ReviewUse of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants: The increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens
Introduction
Biomarkers are playing an increasing role in the assessment of human exposure to hazardous environmental pollutants and in risk assessment to these compounds [1], [2]. As indicated in Fig. 1, biomarkers may be applied at any stage in the toxicological process, ranging from measurement of the external dose as an indicator of exposure to determining altered structure and function of cells as a biomarker of effect (Fig. 1).
All of these biomarkers have value in specific circumstances. Thus, for example, biomarkers towards the right of the scheme advise more on health effects, whereas those towards the left of the scheme inform us more on the nature of the environmental agent and its source and concentration.
In the ideal situation one would like to know the linkages between biomarkers of exposure to biomarkers of effect and susceptibility and to adverse health effects, in order that one could derive risk assessment from the former. Although some examples exist where such relationships are known, e.g., blood levels of lead [3], and blood and hair levels of mercury [4], used as biomarkers for neurodevelopmental effects, this is generally not the case. More commonly, highly sensitive assays of exposure have been developed but the health effects associated with these are unknown, i.e., the nature of the dose–response relationship at low doses is unknown.
Endogenous formation of some biomarkers may additionally complicate the assessment of the external exposure, an example being ethylene oxide which is produced endogenously from metabolism of ethylene, possible sources of ethylene/ethylene oxide being methionine oxidation, lipid peroxidation, and the metabolizing activity of intestinal bacteria [5]. Finally as environmental pollutants are normally present in complex mixtures there is also the possibility of synergistic or antagonistic interactions which may affect the toxicity associated with a particular component.
In this review we will primarily focus on the determination of DNA adducts by mass spectrometry that indicates the biologically effective dose of environmental genotoxic carcinogens in humans. We will try to illustrate the progress in this field when compared to analysis of DNA adducts by other techniques and also highlight the limitations associated with the interpretation of DNA adduct determinations for genotoxic exposure and how these are being overcome.
Section snippets
Biomarkers of biologically effective dose of genotoxic carcinogens: DNA adduct determination
Genotoxic carcinogens interact with nucleic acids to produce adducts, measurement of which is an indicator of the dose of active material which has reached the cells under study, termed the biologically active dose, in the individual being investigated. This thereby incorporates the effects of inter-individual variation in absorption, metabolism and excretion of the compound which may affect risk assessment.
Conclusion
Mass spectrometry has made enormous gains in its applicability for the detection of DNA adducts, and it is now possible to determine DNA adducts by MS with a sensitivity comparable to that of the other analytical approaches available for adduct detection, such as 32P-postlabeling or immunoassays. Highly accurate and reproducible data can be obtained indicating that MS should provide more reliable results for biomonitoring of exposure to genotoxic carcinogens in human molecular epidemiological
Acknowledgements
The author acknowledges the Medical Research Council, grant number G0100873 for financial support. The authors are members of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility) a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract 513943).
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