PRINCIPLES OF TOXICOLOGY

494 EXAMPLE OF RISK ASSESSMENT APPLICATIONS
the cynomolgus monkey at a concentration of 2 mg/m 3 , 7 h/day, 5 days per week for 24 months.
Importantly, rats, but not monkeys, developed significant alveolar epithelial hyperplastic, inflammatory,
and septal fibrotic responses to the retained particles. These data indicate that if human lungs
respond more like the monkey than the rat, the pulmonary response of the rat to particles may not be
predictive of the response in humans at particle concentrations representing high occupational
exposures.
While “particle overload” alone does not necessarily account for the lung toxicity of antimony
trioxide in the Newton et al. study, it is possible that decreased clearance of particulates from the lung
may be the cause of lung tumors seen in the Groth et al. and Watt studies. Hext (1994) compared the
results of studies demonstrating particle-related pulmonary tumors by agents such as antimony
trioxide, diesel exhaust, coal, carbon black, titanium dioxide, and others. To compare particle exposure
between the studies, Hext calculated cumulative particle exposure in mg/m 3 -hr. This comparison is
presented for selected agents below.
Test Material
Duration
(months)
Exposure
rate
(hrs/wk)
Exposure
period
(hrs)
Concentration
(mg/m 3 )
Cumulative
exposure
(mg/m 3 -hr)
Tumor
incidence
(percent)
*Antimony trioxide 12 35 1820 38 69,160 27
Carbon black 20 85 7395 6.0 44,370 25
24 80 8400 2.5 21,000 11
24 80 8400 6.5 54,600 67
Talc 28 30 3660 6 21,960 0
28 30 3660 18 65,880 54
*Female rats only
Adapted from Hext, 1994
At similar cumulative particle exposures, antimony trioxide caused fewer tumors than did carbon
black or talc, two substances generally regarded as relatively nontoxic. Although the differences in
cancer incidence between antimony trioxide-treated rats and carbon black and talc-treated rats may
partly result from differences in experimental design, the size of particles tested, and other factors, it
nonetheless suggests that tumors observed by Groth et al. may result from reduced lung clearance
caused by “particle overload.”
Of the available antimony trioxide inhalation studies, only the Newton et al. study used an
experimental design that permits a dose–response assessment of the effects of inhaled antimony
trioxide at concentrations above and below the concentrations that affect particle clearance from the
lung. The technical deficiencies of the Watt and Groth et al. studies limit interpretation of the study
results.
Weight of Evidence Characterization of the Potential Carcinogenicity of Inhaled Antimony
Trioxide to Humans
According to all weight-of-evidence schemes, the greatest emphasis is placed on the results of
well-conducted human epidemiology studies. In the case of antimony trioxide, human evidence is
inadequate to establish a link between antimony trioxide exposure and cancer.
According to NRC and USEPA criteria, weight of evidence for the carcinogenicity of inhaled
antimony trioxide in animals must also be regarded as equivocal. Although two studies in rats indicate
that high concentrations of inhaled antimony trioxide cause lung tumors in female rats (Watt, 1983;
Groth et al., 1986), male rats did not develop lung tumors in two studies that males were tested (Groth
et al., 1986 and Newton et al., 1994). Neither female nor male rats developed lung tumors in the Newton
et al. study. Watt observed lung tumors in rats at only one of two antimony trioxide concentrations
tested. Groth et al. tested only one concentration of antimony trioxide. Thus, there is little dose–re-