PRINCIPLES OF TOXICOLOGY

444 RISK ASSESSMENT
• It identifies potential effects that might be produced in humans. To some extent, the consistency
with which an effect is observed among different species provides greater confidence that this
effect will occur in humans as well. An effect that occurs in some species but not others, or one
sex but not the other, signals that great care will be needed in extrapolating findings in animals
to humans without some form of corroborating human data.
• A comparison of effects within species (e.g., sedation vs. hepatotoxicity vs. lethality) helps
establish a rank order of the toxic effects manifested as the dose increases. This aids in
identifying the most sensitive effect. Often this effect becomes the focus of a risk assessment,
since protecting against this effect will protect against all effects. Also, comparisons of
dose–response relationships within species can provide an estimation of the likelihood that
one toxic effect will be seen given the appearance of another.
Mechanism of Toxicity Understanding the mechanism of action of a particular chemical helps
establish the right animal species to use in assessing risk, and to determine whether the toxicity is likely
to be caused in humans. For example, certain halogenated compounds are mutagenic and/or carcinogenic
in some test species but not others. Differences in carcinogenicity appear to be related to
differences in metabolism of these chemicals, because their metabolism is an integral part of their
mechanism of carcinogenesis. For these chemicals, then, a key issue in selecting animal data for
extrapolation to humans is the extent to which metabolism in the animal model resembles that in
humans. A second example is renal carcinogenicity from certain chemicals and mixtures, including
gasoline. Gasoline produces renal tumors in male rats, but not female rats or mice of either sex. The
peculiar susceptibility of male rats to renal carcinogenicity of gasoline can be explained by its
mechanism of carcinogenesis. Metabolites of gasoline constituents combine with a specific protein,
α-2µ-globulin, to produce recurring injury in the proximal tubules of the kidney. This recurring injury
leads to renal tumors. Female rats and mice do not produce this protein, explaining why they do not
develop renal tumors from gasoline exposure. Humans do not produce the protein either, making the
male rat a poor predictor of human carcinogenic response in this situation.
In a sense, choosing the best animal model for extrapolation is always a catch-22 situation. Selection of
the best model requires knowledge of how the chemical behaves in both animals and humans, including its
mechanism of toxicity. In the situations in which an animal model is most needed—when we have little data
in humans—we are in the worst position to select a valid model. The choice of an appropriate animal model
becomes much clearer when we have a very good understanding of the toxicity in humans and animals, but
in this situation there is, of course, much less need for an animal model.
In addition to helping identify the best species for extrapolation, knowledge of the mechanism of
toxicity can assist in defining the conditions required to produce toxicity. This is an important aspect
of understanding the hazard posed by a chemical. For example, acetaminophen, an analgesic drug used
in many over-the-counter pain relief medications, can produce fatal liver injury in both animals and
humans. By determining that the mechanism of toxicity involves the production of a toxic metabolite
during the metabolism of high doses, it is possible to predict and establish its safe use in humans,
determine the consequences of various doses, and develop and provide antidotal therapy.
Dosages Tested Typically, animal studies utilize relatively high doses of chemicals so that unequivocal
observations of effect can be obtained. These doses are usually much greater than those received
by humans, except under unusual circumstances such as accidental or intentional poisonings. Thus,
while animal studies might suggest the possibility of a particular effect in humans, that effect may be
unlikely or impossible at lower dosages associated with actual human exposures. The qualitative
information provided by animal studies must be viewed in the context of dose–response relationships.
Simply indicating that an effect might occur is not enough; the animal data should indicate at what
dosage the effect occurs, and equally importantly, at what dosage the effect does not occur.
Validity of Information in the Literature Any assessment of the intrinsic toxicity of a chemical
begins with a comprehensive search of the scientific literature for relevant studies. While all of the