Toxicology of Industrial Compounds

compensates for individual or species differences in the operation of
metabolic and biokinetic factors that control the quantitative (and
qualitative) relationships between the exposure and the dose of the ultimate
toxicant delivered to the target. Measurements of target dose may be
applied to improve the extrapolation of risk data from experimental
models to humans and may also provide improved definitions of risks to
individuals. The determination of target dose in humans may be viewed,
therefore, as an approach towards direct risk monitoring as well as a more
relevant approach to monitor human exposures to genotoxic chemicals.
Determination of target dose
The determination of target dose raises numerous technical and theoretical
problems. Target dose can be determined by measuring primary products,
e.g. DNA adducts, formed when genotoxic agents react with DNA. The
kinetics of formation and decay of these adducts must also be determined
(vide infra) in order to transform measurements of amounts of adducts into
estimates of target dose. Human tissue DNA is not readily accessible for
monitoring purposes: surrogate dose monitors are required. There are
numerous possibilities including the determination of adducts in white
blood cell DNA or of the corresponding adducts in the haemoglobin of
circulating erythrocytes.
Such indirect approaches require validation. Haemoglobin is the most
extensively studied surrogate, not only because of its accessibility and
relative abundance but also because of the relative stability of haemoglobin
adducts and the longevity of erythrocytes which permit retrospective
estimates of dose received by the erythrocytes over a period of about 4
months. Current evidence indicates that all electrophiles that undergo
covalent reactions with DNA also react with haemoglobin. Furthermore
the amounts of haemoglobin adducts are quantitatively related to the rates
of formation of DNA adducts in the tissues. However the proportional
relationships between the doses delivered to tissue DNA and to
haemoglobin or to any other surrogate will vary from chemical to chemical
and will have to be established using experimental models.
Measurement of haemoglobin adducts
A.S.WRIGHT ET AL. 189
Genotoxic chemicals undergo covalent reactions with a variety of
nucleophilic centres in haemoglobin including the sulphydryl group of
cysteine, the N 1 and N 3 atoms of histidine and the amino groups of Nterminal
valine residues. Ehrenberg’s group (Osterman-Golkar et al., 1976;
Calleman et al, 1978; Törnqvist et al., 1986a) has pioneered the
development of methods to detect, identify and quantify adducts formed at
each of these centres. A review of these and methods for the analysis of