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

CHAPTER 4

Biochemical Mechanisms of Biphasic

Dose-Response Relationships:

Role of Hormesis

Harihara M. Mehendale, Department of Pharmacology and Toxicology,
University of Mississippi Medical Center, Jackson, Mississippi

INTRODUCTION

A fundamental principle underlying the toxic actions of chemical and
physical agents is that greater toxicities are manifested with increasing
doses.1 With the exception of cancer and certain immune reactions, it is
generally recognized that there is a threshold dose before which toxic mani­
festations do not begin to appear. Living organisms have a remarkable
capability to overcome injury from physical or chemical agents encountered
in their environment. In an attempt to enhance survival from many kinds of
noxious injuries, organisms have developed several kinds of cellular and
tissue defense mechanisms. While unicellular organisms may rely on cellular
defense mechanisms for survival, multicellular organisms have developed
additional integrated defense mechanisms through the evolved sophistica­
tion of tissues and organs, with matching structural and functional com­
plexity. Generally speaking, such mechanisms might be classified into two
major categories, and each category might be viewed as a component of a
two-tier defense system. One category is represented by biochemical mecha­

nisms that enable the organism to prevent infliction of injury after a nox­
ious insult. The second is a biological response intended to overcome injury,
by promoting tissue healing after the fact. Although much attention has
been focused on the endogenous biochemical defense mechanisms that par­
ticipate in preventing the infliction of cellular and tissue injury by directly
or indirectly interfering with the inflictive mechanisms, the biology of
endogenous mechanisms that might be recruited to overcome tissue injury
after it occurs has received little attention.
The threshold for toxic actions of a toxic chemical at the first tier might
be defined by the extent to which the cellular or tissue defense mechanisms

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