DNA Adducts as Exposure Biomarkers and Indicators of Cancer Risk
Miriam C. Poirier
Laboratory of Cellular Carcinogenesis and Tumor Promotion,
National Cancer Institute, Bethesda, Maryland
Abstract
Quantitation of DNA adducts in human tissues has been achieved with highly sensitive techniques based on adduct radiolabeling, antisera specific for DNA adducts or modified DNA, and/or adduct structural characterization using chemical instrumentation. Combinations of these approaches now promise to elucidate specific adduct structures and provide detection limits in the range of 1 adduct/109 nucleotides. Documentation of human exposure and biologically effective dose (i.e., chemical bound to DNA) has been achieved for a wide variety of chemical carcinogens, including polycyclic aromatic hydrocarbons (PAHs), aromatic amines, heterocyclic amines, aflatoxins, nitrosamines, cancer chemotherapeutic agents, styrene, and malondialdehyde. Due to difficulties in exposure documentation, dosimetry has not been precise with most environmental and occupational exposures, even though increases in human blood cell DNA adduct levels may correlate approximately with dose. Perhaps more significant are observations that lowering exposure results in decreasing DNA adduct levels. DNA adduct dosimetry for environmental agents has been achieved with dietary contaminants. For example, blood cell polycyclic aromatic hydrocarbon-DNA adduct levels were shown to correlate with frequency of charbroiled meat consumption in California firefighters. In addition, in China urinary excretion of the aflatoxin B1-N7-guanine (AFB1-N7-G) adduct was shown to increase linearly with the aflatoxin content of ingested food. Assessment of DNA adduct formation as an indicator of human cancer risk requires a prospective nested case-control study design. This has been achieved in one investigation of hepatocellular carcinoma and urinary aflatoxin adducts using subjects followed by a Shanghai liver cancer registry. Individuals who excreted the AFB1-N7-G adduct had a 9.1-fold adjusted increased relative risk of hepatocellular carcinoma compared to individuals with no adducts. Future advances in this field will be dependent on chemical characterization of specific DNA adducts formed in human tissues, more precise molecular dosimetry, efforts to correlate DNA adducts with cancer risk, and elucidation of opportunities to reduce human DNA adduct levels. -- Environ Health Perspect 105(Suppl 4):907-912 (1997)
Key words: human, environment, carcinogen, DNA binding, dosimetry
This paper is based on a presentation at the symposium on Mechanisms and Prevention of Environmentally Caused Cancers held 21-25 October 1995 in Santa Fe, New Mexico. Manuscript received at EHP 16 April 1996; accepted 4 October 1996.
The secretarial assistance of M. Taylor is much appreciated.
Address correspondence to Dr. M.C. Poirier, National Cancer Institute, Building 37, Room 3B25, MSC-4255, 37 Convent Drive, Bethesda, MD 20892-4255. Telephone: (301) 402-1835. Fax: (301) 496-8709. E-mail: poirierm@dc37a.nci.nih.gov
Abbreviations used: AFB1-N7-G, aflatoxin B1-N7-guanine; B[a]P, benzo[a]pyrene; CB, charbroiled; ECC, electrochemical conductance; ELISA, enzyme-linked immunosorbent assay; GC-MS, gas chromatography-mass spectrometry; HPLC, high-performance liquid chromatography; PAHs, polycyclic aromatic hydrocarbons; RIA, radioimmunoassay; SFS, synchronous fluorescence spectrometry; TLC, thin layer chromatography.
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Last Update: June 20, 1997