PRINCIPLES OF TOXICOLOGY

19.6 REEVALUATION OF THE CARCINOGENIC RISKS OF INHALED ANTIMONY TRIOXIDE 493
mg/m 3 for 6 h/day, 5 days/week for 12 months. In addition to clinical observations and microscopic
pathology assessments, the authors measured antimony tissue levels in the lung at different time during
the exposure period and during the observation period. Although inflammatory lung changes were
observed at the 4.5 mg/m 3 exposure level, no increase in lung tumors was observed in either sex at any
of the exposure levels. The authors concluded that the lung burden resulting from the highest exposure
level decreased pulmonary clearance approximately 80%, with an increase in clearance half-time of
2–10 months.
The differences in carcinogenic outcome in the positive Watt (1983) and Groth et al. (1986) studies
and the negative Newton et al. (1994) study may be the result of differences in the amount of antimony
deposited in the lung. Newton et al. suggested that the different results may be due to higher exposure
levels in the Watt study than were actually reported. The increased lung burden of particles in the Watt
and Groth reports and the lung damage resulting from antimony trioxide may explain the positive lung
tumor results in contrast to the negative results of Newton. Increasing lung burdens result in impaired
clearance of particles from the lung, leading to prolonged and more severe chronic lung damage (Strom
et al., 1989; Pritchard, 1989; Morrow, 1992).
Short-Term Genetic Toxicity Studies
Short term genetic toxicity (genotoxicity) studies are believed to provide important information
regarding the potential carcinogenicity of a chemical. These studies evaluate the potential for chemicals
to cause genetic damage such as gene mutations, damage to chromosomes, and changes in the number
of chromosomes (aneuploidy). Chemically-induced genetic damage is believed to be an important
event in chemical carcinogenesis.
The results of genotoxicity studies of antimony trioxide are mixed and provide no clear indication
that inhaled antimony trioxide is genotoxic. Studies of antimony trioxide mutagenicity in bacteria are
largely negative, (CalEPA, 1997) although antimony trioxide is reported to cause DNA damage in the
bacterium B. subtilis. Antimony trioxide was not mutagenic in the mouse lymphoma cell assay but
caused chromosomal aberrations in human lymphocytes and leukocytes (CalEPA, 1997). Both positive
and negative results have been obtained from whole animal tests of the ability of antimony trioxide to
cause chromosomal damage. These whole animal studies used orally administered antimony trioxide.
The applicability of these oral studies to the genotoxic potential of inhaled antimony trioxide is
unknown.
Putative Carcinogenic Mechanism of Antimony Trioxide in the Rat Lung
As discussed by Newton et al. (1994), the high lung burden of antimony trioxide resulting from
exposures used in the Watt and Groth et al. studies may explain the positive carcinogenic effect. At the
high concentrations used in the Watt and Groth et al. studies, clearance of antimony trioxide particles
from the lung is reduced. The result of reduced lung clearance is increased retention of particles in the
lung. Even particles of relatively innocuous materials such as titanium dioxide may cause lung tumors
in the rat. These tumors appear to result as a secondary effect of impaired lung clearance, leading to
inflammation and hyperplasia of the surrounding lung tissue. The putative mechanism of carcinogenity
of these chemically inert particles appears to result from the inflammatory response of the rat lung to
foreign particles rather than from a chemical-specific response. The impairment of lung clearance and
subsequent response of the lung to retained foreign bodies is believed to explain the carcinogenicity
of relatively nontoxic and insoluble particles including talc, carbon black, and titanium dioxide in the
rat (Nikula et al., 1997).
The results of a recent study by Nikula (Nikula et al., 1997) support the doubts of the relevance of
inhalation studies in rats to humans. As reviewed by Nikula et al., the lung of the cynomolgus monkey
is anatomically much more like the human lung. Furthermore, particle clearance rates from the lung
of the cynomolgus monkey are similar to humans and unlike the rat. Nikula et al. evaluated the effect
of coal dust, diesel soot, and a mixture of coal dust and diesel soot on the lungs of Fisher 344 rats and