Toxicology of Industrial Compounds

A.S.WRIGHT ET AL. 183
viewed as too remote to be of value in estimating cancer risks. The trend is
towards increasingly sensitive and precise technology—particularly generic
methods with potential for direct application in humans.
Advances in molecular biology have permitted the development of a new
generation of point mutation assays based on DNA base mismatch
technology (Thilly, 1991; Lu and Hsu, 1992). This technology has a
precision far exceeding that of conventional biological methods and a
sensitivity permitting direct applications in humans. The full potential of this
technology has not yet been realised. However, it seems probable that
detection levels will ultimately obviate a need for prior phenotypic
selection: paving the way to universal application. Avoidance of phenotypic
selection would represent a powerful advantage over existing
methodologies by providing a much more direct and reliable route to
determining overall background mutation rates and increments due to
specific exposures of key relevance to cancer risk assessment (vide infra).
The most prospective of the current assays are those designed to detect
primary DNA damage. Among these procedures, 32 P-post-radiolabelling
technology developed by Randerath et al. (1981) to detect DNA adducts is
by far the most sensitive. The justification for application of such a
prospective approach to detect exposure to genotoxic carcinogens hinges
on the causal relationship established between genotoxic activity and
cancer. In general, genotoxic character is conferred by possession of a
centre(s) of electrophilic reactivity. This reactivity permits the chemical to
undergo chemical reactions with nucleophilic centres in the target molecule
(DNA). In many instances the electrophilic centre(s) is introduced into an
inactive precursor chemical by metabolic activation. Primary products, e.g.
DNA adducts, formed when genotoxic chemicals react with DNA are
generally promutagenic (or lethal) and their occurrence leads to an
increased risk of mutation and cancer. There is no known category of
chemical which forms DNA adducts that can be excluded from this
generalisation. Not all DNA adducts are strongly promutagenic. However,
because electrophiles do not display absolute specificity in their reactions
with nucleophiles, the detection of even a weakly promutagenic adduct,
e.g. N 7 -alkyldeoxyguanosine, signals the formation of a more strongly
promutagenic adduct, e.g. O 6 -alkyldeoxyguanosine. If follows that the
detection of DNA adducts provides qualitative evidence of (human)
exposure to a genotoxic carcinogen.