PRINCIPLES OF TOXICOLOGY

chemical(s) that may be relevant to the risk assessment. While this may appear to be a straightforward
exercise, in reality it requires a good deal of careful analysis and scientific judgment. The reason for
this is that the risk assessor rarely has the luxury of information that adequately describes the toxicity
of a chemical under the precise set of circumstances to be addressed in the risk assessment. Instead,
the risk assessor typically must rely on incomplete data derived from species other than the one of
interest, under exposure circumstances very different from those being evaluated in the risk assessment.
The existence in the scientific literature of poorly designed studies with misleading results and
conclusions, as well as conflicting data from seemingly sound studies, further complicates the task.
This section of the chapter discusses some of the considerations when reviewing and evaluating
the toxicological literature for assessment of intrinsic toxicity. Many of these considerations address
suitability of data for extrapolation from one set of circumstances to another, while others pertain to
the fundamental reliability of the information. Much of the discussion regarding extrapolation deals
with assessing the value of animal data in predicting responses in humans, since human health risk
assessments are forced to rely predominantly on animal studies for toxicity data. Keep in mind that
most of the same extrapolation issues are equally relevant for ecological risk assessments, where
toxicity in wildlife species has to be inferred from data available only from laboratory animal species.
Information from Epidemiologic Studies and Case Reports
Observations of toxicity in humans can be extremely valuable in hazard identification. They offer the
opportunity to test the applicability of observations made in animal studies to humans and may even
provide an indication of the relative potency of the chemical in humans versus laboratory animal
models. If the human studies are of sufficient size and quality, they may stand alone as the basis for
hazard identification in human health risk assessment.
Despite the attractiveness of human studies, it is important to keep in mind that they often have significant
limitations. For example, it may be impossible to eliminate all of the confounding variables in any
epidemiological study (see Chapter 21). A less-than-rigorous effort to properly match exposed and control
populations makes it difficult or impossible to attribute with confidence any observed differences in health
effects to chemical exposure. Even in well-designed epidemiologic studies, there is always the possibility
that an unknown critical factor causally related to the health effect of interest has been missed. For this
reason, a consistent association between chemical exposure and a particular effect in several studies is
important in establishing whether the chemical produces that effect in humans.
Other criteria in evaluating epidemiologic studies include the following:
• The positive association (correlation) between exposure and effect must be seen in individuals
with definitive exposure.
• The positive association cannot be explained by bias in recording, detection, or experimental
design.
• The positive association must be statistically significant.
• The positive association should show both dose and exposure–duration dependence.
Information from Animal Studies
18.2 HAZARD IDENTIFICATION 443
Typically, data from studies using laboratory animals must be used for some or all of the intrinsic
toxicity evaluation of a chemical in humans. There are several aspects that need to be considered when
interpreting the animal data, as discussed below.
Breadth and Variety of Toxic Effects The toxicological literature should be reviewed in terms of the
types of effects observed in various test species. This is an important first step in chemical toxicity
evaluation because: