Toxicology of Industrial Compounds

188 MOLECULAR APPROACHES TO ASSESS CANCER RISKS
haemocyanin or bovine serum albumin, for the immunisation of mice. This
strategy is usually effective in the case of strongly antigenic haptens, e.g.
aromatic nitro compounds of PCA-DNA adducts. However, all of our
attempts to use this approach to generate antibodies against relatively low
MW and weakly antigenic mercapturic acids, e.g. S-(2-hydroxyethyl)-Nacetylcysteine,
failed. Antibodies were generated but these were directed
against the strongly antigenic carrier protein(s).
Covalent binding to macromolecules is believed to provide the basis of
allergic responses, e.g. skin sensitisation reactions, to small molecules and,
possibly, a basis for the induction of auto-immune responses. Thus, the
binding of the small molecule transforms normal proteins into ‘foreign’
proteins which trigger an immune response. Recently we have employed
this principle in an attempt to direct the immune response specifically
against mercapturic acid haptens by immunising mice with the haptens
bound to a non-antigenic carrier protein, i.e. mouse serum albumin.
Preliminary results indicate that this tactic has been successful. Overall the
treatment induced fewer antibody-producing cells. However, the antibodies
that were generated show high affinities and specificity toward model
mercapturic acids including S-(2-hydroxyethyl) and S-phenylmercapturic
acid. Studies are in progress to investigate the performance of these
antibodies in an immunoenrichment mode.
The preliminary results of our studies using non-antigenic protein
carriers are very encouraging and have provided fresh insights which may
assist in directing immune responses against the specific structural features
of interest. Improvements in our ability to tailor the antibody will prove
extremely valuable in optimising the properties of antibodies to meet
specific needs, e.g. to enrich DNA, protein or mercapturic acid adducts for
application in identifying the chemical initiators of human cancer and
quantifying exposures to these agents.
Cancer risk assessment
Human exposure monitoring (determination of dose)
The assessment of cancer risks posed by exposure to genotoxic chemicals
has two components: determination of the dose and determination of the
effect (increment in cancer incidence) caused by that dose. The introduction
of the target dose concept by Ehrenberg in the early 1970s has provided the
key to modern strategies to assess genotoxic risks (Ehrenberg, 1974, 1979;
Ehrenberg et al., 1974). This new dose concept was developed to provide a
measure of the critical dose, i.e. the dose of the ultimate genotoxic agent(s)
penetrating to DNA. Target dose is much more relevant to risk assessment
than is exposure dose. The determination of target dose automatically