoxicity test results revealed that BZ and its metabolites did not produce reverse mutations in Salmonella typhimurium but were clastogenic and aneugenic, producing micronuclei, chromosomal aberrations, sister chromatid exchanges and DNA strand breaks. Rodent and human data were compared, and BZ genotoxicity results in both were similar for the available tests. Also, the biotransformation of BZ was qualitatively similar in rodents, humans and non-human primates, further indicating that rodent and human genotoxicity data were compatible. The genotoxicity test results for BZ and its metabolites were the most similar to those of topoisomerase II inhibitors and provided less support for proposed mechanisms involving DNA reactivity, mitotic spindle poisoning or oxidative DNA damage as genotoxic mechanisms; all of which have been demonstrated experimentally for BZ or its metabolites. Studies of the chromosomal translocations found in BZ-exposed persons and secondary human leukemias produced by topoisomerase II inhibitors provide some additional support for this mechanism being potentially operative in BZ-induced leukemia.