Toxicology of Industrial Compounds

190 MOLECULAR APPROACHES TO ASSESS CANCER RISKS
‘labile’ adducts formed, for example, during exposure to aromatic amines
(Green et al., 1984; Albrecht and Neumann, 1985) is beyond the scope of
this paper (for reviews see Farmer, 1991; Skipper and Naylor, 1991).
However, probably the most powerful and valuable approach was
developed by Törnqvist et al. (1986a, b) who showed that adducts with the
N-terminal valine residues of haemoglobin could be specifically enriched by
scission in a modified Edman reaction followed by extraction. This
enrichment procedure greatly facilitates sample analysis by GC/MS.
Immunoassays are also being introduced as alternatives to physicochemical
methods for the determination of protein adducts (Wraith et al., 1988).
However, as in the case of DNA adducts, the biggest impact of
immunotechnology on the analysis of protein adducts will probably be in
the immunoenrichment of low levels of adducts for analysis by physicochemical
methods.
Determination of biological effects
Tumour incidence
The determination of target dose is essential for assessing cancer risks
posed by low-level exposures to genotoxic chemicals. The other requisite is
know ledge of the human dose-carcinogenic response relationships in the
low-dose range. The lack of intrinsic resolving power of classical
epidemiological methods (vide supra) prevents effective applications to
detect small carcinogenic effects associated with low exposures to any
particular genotoxic chemical. Furthermore, the detection limits of animal
cancer studies fall short of ‘acceptable’ risk limits by three to four orders of
magnitude (Wright, 1991). This poor sensitivity compels the use of high
test doses in order to ensure that significant carcinogens do not go
undetected. However, it is generally accepted that high doses of chemicals
may induce tumours by non-specific mechanisms, e.g. via tissue injury and
compensatory cell proliferation, that do not operate at low doses (Ames,
1989; Wright, 1991). Many, if not all genotoxic chemicals induce cell
injury at high (thresholded) doses. Clearly, extrapolation of such high dose
risk data to the relevant low-dose range may, at the very least, lead to a
gross overestimation of risk.
Determination of mutagenic potency
In considering the impact that a low-level exposure to a genotoxic
chemical may have on cancer incidence, it is reasonable to suggest that the
mutagenic propensity of the chemical, although of a low order, would
nevertheless be the overriding risk factor. Thus, it is probable that any