BIPHASIC DOSE-RESPONSE RELATIONSHIPS 85In addition to these opportunities, the two-stage concept of chemical
toxicity also embodies implications of significant interest in the assessment
of risk from exposure to toxic chemicals. The existence of a threshold for
chemical toxicity is evident, as indicated by observation of the stimulation
of tissue repair mechanisms, directed to tissue healing and recovery, after
the administration of subtoxic levels of toxic chemicals, when exposure
involves singular chemicals. The existence of a two-level or two-stage
threshold is apparent from the two-tier hormetic response: one threshold
level for each stage of the two-stage model (Figure 4.7). Generally speaking,
the threshold for Stage I of toxicity must lie in the cytoprotective mecha
nisms (cellular hormesis). The threshold for Stage II of toxicity appears to
be in the tissue’s ability to respond promptly by augmenting tissue-healing
mechanisms. These two thresholds may be quantitatively the same or differ
ent, but clearly have mechanistic basis at different levels.
From a public health perspective, exposure to singular chemicals is sel
dom involved. Multiple exposures to chemical combinations and/or singu
lar components simultaneously, intermittently, or sequentially are almost
always the rule. In this regard, antagonistic interactive toxicity or inconse
quential interactions are also of interest. Of greater interest from a public
health perspective is the finding that the hormetic mechanisms that consti
tute the threshold for physical or chemical toxicity can be mitigated in the
interactive toxicology of chemical and physical agents, resulting in highly
accentuated toxicity.
Of significantly greater interest to regulatory toxicology is the need to
take into account in the risk assessment process the hormetic mechanisms
operating particularly at the low levels of exposure to chemicals. The recog
nition of the existence of cellular and tissue hormesis provides the mechanis
tic basis to recognize thresholds for toxic effects, thereby permitting us to
take into consideration the lack of recognizable adverse health effects at
low levels of exposure to chemicals in our environment.
ACKNOWLEDGMENTS
The author’s research was supported by grant support from the Depart
ment of the Air Force AFOSR-88-0009, the Harry G. Armstrong Aerospace
Medical Research Laboratory through U.S. EPA CR-814053, and by the
1988 Burroughs Wellcome Toxicology Scholar Award.
REFERENCES
- Klaassen, C. D., and J. Doull. “Evaluation of Safety: Toxicological Evalua
tion,” in Toxicology: The Basic Science of Poisons, 4th ed., J. Doull, C. D.
Klaassen, and M. O. Amdur, Eds. (New York: Pergamon Press, New York,
1991), pp. 11-27.