PRINCIPLES OF TOXICOLOGY - Biology East Borneo

494 EXAMPLE OF RISK ASSESSMENT APPLICATIONSthe 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 lungsrespond more like the monkey than the rat, the pulmonary response of the rat to particles may not bepredictive of the response in humans at particle concentrations representing high occupationalexposures.While “particle overload” alone does not necessarily account for the lung toxicity of antimonytrioxide in the Newton et al. study, it is possible that decreased clearance of particulates from the lungmay be the cause of lung tumors seen in the Groth et al. and Watt studies. Hext (1994) compared theresults of studies demonstrating particle-related pulmonary tumors by agents such as antimonytrioxide, diesel exhaust, coal, carbon black, titanium dioxide, and others. To compare particle exposurebetween the studies, Hext calculated cumulative particle exposure in mg/m 3 -hr. This comparison ispresented for selected agents below.Test MaterialDuration(months)Exposurerate(hrs/wk)Exposureperiod(hrs)Concentration(mg/m 3 )Cumulativeexposure(mg/m 3 -hr)Tumorincidence(percent)*Antimony trioxide 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 28 30 3660 6 21,960 028 30 3660 18 65,880 54*Female rats onlyAdapted from Hext, 1994At similar cumulative particle exposures, antimony trioxide caused fewer tumors than did carbonblack or talc, two substances generally regarded as relatively nontoxic. Although the differences incancer incidence between antimony trioxide-treated rats and carbon black and talc-treated rats maypartly result from differences in experimental design, the size of particles tested, and other factors, itnonetheless suggests that tumors observed by Groth et al. may result from reduced lung clearancecaused by “particle overload.”Of the available antimony trioxide inhalation studies, only the Newton et al. study used anexperimental design that permits a dose–response assessment of the effects of inhaled antimonytrioxide at concentrations above and below the concentrations that affect particle clearance from thelung. The technical deficiencies of the Watt and Groth et al. studies limit interpretation of the studyresults.Weight of Evidence Characterization of the Potential Carcinogenicity of Inhaled AntimonyTrioxide to HumansAccording to all weight-of-evidence schemes, the greatest emphasis is placed on the results ofwell-conducted human epidemiology studies. In the case of antimony trioxide, human evidence isinadequate to establish a link between antimony trioxide exposure and cancer.According to NRC and USEPA criteria, weight of evidence for the carcinogenicity of inhaledantimony trioxide in animals must also be regarded as equivocal. Although two studies in rats indicatethat 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 (Grothet al., 1986 and Newton et al., 1994). Neither female nor male rats developed lung tumors in the Newtonet al. study. Watt observed lung tumors in rats at only one of two antimony trioxide concentrationstested. Groth et al. tested only one concentration of antimony trioxide. Thus, there is little dose–re-