Hemoglobin adducts for in vivo dose monitoring and cancer risk estimation

For the estimation of cancer risks from environmental chemicals, knowledge of the target dose is essential, dose being defined as the time integral of concentration in target tissues. In vivo doses from chronic or intermittent exposures are best determined from established steady-state levels of macromolecule adducts of reactive compounds or intermediates. For dose monitoring, hemoglobin (Hb) is preferred to DNA for several reasons: accessibility in large amounts, availability of methods for chemical identification, and well-determined life span due to absence of repair. For these reasons, and because of the proportionality of rates of DNA and Hb adduct formation, Hb adduct levels give better information on cumulative DNA adduct levels than do direct measurement of DNA adducts. The scientific background of Hb adduct measurement, target dose determination, and risk estimation based on the relative genotoxic potency, with gamma-radiation as reference standard, is reviewed and exemplified. The sensitivity of the method for Hb adduct measurement permits determination of exposures where the associated annual cancer risk is less than 1 per million. Besides application for studies of metabolism by determination of in vivo doses in exposed animals and humans, as a basis for risk estimation, Hb adduct measurement is used for hygienic surveillance of occupational exposures. Determination of Hb adducts by mass-spectrometric techniques gives a tool for identification of reactive metabolites, not only in individuals with known exposure, but also for characterization of adducts to Hb from compounds acting as mutagens (initiators) in the background carcinogenesis. This is the large fraction of the total number of cancer cases that occur among individuals without known exposure.