Revival: Biological Effects of Low Level Exposures to Chemical and Radiation (1992)

56 BIOLOGICAL EFFECTS OF LOW LEVEL EXPOSURES

for the protein) are likely to bring rapid further understanding in this area.24
It is clear that there is an alkyltransferase activity in rat liver, which is
inducible by alkylating agents.25 This activity may play an important part in
the removal of 0 6-methylguanine after chronic exposure.26 The effect may
be part of a nonspecific tissue response. The only liver cells that demon­
strate the response are parenchymal cells,27 and the level of response, which
is less than 10-fold in rat (compared to over 100-fold in bacteria). There is
not a similar induction in any other system, although ionizing radiation
induces the alkyltransferase in different systems.27 The situation in humans
is unclear.27
It is clear that toxicants can stimulate repair. This is important in under­
standing how toxicants will interact in inducing damage; it is especially
germane to the problems of assessing human risk to low levels of agents
because agents are almost never presented alone, but in mixtures with other
toxicants. At the level of genomic damage, the focus has been on whether
DNA-damaging agents are additive or synergistic. But evidence is building
that antagonism must also be considered, as it is for metabolism and other
factors in human risk.1 The relevance of this consideration to hormesis is
especially interesting.28 In certain situations, exposure to an agent may pre­
dispose cells to be less sensitive to other agents — perhaps especially true for
low levels of radiation.

CONCLUSION

In evaluating the risk associated with low levels of exposure to toxicants,
it is clear that DNA repair, one of the main defenses against agent damage,
is not a constant. It can be modified by age, time of day, and physiological
state. Nutrition, especially CR, can modify almost every step in the process
of protecting genomic integrity. And history of exposure can modify DNA
repair. Thus, the conditions of exposure are almost as important to toxicity
as the exposure level itself, even at the level of DNA repair. Extrapolation
from high to low dose, to be consistent with what is known, should be less a
mathematical exercise (as it is at present) than a exercise in toxicological
judgment, which puts the exposure in proper perspective. This appears to be
true at almost every level in the process inducing a response with atoxic
stimulus, even those often thought to be very basic, such as DNA repair.

REFERENCES

1. Interagency Staff Group. “Chemical Carcinogens: A Review of the Science and
   Associated Principles,” Environ. Health Perspect. 67:201-282 (1986).


2. Ames, B., and L. Gold. “Too Many Rodent Carcinogens: Mitogenesis Increases
   Mutagenesis,” Science 249:970-971 (1990).


3. Turturro, A., and R. Hart. “DNA Repair Mechanisms in Aging,” in Compara-