Barbara Cohrssen Ms Cih Charles H Powell ScD CIH

1.4 Toxic Effects

1.4.1 Experimental Studies

Inhalation Studies

Inhalation studies have had technical problems due to the lack of methods to determine accurately the amount of talc inhaled by exposed animals.

1.4.1.1 Acute Toxicity Rats exposed to a "very dense" cloud of talc, whose particle size was less than 5 mm, for 3 hours per day up to 12 days may have died because of suffocation (10).

1.4.1.2 Chronic and Subchronic Toxicity None of a group of rats exposed to 30-383 mg/m of "technical/pharmaceutical grade" talc for 6 hours per day, six days a week for up to nine months died as a specific consequence of exposure. However, they developed chronic inflammatory changes, including thickening of the pulmonary artery walls and eventually emphysema (11).

Hamsters exposed by inhalation to 8 mg/m respirable "baby talc" for up to 150 minutes per day, five days a week for 300 days showed no negative effects (12, 13). According to a study conducted by Hildick Smith, hamsters exposed to respirable cosmetic grade talc dust showed no difference in incidence, nature, or pathological lesions from those observed in a group of untreated animals (14).

Heavy dosing of rats by inhalation of talc caused severe dyspnea. However, no histological change was observed within 20 days, and talc particles were trapped by alveolar macrophages (10).

Minimal fibrosis was observed in rats exposed by inhalation to 10.8 mg/m of Italian talc (grade 00000, ready milled, mean particle size 25 mm) for three months; this did not change during the postexposure period. The rats exposed for one year had minimal to slight fibrosis, whose degree had increased to moderate within one year after exposure ceased (15).

However, Syrian golden hamsters exposed to 8 mg/m of talc aerosols for up to 150 minutes per day, five days per week for 30 days showed no histopathological change in the lungs, heart, liver, renal tissues, stomach, or uterus (12, 13, 16).

The National Toxicology Program (NTP) (17) conducted a lifetime study of talc in rats. This study

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consisted of groups of 49 or 50 male and 50 female rats exposed to aerosols of 0, 6, or 18 mg/m of talc until mortality in any exposure group reached 80%. This occurred at 113 weeks for males and 122 weeks for females. These exposures were based on 4-week inhalation studies of terminal lung talc burden in F344/M rats; concentrations greater than 18 mg/m 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. 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 were slightly lower than those of controls after week 65. No clinical findings were attributed to talc exposure.

In another study, conducted by the NTP (17), groups of 22 male and 22 female rats were similarly exposed and examined for interim pathology or pulmonary function after 6, 11, 18, and 24 months and for lung biochemistry and cytology after 24 months. Absolute and relative lung weights of male rats exposed to 18 mg/m were significantly greater than those of controls at the 6, 11, and 18 month interim evaluations and at the end of the lifetime study, whereas those of female rats exposed to 18 mg/m were significantly greater at the 11, 18, and 24 month interim evaluations and at the end of the lifetime study. Lung talc burdens of male and female rats exposed to 6 mg/m were similar and

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increased progressively from 6 to 24 months. Lung talc burdens of females exposed to 18 mg/m also increased progressively from 6 to 24 months, whereas those of males exposed to 18 mg/m remained about the same after 18 months. Lung burdens were generally proportional to exposure concentrations at each interim evaluation. It was also noted that a concentration-related impairment of respiratory function increased in severity with increasing exposure duration. The impairment was characterized by reductions in lung volume, lung compliance, gas exchange efficiency and nonuniform intrapulmonary gas distribution.

The NTP (17) also conducted a 2-year study of exposure to talc by mice. Groups of 47 to 49 male and 48 to 50 female mice were exposed to an aerosol containing 0, 6, or 18 mg/m 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 were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provided a dose equivalent of 0, 2, or 6 mg/kg per day for male mice and 0, 1.3, or 3.9 mg/kg for female mice. 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.

In a special study by the NTP, additional groups of 39 or 40 male and 39 or 40 female mice similarly exposed, were examined for interim pathology, lung biochemistry, and cytology after 6, 12, and 18 months of exposure. Lung talc burdens of mice exposed to 6 mg/m 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 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 were disproportionately greater than those of mice exposed to 6 mg/m , suggesting that clearance of talc from the lung was impaired or impaired to a greater extent in mice exposed to

33 18 mg/m than in mice exposed to 6 mg/m (17). Oberdorster comments on the study that analysis of the particle accumulation kinetics in lungs of the rats shows that lung overload had been reached at both the 6 and 18 mg/m concentrations, resulting in increased talc accumulation of high lung burdens (18).

In a previous study, a group of 24 male and 24 female Wistar-derived rats, six to eight weeks of age, was exposed by inhalation to a mean respirable dust concentration of 10.8 mg/m Italian talc (grade 00000; ready milled; mean particle size 25 mm; containing 92% talc, 3% chlorite, 1% carbonate minerals, and 0.5 to 1% quartz) for 7.5 hours per day, five days a week for six or twelve months. Ten days after the end of each exposure period, six rats in each group were killed; another four rats were killed in each group one year later. Within 28 months of the start of the study, another 12 animals in each group had died. No lung tumors were observed in rats exposed to talc for six months, whereas one lung adenoma occurred among those exposed for 12 months. No lung tumors were found in 24 male or 24 female controls (15).

Three groups of 50 male and 50 female Syrian golden hamsters, four weeks old, were exposed to an aerosol of talc baby powder, prepared from Vermont talc by flotation, for 3, 30, or 150 minutes per day, five days a week for 30 days. The mean total aerosol concentration was 37.1 mg/m with a

mean respirable fraction of 9.8 mg/m . Two other groups of hamsters, seven weeks old, were exposed to a talc aerosol concentration of 27.4 mg/m with a mean respirable fraction of 8.1 mg/m . Two control groups of 25 males and 25 females were sham exposed. No primary neoplasms were found in the respiratory system of any hamster. The incidence of alveolar cell hyperplasis was 25% in the groups exposed to aerosols for 30 or 150 minutes per day for 300 days compared with 10% in the control group (13, 14).

Guinea pigs exposed for eight weeks to continuously circulating talcum dust were sacrificed at intervals after dust exposure, and sections of the lungs were examined histologically. Chronic inflammatory changes were noted in one animal sacrificed immediately after four weeks of exposure. There was no nodule formation and no increase in connective tissue, although masses of dust particles had accumulated in the lungs. In another animal exposed to talc for four weeks and not sacrificed for six months, fewer inflammatory changes were found, and there was much less dust present (19).

Pickrell et al. studied the lung deposition and effects of inhalation exposure in F344/Crl rats and B6C3Fj mice. The rats were exposed to aerosols containing 2.3, 4.3, or 17 mg/m talc for 6 hours a day, 5 days a week for 4 weeks. The mice were similarly exposed to 2.2, 5.7, or 20.4 mg/m talc. The animals were killed 24 hours after the last exposure. Talc accumulated in the lungs in a dose-dependent manner. The average talc lung burdens in rats ranged from 0 to 0.72 mg per gram of lung tissue and in mice from 0 to 1.0 mg per gram. No exposure-related lung lesions were seen other than slight diffuse increases in the number of free macrophages containing talc particles within the alveolar spaces of rats and mice exposed to the highest doses (20).

Ingestion

Groups of 25 male and 25 female Wistar rats, ten weeks old, received about 50 mg/kg body weight per day of commercial talc (characteristics unspecified) in their diets for life (average survival 649 days). No significant difference in tumor incidence was found compared with controls (21).

A group of 16 male and 16 female Wistar-derived rats, 21-26 weeks of age, was exposed to 100 mg of Italian talc (grade 00000, ready milled; mean particle size 25 mm; containing 92% talc, 3% chlorite, 1% carbonate minerals, and 0.5 to 1% quartz) per day per rat in the diet for five months and then maintained on a basal diet for life (average survival 614 days). A control group of 16 rats was fed a basal diet. No difference in tumor incidence was found between the two groups (15).

Rats fed 100 mg of talc for 101 days showed no significant depression of mean life span (15).

Phillips et al. studied the effects of tritium-labeled talc fed to male albino Wistar rats, female LACA mice, female guinea pigs and intravaginally instilled in large white female rabbits. In rats, 75% of the single dose was excreted in feces in 24 hours; after 96 hours, 95.8% of the dose had been eliminated. Kidneys of rats that received multiple doses had less than 0.02% radioactivity. In the guinea pigs, nearly all of the radioactive dose was excreted in 96 hours, and less than 0.2% was in the urine. For the mice, all of the radioactivity was found in the GI tract and feces, and none in other tissues. In rabbits, after 72 hours, radioactivity was found only at the site of a single installation and at the site of administration (22).

Intravenous

Guinea pigs that received two or three 25-mg intravenous injections of talc in saline showed significant mortality (23). Guinea pigs that received single 200-mg intraperitoneal injections of one of several industrial grade talcs (up to 52% talc, up to 82% tremolite, and traces of quartz) developed nodules consisting of macrophages and giant cells after 10 days on the ventral parietal surface which became smaller after a 15-month period. Fibroblastic proliferation was pronounced in the early phases (24).

In contrast, there were no treatment-related deaths of rabbits injected daily for two weeks with 100 mg of talc in saline (25), of rabbits that received 50-mg injections of talc two times a week for ten weeks, or of rats that received injections of talc over a nine week period, total dose 100 mg. (26). In another study, rabbits were observed to have transient convulsions after cisternal injection of 1 mL of a 1:9 or 1:4 suspension of talc in saline (27).

Rats that received a single 50-mg/mL intratracheal injection of talc in water suffered a 79% mortality rate. Subsequently, it was found the rats could tolerate the dose if they were given two 25-mg/0.5 mL

injections at weekly intervals (28). Rats injected intratracheally with 25 mg tremolitic talc/mL of water had a 40% mortality rate. In another study of rats, granulomas at the injection site were common, and one small pulmonary adenoma was observed two years after the injection of 20 mg of Italian talc into the right pleural cavity, but no other relevant pathology was observed in the lungs (15). Albino rats that received an intraperitoneal injection of approximately 400 mg of talcum powder of the type used on surgical gloves exhibited typical granulomas and numerous foreign body giant cells when laparotomized six months later (29). No acute toxicity was observed after a single 10-mg injection into the bursa of rats (30). Three of 11 rats died within one day following injection of 1400 mg/kg body weight of talc into the lower pole of the spleen (31). Hamilton et al. studied the effects of talc on the ovaries of Sprague-Dawley rats. Animals were sacrificed at 1, 3, 6, 12, and 18 months. They concluded that changes in the ovarian surface may be related to the direct effects of talc or may be due to the buildup of high concentrations of steroid hormones in the distended bursa (30).

Two out of 14 chinchillas given five 40-mg intratracheal injections of talc in saline died (32). Chinchillas that received a single or several 40-mg intratracheal injections of "purified" talc in saline exhibited chronic pulmonary irritation, proliferative pneumonia, giant cell granulomas, and adjacent metaplasia of the alveolar epithelium. The hyperplastic cells subsequently transformed into cuboid cells that formed a continuous lining of the affected alveoli and finally acquired an adenomatous appearance (32).

Mice injected with 10 mg of talc (containing asbestos fibers) into the pleural cavity produced granulomas, some of which were firmly attached to the surface of the lungs or other chest contents and occasionally to the lung lobes (33). No acute toxicity was observed after a suprascapular subcutaneous 600-mg injection into mice (34).

1.4.1.3 Pharmacokinetics, Metabolism, and Mechanisms Seven different types of talc were administered in vitro to mouse peritoneal macrophages. All of the talcs caused cytoxcity as determined by the release of lactate dehydrogenase and beta-glucuronidase. All of the talcs were of high purity, except for one talc that contained high amounts of chlorite (35).

Mice that received a sterile subcutaneous injection of talc were studied by measuring the incorporation of radioactive leucine and glucosamine into liver and plasma proteins and the talc granuloma at various intervals between 2 and 528 hours after injection. Incorporation into plasma proteins indicated a biphasic response with a marked increased incorporation into the perchloric acid insoluble fraction at 21 hours, a return to normal values at 45 hours, and a similar marked increase into the perchloric acid soluble fraction at 45 hours with a gradual return toward normal values. The response was dependent upon the amount of talc injected (36).

Using radioactive tracer techniques in rats, mice, guinea pigs, and hamsters, no intestinal absorption or translocation of ingested talc to the liver and kidneys was detected (37).

In hamsters, the deposition, translocation, and clearance of talc was followed by giving them a single nose-only inhalation exposure to 40-75 mg/m neutron-activated talc for 2 hours. High cosmetic talc was used, consisting of 95% platy talc. Alveolar deposition was approximately 6 to 8% of the inhaled amount. The biological half-life of talc deposited in the alveoli was 7 to 10 days, and the alveolar clearance was basically complete four months after exposure. No translocation of talc to liver, kidneys, ovaries, or other parts of the body was found (12, 38).

Rats that were exposed to aerosols of Italian talc retained 2.5, 4.7, and 12.2 mg per rat following exposures for 3, 6, and 12 months, respectively. These levels were roughly proportional to the

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cumulative exposures (15). In rats exposed for 2.3, 4.3, and 17 mg/m of respirable talc for 6 hours per day, five days a week for 4 weeks, the amounts retained in the lung at the end of exposure were 77,187, and 806 micrograms talc per gram of lung (39).

In the NTP two-year study conducted of exposure of rats to talc which was discussed earlier, male rats exposed to 6 mg/m talc had a significant increase in beta-glucuronidase and polymorphonuclear leukocytes after 24 months. Males exposed to 18 mg/m had significant increases in beta-glucuronidase, lactate dehydrogenase, alkaline phosphatase, and total protein in bronchoalveolar lavage fluid. All exposed females had significantly increased alpha-glucuronidase, lactate dehydrogenase, alkaline phosphatase, total protein, and polymorphonuclear leukocytes; females exposed to 18 mg/m also had significantly increased glutathione reductase. Viability and phagocytic activity of macrophages recovered from lavage fluid were not affected by talc exposure. The total lung collagen was significantly increased in rats at both exposure concentrations after 24 months whereas 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 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.

In the NTP study conducted of exposure of mice to talc which was discussed above, 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

33 exposed to 18 mg/m , although some parameters were also increased in mice exposed to 6 mg/m .

The amount of collagenous peptides in lavage fluid and total lung collagen were increased in male and female mice exposed to 18 mg/m . Acid proteinase activity, principally cathepsin D-like activity of lung homogenate supernatant fluid was also significantly increased in mice at the 18 mg/m exposure.

Guinea pigs given a single 200-mg intraperitoneal injection of one of seven commercial talc samples were examined at intervals up to 15 months. Talc particles were found mainly on the ventral parietal surface of the peritoneum within macrophages and giant cells (24).

1.4.1.4 Reproductive and Developmental Talc produced nonspecific abnormalities in chicken eggs at an incidence similar to that induced by thalidomide and sulphadimethoxine (40).

No teratolological effects were observed in hamsters, rats, mice, or rabbits after oral administration of the following doses of talc: 1600 mg/kg body weight to rats on days 6-15 of gestation, 1600 mg/kg body weight to mice on days 6-15 of gestation, 1200 mg/kg body weight to hamsters on days 6-10 of gestation, and 900-mg/kg body weight to rabbits on days 6-18 of gestation (41).

Talc was not mutagenic to Salmonella typhimurium TA 1530, his G46, or Saccharomyces cerevisiae D3 in vitro or in host-mediated assays in mice given 30 to 5000 mg/kg body weight (42).

In human W138 cells treated with talc at 2 to 200 mg/mL, chromosomal aberrations were not induced nor were dominant lethal mutations induced in rats following oral administration of 305000 mg/kg body weight of talc (42).

Single 20-mg intraperitoneal injections of talc plus 2 mg of particulate prednisolone acetate in saline into mice induced significant numbers of multinucleated giant cells within 48 hours. Neither compound alone induced this response. The multinucleated cells arose by cell fusion, and the resultant polykarions exhibited severe chromosomal abnormalities. Prednisone in combination with talc also elicited the formation of multinucleated giant cells. Polykarions were not observed when talc was injected in combination with cortexone acetate, cortisone, or testosterone isobutyrate (43).

1.4.1.5 Carcinogenesis Hamsters given 10- or 25-mg intrapleural injections of tremolitic talc and maintained for 600 days were studied for tumorigenic effects. No tumors were seen in animals treated with talc (44).

The NTP conducted a 2-year inhalation study with talc in rats and mice. In this study, male and female F344/N rats were exposed to aerosols of 0, 6, or 18 mg of nonfibrous talc/m , free of SiO2

and asbestiform minerals, for 6 hours per day, 5 days per week for up to 113 weeks (males) and 122 weeks (females). Groups of B6C3Fj mice were exposed similarly for up to 104 weeks. These exposures resulted in concentration-related chronic inflammation, cell proliferation, and fibrosis in the lungs of both male and female rats, and 13 out of 50 of the female rats of the high-exposure group developed lung tumors. The mice showed only limited chronic inflammation and no increased cell proliferative, fibrotic, or tumorigenic responses in their lungs (17).

A four-week talc inhalation study on rats was also conducted by the NTP. This study determined that exposure concentrations in excess of 18 mg/m overwhelmed the lung clearance mechanisms and impaired the lung function of the animals (18). 1.4.2 Human Experience Pathology

In persons exposed to talc by inhalation, gross examination of the lungs may reveal diffuse pleural thickening and fibrous adhesions of pleural surfaces. In some cases, localized pleural plaques, located on the costal parietal pleura and diaphragmatic surfaces may calcify. According to J.F. Gamble and M. Kleinfeld (7, 45), pulmonary parenchymal lesions may be classified in three general groups:

1. Diffuse interstitial fibrosis with collagen deposition in the alveolar walls and dust laden macrophages both in the alveolar septa and free in the alveolar spaces. Bronchi and bronchioles may be distended and distorted, and normal lung architecture may be obliterated with dilated spaces lined with cuboidal metaplastic cells replacing the alveoli.

2. Lesions of widespread, poorly defined nodules which consist of stellate collections of macrophages and fibroblasts. There may be some fine reticulin, but little collagen is found in these lesions.

3. Foreign body granulomata consisting of epitheloid cells and foreign body giant cells. Granulomata may be found in association with nodular fibrosis or isolated in the alveolar interstitium with normal thin alveolar septa intravening.

Health effects found in workers who have inhaled talc vary, depending upon the composition of the dust inhaled. A significant increase in mortality was found for nonmalignant respiratory disease, especially pneumoconiosis and obstructive lung disease. When silica is significant, the lesions resemble those in silicosis. When fibrous materials such as tremolite are present, diffuse interstitial fibrosis resembling that of asbestosis may be found.

1.4.2.3 Epidemiology Studies Merewether was one of the first to observe that rubber tire workers exposed to French chalk showed "diffuse interstitial fibrosis" by chest X-ray and nothing more than "peribronchial increase in the fibrous tissue" after 30 years. Exposure ranged from 10 to 32 years (7).

In 1949, Hogue and Mallett reported on 20 rubber workers exposed to talc for 10 to 36 years. Exposure concentrations averaged 20 mppcf for six tube machine operators, 15 mppcf for three tube bookers, 15 mppcf for 10 tube curemen, and 50 mppcf for a liner reroller. None of them had dyspnea, cough, shortness of breath, cyanosis, or clubbing of the fingers. Chest X-rays were all normal, and their vital capacity range was 71 to 122% with a median of 105% (46).

A number of studies looked at the health effects of mining and milling of talc on workers. The most significant exposures occurred in milling talc. Table 13.1 (47-78) summarizes a number of these studies and includes several studies of rubber workers.

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