Urinary mutagenicity as a biomarker in workers exposed to benzidine: correlation with urinary metabolites and urothelial DNA adducts.
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.
DeMarini
D M
DM
Environmental Carcinogenesis Division, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Brooks
L R
LR
Bhatnagar
V K
VK
Hayes
R B
RB
Eischen
B T
BT
Shelton
M L
ML
Zenser
T V
TV
Talaska
G
G
Kashyap
S K
SK
Dosemeci
M
M
Kashyap
R
R
Parikh
D J
DJ
Lakshmi
V
V
Hsu
F
F
Davis
B B
BB
Jaeger
M
M
Rothman
N
N
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*
D001560:Benzidines; D015415:Biomarkers; D018736:DNA Adducts; D009153:Mutagens