Current Research on Hemoglobin Adducts and Cancer Risks: An Overview

  • Margareta Törnqvist
Part of the NATO ASI Series book series (NSSA, volume 250)


Most known chemical carcinogens are electrophilically reactive compounds (RX) or are formed in vivo from non-reactive precursors (A) (Miller and Miller, 1966). The electrophiles react with nucleophilic atoms (Y) of biomacromolecules giving rise to adducts (RY):
$$A \to RX\xrightarrow[{({k_y})}]{{ + {Y^ - }}}RY + {X^ - }$$
The measurement of adducts to sufficiently stable macromolecules may be used for identification of electrophiles in vivo and for dose monitoring as a basis for risk estimation. For reasons to be discussed below, the Stockholm group has used hemoglobin (Hb) for in vivo dose monitoring of chemical carcinogens in animals and humans.


Cancer Risk Ethylene Oxide Environmental Tobacco Smoke Adduct Level Protein Adduct 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 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.PubMedGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. Bailey, E., Farmer, P.B., Tang, Y.-S., Vangikar, H., Gray, A., Slee, D., Ings, R.M.J., Campbell, D.B., McVie, J.G., and Dubbelman, R., 1991, Hydroxyethylation of hemoglobin by l-(2-chloroethyl)-l- nitrosoureas, Chem. Res. Toxicol. 4:462.PubMedCrossRefGoogle Scholar
  4. Bechtold, W.E., Willis, J.K., Sun, J.D., Griffith, W.C., and Reddy, T.V., 1992, Biological markers of exposure to benzene: S-phenylcysteine in albumin, Carcinogenesis 13:1217.PubMedCrossRefGoogle Scholar
  5. Bergmark, E., Calleman, C.J., He, F., and Costa, L.G., 1992, Hemoglobin adducts in humans occupationally exposed to acrylamide, Toxicol. Appl Pharmacol, (submitted).Google Scholar
  6. Bryant, M.S., Skipper, P.L., Tannenbaum, S.R., and Maclure, M., 1987, Hemoglobin adducts of 4- aminobiphenyl in smokers and nonsmokers, Cancer Res. 47:602.PubMedGoogle Scholar
  7. Bryant, M.S., Vineis, P., Skipper, P.L., and Tannenbaum, S.R., 1988, Hemoglobin adducts of aromatic amines: Associations with smoking status and type of tobacco, Proc. Natl. Acad. Sci. USA 85:9788.PubMedCrossRefGoogle Scholar
  8. Bryant, M.S., Vineis, P., Skipper, P.L., and Tannenbaum, S.R., 1988, Haemoglobin adducts of aromatic amines in people exposed to cigarette smoke, in: “Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention,” H. Bartsch, K. Hemminki, and I.K. O’Neill, eds., Bryant, M.S., Vineis, P., Skipper, P.L., and Tannenbaum, S.R. 89, IARC, Lyon.Google Scholar
  9. Calleman, C.J., Ehrenberg, L., Jansson, B., Osterman-Golkar, S., Segerbäck, D., Svensson, K., and Wachtmeister, CA., 1978, Monitoring and risk assessment by means of alkyl groups in hemoglobin in persons occupationally exposed to ethylene oxide, J. Environ. Pathol. Toxicol. 2:427.PubMedGoogle Scholar
  10. Calleman, C.J., Ehrenberg, L., Osterman-Golkar, S., and Segerbäck, D., 1979, Formation of S-alkylcysteines as artifacts in acid protein hydrolysis, in the absence and in the presence of 2-mercaptoethanol, Acta Chem. Scand. B 33:488.CrossRefGoogle Scholar
  11. Cannella, S.G., Kagan, S.S., Kagan, M., Foiles, P.G., Palladino, G., Quart, A.M., Quart, E., and Hecht, S.S., 1990, Mass spectrometric analysis of tobacco-specific nitrosamine hemoglobin adducts in snuff dippers, smokers, and nonsmokers, Cancer Res. 50:5438.Google Scholar
  12. Christakopoulos, A., Bergmark, E., Zorcec, V., and Osterman-Golkar, S., 1989, Monitoring of occupational exposure to styrene through measurements of haemoglobin adducts and of metabolites in blood, Chem.-Biol. Interact, (submitted).Google Scholar
  13. Day, B.W., Skipper, P.L., Wishnok, J.S., Coghlin, J., Hammond, S.K., Gann, P., and Tannenbaum, S.R., 1990, Identification of an in vivo chrysene diol epoxide adduct in human hemoglobin, Chem. Res. Toxicol. 3:340.PubMedCrossRefGoogle Scholar
  14. Duus, U., Osterman-Golkar, S., Törnqvist, M., Mowrer, J., Holm, S., and Ehrenberg, L., 1989, Studies of determinants of tissue dose and cancer risk from ethylene oxide exposure, in: L. Freij, ed., “Proc. Symp. Management of Risk from Genotoxic Substances in the Environment,” Swedish National Chemicals Inspectorate, Solna, Sweden.Google Scholar
  15. Ehrenberg, L., 1984, Aspects of statistical inference in testing for genetic toxicity, in: “Handbook of Mutagenicity Test Procedures, Second Edition,” B.J. Kilbey et al., eds., Elsevier, New York.Google Scholar
  16. Ehrenberg, L., and Osterman-Golkar, S., 1980, Alkylation of macromolecules for detecting mutagenic agents, Teratog. Carcinog. Mutagen. 1:105.PubMedCrossRefGoogle Scholar
  17. Ehrenberg, L., and Törnqvist, M., 1992, Use of biomarkers in epidemiology: quantitative aspects, Toxicol. Lett. 64/65 (in press).Google Scholar
  18. Ehrenberg, L., Moustacchi, E., and Osterman-Golkar, S., 1983, Dosimetry of genotoxic agents and dose- response relationships of their effects, Mutat. Res. 123:121.PubMedCrossRefGoogle Scholar
  19. Ehrenberg, L., Törnqvist, M., and Vaca, C, 1992, Cancer risks from low doses of ionizing radiation and electrophilic chemicals: similarities and differences. Ms.Google Scholar
  20. Farmer, P.B., Bailey, E., Gorf, S.M., Törnqvist, M., Osterman-Golkar, S., Kautiainen, A., and Lewis-Enright, D.P., 1986, Monitoring human exposure to ethylene oxide by the determination of haemoglobin adducts using gas chromatography — mass spectrometry, Carcinogenesis 7:637.PubMedCrossRefGoogle Scholar
  21. Fedtke, N., and Swenberg, J.A., 1991, Quantitative analysis of DNA adducts: the potential for mass spectrometric techniques, in: “Molecular Dosimetry and Human Cancer: Analytical, Epidemiological, and Social Considerations,” J.D. Groopman, and P.L. Skipper, eds., CRC Press, Boston.Google Scholar
  22. Filser, J.G., Denk, B., Törnqvist, M., Kessler, W., and Ehrenberg, L., 1992, Pharmacokinetics of ethylene in man; body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene, Arch. Toxicol. 66:157.PubMedCrossRefGoogle Scholar
  23. Foiles, P.G., Akerkar, S.A., Cannella, S.G., Kagan, M., Stoner, G.D., Resau, J.H., and Hecht, S.S., 1991, Mass spectrometric analysis of tobacco-specific nitrosamine — DNA adducts in smokers and nonsmokers, Chem. Res. Toxicol. 4:364.PubMedCrossRefGoogle Scholar
  24. Föst, U., Marczynski, B., Kasemann, R., and Peter, H., 1989, Determination of 7-(2-hydroxyethyl)guanine with gas chromatography/mass spectrometry as a parameter for genotoxicity of ethylene oxide, Arch. Toxicol, Suppl. 13:250.CrossRefGoogle Scholar
  25. Gan, L.-S., Skipper, P.L., Peng, X., Groopman, J.D., Chen, J., Wogan, G.N., and Tannenbaum, S.R., 1988, Serum albumin adducts in the molecular epidemiology of aflatoxin carcinogenesis: correlation with aflatoxin B1 intake and urinary excretion of aflatoxin M1, Carcinogenesis 9:1323.PubMedCrossRefGoogle Scholar
  26. Granath, F., Ehrenberg, L., and Törnqvist, M., 1993, Degree of alkylation of macromolecules in vivo from variable exposure, Mutai Res. (in press).Google Scholar
  27. Hecht, S.S., Cannella, S.G., and Murphy, S.E., 1992, Tobacco-specific nitrosamine hemoglobin adducts, in: “Methods in Enzymology,” J.N. Abelson, and M.I. Simon, eds.-in-chief, Academic Press, Inc., New York (in press).Google Scholar
  28. Högstedt, B., Bergmark, E., Törnqvist, M., and Osterman-Golkar, S., 1990, Chromosomal abenations and micronuclei in lymphocytes in relation to alkylation of hemoglobin in workers exposed to ethylene oxide and propylene oxide, Hereditas 113:133.PubMedCrossRefGoogle Scholar
  29. Iwasaki, K., Ito, I., and Kagawa, J., 1989, Biological exposure monitoring of methyl bromide workers by determination of hemoglobin adducts, Indust. Health 27:181.CrossRefGoogle Scholar
  30. Kautiainen, A., Osterman-Golkar, S., and Ehrenberg, L., 1986, Misincorporation of alkylated amino acids into hemoglobin — a possible source of background alkylations, Acta Chem. Scand. B 40:453.PubMedCrossRefGoogle Scholar
  31. Kautiainen, A., Törnqvist, M., Svensson, K., and Osterman-Golkar, S., 1989, Adducts of malonaldehyde and a few other aldehydes to hemoglobin, Carcinogenesis 10:2123.PubMedCrossRefGoogle Scholar
  32. Kautiainen, A., Törnqvist, M., Anderstam, B., and Vaca, CE., 1991, In vivo hemoglobin dosimetry of malonaldehyde and ethene in mice after induction of lipid peroxidation. Effects of membrane lipid fatty acid composition, Carcinogenesis 12:1097.PubMedCrossRefGoogle Scholar
  33. Kolman, A., Segerbäck, D., and Osterman-Golkar, S., 1988, Estimation of the cancer risk of genotoxic chemicals by the rad-equivalence approach, in: “Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention,” H. Bartsch, K. Hemminki, and I.K. O’Neill, eds., Kolman, A., Segerbäck, D., and Osterman-Golkar, S. 89, IARC, Lyon.Google Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. Miller, E.C., and Miller, J.A., 1966, Mechanisms of chemical carcinogenesis: Nature of proximate carcinogens and interactions with macromolecules, Pharmacol. Rev. 18:805.PubMedGoogle Scholar
  36. Mustonen, R., and Hemminki, K., 1992, 7-methylguanine levels in DNA of smokers’ and non-smokers’ total white blood cells, granulocytes and lymphocytes, Carcinogenesis (in press).Google Scholar
  37. NRC, National Research Council, 1990, Committee on the Biological Effects of Ionizing Radiations. “Health Effects of Exposure to Low Levels of Ionizing Radiation. BEIR V Report,” National Academy Press, Washington DC.Google Scholar
  38. Osterman-Golkar, S., Ehrenberg, L., Wachtmeister, CA., 1970, Reaction kinetics and biological action in barley of mono-functional methanesulfonic esters, Radial Bot. 10:303.CrossRefGoogle Scholar
  39. Randerath, E., Miller, R.H., Mittal, D., Avitts, T.A., Dunsford, H.A.. and Randerath, K., 1989, Covalent DNA damage in tissues of cigarette smokers as determined by 32p-postlabeling assay, J. Natl. Cancer Inst. 81:341.PubMedCrossRefGoogle Scholar
  40. Sawada, S., and Totsuka, T., 1986, Natural and anthropogenic sources and fate of atmospheric ethylene, Atmos. Environ. 20:821.CrossRefGoogle Scholar
  41. Schut, H.A.J., and Shiverick, K.T., 1992, DNA adducts in humans as dosimeters of exposure to environmental, occupational, or dietary genotoxins, FASEBJ. 6:2942.Google Scholar
  42. Segerbäck, D., 1983, Alkylation of DNA and hemoglobin in the mouse following exposure to ethene and ethylene oxide, Chem.-Biol. Interact. 45:139.PubMedCrossRefGoogle Scholar
  43. Segerbäck, D., 1985, In vivo dosimetry of some alkylating agents as a basis for risk estimation, Ph.D. thesis, Stockholm University, Stockholm.Google Scholar
  44. Segerbäck, D., 1990, Reaction products in hemoglobin and DNA after in vitro treatment with ethylene oxide and N-(2-hydroxyethyl)-iV-nitrosourea, Carcinogenesis 11:307.PubMedCrossRefGoogle Scholar
  45. Shields, P.G., Povey, A.C., Wilson, V.L., Weston, A., and Harris, C.C., 1990, Combined high-performance liquid chromatography/32P-postlabeling assay of N 7-methyldeoxyguanosine, Cancer Res. 50:6580.PubMedGoogle Scholar
  46. Van Sittert, N.J., De Jong, G., Clare, M.G., Davies, R., Dean, B.J., Wren, L.J., and Wright, A.S., 1985, Cytogenetic, immunological, and haematological effects in workers in an ethylene oxide manufacturing plant, Br. J. Indust. Med. 42:19.Google Scholar
  47. Skipper, P.L., and Stillwell, W.G., 1992, Aromatic amine — hemoglobin adducts, in: “Methods in Enzymology,” J.N. Abelson, and M.I. Simon, eds.-in-chief, Academic Press, Inc., New York (in press).Google Scholar
  48. Svensson, K., and Osterman-Golkar, S., 1987, In vivo 2-oxoethyl adducts in hemoglobin and their possible origin, in: “Application of Short-Term Bioassays in the Analysis of Complex Environmental Mixtures V,” S.S. Sandhu, D.M. DeMarini, M.J. Mass, M.M. Moore and J.S. Mumford, eds., Plenum Press.Google Scholar
  49. Taghizadeh, K., and Skipper, P.L., 1992, Benzo(a)pyrene diol epoxide and related polynuclear aromatic hydrocarbon adducts, in: “Methods in Enzymology,” J.N. Abelson, and M.I. Simon, eds.-in-chief, Academic Press, Inc., New York (in press).Google Scholar
  50. Tannenbaum, S.R. et al., 1992, Xenobiotic adducts of human hemoglobin, in: “Methods in Enzymology,” J.N. Abelson, and M.I. Simon, eds.-in-chief, Academic Press, Inc., New York (in press).Google Scholar
  51. Tates, A.D., Grummt, T., Törnqvist, M., Farmer, P.B., van Dam, F.J., van Mossel, H., Schoemaker, H.M., Osterman-Golkar, S., Uebel, Ch., Tang, Y.S., Zwinderman, A.H., Natarajan, A.T., and Ehrenberg, L., 1991, Biological and chemical monitoring of occupational exposure to ethylene oxide, Mutat. Res. 250:483.PubMedCrossRefGoogle Scholar
  52. Törnqvist, M., 1989, Monitoring and cancer risk assessment of carcinogens, particularly alkenes in urban air, Ph.D. thesis, University of Stockholm, Stockholm.Google Scholar
  53. Törnqvist, M., 1990, Formation of reactive species that lead to hemoglobin adducts during storage of blood samples, Carcinogenesis 11:51.PubMedCrossRefGoogle Scholar
  54. Törnqvist, M., 1992, Epoxide adducts to N-terminal valines, in: “Methods in Enzymology,” J.N. Abelson, and M.I. Simon, eds.-in-chief, Academic Press, Inc., New York (in press).Google Scholar
  55. Törnqvist, M., and Ehrenberg, L., 1990, Approaches to risk assessment of automotive engine exhausts, in: “Complex Mixtures and Cancer Risk,” H. Vainio, M. Sorsa, and A.J. McMichael, eds., IARC Sci. Publ. 104, IARC, Lyon.Google Scholar
  56. Törnqvist, M., and Ehrenberg, L., 1992, On cancer risk estimation of urban air pollution, Environ. Health Perspect. (submitted).Google Scholar
  57. Törnqvist, M., and Kautiainen, A., 1992, Adducted proteins for identification of endogenous electrophiles, Environ. Health Perspect. 99 (in press).Google Scholar
  58. Törnqvist, M., and Osterman-Golkar, S., 1991, Monitoring of in vivo dose by macromolecular adducts: Usefulness in risk estimation, in: “Molecular Dosimetry and Human Cancer: Analytical, Epidemiological and Social Considerations,” J.D. Groopman, and P.L Skipper, eds., CRC Press, Boca Raton, Ann Arbor, Boston.Google Scholar
  59. Törnqvist, M., Mowrer, J., Jensen, S., and Ehrenberg, L., 1986a, Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method, Anal. Biochem. 154:255.PubMedCrossRefGoogle Scholar
  60. Törnqvist, M., Osterman-Golkar, S., Kautiainen, A., Jensen, S., Farmer, P.B., and Ehrenberg, L., 1986b, Tissue doses of ethylene oxide in cigarette smokers determined from adduct levels in hemoglobin, Carcinogenesis 7:1519.PubMedCrossRefGoogle Scholar
  61. Törnqvist, M., Osterman-Golkar, S., Kautiainen, A., Näslund, M., Calleman, C. J., and Ehrenberg, L., 1988, Methylations in human hemoglobin, Mutat. Res. 204:521.PubMedCrossRefGoogle Scholar
  62. Törnqvist, M., Almberg, J., Nilsson, S., and Osterman-Golkar, S., 1989a, Ethylene oxide doses in ethene- exposed fruit store workers, Scand. J. Work Environ. Health 15:436.PubMedCrossRefGoogle Scholar
  63. Törnqvist, M., Gustafsson, B., Kautiainen, A., Harms-Ringdahl, M., Granath, F., and Ehrenberg, L., 1989b, Unsaturated lipids and intestinal bacteria as sources of endogenous production of ethene and ethylene oxide, Carcinogenesis 10:39.PubMedCrossRefGoogle Scholar
  64. Törnqvist, M., Segerbäck, D., and Ehrenberg, L., 1991, The ‘rad-equivalence approach’ for assessment and evaluation of cancer risks, exemplified by studies of ethylene oxide and ethene, in: “Human Carcinogen Exposure: Biomonitoring and Risk Assessment,” R.C. Garner, P.B. Farmer, G.T. Steel, and A.S. Wright, eds., Oxford University Press, Oxford.Google Scholar
  65. Törnqvist, M., Magnusson, A.-L., Farmer, P.B., Tang, Y-S., Jeffrey, A.M., Wazneh, L., Beulink, G.D.T., van der Waal, H., and van Sittert, N.J., 1992a, Ring test for low levels of N-(2-hydroxyethyl)valine in human hemoglobin, Anal. Biochem. 203:357.PubMedCrossRefGoogle Scholar
  66. Törnqvist, M., Svartengren, M., and Ericsson, C.H., 1992b, Methylations in hemoglobin from monozygotic twins discordant for cigarette smoking: hereditary and tobacco-related factors, Chem.-Biol. Interact. 82:91.PubMedCrossRefGoogle Scholar
  67. Turtóczky, I., and Ehrenberg, L., 1969, Reaction rates and biological action of alkylating agents preliminary report on bactericidal and mutagenic action in E. coli, Mutat. Res. 8:229.CrossRefGoogle Scholar
  68. Umemoto, A., Monden, Y., Grivas, S., Yamashita, K., and Sugimura, T., 1992, Determination of human exposure to the dietary carcinogen 3-amino-l,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) from hemoglobin adduct: the relationship to DNA adducts, Carcinogenesis 13:1025.PubMedCrossRefGoogle Scholar
  69. U.S. EPA, 1990, Cancer risk from outdoor air toxics. Vol. 1, United States Environmental Protection Agency, Washington DC.Google Scholar
  70. Vaessen, H.A.M.G., Jekel, A.A., and Wilbers, A.A.M.M., 1988, Dietary intake of polycyclic aromatic hydrocarbons, Toxicol. Environ. Chem. 16:281CrossRefGoogle Scholar
  71. Waldman, J.M., Lioy, P.J., Greenberg, A., and Butler, J.P., 1991, Analysis of human exposure to benzo(a)pyrene via inhalation and food ingestion in the total human environmental exposure study (thees), Exposure Anal. Environ. Epidemiol. 1:193.Google Scholar
  72. Weston, A., Rowe, M.L., Manchester, D.K., Farmer, P.B., Mann, D.L., and Harris, C.C., 1989, Fluorescence and mass spectral evidence for the formation of benzo[a]pyrene anti-diol-epoxide-DNA and — hemoglobin adducts in humans, Carcinogenesis 10:251.PubMedCrossRefGoogle Scholar
  73. Wilson, V.L. et al., 1989, Alkyl and aryl carcinogen adducts detected in human peripheral lung: short communication, Carcinogenesis 10:2149.PubMedCrossRefGoogle Scholar
  74. Wraith, M.J., Watson, W.P., Eadsforth, C.V., van Sittert, N.J., Törnqvist, M., and Wright, A.S., 1988, An immunoassay for monitoring human exposure to ethylene oxide, in: “Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention,” H. Bartsch, K. Hemminki, and I.K. O’Neill, eds., Wraith, M.J., Watson, W.P., Eadsforth, C.V., van Sittert, N.J., Törnqvist, M., and Wright, A.S. 89, IARC, Lyon.Google Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Margareta Törnqvist
    • 1
  1. 1.Department of RadiobiologyStockholm UniversityStockholmSweden

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