A range of cellular processes, external factors, and/or disease states can lead to the formation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS), and these themselves have ongoing (and usually detrimental) effects in humans (Fig. 1). For example, chronic inflammatory processes produce an excess of ROS as well as DNA-reactive aldehydes including trans-4hydroxy-2-nonenal and malondialdehyde from lipid peroxidation (LPO) (1). There is evidence that individuals with chronic inflammatory conditions, including chronic pancreatitis, ulcerative colitis, and Crohn’s disease, show elevated levels of oxidative damage including modified DNA bases in various organs, as compared with the normal population (2). They are also at increased risk of cancer. Therefore, dietary modifications that reduce the steady-state levels of these modified bases may be likely to protect against cancer. Not only are there several different ROS and RNS, but these also lead to a range of effects on different macromolecules (Table 1). Protection against ROS primarily occurs through exogenous dietary antioxidants (of which an important class are free radical scavengers) or through enzymatic cellular defense mechanisms. Major mechanisms here are inhibitors of prooxidant enzymes or inducers of endogenous defenses. Important groups of free radical scavengers in the human diet are derived from plants, including ascorbic acid (vitamin C), vitamin E, carotenoids, and certain plant polyphenols (1,3). Potentially more interesting may be molecules such as isothiocyanates that are oxidants themselves but also upregulate the expression of cellular antioxidant proteins and detoxification enzymes (4). Potentially at least, increasing the intake of antioxidants can reduce the levels of ROS or RNS and may affect the efficacy of DNA repair processes. However, proving the efficacy of such measures is not simple, nor are preferred methodologies agreed on. Although a number of studies report on tests of antioxidant activity in vitro or in animal experimental models (e.g., 5), there are a considerable number of uncertainties in extrapolating such data to humans. The most definitive proof that a certain dietary antioxidant is beneficial to humans is to test whether supplementing human diets with the relevant material can decrease their cancer risk. However, the unexpected result that supplementation with b-carotene increased, not decreased, human cancer risk in certain high-risk groups (6) shows the dangers of waiting until cancer develops. Thus, most human trials do not go as far as cancer but utilize a surrogate biomarker that implies (but does not prove) disease risk (7). In considering the ability of a given individual or population group to cope with oxidative stress, one obvious method is to measure levels of free radical scavengers in the plasma. Examples that have been commonly studied thus include all the plantrelated chemicals identified above, at the indicated levels to be expected in plasma: ascorbic acid, 20–80 mM; vitamin E, 50 mM; carotenoids, 0.1–0.4 mM; plant polyphenols, 0.01–0.1 mM; and isothiocyanates, 0.1–1 mM. It is also possible to measure the ability of plasma to scavenge free radicals using, for example, Trolox equivalent antioxidant activity (TEAC) or oxygen radical absorbance activity (ORAC) assays (8). However, this gives only a part of the picture. A considerable number of biomarker studies have assayed excretory products in the urine. For example, etheno-DNA adducts can be measured using an immuno-enriched HPLC fluorescence methodwith a sensitivity of;5 fmol/ml (9). Similarly, 7-hydroxy8-oxo-2#-deoxyguanosine (8-OxodG) (or the corresponding base 8-oxoGua) is a commonly formed modified DNA base product that can be detected in urine after oxidative stress, has been shown to be mutagenic in vivo, and can be measured with high sensitivity (10). Thus, measures of urinary levels of this modified base have been supported as a biomarker of the total extent of oxidative damage to DNA, and a reduction in urinary excretion rates of this molecule interpreted as revealing dietary protection (10). Such methods take advantage of the fact that there is 1 Published in a supplement to The Journal of Nutrition. Presented as part of the conference ‘‘The Use and Misuse of Biomarkers as Indicators of Cancer Risk Reduction Following Dietary Manipulation’’ held July 12–13, 2005 in Bethesda, MD. This conference was sponsored by the Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA), Department of Health and Human Services (DHHS); the Office of Dietary Supplements (ODS), National Institutes of Health, DHHS; and the Division of Cancer Prevention (DCP), National Cancer Institute, National Institutes of Health, DHHS. Guest Editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; and Claudine Kavanaugh, CFSAN, FDA. Guest editor disclosure: H.E. Seifried, no relationships to disclose; C. Kavanaugh, no relationships to disclose. 2 This work was supported by grants from the Auckland Cancer Society. The contents are solely the responsibility of the authors. 3 Author disclosure: no relationships to disclose. 4 Abbreviations used: FPG, formamidopyrimidine DNA glycosylase; LPO, lipoid peroxidation; ORAC, oxygen radical absorbance activity; RNS, reactive nitrogen species; ROS, reactive oxygen species; TEAC, Trolox equivalent antioxidant activity. * To whom correspondence should be addressed. E-mail: ferguson@auckland.ac.nz.