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Part of the book series: NATO ASI Series ((NSSA,volume 250))

Abstract

Exposure to genotoxic carcinogens results in the formation of covalently bound adducts between the genotoxin and DNA, which may cause mutation and cytogenetic alterations. The dose of the genotoxic carcinogenic compounds involved in the exposure may be monitored by quantitative analysis of DNA adducts, and these data may also be used as an indicator of genotoxic risk. The analytical techniques required for adduct measurements need to be of exceptional sensitivity and include 32P-postlabelling, mass spectrometry and immunoassay. Exposure to alkylating carcinogens may also be monitored by measurement of adducts formed with amino acids in haemoglobin (Hb). Since, for a variety of compounds, the extent of protein-adduct formation relates quantitatively with that of DNA adducts, measurement of the former may indicate the biologically-effective dose of the compound received.

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References

  • Albrecht, W. and Neumann, H-G., 1985, Biomonitoring of aniline and nitrobenzene. Hemoglobin binding in rats and analysis of adducts. Arch. Toxicol. 57:1.

    Article  PubMed  CAS  Google Scholar 

  • Bailey, E., Connors, T.A., Farmer, P.B., Gorf, S.M and Rickard, J., 1981, Methylation of cysteine in hemoglobin following exposure to methylating agents. Cancer Res. 41:2514.

    PubMed  CAS  Google Scholar 

  • Bailey, E., Farmer, P.B., Bird, I., Lamb, J.H. and Peal, J.A., 1986, Monitoring exposure to acrylamide by the determination of S-(2-carboxyethyl)cysteine in hydrolyzed hemoglobin by gas chromatography-mass spectrometry. Anal, Biochem. 157:241.

    Article  CAS  Google Scholar 

  • Bailey, E., Brooks, A.G.F., Dollery, CT., Farmer, P.B., Passingham, B.J., Sleightholm, M.A. and Yates, D.W., 1988, Hydroxyethylvaline adduct formation in haemoglobin as a biological monitor of cigarette smoke intake. Arch. Toxicol. 62:247.

    Article  PubMed  CAS  Google Scholar 

  • Bailey, E., Brooks, A.G., Bird, I., Farmer, P.B. and Street, B., 1990, Monitoring exposure to 4,4’-methylenedianiline by the gas chromatography-mass spectrometry determination of adducts to hemoglobin. Anal. Biochem. 190:175.

    Article  PubMed  CAS  Google Scholar 

  • Bailey, E., Brooks, A.G., Farmer, P.B. and Street, B., 1992, Monitoring exposure to 4,4’-methylene-bis(2-chloroaniline) through the gas chromatography-mass spectrometry measurement of adducts to hemoglobin. Environ. Health Perspec. in press.

    Google Scholar 

  • Bechtold, W.E., Sun, J.D., Wolff, R.K., Griffith, W.S., Kilmer, J.W. and Bond, J.A., 1991, Globin adducts of benzo[a]pyrene: markers of inhalation exposure as measured in F344/N rats. 7. Appl. Toxicol 11:115.

    Article  CAS  Google Scholar 

  • Bechtold, W.E., Sun, J.D., Birnbaum, L.S., Yin, S.N., Guilan, L.L., Kasicki, S., Lucier, G. and Henderson, R.F., 1992, S-Phenylcysteine formation in hemoglobin as a biological exposure index for benzene. Arch. Toxicol 66:303.

    Article  PubMed  CAS  Google Scholar 

  • Beland, F.A., Fullerton, N.R, Kinouchi, T., Smith, B.A. and Poirier, M.C., 1990, DNA adduct formation in relation to tumorigenesis in mice chronically fed 2-acetylaminofluorene. Prog. Clin, Biol. Res. 331:121.

    CAS  Google Scholar 

  • Belinksy, S.A., Foley, J.F., White, CM., Anderson, M.W. and Maronpot, R.R., 1990, Dose-response relationship between O6-methylguanine formation in Clara cells and induction of pulmonary neoplasia in the rat by 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone. Cancer Res. 50:3772.

    Google Scholar 

  • Bergmark, E., Calleman, C.J. and Costa, L.C., 1991, Formation of hemoglobin adducts of acrylamide and its epoxide metabolite glycidamide in the rat. Toxicol Appl Pharmacol. 111:352.

    Article  PubMed  CAS  Google Scholar 

  • Boucheron, J.A., Richardson, F.C., Morgan, RH. and Swenberg, J.A., 1987, Molecular dosimetry of O4-ethyldeoxythymidine in rats continuously exposed to diethylnitrosamine. Cancer Res. 47:1577.

    PubMed  CAS  Google Scholar 

  • Bryant, M.S., Skipper, P.L., Tannenbaum, S.R. and Maclure, M., 1987, Hemoglobin adducts of 4-aminobiphenyl in smokers and non-smokers. Cancer Res. 47:602.

    PubMed  CAS  Google Scholar 

  • Cannella, S.G., Kagan, S.S., Spratt, T.E. and Hecht, S.S., 1990, Evaluation of cysteine adduct formation in rat hemoglobin by 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone and related compounds. Cancer Res. 50:5453.

    Google Scholar 

  • Cannella, S.G., Kagan, S.S. and Hecht, S.S., 1992, Evidence that a hemoglobin adduct used for dosimetry of 4-(niethylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) is a carboxylic ester. Environ. Health Perspec. in press.

    Google Scholar 

  • Chen, T.H., Kuslikis, B.I. and Braseton Jr., W.E., 1991, Unlabelled hemoglobin adducts of 4,4’-methylene bis (2-chloroaniline) in rats and guinea pigs. Arch. Toxicol. 65:177.

    Article  PubMed  CAS  Google Scholar 

  • Day, B.W., Naylor, S., Gan, L.S., Sahali, Y., Nguyen, T.T., Skipper, PL., Wishnok, J.S. and Tannenbaum, S.R., 1990, Molecular dosimetry of polycyclic aromatic hydrocarbon epoxides and diolepoxides via hemoglobin adducts. Cancer Res. 50:4611.

    PubMed  CAS  Google Scholar 

  • Day, B.W., Naylor, S., Gan, L.S., Sahali, Y, Nguyen, T.T., Skipper, PL., Wishnok, J.S. and Tannenbaum, S.R., 1991, Gas chromatographic-mass spectrometric analysis of diols and tetrols from reactions of polycyclic aromatic hydrocarbon epoxides with hemoglobin. J. Chromatog. Biomed. Appl 562:563.

    Article  CAS  Google Scholar 

  • Ehrenberg, L., Hiesche, K.D., Osterman-Golkar, S. and Wennberg, I., 1974, Evaluation of genetic risks of alkylating atents: tissue doses in the mouse from air contaminated with ethylene oxide. Mut. Res. 24:83.

    Article  CAS  Google Scholar 

  • Ehrenberg, L., Osterman-Golkar, S., Segerbäck, D, Svensson, K. and Calleman, C.J., 1977, Evaluation of genetic risks of alkylating agents. III. Alkylation of haemoglobin after metabolic conversion of ethene to ethene oxide in vivo. Mut. Res. 45:175.

    Article  CAS  Google Scholar 

  • Farmer, P.B., Bailey, E., Lamb, J.H. and Connors, T.A., 1980, Approach to the quantitation of alkylated amino acids in haemoglobin by gas chromatography-mass spectrometry. Biomed. Mass Spectrom. 7:41.

    Article  PubMed  CAS  Google Scholar 

  • Farmer, P.B., Gorf, S.M. and Bailey, E., 1982, Determination of hydroxypropyl-histidine in haemoglobin as a measure of exposure to propylene oxide using high resolution gas chromatography mass spectrometry. Biomed. Mass Spectrom. 9:69.

    Article  PubMed  CAS  Google Scholar 

  • Fennell, T.R., Macneela, J.P., Turner, M.J. and Swenberg, J.A., 1991, Haemoglobin adduct formation by acrylonitrile in rats and mice, in “Human Carcinogen Exposure. Biomonitoring and Risk Assessment”, R.C. Garner, RB. Farmer, G.T. Steel and A.W. Wright, ed., Oxford University Press, Oxford, pp 241–246.

    Google Scholar 

  • Gan, L.S., Wishnok, IS., Fox, J.G. and Tannenbaum, S.R., 1989, Quantitation of methylated hemoglobin via hydrolysis of methyl esters to yield methanol. Anal Biochem. 179:326.

    Article  PubMed  CAS  Google Scholar 

  • IARC Scientific Publication No. 89. 1988. Methods for detecting DNA damaging agents in humans: applications in cancer epidemiology and prevention. H. Bartsch, K. Hemminki and I.K. O’Neill, eds., I.A.R.C., Lyon.

    Google Scholar 

  • Lewalter, J. and Korallus, U., 1985, Blood protein conjugates and acetylation of aromatic amines. New findings on biological monitoring. Int. Arch. Occup. Environ. Health, 56:179.

    Article  PubMed  CAS  Google Scholar 

  • Melikian, A.A., Prahalad, A.K. and Coleman, S., 1992, Isolation and characterization of two benzene-derived hemoglobin adducts in vivo in rats. Cancer Epidemiology Biomarkers and Prevention. 1:307.

    CAS  Google Scholar 

  • Murphy, S.E., Palomino, A., Hecht, S.S. and Hoffmann, D., 1990, Dose-response study of DNA and hemoglobin adduct formation by 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone in F344 rats. Cancer Res. 50:5446.

    PubMed  CAS  Google Scholar 

  • Murthy, M.S.S., Calleman, C.J., Osterman-Golkar, S., Sedgerbäck, D. and Svensson, K., 1984, Relationships between ethylation of hemoglobin, ethylation of DNA and administered amount of ethyl methanesulfonate in the mouse. Mut. Research. 127:1.

    Article  CAS  Google Scholar 

  • Neumann, H.G., 1980, Dose-response relationship in the primary lesion of strong electrophilic carcinogens. Arch. Toxicol. 3:69.

    Article  CAS  Google Scholar 

  • Neumann, H.G., 1984, Analysis of hemoglobin as a dose monitor for alkylating and arylating agents. Arch. Toxicol. 56:1.

    Article  PubMed  CAS  Google Scholar 

  • Osterman-Golkar, S., Farmer, P.B., Segerbäck, D, Bailey, E., Calleman, C.J., Svensson, K. and Ehrenberg, L., 1983, Dosimetry of ethylene oxide in the rat by • quantitation of alkylated histidine in hemoglobin. Teratog. Carcinog. Mutagen. 3:395.

    Article  PubMed  CAS  Google Scholar 

  • Phillips, D.H., Hewer, A., Martin, C.N., Garner, R.C. and King, M.M., 1988, Correlation of DNA adduct levels in human lung with cigarette smoking. Nature. 336:790.

    Article  PubMed  CAS  Google Scholar 

  • Phillips, D.H., Schoket, B., Hewer, A., Bailey, E., Kostic, S. and Vincze, I., 1990, Influence of cigarette smoking on the levels of DNA adducts in human bronchial epithelium and white blood cells. Int. J. Cancer. 46:569.

    Article  PubMed  CAS  Google Scholar 

  • Potter, D., Blair, D., Davies, R., Watson, W.P. and Wright, A.S., 1989, The relationships between alkylation of haemoglobin and DNA in Fischer 344 rats exposed to [14C]ethylene oxide. Arch. Toxicol., Suppl. 13:254.

    Article  CAS  Google Scholar 

  • Ross, R.K., Yuan, Y-M., Yu, M.C., Wogan, G.N., Qian, G-S., Tu, J.T., Groopman, J.D., Gao, Y-T. and Henderson, B.E., 1992, Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet. 339:943.

    Article  PubMed  CAS  Google Scholar 

  • Sabbioni, G. and Neumann, H.G., 1990, Quantification of haemoglobin binding of 4,4′-methylenebis (2-chloroaniline) (MOCA) in rats. Arch. Toxicol.. 64:451.

    Article  PubMed  CAS  Google Scholar 

  • Segerbäck, D., 1983, Alkylation of DNA and hemoglobin in the mouse following exposure to ethene and ethene oxide. Chem.-Biol. Interactions. 45:139.

    Article  Google Scholar 

  • Sepai, O., Anderson, D., Street, B., Bird, I., Farmer, P.B. and Bailey, E., 1992, The monitoring of exposure to styrene oxide by GC-MS analysis of phenylhydroxyethyl esters in hemoglobin. Arch. Toxicol, in press.

    Google Scholar 

  • Stillwell, W.G., Bryant, M.S. and IS. Wishnok., 1987, GC/MS analysis of biologically important aromatic amines. Application to human dosimetry. Biomed. Environ. Mass Spectrom. 14:221.

    Article  PubMed  CAS  Google Scholar 

  • Svensson, K., 1988, Alkylation of protein and DNA in mice treated with urethane. Carcinogenesis. 9:2197.

    Article  PubMed  CAS  Google Scholar 

  • Swenberg, J.A., Walker, V.E., McNeela, IP. and Fennell, T.R., 1992, Molecular dosimetry of DNA and hemoglobin adducts in mice and rats exposed to ethylene oxide for up to four weeks. Environ. Health Perspec. in press.

    Google Scholar 

  • Ting, D., Smith, M.T., Doane-Setzer, P. and Rappaport, S.M., 1990, Analysis of styrene oxide-globin adducts based upon reaction with Raney nickel. Carcinogenesis. 11:755.

    Article  PubMed  CAS  Google Scholar 

  • Tornqvist, M., Mowrer, I, Jensen, S. and Ehrenberg, L., 1986, Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman Degradation method. Anal. Biochem. 154:255.

    Article  PubMed  CAS  Google Scholar 

  • Tornqvist, M., Kautiainen, A., Gatz, R.N. and Ehrenberg, L., 1988, Hemoglobin adducts in animals exposed to gasoline and diesel exhausts. J. Appl. Toxicol. 8:159.

    Article  CAS  Google Scholar 

  • Walker, V.E., MacNeela, IP., Swenberg, I A., Turner, M.I and Fennell, T.R., 1992a, Molecular dosimetry of ethylene oxide: formation and persistence of N-(2-hydroxyethyl)valine in hemoglobin following repeated exposures of rats and mice. Cancer Res. 52:4320.

    PubMed  CAS  Google Scholar 

  • Walker, V.E., Fennell, T.R., Upton, P.B., Skopek, T.R., Prevost, V., Shuker, D.E.G. and Swenberg, I A., 1992b, Molecular dosimetry of ethylene oxide: formation and persistence of 7-(2-hydroxyethyl)guanine in DNA following repeated exposures of rats and mice. Cancer Res. 52:4328.

    PubMed  CAS  Google Scholar 

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Farmer, P.B. (1993). Biomarkers as Molecular Dosimeters of Genotoxic Substances. In: Travis, C.C. (eds) Use of Biomarkers in Assessing Health and Environmental Impacts of Chemical Pollutants. NATO ASI Series, vol 250. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-2052-2_6

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  • DOI: https://doi.org/10.1007/978-1-4899-2052-2_6

  • Publisher Name: Springer, Boston, MA

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