Benzene Adducts with Rat Nucleic Acids and Proteins: Dose-Response Relationship after Treatment In Vivo

Abstract

The dose-response relationship of the benzene covalent interaction with biological macromolecules from rat organs was studied. The administered dose range was 3.6 x 107 starting from the highest dosage employed, 486 mg/kg, which is oncogenic for rodents, and included low and very low dosages. The present study was initially performed with tritium-labeled benzene, administered by IP injection. In order to exclude the possibility that part of the detected radioactivity was due to tritium incorporated into DNA from metabolic processes, "4C-benzene was then also used following a similar experimental design. By HPLC analysis, a single adduct from benzene-treated DNA was detected; adduct identification will be attempted in the near future. Linear dose-response relationship was observed within most of the range of explored doses. Linearity was particularly evident within low and very low dosages. Saturation of benzene metabolism did occur at the highest dosages for most of the assayed macromolecules and organs, especially in rat liver. This finding could be considered as indicative of the dose-response relationship of tumor induction and could be used in risk assessment.

ATSDR evaluation of health effects of benzene and relevance to public health

“…Rothman, et al (1995) used the glycophorin A (GPA) gene loss mutation assay to assess the nature of DNA damage in workers heavily exposed to benzene. The GPA assay measures the frequency of variant cells that have lost the Arfellini, et al (1985), Creek, et al (1997), Mani, et al (1999), Turteltaub and Mani (2003) Rat (bone marrow) DNA adducts + Arfellini, et al (1985), Creek, et al (1997), Lévay, et al (1996), Pathak, et al (1995, Turteltaub and Mani (2003) Rat (liver) DNA adducts + Arfellini, et al (1985), Creek, et al (1997), Lutz and Schlatter (1977), Mani, et al (1999), Mazzullo, et al (1989), Turteltaub and Mani (2003) Rothman, et al (1995) reported a significant increase in the frequency of NN cells in benzene-exposed workers (compared with unexposed control subjects) in the absence of a significant effect on the frequency of NØ cells. These results suggest that benzene induces gene duplicating, but not geneinactivating, mutations at the GPA locus in benzene-exposed humans.…”

“…In addition to oral and inhalation routes, many researchers tested subcutaneous and intraperitoneal routes as well; the results for these alternate routes of exposure were largely positive for chromosomal aberrations in bone marrow (Anderson and Richardson, 1981;Speck, 1972, 1973;Kolachana, et al, 1993;Meyne and Legator, 1980;Philip and Jensen, 1970), micronuclei in bone marrow (Diaz, et al, 1980), and sister chromatid exchange in mouse fetus liver cells (Sharma, et al, 1985). Binding of benzene and/or its metabolites to DNA, RNA, and proteins has been consistently observed in rats and mice (Arfellini, et al, 1985;Creek, et al, 1997;Lévay, et al, 1996;Mani, et al, 1999;Mazzullo, et al, 1989;Turteltaub and Mani, 2003). Arfellini, et al (1985) noted that binding to RNA and proteins was more prevalent than binding to DNA.…”

Benzene and non-Hodgkin's lymphoma

“…It is likely that this will focus on the measurement of adduct compounds formed by covalent bonding between DNA and benzene metabolites as part of the process of genetic damage by the latter. [105][106][107] Adducts of unique structure are formed by many carcinogens in interaction with DNA and their levels within tissues reflect a combination of a subject's exposure and the subject's metabolic capacity to generate the genotoxic metabolites. 108 They are believed to undergo repair with time, leading to a gradual diminution in their number, the rate being dependent on the nature of the carcinogen and its site of adduct formation within DNA.…”

Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: implications for molecular dosimetry.

“…In contrast to these in vitro findings, evidence for the formation of DNA adducts in animals treated with benzene has been contradictory. Dose-dependent binding of radiolabeled benzene to DNA, RNA, and protein in various tissues of mice and rats has been reported (20)(21)(22). 32P-Postlabeling studies by Bauer et al (23) have demonstrated DNA adduct formation in the liver of rabbits treated with benzene; however, Reddy et al (24)(25)(26) were unable to detect the formation of DNA adducts in various tissues of either Sprague-Dawley rats or B6C3F1 mice administered benzene or its hydroxylated metabolites.…”