PRINCIPLES OF TOXICOLOGY - Biology East Borneo

19.6 REEVALUATION OF THE CARCINOGENIC RISKS OF INHALED ANTIMONY TRIOXIDE 493mg/m 3 for 6 h/day, 5 days/week for 12 months. In addition to clinical observations and microscopicpathology assessments, the authors measured antimony tissue levels in the lung at different time duringthe exposure period and during the observation period. Although inflammatory lung changes wereobserved at the 4.5 mg/m 3 exposure level, no increase in lung tumors was observed in either sex at anyof the exposure levels. The authors concluded that the lung burden resulting from the highest exposurelevel decreased pulmonary clearance approximately 80%, with an increase in clearance half-time of2–10 months.The differences in carcinogenic outcome in the positive Watt (1983) and Groth et al. (1986) studiesand the negative Newton et al. (1994) study may be the result of differences in the amount of antimonydeposited in the lung. Newton et al. suggested that the different results may be due to higher exposurelevels in the Watt study than were actually reported. The increased lung burden of particles in the Wattand Groth reports and the lung damage resulting from antimony trioxide may explain the positive lungtumor results in contrast to the negative results of Newton. Increasing lung burdens result in impairedclearance of particles from the lung, leading to prolonged and more severe chronic lung damage (Stromet al., 1989; Pritchard, 1989; Morrow, 1992).Short-Term Genetic Toxicity StudiesShort term genetic toxicity (genotoxicity) studies are believed to provide important informationregarding the potential carcinogenicity of a chemical. These studies evaluate the potential for chemicalsto cause genetic damage such as gene mutations, damage to chromosomes, and changes in the numberof chromosomes (aneuploidy). Chemically-induced genetic damage is believed to be an importantevent in chemical carcinogenesis.The results of genotoxicity studies of antimony trioxide are mixed and provide no clear indicationthat inhaled antimony trioxide is genotoxic. Studies of antimony trioxide mutagenicity in bacteria arelargely negative, (CalEPA, 1997) although antimony trioxide is reported to cause DNA damage in thebacterium B. subtilis. Antimony trioxide was not mutagenic in the mouse lymphoma cell assay butcaused chromosomal aberrations in human lymphocytes and leukocytes (CalEPA, 1997). Both positiveand negative results have been obtained from whole animal tests of the ability of antimony trioxide tocause 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 isunknown.Putative Carcinogenic Mechanism of Antimony Trioxide in the Rat LungAs discussed by Newton et al. (1994), the high lung burden of antimony trioxide resulting fromexposures used in the Watt and Groth et al. studies may explain the positive carcinogenic effect. At thehigh concentrations used in the Watt and Groth et al. studies, clearance of antimony trioxide particlesfrom the lung is reduced. The result of reduced lung clearance is increased retention of particles in thelung. Even particles of relatively innocuous materials such as titanium dioxide may cause lung tumorsin the rat. These tumors appear to result as a secondary effect of impaired lung clearance, leading toinflammation and hyperplasia of the surrounding lung tissue. The putative mechanism of carcinogenityof these chemically inert particles appears to result from the inflammatory response of the rat lung toforeign particles rather than from a chemical-specific response. The impairment of lung clearance andsubsequent response of the lung to retained foreign bodies is believed to explain the carcinogenicityof relatively nontoxic and insoluble particles including talc, carbon black, and titanium dioxide in therat (Nikula et al., 1997).The results of a recent study by Nikula (Nikula et al., 1997) support the doubts of the relevance ofinhalation studies in rats to humans. As reviewed by Nikula et al., the lung of the cynomolgus monkeyis anatomically much more like the human lung. Furthermore, particle clearance rates from the lungof the cynomolgus monkey are similar to humans and unlike the rat. Nikula et al. evaluated the effectof coal dust, diesel soot, and a mixture of coal dust and diesel soot on the lungs of Fisher 344 rats and