title: Urinary mutagenicity as a biomarker in workers exposed to benzidine: correlation with urinary metabolites and urothelial DNA adducts.
abstract: Urinary mutagenicity has been used in occupational and epidemiological studies for over two decades as a cost-effective, general biomarker of exposure to genotoxic agents. However, few studies have compared urinary mutagenicity to additional biomarkers determined among low- and high-exposed groups. To address this issue, we evaluated the relationship between urinary mutagenicity and other types of biomarkers in a cross-sectional study involving 15 workers exposed to the urinary bladder carcinogen benzidine (BZ, high exposure), 15 workers exposed to BZ-dyes (low exposure), and 13 unexposed controls in Ahmedabad, India. Urinary organics were extracted by C18/methanol and evaluated for mutagenicity in the presence of S9 in the Salmonella strain YG1024, which is a frameshift strain that overproduces acetyltransferase. The results were compared to biomarker data reported recently from the same urine samples (Rothman et al., Proc. Natl Acad. Sci. USA, 93, 5084-5089, 1996) that included a metabolite biomarker (the sum of the urinary levels of BZ + N-acetylbenzidine + N,N'-diacetylbenzidine) and a DNA adduct biomarker [a presumptive N-(3'-phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine (C8dG-ABZ) DNA adduct in exfoliated urothelial cells]. The mean +/- SE urinary mutagenicity (revertants/micromol of creatinine) of the low-exposure (BZ-dye) workers was 8.2 +/- 2.4, which was significantly different from the mean of the controls (2.8 +/- 0.7, P = 0.04) as was that of the mean of the high-exposure (BZ) workers (123.2 +/- 26.1, P < 0.0001). Urinary mutagenicity showed strong, positive correlations with urinary metabolites (r = 0.88, P < 0.0001) and the level of the presumptive C8dG-ABZ urothelial DNA adduct (r = 0.59, P = 0.0006). A strong association was found between tobacco use (bidi smoking) and urinary mutagenicity among the controls (r = 0.68, P = 0.01) but not among the exposed workers (r = 0.18, P = 0.11). This study confirms the ability of a biomarker such as urinary mutagenicity to detect low-dose exposures, identify additional genotoxic exposures among the controls, and correlate strongly with urinary metabolites and DNA adducts in the target tissue (urinary bladder epithelia) in humans.
authors.affiliation: Environmental Carcinogenesis Division, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: DeMarini
authors.forename: L R
authors.initials: LR
authors.lastname: Brooks
authors.forename: V K
authors.initials: VK
authors.lastname: Bhatnagar
authors.forename: R B
authors.initials: RB
authors.lastname: Hayes
authors.forename: B T
authors.initials: BT
authors.lastname: Eischen
authors.forename: M L
authors.initials: ML
authors.lastname: Shelton
authors.forename: T V
authors.initials: TV
authors.lastname: Zenser
authors.forename: G
authors.initials: G
authors.lastname: Talaska
authors.forename: S K
authors.initials: SK
authors.lastname: Kashyap
authors.forename: M
authors.initials: M
authors.lastname: Dosemeci
authors.forename: R
authors.initials: R
authors.lastname: Kashyap
authors.forename: D J
authors.initials: DJ
authors.lastname: Parikh
authors.forename: V
authors.initials: V
authors.lastname: Lakshmi
authors.forename: F
authors.initials: F
authors.lastname: Hsu
authors.forename: B B
authors.initials: BB
authors.lastname: Davis
authors.forename: M
authors.initials: M
authors.lastname: Jaeger
authors.forename: N
authors.initials: N
authors.lastname: Rothman
mesh_terms: D001560:Benzidines; D015415:Biomarkers; D018736:DNA Adducts; D006801:Humans; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000032:analysis*; D016273:Occupational Exposure; D012486:Salmonella typhimurium; D014556:Urine / Q000737:chemistry*; D019459:Urothelium / Q000737:chemistry*
chemical_list: D001560:Benzidines; D015415:Biomarkers; D018736:DNA Adducts; D009153:Mutagens