HEMOGLOBIN ADDUCTS FOR IN-VIVO DOSE MONITORING AND CANCER RISK-ESTIMATION

For the estimation of cancer risks from environmental chemicals, Knowl edge of the target dose is essential, dose being defined as the time i ntegral 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 interm ediates. For dose monitoring, hemoglobin (Hb) is preferred to DNA for several reasons: accessibility in large amounts, availability of metho ds for chemical identification, and well-determined life span due to a bsence of repair. For these reasons, and because of the proportionalit y of rates of DNA and Hb adduct formation, Hb adduct levels give bette r information on cumulative DNA adduct levels than do direct measureme nt 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 revi ewed and exemplified. The sensitivity of the method for Hb adduct meas urement permits determination of exposures where the associated annual cancer risk is less than 1 per million. Besides application for studi es of metabolism by determination of in vivo doses in exposed animals and humans, as a basis for risk estimation, Hb adduct measurement is u sed for hygienic surveillance of occupational exposures. Determination of Hb adducts by mass-spectrometric techniques gives a tool for ident ification of reactive metabolites, not only in individuals with known exposure, but also for characterization of adducts to Hb from compound s acting as mutagens (initiators) in the background carcinogenesis. Th is is the large fraction of the total number of cancer cases that occu r among individuals without known exposure.