Carcinogenesis, Vol. 21, No. 9, 1661-1669,
September 2000
© 2000 Oxford University Press
Molecular Epidemiology and Cancer Prevention |
Biomarkers of exposure and effect as indicators of potential carcinogenic risk arising from in vivo metabolism of ethylene to ethylene oxide
1 Department of Pathology and
2 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill,NC 27599-7525,
3 Bushy Run Research Center, Union Carbide Corp., Export, PA 15632 and
4 Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA
The purposes of the present study were: (i) to investigate the potential use of several biomarkers as quantitative indicators of the in vivo conversion of ethylene (ET) to ethylene oxide (EO); (ii) to produce molecular dosimetry data that might improve assessment of human risk from exogenous ET exposures. Groups (n = 7/group) of male F344 rats and B6C3F1 mice were exposed by inhalation to 0 and 3000 p.p.m. ET for 1, 2 or 4 weeks (6 h/day, 5 days/week) or to 0, 40, 1000 and 3000 p.p.m. ET for 4 weeks. N-(2-hydroxyethyl)valine (HEV), N7-(2-hydroxyethyl) guanine (N7-HEG) and Hprt mutant frequencies were assessed as potential biomarkers for determining the molecular dose of EO resulting from exogenous ET exposures of rats and mice, compared with background biomarker values. N7-HEG was quantified by gas chromatography coupled with high resolution mass spectrometry (GC–HRMS), HEV was determined by Edman degradation and GC–HRMS and Hprt mutant frequencies were measured by the T cell cloning assay. N7-HEG accumulated in DNA with repeated exposure of rodents to 3000 p.p.m. ET, reaching steady-state concentrations around 1 week of exposure in most tissues evaluated (brain, liver, lung and spleen). The dose–response curves for N7-HEG and HEV were supralinear in exposed rats and mice, indicating that metabolic activation of ET was saturated at exposures 
1000 p.p.m. ET. Exposures of mice and rats to 200 p.p.m. EO for 4 weeks (as positive treatment controls) led to significant increases in Hprt mutant frequencies over background in splenic T cells from exposed rats and mice, however, no significant mutagenic response was observed in the Hprt gene of ET-exposed animals. Comparisons between the biomarker data for both unexposed and ET-exposed animals, the dose–response curves for the same biomarkers in EO-exposed rats and mice and the results of the rodent carcinogenicity studies of ET and EO suggest that too little EO arises from exogenous ET exposure to produce a significant mutagenic response or a carcinogenic response under standard bioassay conditions.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. P. Wild Environmental exposure measurement in cancer epidemiology Mutagenesis, March 1, 2009; 24(2): 117 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Pottenger, L. A. Malley, M. S. Bogdanffy, E. M. Donner, P. B. Upton, Y. Li, V. E. Walker, J. R. Harkema, M. I. Banton, and J. A. Swenberg Evaluation of Effects from Repeated Inhalation Exposure of F344 Rats to High Concentrations of Propylene Toxicol. Sci., June 1, 2007; 97(2): 336 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-H. L. Hong, C. D. Houle, T.-V. T. Ton, and R. C. Sills K-ras Mutations in Lung Tumors and Tumors from Other Organs are Consistent with a Common Mechanism of Ethylene Oxide Tumorigenesis in the B6C3F1 Mouse Toxicol Pathol, January 1, 2007; 35(1): 81 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Houle, T.-V. T. Ton, N. Clayton, J. Huff, H.-H. L. Hong, and R. C. Sills Frequent p53 and H-ras Mutations in Benzene- and Ethylene Oxide-Induced Mammary Gland Carcinomas from B6C3F1 Mice Toxicol Pathol, October 1, 2006; 34(6): 752 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Recio, M. Donner, D. Abernethy, L. Pluta, A.-M. Steen, B. A. Wong, A. James, and R.J. Preston In vivo mutagenicity and mutation spectrum in the bone marrow and testes of B6C3F1 lacI transgenic mice following inhalation exposure to ethylene oxide Mutagenesis, May 1, 2004; 19(3): 215 - 222. [Abstract] [Full Text] [PDF]
|
|