PRINCIPLES OF TOXICOLOGY - Biology East Borneo

492 EXAMPLE OF RISK ASSESSMENT APPLICATIONSTABLE 19.8 Summary of Rodent Inhalation Studies of Antimony TrioxideSpecies Exposure Animals with Lung Tumors ReferenceRat (female;Fischer)Rat (male andfemale; Wistar)Rat (male andfemale; Fischer344)0, 1.6, 4.2 mg/m 3 6 h/day, 5days/week for 13 months; 1year postexposure observation45 mg/m 3 7 h/day, 5 days/weekfor 52 weeks; 20 weekspostexposure observation0, 0.06, 0.51, and 4.50 mg/m 3 6h/day, 5 days/week for 52weeks; 12-monthpostexposure observation0 mg/m 3 —0/131.6 mg/m 3 —1/174.2 mg/m 3 —14/18Male rats—no lung tumors;Female rats—19/70Male rats—no lung tumors;Female rats—no lung tumorsWatt (1983)Groth et al. (1986)Newton et al. (1994)The Watt study is limited by the use of only one sex for carcinogenicity testing. In addition, theprecision of dose measurements in this study has been questioned, suggesting that antimony trioxideexposures may have actually been higher than reported (Newton et al., 1994).Groth et al. (1986) treated male and female Wistar rats with 0 or 45 mg/m 3 (time-weighted average)antimony trioxide for 7 h/day, 5 days/week for 52 weeks followed by a 18–20 observation period beforeterminal sacrifice (71–73 weeks after initiation of the study). Groth et al. (1986) also reportedsignificant fluctuations in the antimony exposure concentrations generated in the exposure chambers.During the latter 6 months of exposure, air concentrations occasionally exceeded the calculatedtime-weighted average concentration by 50–100 percent. Lung changes in treated rats includedinterstitial fibrosis, alveolar-wall hypertrophy and hyperplasia, and cuboidal and columnar cellmetaplasia. These changes were more severe with increasing duration of exposure. The extent ofinterstitial fibrosis continued to progress even after exposure ceased. Overall, 27% of treated females(19/70) were observed with lung tumors. It is unusual that no tumors were observed in treated males.Interpretation of the results of the Groth et al. study is limited by the use of only one very high doselevel, so no dose-response information can be derived from the study. Chronic tissue injury appearslikely as the mechanism for the eventual neoplasms, yet no insight can be gained from this studyregarding possible no-effect levels. Also, there is considerable uncertainty in the actual exposure levelsexperienced by the test animals. Taken together, there are significant limitations in relying on this studyto extrapolate any potential human carcinogenic potential of antimony.Newton et al. reported the effects of subchronic and chronic inhalation toxicity of antimony trioxidein Fischer 344 rats. Male and female rats were exposed to air concentrations of 0, 0.06, 0.51 or 4.5TABLE 19.9 Toxicity of Antimony Trioxide versus Carcinogenicity Potentials for Carbon Black andTalcum PowderTest MaterialDuration(months)ExposureRate(h/week)ExposurePeriod (h)Concentration(mg/m 3 )CumulativeExposure[(mg/m 3 ) (h)]TumorIncidence(percent)Antimony trioxide a 12 35 1820 38 69,160 27Carbon black 20 85 7395 6.0 44,370 2524 80 8400 2.5 21,000 1124 80 8400 6.5 54,600 67Talc a 28 30 3660 6 21,960 028 30 3660 18 65,880 54Source: Adapted from Hext (1994).a Female rats only.