PRINCIPLES OF TOXICOLOGY

19.6 REEVALUATION OF THE CARCINOGENIC RISKS OF INHALED ANTIMONY TRIOXIDE 491
mechanisms other than the default regulatory position. For example, California’s Proposition 65
defaults to the position that there is no threshold for the carcinogenic effect of a chemical “known to
the State to cause cancer.” This “no threshold” default policy assumes that at low levels of exposure,
the cancer risk associated with exposure to a carcinogen is linear to an exposure level at zero. Simply
stated, calculated cancer risk is zero only when there is zero exposure to the chemical.
In contrast to the “no threshold” default policy of chemical carcinogenesis, a review of recent
evidence suggests that some agents that are carcinogenic to the rat lung at very high levels of exposure
may not be carcinogenic at lower, more environmentally relevant levels of exposure in humans. These
studies suggest that the response of the rat lung to accumulated particles is different from the mouse
and human. Even in the rat, exposure to lower concentrations of particles that do not overwhelm lungs’
ability to clear the particles do not appear to be carcinogenic. Importantly, these observations suggest
that the rat may not be the best model for assessing the carcinogenicity of particular chemicals in
humans. However, even if the rat is considered to be a relevant model for humans, studies in the rat
suggest that the response in the rat lung at high levels of exposure is different that that seen at
environmentally relevant levels of exposure. The response of the rat lung to antimony trioxide particles
appears to fit the pattern of a threshold response—lung tumors develop at very high concentrations of
particle exposure but do not occur at lower levels of exposure. For this reason, the default regulatory
position of no carcinogenic threshold does not appear applicable to antimony trioxide.
Antimony trioxide is used as a flame retardant in a diverse array of products. As a result of the
International Agency for Research on Cancer (IARC) ranking of antimony trioxide as “possibly
carcinogenic to humans (Group 2B)” in 1989, antimony trioxide was listed as a chemical “known to
the State to cause cancer” on October 1, 1990 under the State of California’s Proposition 65. The IARC
classification of antimony trioxide as “possibly carcinogenic to humans” is based on two studies of
inhaled antimony trioxide in rats conducted in the 1980s. Unlike IARC and State of California, the
USEPA does not consider antimony trioxide to be a potential human carcinogen. In this way, antimony
trioxide is an example of inconsistencies that may exist between regulatory agencies regarding the
risks resulting from chemical exposure.
A review of information published before and after the 1990 listing of antimony trioxide as
“Possibly Carcinogenic to Humans” is presented below. This information is particularly important to
the hazard identification step in assessing the human health risks from inhaled antimony trioxide. As
such, inclusion of this updated information is a new iteration in the assessment of health risks resulting
from inhalation of antimony trioxide.
Human Studies of Antimony Carcinogenicity
In cancer risk assessment, the results of well-conducted human epidemiology studies are generally
preferable to animal studies since interspecies extrapolation is not required. In the case of antimony
trioxide, two studies of antimony exposed workers were available for review (Jones, et al., 1994;
Schnorr et al., 1995) (see Table 19.7). However, neither of these studies was considered to provide
conclusive evidence for or against a carcinogenic effect of antimony trioxide in humans.
Carcinogenicity Studies of Antimony Trioxide in Rodents
The results of three carcinogenicity studies of inhaled antimony trioxide in rats are summarized in
Tables 19.8 and 19.9.
On initial review, the rodent studies of Watt (1983) and Groth et al. (1986) appear to indicate that
antimony trioxide is a rat lung carcinogen. However, in-depth examination of the mechanism of
antimony trioxide toxicity to the rat lung and the technical problems with these studies suggest that
such a conclusion is uncertain. In addition, the results of the most recent and well-designed study find
no evidence that antimony trioxide is a potential lung carcinogen in rats (Newton, et al., 1994).