Toxicology of Industrial Compounds

A.S.WRIGHT ET AL. 193
which need not be linear, would indicate proportionality over the low dose
range of interest and would permit the mutagenic potency of the chemical
to be expressed in terms of radiation equivalents, i.e. the number of rads
giving the same response or risk as a unit of chemical dose (expressed in
terms of target dose, e.g. millimolar hour, mM h). The significance of such
radiation dose-equivalents hinges on their possible extrapolative value.
Thus, in order to be useful in assisting the translation of experimentallydetermined
mutagenicity data, the rad-equivalence value for the test
chemical must have a similar numerical value in both the test system used
to determine mutagenicity and in humans. However, it is improbable that
rad-equivalence values can be directly determined in humans.
Rad-equivalence values for the induction of mutations have been
determined for a number of intrinsically reactive monofunctional alkylating
agents using a wide range of genetic endpoints in a variety of biological
systems including bacteria, plants and mammalian species—the latter,
mainly in vitro (Ehrenberg et al., 1974; Ehrenberg, 1976, 1979; Calleman,
1984; Kolman et al., 1989). The rad-equivalence value for a given
alkylating agent was approximately the same (within a factor of two) in
each of the test systems. On the basis of such evidence Calleman et al.
(1978) concluded that there was no reason to presume that a value for radequivalence
established in these disparate systems would differ in humans.
The best studied example is ethylene oxide. Currently a conjoint programme
is underway at the Universities of Stockholm and Leiden to determine radequivalence
values in rodents in vivo using a variety of endpoints including
the clonal HGPRT mutation assay and induction of pre-neoplastic nodules
in rat liver. Preliminary findings are encouraging (Ehrenberg, personal
communication).
Demonstration of their extrapolative value would justify application of
rad-equivalence values to compute small increments in mutation induced in
humans by low exposures (determined as target dose) to genotoxic
chemicals. The determination of these increments is the basis of the risk
model (vide supra) in which the increment in cancer risk due to a particular
chemical in a population is viewed as approximating to the increment in
mutation induced by the chemical. However, the fact that risk coefficients
have not yet been established for radiation-induced mutations in humans
precludes applications of rad-equivalence values to estimate mutational
risks, e.g. small increments in mutation, in humans. Of course, Ehrenberg
realised that a genotoxic chemical(s) may prove to be superior to radiation
as a reference standard for estimating mutational risks. Indeed, the use of
chemicals that are representative of classes of genotoxic chemicals, repair
pathways, etc. is envisaged in this developing ‘equivalence’ strategy
(Törnqvist and Osterman-Golkar, 1991). However, at the time the original
strategy was formulated there was and still is no reliable data relating low
level exposure to a genotoxic chemical and the attendant risk of mutation