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  • Title: NTP Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6)(Non-Asbestiform) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
    Author: National Toxicology Program .
    Journal: Natl Toxicol Program Tech Rep Ser; 1993 Sep; 421():1-287. PubMed ID: 12616290.
    Abstract:
    Talc ore may contain several other minerals including calcite, dolomite, magnesite, tremolite, anthophyllite, antigorite, quartz, pyrophyllite, micas, or chlorites. Talc products are sold in a multitude of grades which have physical or functional characteristics especially suited for particular applications, so occupational and consumer exposures to talc are complex. Epidemiology studies have suggested an association between non-fibrous talc and lung cancer risk. Talc was nominated by the National Institute of Occupational Safety and Health (NIOSH) for study by the NTP because of widespread human exposure and because of the lack of adequate information on its chronic toxicity and potential carcinogenicity. Toxicology and carcinogenicity studies of talc (non-asbestiform, cosmetic grade), a finely powdered hydrous magnesium silicate, were conducted by exposing groups of F344/N rats to aerosols for 6 hours per day, 5 days per week for up to 113 weeks (males) or 122 weeks (females). Groups of B6C3F1 mice were exposed similarly for up to 104 weeks. LIFETIME STUDY IN RATS: Groups of 49 or 50 male and 50 female rats were exposed to aerosols of 0, 6, or 18 mg/m(3) talc until mortality in any exposure group reached 80% (113 weeks for males and 122 weeks for females). These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in F344/N rats; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provided a dose equivalent of 0, 2.8, or 8.4 mg/kg per day for male rats and 0, 3.2, or 9.6 mg/kg per day for female rats. In a special study, additional groups of 22 male and 22 female rats were similarly exposed and examined for interim pathology evaluations or pulmonary function tests after 6, 11, 18, and 24 months and lung biochemistry and cytology studies after 24 months. The talc aerosols had a median mass aerodynamic diameter of 2.7 mm in the 6 mg/m(3) chamber and a median diameter of 3.2 mm in the 18 mg/m(3) chamber, with geometric standard deviations of 1.9 mm. However, there was a 7-week period beginning at study week 11 during which the chamber concentration for the 18 mg/m(3) rats varied from approximately 30 to 40 mg/m(3) because of difficulties with the aerosol concentration monitoring system. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: The survival of male and female rats exposed to talc was similar to that of the controls. Mean body weights of rats exposed to 18 mg/m(3) were slightly lower than those of controls after week 65. No clinical findings were attributed to talc exposure. Pathology Findings: Absolute and relative lung weights of male rats exposed to 18 mg/m(3) were significantly greater than those of controls at the 6-, 11-, and 18-month interim evaluations and at the end of the lifetime study, while those of female rats exposed to 18 mg/m(3) were significantly greater at the 11-, 18-, and 24-month interim evaluations and at the end of the lifetime study. Inhalation exposure of rats to talc produced a spectrum of inflammatory, reparative, and proliferative processes in the lungs. Granulomatous inflammation occurred in nearly all exposed rats and the severity increased with exposure duration and concentration. Hyperplasia of the alveolar epithelium and interstitial fibrosis occurred in or near foci of inflammation in many exposed rats, while squamous metaplasia of the alveolar epithelium and squamous cysts were also occasionally seen. Accumulations of macrophages (histiocytes), most containing talc particles, were found in the peribronchial lymphoid tissue of the lung and in the bronchial and mediastinal Iymph nodes. In female rats, the incidences of alveolar/bronchiolar adenoma, carcinoma, and adenoma or carcinoma (combined) in the 18 mg/m(8 mg/m(3) group were significantly greater than those of controls. The incidences of pulmonary neoplasms in exposed male rats were similar to those in controls. Minor alterations attributed to talc exposure were also observed in the upper respiratory tract. Hyperplasia of the respiratory epithelium of the nasal mucosa in males and accumulation of cytoplasmic, eosinophilic droplets in the nasal mucosal epithelium in male and female rats occurred with a concentration-related increased incidence in the exposed groups. Adrenal medulla pheochromocytomas [benign, malignant, or complex (combined)] occurred with a significant positive trend in male and female rats, and the incidences in the 18 mg/m(3) groups were significantly greater than those of controls. Although adrenal medulla hyperplasia occurred with similar frequency among exposed and control females, the incidences of hyperplasia in exposed males were significantly lower than in controls. Lung Talc Burden: Lung talc burdens of male and female rats exposed to 6 mg/m(3) were similar and increased progressively from 6 to 24 months. Lung talc burdens of females exposed to 18 mg/m(3) also increased progressively from 6 to 24 months, while those of males exposed to 18 mg/m(3) remained about the same after 18 months. Lung burdens were generally proportional to exposure concentration at each interim evaluation. Pulmonary Function, Bronchoalveolar Lavage, and Lung Biochemistry: In exposed male and female rats there was a concentration-related impairment of respiratory function which increased in severity with increasing exposure duration. The impairment was characterized by reductions in lung volume (total lung capacity, vital capacity, and forced vital capacity), lung compliance, gas exchange efficiency (carbon monoxide diffusing capacity), and nonuniform intrapulmonary gas distribution. After 24 months, males exposed to 6 mg/m(3) talc had a significant increase in beta-glucuronidase and polymorphonuclear leukocytes; males exposed 18 mg/m(3) had significant increases in b -glucuronidase, lactate dehydrogenase, alkaline phosphatase, and total protein in bronchoalveolar lavage fluid. All exposed females had significantly increased a-glucuronidase, lactate dehydrogenase, alkaline phosphatase, total protein, and polymorphonuclear leukocytes; 18 mg/m(3) females also had significantly increased glutathione reductase. Viability and phagocytic activity of macrophages recovered from lavage fluid were not affected by talc exposure. Total lung collagen was significantly increased in rats at both exposure concentrations after 24 months, while collagenous peptides in lavage fluid and the percentages of newly synthesized protein from females, but not males, were also significantly increased at the 6 or 18 mg/m(3) levels. In addition, lung proteinase activity, primarily cathepsin D-like activity, was significantly greater in exposed males and females. Rats exposed to talc also had significant increases in collagenous peptides and acid proteinase in lung homogenates. 2-YEAR STUDY IN MICE: Groups of 47 to 49 male and 48 to 50 female mice were exposed to aerosols containing 0, 6, or 18 mg/m(3) talc for up to 104 weeks. These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in B6C3F1 mice; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provide a dose equivalent of 0, 2, or 6 mg/kg per day for male mice and 0, 1.3, or 3.9 mg/kg per day for female mice. In a special study, additional groups of 39 or 40 male and 39 or 40 female mice similarly exposed were examined for interim pathology evaluations, lung biochemistry, and cytology studies after 6, 12, and 18 months of exposure. The talc aerosols had a median mass aerodynamic diameter of 3.3 mm with a geometric standard deviation of 1.9 mm in the 6 mg/m(3) chamber, and a median diameter of 3.6 mm with a geometric standard deviation of 2.0 mm in the 18 mg/m(3) chamber. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: Survival and final mean body weights of male and female mice exposed to talc were similar to those of the controls. There were no clinical findings attributed to talc exposure. Pathology Findings: Inhalation exposure of mice to talc was associated with chronic active inflammation and the accumulation of macrophages in the lung. In contrast to rats, hyperplasia of the alveolar epithelium, squamous metaplasia, or interstitial fibrosis were not associated with the inflammatory response in mice, and the incidences of pulmonary neoplasms in exposed and control groups of mice were similar. Accumulations of macrophages (histiocytes) containing talc particles were also present in the bronchial Iymph node. In the upper respiratory tract, cytoplasmic alteration, consisting of the accumulation of cytoplasmic eosinophilic droplets in the nasal mucosal epithelium, occurred with a concentration-related increased incidence in exposed male and female mice. Lung Talc Burden: Lung talc burdens of mice exposed to 6 mg/m(3) were similar between males and females and increased progressively from 6 to 24 months, except for males at 18 months. The lung talc burdens of mice exposed to 18 mg/m(3) were also similar between the sexes at each interim evaluation. Although the talc burdens of males and females increased substantially from 6 to 24 months, the values at 12 and 18 months were similar. Generally, lung burdens of mice exposed to 18 mg/m(3) were disproportionately greater than those of mice exposed to 6 mg/m(3), suggesting that clearance of talc from the lung was impaired, or impaired to a greater extent, in mice exposed to 18 mg/m(3) than in mice exposed to 6 mg/m(3). Bronchoalveolar Lavage and Lung Biochemistry: Increases in total protein, beta-glucuronidase, lactate dehydrogenase, glutathione reductase, total nucleated cells, and polymorphonuclear leukocytes in bronchoalveolar lavage fluid were observed primarily in mice exposed to 18 mg/m(3), although some parameters were also increased in mice exposed to 6 mg/m(3). The amount of collagenous peptides in lavage fluid and total lung collagen were increased in male and female mice exposed to 18 mg/m(3). Acid proteinase activity, principally cathepsin D-like activity, of lung homogenate supernatant fluid was also significantly increased in mice at the 18 mg/m(3) exposure concentration. CONCLUSIONS: Under the conditions of these inhalation studies, there was some evidence of carcinogenic activity of talc in male F344/N rats based on an increased incidence of benign or malignant pheochromocytomas of the adrenal gland. There was clear evidence of carcinogenic activity of talc in female F344/N rats based on increased incidences of alveolar/bronchiolar adenomas and carcinomas of the lung and benign or malignant pheochromocytomas of the adrenal gland. There was no evidence of carcinogenic activity of talc in male or female B6C3F1 mice exposed to 6 or 18 mg/m(3). The principal toxic lesions associated with inhalation exposure to the same concentrations of talc in rats included chronic granulomatous inflammation, alveolar epithelial hyperplasia, squamous metaplasia and squamous cysts, and interstitial fibrosis of the lung. These lesions were accompanied by impaired pulmonary function characterized primarily by reduced lung volumes, reduced dynamic and/or quasistatic lung compliance, reduced gas exchange efficiency, and nonuniform intrapulmonary gas distribution. In mice, inhalation exposure to talc produced chronic inflammation of the lung with the accumulation of alveolar macrophages. Synonyms: talcum; agalite; emtal 596; non-asbestiform talc; non-fibrous talc; steatite; hydrous magnesium silicate
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