Cancer and degenerative diseases are major causes of morbidity and death, derived from the permanent modification of key biopolymers such as DNA and regulatory proteins by usually smaller, reactive molecules, present in the environment or generated from endogenous and xenobiotic components by the body's own biochemical mechanisms (molecular adducts). In particular, protein adducts with organic electrophiles have been studied for more than 30 [see, e.g., Calleman et al., 1978] years essentially for three purposes: (a) as passive monitors of the mean level of individual exposure to specific chemicals, either endogenously present in the human body or to which the subject is exposed through food or environmental contamination; (b) as quantitative indicators of the mean extent of the individual metabolic processing which converts a non-reactive chemical substance into its toxic products able to damage DNA (en route to cancer induction through genotoxic mechanisms) or key proteins (as in the case of several drugs, pesticides or otherwise biologically active substances); (c) to relate the extent of protein modification to that of biological function impairment (such as enzyme inhibition) finally causing the specific health damage. This review describes the role that contemporary mass spectrometry-based approaches employed in the qualitative and quantitative study of protein-electrophile adducts play in the discovery of the (bio)chemical mechanisms of toxic substances and highlights the future directions of research in this field. A particular emphasis is given to the measurement of often high levels of the protein adducts of several industrial and environmental pollutants in unexposed human populations, a phenomenon which highlights the possibility that a number of small organic molecules are generated in the human organism through minor metabolic processes, the imbalance of which may be the cause of "spontaneous" cases of cancer and of other degenerative diseases of still uncharacterized etiology. With all this in mind, it is foreseen that a holistic description of cellular functions will take advantage of new analytical methods based on time-integrated metabolomic measurements of a new biological compartment, the "adductome," aimed at better understanding integrated organism response to environmental and endogenous stressors.

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Benzene is a human carcinogen and an ubiquitous environmental pollutant. Identification of specific and sensitive biological markers is critical for the definition of exposure to low benzene level and the evaluation of the health risk posed by this exposure. This investigation compared urinary trans,trans-muconic acid (t,t-MA), Sphenylmercapturic acid, and benzene (U-benzene) as biomarkers to assess benzene exposure and evaluated the influence of smoking and the genetic polymorphisms CYP2E1 (RsaI and DraI) and NADPH quinone oxidoreductase-1 on these indices. Gas station attendants, urban policemen, bus drivers, and two groups of controls were studied (415 subjects). Median benzene exposure was 61, 22, 21, 9 and 6 Mg/m 3 , respectively, with higher levels in workers than in controls. U-benzene, but not t,t-MA and S-phenylmercapturic acid, showed an exposure-related increase. All the biomarkers were strongly influenced by cigarette smoking, with values up to 8-fold higher in smokers compared with nonsmokers. Significant correlations of the biomarkers with each other and with urinary cotinine were found. A possible influence of genetic polymorphism of CYP2E1 (RsaI and/or DraI) on t,t-MA