HEMOGLOBIN ADDUCTS OF N-SUBSTITUTED ARYL COMPOUNDS IN EXPOSURE CONTROL AND RISK ASSESSMENT

Arylamines, nitroarenes, and azo dyes yield a common type of metabolit e, the nitrosoarene, which produces a hydrolyzable adduct with protein and is closely related to the critical, ultimate toxic and genotoxic metabolite. The target dose as measured by hemoglobin adducts in eryth rocytes reflects not only the actual uptake from the environment but a lso an individual's capacity for metabolic activation and is therefore an improved dosimeter for human exposure. The usefulness of hemoglobi n adducts in molecular epidemiology is now widely recognized. With reg ard to risk assessment, many questions need to be answered. The descri bed experiments in rats address some of these questions. The relations hip between binding to hemoglobin in erythrocytes and to proteins in p lasma has been found to vary considerably for a number of diamines. Th e fraction of hydrolyzable adducts out of the total protein adducts fo rmed also varies in both compartments. This indicates that the kind of circulating metabolites and their availability in different compartme nts is compound specific. This has to do with the complex pattern Of c ompeting metabolic pathways, and the role of N-acetylation and deacety lation is emphasized. An example of nonlinear dose dependence adds to the complexity. Analysis of hemoglobin adducts reveals interesting ins ights into prevailing pathways, which not only apply to the chemical, but may also be useful to assess an individual's metabolic properties. In addition, it is demonstrated that the greater part of erythrocytes and benzidine-hemoglobin adducts are eliminated randomly in rats, i.e ., following first-order kinetics.