PRINCIPLES OF TOXICOLOGY

454 RISK ASSESSMENT
divided by a dermal SHD to derive the HQ for this route of exposure. Typically, the HQ values for
each relevant route of exposure are summed to derive a hazard index (HI) for that chemical.
Interpretation of the HI is analogous to the HQ—values less than one indicate that the safe dose (in
this case, in the aggregate from all routes of exposure) has not been exceeded. A value greater than
one suggests that effects are possible, although not necessarily likely. The HI is also a means by which
effects of different chemicals with similar toxicities can be combined to provide an estimate of total
risk to the individual. This is discussed in more detail in Section 18.7.
Another means to convey the relationship between estimated and safe levels of exposure is through
calculation of a margin of exposure. This is most often used in the context of the BMD approach. The
margin of exposure is the BMD divided by the estimated dose. An acceptable margin of exposure is
usually defined by the uncertainty factors applied to the BMD. If, for example, available data suggest
that a total uncertainty factor of 1000 should be applied to the BMD for a specific chemical and effect,
and the margin of exposure for that chemical is greater than 1000 (i.e., the estimated dose is less than
the BMD divided by 1000), the exposure would be regarded as safe.
The above-described methods are almost universally applied in assessing the potential for noncancer
health effects. There is, however, one exception for which a radically different approach is used:
the evaluation of noncancer effects from lead in children. The Public Health Service has determined
that blood lead concentrations in children should not exceed 10 µg/dL in order to avoid intellectual
impairment. Thus, the main objective in lead risk assessment is to determine whether childhood lead
exposure is sufficient to result in an unacceptable blood lead level. For this purpose, the USEPA has
developed a PBPK model known as the “integrated exposure uptake biokinetic model for lead in
children” (IEUBK). The IEUBK model has four basic components (i.e., exposure, uptake, biokinetics;
and probability distribution) and uses complex mathematics to describe age-dependent anatomical and
physiological functions that influence lead kinetics. The model predicts the blood concentration (the
dose metric most closely related to the health effect of interest) that results from an endless variety of
exposure scenarios that can be constructed by the risk assessor (i.e., exposure to various concentrations
of lead in soil, dust, water, food, and/or ambient air). The model also predicts the probability that
children exposed to lead in environmental media will have a blood lead concentration exceeding a
health-based level of concern (e.g., 10 µg/dL) (see Figure 18.5). The IEUBK approach is rather unique
because it is among the few approaches that rely on an internal dose metric (i.e., blood lead level) and
PBPK modeling for risk assessment purposes.
Figure 18.5 Example of output from the IEUBK model. The curve displays the cumulative probability of
developing a blood lead concentration at varying levels as a result of the specified exposure. In this example, there
is a probability of virtually 100% that the modeled exposure will result in a blood lead concentration greater than
1 µg/dL, but only about a 9% probability that the blood lead concentration will exceed 10 µg/dL.