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This reevaluation of the current U.S. EPA cancer potency factor for toxaphene is based upon a review of toxaphene carcinogenesis bioassays in mice conducted by Litton Bionetics (unpublished report, 1978) and the National Cancer Institute (NCI) (Technical Report Series No. 37, conducted by Gulf South Research Institute, 1979). The mechanistic data available for toxaphene, including consideration of the potential of the compound to induce genotoxicity, was examined with an emphasis on whether this information supports a change in the cancer potency factor. If a quantitative dose-response assessment for toxaphene is to be performed, the data from both the NCI and Litton cancer bioassays should be used. Additionally, liver tumor results from female mice, rather than male mice, should be used for estimating potential human cancer risk because the background rate of liver tumors in females is lower and less variable than that exhibited by males. An ED(10) was estimated as the point of departure. The mechanistic data were not sufficient to fully support a margin of exposure approach. Therefore, we believe that applying a linear extrapolation from the ED(10) to the origin is an appropriate means to estimate risk at low doses. This is a highly conservative approach and, when it is applied, we conclude that the current EPA cancer potency factor should be reduced from 1.1 (mg/kg/day)(-1) to 0.1 (mg/kg/day)(-1).

Phosphine is a highly toxic gas used as a fumigant, a dopant in semiconductor manufacturing, and in the production of organophosphines. In a chronic toxicity and oncogenicity study of phosphine, 60 male and female F344 rats per group were exposed via whole-body inhalation for 6 h/day, 5 days/wk for up to 104 wk to mean concentrations of 0, 0.3, 1, or 3 ppm phosphine. Three parts per million was considered the maximum exposure level because of lethality seen at higher exposure levels in previous repeat dose studies. Ten rats per sex per group were sacrificed after 52 wk of exposure. Survivors were sacrificed after 104 wk of exposure. There were no phosphine-related effects seen on clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, or ophthalmology. There were no phosphine-related macroscopic findings or effect on absolute or relative organ weights. No histomorphologic alterations attributable to phosphine exposure were seen. In conclusion, under the conditions of this study, there were no treatment-related changes suggestive of a toxic or carcinogenic effect seen in rats following 52 wk or 2 yr of whole-body inhalation exposure to 0.3, 1, or 3 ppm phosphine.

The carcinogenicity of vinyl bromide was evaluated during an inhalation study in which Sprague-Dawley rats were exposed for 6 hr daily, 5 days per week for 2 years, in 6-m3 stainless steel and glass inhalation chambers. The four exposure levels to vinyl bromide in air were 9.7, 52, 247, and 1235 ppm. The controls were exposed to filtered and conditioned outside air. Moribund rats and rats in groups scheduled for termination from the control and exposed levels following 6, 12, 18, and 24 months of exposure were necropsied and examined for histopathologic changes. Body weights, mortality, hematology, urinalysis, clinical chemistry, terminal organ weights, histopathology, and analytical observations were conducted. A decline in body weights was evident among all exposure levels. Microcytic anemia, elevated serum bromide levels, decreased BUN, elevated alkaline phosphatase, elevated LDH, and hematuria were observed. Angiosarcomas, primarily of the liver, were induced in both male and female rats in all four exposure groups. An increase in the number of Zymbal's gland neoplasms was found in both male and female rats at 52-, 247-, and 1235-ppm exposure levels. An increased incidence of primary hepatocellular neoplasms was seen in males exposed to 247 ppm and in females exposed to 9.7, 52, and 247 ppm. The increase in primary hepatocellular neoplasms was detected primarily in animals that survived the 24-month exposure or died following 18 months of exposure. No exposure-related pathology was observed in the brains of the rats.

This study was initiated because of a suspected increase in incidence of lung cancer in antimony smelter workers in England. Three groups of 8-mo-old Wistar-derived rats (90 males and 90 females per group) were exposed by inhalation to either Sb2O3 [time-weighted average (TWA) 45 mg/m3], Sb ore concentrate (TWA 36 + 40 mg/m3), or filtered air (controls) for 7 h/d, 5 d/wk, for up to 52 wk and sacrificed 20 wk after terminating exposures. Serial sacrifices (5 rats/sex/group) were performed at 6, 9, and 12 mo. Autopsies and histopathological examinations were performed on all animals. The dusts and animal tissues were analyzed for Sb, arsenic, and other inorganic elements by atomic absorption and proton-induced X-ray emission methods. The most significant findings were the presence of lung neoplasms in 27% of females exposed to Sb2O3 and 25% of females exposed to Sb ore concentrate (p less than 0.01). None of the male rats in any group or the female controls developed lung neoplasms. There were no significant differences in incidences of cancer of other organs between exposed and control rats. These results were compared with other published results, including an animal inhalation study with Sb2O3 in which lung tumors were also induced. Higher concentrations of arsenic were found in tissues from female rats than from male rats. For example, arsenic levels in blood of control males, control females, Sb2O3 males, Sb2O3 females, Sb ore males, and Sb ore females were 60, 123, 115, 230, 71, and 165 micrograms arsenic/g dry blood, respectively, 9 mo after initiating exposures.

A brief literature review on manganese toxicity is presented; as related to designing a chronic inhalation study for evaluating methylcyclopentadienyl manganese tricarbonyl when utilized as a motor fuel additive. The experimental design of this study is described. The generation system utilized to simulate the manganese aerosol produced by an internal combustion engine is described in detail. This generation system operated twenty-four hours per day, seven days per week producing aerosols at 11.6, 112.5, and 1152 micrograms Mn/m3 with an aerodynamic diameter of approximately 0.11 micron.

Guinea pigs were exposed in inhalation chambers to 25 mg/m 3 sulfuric acid mist 6 h/d for 2 d, and the acute respiratory effects were correlated by light and electron microscopy. This concentration of acid was selected since lower concentrations result in only slight effects while higher concentrations result in death. By light microscopy, the most prominent pulmonary lesion at 48 h was segmental alveolar hemorrhage and edema accompanied by proliferation of alveolar macrophages and type 2 pneumocytes. The segmental distribution of the pulmonary lesion was reaffirmed by scanning electron microscopy, while transmission electron microscopy showed injury to the distal airways and changes in the vascular endothelium.

Cynomolgus monkeys exposed 6 hr daily, 5 days/week for 6 months to atmospheres containing synthetic detergent dust at 1, 10, or 100 mg/m 3 together with enzyme dust at 0.001, 0.01, 0.1, or 1 mg/m 3 , or to the detergent dust alone at 100 mg/m 3 , or to the enzyme dust alone at 1 mg/m 3 . The enzyme was a mixture of two enzymes manufactured for use in commercial detergents: Novo Alcalase and Milezyme 8X. The mass median (aerodynamic equivalent) diameter of the dust particles was ⋍3 μm. No evident adverse effects were produced by any of the mixtures of 1 mg/m 3 detergent dust with as much as 0.1 mg/m 3 enzyme dust. The detergent dust alone at 100 mg/m 3 produced gross signs of respiratory distress, pulmonary histopathological effects, and pulmonary function impairment. This impairment, measured by the nitrogen washout method, was indicative of constricted small airways. Exposure to 10 or 100 mg/m 3 detergent dust together with 0.01 or 1 mg/m 3 enzyme dust produced the same effects along with diminished weight gain or weight losses. The 100 mg/m 3 level of detergent dust, alone and with enzyme, caused some mortality. At least one animal in each group exposed to enzyme dust had precipitating antibodies to the enzyme. Evidence of respiratory toxicity diminished greatly in animals that were held for 4 to 6 weeks after their last exposure to the dust, but single 6-hr reexposures of some of these animals reinstated many of their overt symptoms. The dust exposures had no apparent effects on total respiratory system flow resistance, diffusion capacity, hematology, clinical chemistry, urinalysis, intradermal or skin-prick challenge test results, or chest radiographs.

Groups of cynomolgus monkeys and guinea pigs were exposed to mixtures of sulfur dioxide, fly ash, and sulfuric acid mist. The exposure concentrations varied between 0.1 and 5.0 ppm for sulfur dioxide, 0.1 and 1 mg/cu m for sulfuric acid mist, while a concentration of approximately 0.5 mg/cu m was used for fly ash. The duration of exposure was 52 weeks for guinea-pigs and 78 weeks for monkeys. Pulmonary function tests and serum biochemical and hematological analyses were conducted prior to and periodically during the exposure period. At the termination of exposure, the lungs were examined microscopically. Analysis of the data revealed that in groups exposed to the mixtures of pollutants, sulfuric acid mist was responsible for the effects observed. No synergistic action between the pollutants was detected.

Groups of cynomolgus monkeys were exposed io sulfuric acid mist at concentrations varying from 0.38 to 4.79 mg/cu m. Particle size varied from submicronic to 4μ, mass median diameter (MMD). Groups of guinea pigs were exposed at 0.10 or 0.08 mg/cu m with MMD of 2.8, and 0.8μ, respectively. Exposures were continuous for 78 weeks in monkeys and 52 weeks in guinea pigs. The results signified no deleterious effects due to sulfuric acid mist exposure of guinea pigs. In cynomolgus monkeys, concentrations of 2.43 and 4.79 mg/cu m with particles of 3.60μ and 0.73μ MMD, respectively, were sufficient to produce definite deleterious effects on pulmonary structures and deterioration in pulmonary function. At lower concentrations the effects on pulmonary structures or deterioration in pulmonary function were less pronounced or absent. Microscopic changes observed were principally characterized by focal epithelial hyperplasia and focal thickening of the bronchiolar walls.

Female Golden Syrian hamsters, F-344 rats, Swiss CD-1 mice, and B6C3F1 hybrid mice were exposed 6 hr/day, 5 days/week to carcinogenic levels of vinyl chloride (VC) for 6, 12, 18, or 24 months (rats and hamsters only). Other groups of rodents were held for 6 or 12 months and then exposed for 6 or 12 months. At the end of the study the incidence of VC-induced neoplasms was compared in each of the groups to assess the effects of duration of exposure and age at the start of exposure on carcinogenicity of VC. In rats, with early initial exposure, hemangiosarcomas, hepatocellular carcinomas, and mammary gland carcinomas occurred with increasing incidence with longer exposure duration. Rats held for 6 months before exposure developed VC-related neoplasms, while rats held 12 months before the start of exposure failed to show a significantly increased incidence of these neoplasms. In hamsters, hemangiosarcomas, mammary gland carcinomas, gastric adenocarcinomas, and skin carcinomas resulted from VC exposure. The highest incidence of malignant neoplasms occurred in hamsters exposed for the first 12 months, whereas exposure begun after 12 months of age did not cause neoplasms. In both strains of mice, VC exposure during the first 6 months of the experiment induced a high incidence of hemangiosarcomas and mammary gland carcinomas. Swiss mice also developed lung carcinomas after only 6 months of exposure. In all three rodent species an initial 12 month exposure to VC was adequate to detect its carcinogenic potential, but the shortened survival of VC exposed mice and hamsters precluded a meaningful comparison with longer periods of exposure. Exposures were most effective when started early in life.

Monkeys and rats were exposed to 11.6, 112.5, or 1152 microgram Mn/m3 as an Mn3O4 aerosol twenty-four hours per day for nine months. Various serum biochemical, and hematologic evaluations were conducted on both specie. Body weight gain was accelerated in rats exposed to 1152 microgram Mn/m3. Hemoglobin concentrations were slightly elevated for both sexes and both specie exposed to 1152 microgram Mn/m3; however, the effect may not be directly related to Mn. Some evidence of hypophosphatemia was observed. No exposure related effects were demonstrated by organ weight or histopathologic observations.

Cynomolgus monkeys were exposed to sulfur dioxide while a control group was exposed to filtered air. The exposure was for 24 hours a day, seven days a week, for 78 weeks. Frequent measurements were made to evaluate mechanical properties of the lung, distribution of pulmonary ventilation, diffusing capacity of the lung, and arterial blood oxygen tension. Hematological and clinical biochemical determinations were conducted. Microscopic evaluation of organs and tissues was conducted at termination of the exposure of the animals. No deleterious effect could be attributed to SO2 exposure at concentrations of 0.14 to 1.28 ppm. Following 30 weeks of exposure to 4.69 ppm, an overexposure occurred in this group. This was followed by deterioration in pulmonary function which persisted during the following 48 weeks of observation, and alterations in pulmonary tissues were observed upon microscopic examination.

This study gives the results of exposing cynomolgus monkeys—22 hr/day, 7 days/week, for two years—to 19.86 and 65.46 ppm of carbon monoxide (CO) on the average. Nine monkeys were exposed to each level of CO and nine were used as controls maintained under identical conditions with the exception of CO exposures. The only observed dose-related difference between the exposed and control animals was in the blood earhoxyhemoglobin values which were 1.0% to 1.5% higher in the animals exposed to 19.86 ppm CO and 6% to 8% higher in the animals exposed to 65.46 ppm CO. These elevated carboxyhemoglobin levels did not lead to compensatory increases in hematocrit, hemoglobin, or erythrocyte count determinations, nor to cardiac fibrosis or brain pathology. The conclusion is reached that these levels of carboxyhemoglobin for two years did not lead to any biologically significant changes In the cynomolgus monkey.