60 BIOLOGICAL EFFECTS OF LOW LEVEL EXPOSURES
might be able to prevent infliction of injury. An example of this might be
illustrated by the depletion of intracellular glutathione by the ace
taminophen metabolite, acetamido iminoquinone. Since actual infliction of
cellular injury has been attributed to the formation of this active metabolite
in the liver, as long as cellular glutathione levels are not decreased below a
critical (threshold) level, significant injury does not occur. Once the cellular
glutathione level dips to the critical low level (subthreshold), continued
formation of the iminoquinone metabolite would result in covalent binding
of this metabolite to cellular macromolecules, resulting in greater infliction
of injury and cell death. However, even at this stage, all is not lost. After the
injury has occurred, the tissue is able to recruit a second tier of tissue
defense mechanisms.2-4 The dead or dying hepatocytes might be replaced by
new cells via stimulated hepatocellular regeneration and tissue repair.2 As
long as this second tier mechanism itself is not interfered with, as in the case
of limited tissue injury after a low but toxic dose of acetaminophen,3 com
plete recovery occurs with no further adverse consequences.
These endogenous cytoprotective mechanisms, as well as the mechanisms
dependent on the biology of cellular proliferation and tissue repair, are
referred to as hormetic mechanisms. Higher doses of toxic chemicals may
interfere with this tissue defense mechanism, resulting in greater and more
accelerated permissive progression of tissue injury until the tissue is com
pletely destroyed. Therefore, at subthreshold levels of toxic chemicals, the
hormetic mechanisms are not subdued, suppressed, or interfered with in
any other fashion. At doses exceeding the threshold levels, hormesis is
compromised, causing the cellular and tissue injury to progress in an uncon
trolled fashion, resulting in accelerated injury.
Evolution of hormesis as an adaptation mechanism in our struggle to
survive adverse or noxious insult is apparent in several experimental as well
as ambient settings. Resistance to the cytotoxic actions of low-level radia
tion after repeated exposure to even lower levels of radiation has a mecha
nistic basis in hormesis.5 7 Recent evidence also points to activation of hor
metic mechanisms against cytotoxic injury from other free-radical
generating mechanisms.8-10 It was anticipated from studies in which micro
somal incubations of menadione, a redox cycling quinone, were employed
that exposure to repeated phenobarbital administration would result in
greater cytotoxicity to isolated hepatocytes.11 Actual incubations of hepato
cytes isolated from rats preexposed to phenobarbital with menadione
revealed no such increase in toxicity.8 Additional experimental inquiry
revealed that several cytoprotective mechanisms were also induced simulta
neously as the free-radical generating potential was also increased.8-10
The objective of this chapter is to discuss the role of hormetic mecha
nisms in determining the final outcome of toxicity at low versus high doses
of chemicals. The cytoprotective defense mechanisms, along with inducible
hormetic mechanisms, appear to work in tandem to overcome toxicities
associated with low-level exposures to toxic chemicals. Interference with