Analysis of hemoglobin as a dose monitor for alkylating and arylating agents

Abstract

Genotoxic xenobiotics bind covalently to hemoglobin in vivo. The major reaction product of aromatic amines is a sulfinic acid amide resulting from the reaction of arylnitroso derivatives with SH-groups. Alkylating compounds react with cysteine, histidine and the terminal valine. The adducts are formed proportional to dose down to extremely small doses, they are stable throughout the life-span of the erythrocytes and accumulate upon repeated exposure. Methods for their determination in blood samples from experimental animals and humans are becoming available. Moreover, it has been demonstrated that for a given agent, a constant ratio exists between the reaction with tissue DNA and hemoglobin over a wide range of doses, which indicates that the reactions follow apparent first order kinetics. The extent of hemoglobin binding is therefore considered to be a relative measure of tissue dose, and should correlate much better with risk than exposure levels calculated from concentrations in the environment. Not only can the actual uptake be monitored more reliably, but also the individual's capacity to metabolically activate the absorbed agent. Biomonitoring of hemoglobin-bound metabolites represents a novel approach to control exposure to potential carcinogens, to correlate environmental exposure with tissue dose and eventually also with human risk.

Hemoglobin adducts of monohalomethanes.

“…1,2) In a recent letter to this journal, Iwasaki et al3) have applied this methodology to workers exposed to methyl bromide.…”

Biologic Markers in Risk Assessment for Environmental Carcinogens

“…Although the results with EtO are generally encouraging, this may be a somewhat special case because EtO is a stable electrophile that distributes evenly between tissues, in contrast to substances such as vinyl chloride and dimethylnitrosamine, which require metabolism and thus produce less stable intermediates (34). At present, we rarely have comparative data on adducts in humans and laboratory animals with chronic exposure.…”

“…Measurements of EtO-hemoglobin binding in sterilizer plant workers were then used to estimate their tissue dose of EtO in terms of rad equivalents. This rad equivalent measure allowed a calculation of the excess risk of leukemia in the workers (1,(32)(33)(34). The resultant prediction of increased risk ofcancer in this cohort was subsequently borne out by epidemiological studies (3).…”

Aromatische Amine (Anilin, o‐, m‐, p‐Toluidin, 4‐Chlor‐o‐toluidin, 2,4‐ und 2,6‐Toluylendiamin, 4‐Aminodiphenyl, 4,4′‐Diaminodiphenylmethan) [Biomonitoring Methods in German language, 1994]

“…Inhalativ oder dermal aufgenommene Aminoaromaten können über die Methämoglo-binbildung (Met-Hb) [2][3][4] klinisch auffällige Cyanosen induzieren. Sie werden in Abhängigkeit von ihrer Menge, der Verteilungsgeschwindigkeit im Organismus, dem Polymorphismus der beteiligten Enzyme und einem möglichen Synergismus mit weiteren Fremdstoffbelastungen über unterschiedliche Stoffwechselwege wieder ausgeschieden [5][6][7][8].…”