PRINCIPLES OF TOXICOLOGY

452 RISK ASSESSMENT
• As discussed above, an uncertainty factor of up to 10 may be applied if the only value
with which to estimate the threshold dose is a LOAEL value. Division by this uncertainty
factor is meant to accomplish a reduction in the LOAEL to a level at or below the
threshold dose.
• An additional uncertainty factor (or in some terminology, a “modifying factor”) is applied
if the overall quality of the database is poor—the number of animal species tested is few, the
number of toxic endpoints evaluated is small, or the available studies are found to be deficient
in quality.
These uncertainty factors are compounded; that is, an uncertainty factor of 10 for sensitive
individuals combined with an uncertainty factor of 10 for extrapolation of data from animals to
humans results in a total uncertainty factor of 100 (10 × 10). Total uncertainty factors applied to
develop a SHD commonly range between 300 and 1000, and values up to 10,000 or more are
possible, although regulatory agencies may place a cap on the size of compounded uncertainty
factors (e.g., a limit of 3000).
There are two major criticisms of the NOAEL approach for developing a SHD. One is that the
ability of the NOAEL to approximate the threshold dose is dependent on dose selection and spacing
in available studies, and in many cases these are not well suited to determining the threshold. A
second criticism is that the approach fails to consider the shape or slope of the dose–response
curve, focusing instead on results from one or two low doses exclusively. The benchmark dose
(BMD) approach to estimating a SHD avoids both criticisms by making full use of the dose–
response data. Dose–response data for the toxic effect of concern are fit to a mathematical model,
and the model is used to determine the dose corresponding to a predetermined benchmark
response. As an example, dose–response data might be used to determine the dose required to
produce a 10% incidence of malformed fetuses from pregnant mice treated with a chemical. This
dose would be referred to as the ED 10 , or dose effective in producing a 10% incidence of effect.
Often, for regulatory purposes, statistical treatment of the data is used to derive upper and lower
confidence limit estimates of this dose. The more conservative of these is the lower confidence
limit estimate of the dose, which in this case would be designated as the LED 10 (see Figure 18.4).
In order to develop a SHD from the ED 10 or LED 10 , a series of uncertainty factors would be
applied, analogous to the NOAEL approach. In a sense, the BMD approach is like extrapolating
a SHD from a LOAEL, except the LOAEL is much more rigorously defined. The BMD approach
works best if there are response data available for a variety of doses and the data are in a form
such that the percentage of animals responding can be readily ascertained. Other types of data
presentation (e.g., continuous data) make using the BMD approach more difficult, and advantages
of the BMD approach are lost if data from only one or two doses are available.
Although the term “risk” often implies probability of an adverse event, the threshold approach to
assessing chemical risk does not result in risk expression in probability terms. This approach is instead
directed to deriving a safe limit for exposure, and then determining whether the measured or anticipated
exposure exceeds this limit. All doses or exposures below this “safe level” should carry the same
chance that toxicity will occur—namely, zero. With this model the acceptability of the exposure is
basically judged in a “yes/no” manner. The most common quantitative means of expressing hazard
for noncancer health effects is through a hazard quotient (HQ). Agencies such as the USEPA calculate
a HQ as the estimated dose from exposure divided by their form of the SHD, the RfD:
HQ = D
RfD ⎛ ⎜or HQ =
⎝
D ⎞
SHD⎟
⎠
where HQ = hazard quotient
D = dosage (mg/kg⋅day) estimated to result from exposure via the relevant route
RfD = reference dose (mg/kg⋅day)