PRINCIPLES OF TOXICOLOGY

496 EXAMPLE OF RISK ASSESSMENT APPLICATIONS
Other important weight of evidence factors include the potential carcinogenic mechanism or
mechanisms of the chemical of concern. As considered by the USEPA, if the metabolism, toxicokinetics,
and carcinogenic mechanism of action of a chemical are similar in rodents and humans, the
weight of evidence for a carcinogenic effect of the chemical in humans is strengthened. Alternatively,
if data show that the results of animal studies are not relevant to humans, the weight of evidence for a
carcinogenic effect of the chemical in humans is weakened. As discussed above, recent data provide
an indication that rodent inhalation studies may not predict the carcinogenic potential of low-level
antimony trioxide exposure in humans.
The relevance of inhalation tests of high concentrations of particulate chemicals (such as antimony
trioxide) in rats to human exposures has been questioned in recent years. Recent data (Nikula et al.,
1997) indicates that the pattern of accumulation of particles in the rat lung is different from the same
particles in the lung of monkeys. Furthermore, the rat lung shows greater inflammatory response to
the particles than does the lung of the monkey. Because the lung of the monkey is structurally and
functionally much more like the human lung than the rat lung, the recent information suggests that the
relevance of high concentration inhalation studies in rats to humans should be reexamined.
Considered in total, the available evidence does not support a conclusion that inhaled antimony
trioxide is carcinogenic to humans. This conclusion is different from the weight-of-evidence conclusions
reached by IARC in 1989 and the State of California in 1990. However, these agencies did not
have the benefit of important and more recent studies that cast doubt on the carcinogenicity of antimony
trioxide and the relevance of rat inhalation studies of particulates in predicting carcinogenicity in
humans.
Comments
The reassessment of carcinogenicity data demonstrates the need for iteration in risk assessment and
its impact on antimony trioxide. The update of the toxicity assessment of antimony trioxide presented
above suggests that low levels of inhaled antimony trioxide are not carcinogenic to humans.
While current evidence indicates that low-level antimony trioxide exposure may not be carcinogenic
to humans, conservative public health policy may nonetheless require a risk assessor to assume that
antimony trioxide is a potential human carcinogen. Thus, the use of a threshold or a nonlinear method
to assess the possible carcinogenic effects of antimony trioxide may be a more reasonable alternative
to the “no threshold” linearized multistage model used in Proposition 65. While the term “nonlinear”
does not necessarily imply a threshold for the carcinogenic effect, it indicates that the carcinogenic
response declines much more quickly than linearly with dose. A nonlinear model is also appropriate
when the carcinogenic mode of action may theoretically have a threshold, for example, the carcinogenicity
may be a secondary effect of toxicity or of an induced physiological change. Thus, if antimony
trioxide must be considered a potential human carcinogen on the basis of conservative public health
policy, the risk of cancer should be quantified using a nonlinear cancer response model.
19.7 SUMMARY
This chapter illustrates several of the practical problems that often face a risk assessor. Each example
blends the use of default risk assessment procedures with higher tiers of risk evaluation. The example
of lead identifies and addresses the effect of lead on a sensitive individual—the developing fetus. The
antimony example highlights how inconsistency among regulatory agencies may affect the risk
assessment process. The antimony example also addresses the uncertainty associated with extrapolation
of high exposure animal studies to low exposures in humans and the relevance of these studies in
predicting the human carcinogenic response to antimony. Risk assessment of chemical mixtures (see
equations for air and soil exposure in Table 19.10) is evaluated in the petroleum hydrocarbon example.
The example of arsenic evaluates the importance of considering the physical/chemical form of the
chemical and how this may affect the bioavailability, human exposure, and risk.