PRINCIPLES OF TOXICOLOGY

After all, it is commonly assumed in interspecies extrapolation that the target tissue dose required to produce
a biological effect of a given intensity is quantitatively equivalent across species. Therefore, dose–response
curves generated with measures of target tissue dose should be readily extrapolatable across species
since they obviate the need for consideration of interspecies differences in the toxicokinetics of an
administered dose. Unfortunately, dose–response curves of this nature are rare primarily because of
the technical difficulties inherent in internal dose measurement. This is likely to change, however, as
advancements are made in analytical chemistry and physiologically based pharmacokinetic (PBPK)
models find their way into the mainstream. Such models are powerful tools with which to estimate
internal dose measures from an endless variety of exposure scenarios to physiologically diverse
receptors. As such, they are particularly valuable for the purpose of interspecies extrapolation.
Biological monitoring is another means of exposure assessment. When it is conducted to measure
a chemical or its metabolites in the urine, blood, or tissue (including hair and fingernails) of an exposed
individual, the chemical and its metabolites are referred to as biomarkers of exposure. Other potential
biomarkers include DNA and protein adducts, mutations, chromosomal aberrations, genes that have
undergone induction, and a host of other “early” cellular or subcellular events thought to link exposure
and effect. The characterization and quantification of these latter biomarkers is known as molecular
dosimetry. If found to be correlated with susceptibility, exposure, and effect, these biomarkers could
considerably alter conventional approaches to risk assessment. Perhaps the best known example of
such a correlation is urinary aflatoxin-DNA adducts and liver cancer. While molecular dosimetry holds
promise for risk assessment, it is yet to be developed well enough for routine application.
Despite advancements in analytical chemistry, mathematical modeling, and biomonitoring, exposure
assessment remains a challenge. It is important to realize that most exposure assessments result
in estimates rather than definitive values. This stems in part from the fact that site- or situation-specific
values are rarely available for all of the input variables necessary to calculate exposure. Despite the
challenge, efforts should continue toward conducting exposure assessments that reflect realistic
exposures, rather than worst-case scenarios to which no one is exposed. The identification of the dose
metric that best correlates with various toxicities should also be a priority. Since this depends on a
thorough knowledge of a chemical’s mode of action, advancement in exposure assessment is inextricably
linked to advances in toxicology.
18.4 DOSE–RESPONSE ASSESSMENT
In this portion of the risk assessment, the dose–response relationships for the toxicities of concern must
be measured, modeled, or assumed, in order to predict responses to doses estimated in the exposure
assessment. While dose–response relationships could theoretically be obtained for a variety of effects
from each chemical of potential concern, in practice attention is usually centered on the most sensitive
effect of the chemical.
In risk assessment, two fundamentally different types of dose–response relationships are thought
to exist. One is the threshold model, in which all doses below some threshold produce no effect, while
doses above the threshold produce effects that increase in incidence or severity as a function of dose.
The second model has no threshold—any finite, nonzero dose is thought to possess some potential for
producing an adverse effect. The derivation of these two types of dose-response relationships and their
use to provide estimates of risk are very different, as described in the following sections.
Threshold Models
18.4 DOSE–RESPONSE ASSESSMENT 449
It has long been held that for all toxicities other than cancer, there is some dose below which no
observable or statistically measurable response exists. This dose, called the threshold dose, was
graphically depicted in Chapter 1 (see also Figure 18.3). Conceptually, a threshold makes sense for
most toxic effects. The body possesses a variety of detoxification and cell defense and repair