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Talc deposition and effects after 20 days of repeated inhalation exposure of rats and mice to talc.

The relationship between the inhalation exposure concentration of talc and the resulting lung burdens and histologic lesions was studied using groups of 20 F344/Crl rats and 20 B6C3F mice (10 male and 10 female) exposed to one of three concentrations of asbestos-free talc for 6 hr/day, 5 days/week for 4 weeks. Controls were exposed to filtered air using the same schedule. The pulmonary retention of talc and the development of pulmonary pathology were evaluated. The mass median aerodynamic diameter (MMAD) of the talc aerosol was 3.0 microns with a geometric standard deviation (sigma g) of 1.9. The mean exposure concentrations for rats were 0, 2.3, 4.3, and 17 mg talc/m3. Lung burdens in rats averaged 0, 0.07, 0.17, and 0.72 mg talc/g lung after the 20-day inhalation exposure; thus, the amount retained in the lung per unit of exposure concentration increased with increasing concentration. Mean exposure concentrations for the mice were 0, 2.2, 5.7, and 20.4 mg of talc/m3, which resulted in lung burdens of 0, 0.10, 0.29, and 1.0 mg talc/g lung; thus, the relationship between exposure concentration and the amount retained in the lung was approximately constant. Lung burdens from this study were used to project lung burdens that would result from longer exposures of rodents and man. No clinical signs were observed in the rats or mice prior to sacrifice 24 hr after the last exposure day. Histologic alterations in lung tissue consisted of only a modest, diffuse increase of talc-containing, free macrophages within alveolar spaces in both rat and mouse groups exposed to the highest level of talc for 20 days. A model simulating chronic talc inhalation exposure of rats and mice predicted lung burdens of 2-3 mg talc/g lung (wet wt) if animals were exposed to 17 mg talc/m3 for 2 years, and deposition and clearance of talc were unchanged by continued exposure. A potential limitation in this modeling is that if clearance of talc is delayed by continued exposure, the accumulated talc lung burdens would be higher than those projected by the simulation model. Humans exposed to aerosols of respirable talc are projected to accumulate much higher lung burdens than would occur in rodents exposed to the same aerosol, because humans have a higher estimated deposition fraction and slower estimated clearance of the deposited talc dust. Equilibrium lung burdens of greater than or equal to 2 mg talc/g lung were predicted for human exposures at or near the TLV for talc.

Aerosols

Method for determining the lung burden of talc in rats and mice after inhalation exposure to talc aerosols.

A method has been developed to quantitate talc lung burdens in rats and mice after inhalation exposure to talc aerosols. The method is based on acid-insoluble magnesium (Mg) determination by flame atomic absorption. Precipitating protein from homogenates of lungs of unexposed rodents with 5% perchloric acid and washing with 5% trichloroacetic acid removed the soluble and naturally occurring Mg. This resulted in residual Mg content averaging 0.43 micrograms Mg per g lung in rats and less than 0.1 microgram Mg per g lung in mice for young rodents less than 12 weeks old. Rodents 12-18 months old had residual mean (+/- SD) Mg contents of 3.4 +/- 2.0 micrograms Mg per g rat lung (n = 17) and 6.5 +/- 2.9 micrograms Mg per g mouse lung (n = 12). Thus, the background residual acid-insoluble Mg content in rodent lungs appears to increase with age. Negligible quantities of Mg were extracted directly from the talc treated by these procedures. Adding 50-2000 micrograms talc to lungs from unexposed rodents, followed by the sample treatment, gave mean (+/- SD) Mg recoveries of 89 +/- 12% (n = 19) for rat lungs and 96 +/- 26% (n = 15) for mouse lungs. The lung burden of talc in rodents exposed to talc aerosols for 6 h per day, 5 days per week for 4 weeks was determined. Mean lung burdens in rats were 77, 187, and 806 micrograms talc per g lung (n = 10) for exposures at 2.3, 4.3, and 17 mg talc m-3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols

The biology of talc.

Data are presented on the effects on health of talc dusts from exposure in industry and use of talc-containing health products. The mineralogy of talc and the composition of cosmetic and industrial grade talc dusts are described. Studies in animals are reviewed, and epidemiological data are considered in relation to exposures that occur during industrial and consumer uses of talc dusts. Hamsters exposed to 8 mg/m3 of respirable cosmetic grade talc dust for up to 150 minutes a day for 300 consecutive days showed no difference in incidence or nature of pathological lesions from those observed in a group of untreated animals. A retrospective study of the causes of death of 227 talc mine millers exposed to cosmetic grade talc at the threshold limit value for talc (20 million parts per cubic foot) for an average of 15-8 years showed that the causes of death were no different from those in a control cohort not exposed to talc dust. The available data indicate that talc dust exposure in the modern mining of cosmetic grade talc does not appear to be injurious to health. The significantly lower dust exposure in the normal use of cosmetic grade talc dusts in talc-containing health and cosmetic products confirms that their use is not a hazard to health.

Animals

The effects of talc pleurodesis on growing swine.

Talc pleurodesis is an effective means of preventing recurrent pneumothorax. We have successfully applied talc pleurodesis with thoracoscopy in children with cystic fibrosis presenting with pneumothorax. However, little is known about the effects of talc pleurodesis on lung compliance in growing children. Therefore, six young pigs (10 weeks old, weighing 15 +/- 1 kg) were prepared for study. In each pig, one hemithorax underwent thoracoscopy and talc pleurodesis (TALC). The other hemithorax underwent either thoracoscopy alone or no procedure (CONTROL). Dynamic and static respiratory mechanics were studied 5 and 10 weeks later. Air flow and airway pressure were measured to calculate dynamic transpulmonary and transrespiratory compliance, and static transpulmonary compliance. At 5 weeks, dynamic transpulmonary and transrespiratory compliance were less in the TALC lungs when compared with CONTROL lungs. At 10 weeks, the differences in dynamic transpulmonary and transrespiratory compliance between the TALC and CONTROL lungs had resolved. Static compliance was lower in the TALC lungs than in the CONTROL lungs at both 5 and 10 weeks, but this was significant only at 10 weeks. There was an improvement in static compliance in the TALC lungs between 5 and 10 weeks, but this only approached significance. At autopsy, there were marked adhesions and pleural thickening in the talc lungs. Histological examination demonstrated no differences in lung parenchyma between the TALC lungs and the CONTROL lungs. Talc pleurodesis causes a temporary impairment in dynamic transpulmonary and transrespiratory compliance that resolves with time and growth. Static compliance is more persistently compromised, but a trend toward improvement with time and growth exists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Mineralogical analysis of bronchoalveolar lavage in talc pneumoconiosis.

Bronchoalveolar lavage (BAL) fluid obtained from six talc workers with pneumoconiosis was studied by optical and electron microscopy for its mineral content. Two of these workers were mainly exposed to American and Australian talc, and the other four were exposed to French talc (Luzenac). In all lavage fluids, talc particles and talc bodies were abundant, sometimes many years after the end of exposure. A qualitative difference was the presence of tremolite asbestos fibres in the two patients exposed to American and Australian talc and its absence in the four French talc workers. The presence of tremolite in lavage is attributed to a geological association of this mineral with the inhaled talc. On the other hand, chlorite was abundant in BAL of the French talc workers. Hence, we suggest that bronchoalveolar lavage can confirm exposure to talc and provide information about the heterogeneity of inhaled dust.

Aged

Studies of respiratory morbidity in rubber workers. Part IV. Respiratory morbidity in talc workers.

Pulmonary function tests, chest x-rays, and respiratory questionnaires were administered to eighty talc workers and 189 non-exposed rubber workers from three rubber tire manufacturing plants. The talc workers, who were exposed to talc at levels below the current threshold limit value (TLV) of 20 mppcf for nonfibrous talc, had a statistically significantly greater prevalence of productive cough and of positive criteria for chronic obstructive lung disease (COLD) than did the control workers. The talc workers with more than 10 years of exposure had significantly decreased residual FEV 1.0. Multiple regression analysis of FEV 1.0 in the talc workers estimated that each year of exposure to talc dust reduced the FEV 1.0 by 26 ml. Talc workers had a clear increase in respiratory morbidity, despite the absence of chest roentgenographic changes. Based on this study, a safe exposure level for talc appears to be 25 mg/m3 as a time-weighted average.

Bronchitis

Talc: understanding its manifestations in the chest.

Four distinct forms of pulmonary disease caused by talc have been defined. The first form, talcosilicosis, is caused by talc mined with high-silica-content mineral. Findings in this form are identical with those of silicosis. Talcoasbestosis closely resembles asbestosis and is produced by crystalline talc, generally inhaled with asbestos fibers. Pathologic and radiographic abnormalities are virtually identical with those of asbestosis, including calcifications and malignant tumor formation. The third form, talcosis, caused by inhalation of pure talc, may include acute or chronic bronchitis as well as interstitial inflammation; radiographically, it appears as interstitial reticulations or small, irregular nodules, typical of small-airway obstruction. The fourth form, due to intravenous administration of talc, is usually associated with abuse of oral medications and production of vascular granulomas manifested by consolidations, large nodules, and masses. Radiographic abnormalities associated with talc can be predicted when there is sufficient history of the nature of exposure, including the region of origin of the talc in cases of inhalation. Radiographic changes, such as diaphragmatic plaques, often attributed to both talc and asbestos have not been documented to be caused by talc alone. The author provides review of 18 well-documented cases.

Adult

Acute zinc deficiency and trabecular bone loss in rats with talc granulomatosis.

Subcutaneous inflammation induced by magnesium silicate (talc) leads to the suppression of bone elongation, osteoblast insufficiency, and subsequent bone loss in rats. Since bone and immunological changes in talc granulomatosis are similar to those observed in zinc deficiency, we investigated the kinetics of zinc tissue distribution and the effects of zinc supplementation on the development of bone loss in rats with talc-induced inflammation. Decrease in serum zinc concentration was observed between 5 and 15 h in rats with talc granulomatosis. It was paralleled by the accumulation of zinc in the liver and rapid disappearance of osteoblasts from the trabecular bone surfaces. However, talc-injected rats supplemented parenterally and orally with zinc sulfate exhibited a decrease in osteoblast trabecular surface comparable to that of unsupplemented rats bearing granulomas despite normalized serum zinc concentrations. Zinc supplementation slightly increased osteoblast trabecular surface in all supplemented groups, but this effect was not significant. We conclude that zinc is the earliest indicator of the acute-phase response in rats with talc granulomatosis. Although zinc appears to be important for the normal function of bone cells, there is no causative relationship between acute zinc deficiency and decreased osteoblast number and activity in rats with talc granulomatosis.

Acute-Phase Reaction

Talc in liver tissue of intravenous drug abusers with chronic hepatitis. A comparative study.

To determine the frequency of talc microcrystals in liver tissue of intravenous (IV) drug abusers and the significance of this finding, the authors reviewed, with light and polarizing microscopy, sections of liver tissue from 70 patients with chronic hepatitis and a history of active (45) or past (25) IV drug abuse. Birefringent crystalline particles consistent with talc were found in 44 cases (63%), 31 associated with active and 13 with past drug abuse. The microcrystals were situated predominantly in hypertrophied portal macrophages; there were no well-formed granulomas. Scanning electron microscopic and energy-dispersive spectrophotometry performed on eight of the positive cases showed the characteristic "flake-pastry" appearance and chemical composition (silicon and magnesium) of talc. For comparison, the authors similarly examined 70 cases of posttransfusion chronic hepatitis, all of which had negative findings for talc, and 70 cases of chronic hepatitis with no documented risk factors for viral hepatitis, of which two had positive findings for talc, even though IV drug abuse was denied by the two patients. The authors conclude that talc is frequently present in the liver of IV drug abusers and whenever encountered it strongly suggests IV drug abuse. Only two patients (1.4%) with a negative history also had talc.

Adult

Talc granulomatosis in the rat: the relationship between osteoblast insufficiency and adjacent bone marrow hyperplasia.

Bone loss in talc granulomatosis is paralleled by hyperplasia of bone marrow in the rat. To test the hypothetical relation between those two phenomena, bone matrix osteoinduction was employed as a model in which bone formation and bone marrow appearance are separated in time. Implantation of demineralized bone matrix to normal rats was followed by three talc injections (one weekly), starting 1 week after matrix implantation. Implants of demineralized bone and [3H]thymidine-labeled tibial metaphyses from talc-injected and normal rats were analyzed histologically and evaluated for alkaline and tartrate-resistant acid phosphatase activity on days 7, 14, 21, and 30 after matrix implantation. Analysis of tibial autoradiographs showed a marked growth arrest and bone marrow hyperplasia in talc-injected rats 7 days after first talc injection. Alkaline phosphatase activity in homogenates of bone implants was low in talc-injected rats on day 14 after implantation. Moreover, histology of the bone implants showed numerical and functional inhibition of osteoblasts on the same day, causing marked growth delay. Bone marrow appeared as late as day 21 after bone matrix implantation. We conclude that hyperplasia of the adjacent bone marrow is not the cause of bone loss in talc granulomatosis, but rather its compensatory consequence.

Animals

Talc granulomatosis in the rat. Involvement of bone in the acute-phase response.

We investigated the dynamics of the acute-phase response (APR) and osteoblast trabecular surface in rats with subcutaneous inflammation provoked by magnesium silicate (talc). The first visible indicator of the APR was a rapid and profound hypozincemia, paralleled by a decrease in metaphyseal trabecular surfaces covered with osteoblasts in long bones. Both the intensity of serum APR and the decrease in osteoblast trabecular surface were directly proportional to the number of granulomas. Alterations in bone metabolism were specific for the inflammation, whereas mild hypozincemia and decrease in mononuclear and increase in polymorphonuclear peripheral white blood cell fractions developed in animals pair-fed with rats bearing two or four granulomas. Rats with talc granulomatosis had high serum ACTH and corticosterone levels, but neither adrenalectomy nor high doses of hydrocortisone could revert bone alterations in talc-injected animals. Glucocorticoids were necessary for the development of hypozincemia and hypercupremia seen in talc granulomatosis, as well as for normal bone metabolism. Inhibition of prostaglandin synthesis had no effect on bone alterations and serum APR in rats bearing talc-induced granulomas. We conclude that the decrease in bone formation constitutes an important aspect of the host acute-phase response in a rat model of talc granulomatosis.

Acute-Phase Reaction

Intravenous injection of talc-containing drugs intended for oral use. A cause of pulmonary granulomatosis and pulmonary hypertension.

Clinical and morphologic features are described in two patients known to have repeatedly injected intravenously talc-containing drugs intended for oral use. In one patient severe pulmonary hypertension developed; the talc granulomas in him were located predominantly within the pulmonary arteries. The second patient had normal pulmonary arterial pressures, and the talc granulomas in him were located predominantly in the pulmonary interstitium. Of 19 previously described patients with pulmonary talc granulomas, 12 had morphologic evidence of pulmonary hypertension (in three of severe degree); in each, talc granulomas were located predominantly within the pulmonary arteries. In those without signs of pulmonary hypertension, granulomas were located predominantly in the pulmonary interstitium. Why there are differences in the distribution of the talc granulomas is unclear. It is clear, however, as demonstrated by one of our patients, that severe pulmonary hypertension may be a consequence of intravenous injection of drugs intended for oral use.

Adolescent

On talc translocation from the vagina to the oviducts and beyond.

The objective of this study was to investigate whether multiple vaginal depositions of neutron-activated talc in the cynomolgus monkey result in the translocation of this material to the uterus and beyond. Within a 45-day period, six monkeys received 30 applications of 125 mg neutron-activated talc, suspended in 0.3 ml physiological saline solution containing 1% carboxymethyl cellulose as a suspending agent. The suspension was deposited in the posterior vaginal fornix of the sedated monkeys. Two days after the final talc application, the animals were anaesthetized. Abdominal lavage was performed and the lavage fluid collected for gamma-ray analysis. Also collected for gamma-ray analysis were the following tissues/organs: ovaries, oviducts, uterus, and vagina with cervix. Six untreated control monkeys underwent the same procedures. The radioisotopes 46Sc, 60Co, 59Fe and 51Cr in the activated talc served as tracers. Only the samples containing vagina and cervix from the dosed monkeys contained varying quantities of talc. This demonstrates that no measurable quantities of talc, deposited by multiple applications in the vaginal fornix of the cynomolgus monkey, translocated to the uterus or beyond.

Animals

Mortality from lung cancer and respiratory disease among pottery workers exposed to silica and talc.

A cohort mortality study of white men employed for at least one year between 1939 and 1966 at three plants of a single United States company was conducted to evaluate the risk of lung cancer and nonmalignant respiratory disease among workers exposed to silica dust and nonfibrous (nonasbestiform) talc in the manufacture of ceramic plumbing fixtures. Follow-up of 2,055 men through January 1, 1981, indicated a substantial excess of nonmalignant respiratory disease among those with high levels of exposure to silica dust (standardized mortality ratio = 2.26). The risk of nonmalignant respiratory disease rose with the number of years exposed, was not further enhanced by talc exposure, and appeared to be appreciably lower among those exposed in more recent time periods. For lung cancer, men exposed to high levels of silica dust with no talc exposure had a nonsignificant standardized mortality ratio of 1.37. However, those exposed to nonfibrous talc in addition to high levels of silica had a significant 2.5-fold excess risk of lung cancer. Among this group, the lung cancer standardized mortality ratio rose with increasing years of talc exposure to 3.64 among those exposed for 15 or more years. Although the role of silica as a cofactor cannot be ruled out, these data suggest that nonfibrous talc exposure is associated with excess lung cancer risk.

Drug Synergism

An epidemiologic study of a group of talc workers.

Chest roentgenograms, pulmonary function assessment by spirometry, respiratory symptoms, smoking history, and occupational history by questionnaire were obtained from 121 male talc miners and millers exposed to talc containing tremolite and anthophyllite asbestiform fibers. Ninety-three of the employees had worked in talc only at the plant under study. Symptoms were only slightly more prevalent in talc workers when compared to potash miners. Mean pulmonary function (forced expiratory volume in one sec, forced vital capacity, and maximal expiratory flow at 50 and 75 per cent of vital capacity) of talc workers was significantly decreased in comparison to that of potash miners. The prevalence of pleural calcification and pneumoconiosis in talc workers with 15 or more years of employment was higher than in potash miners. The prevalence of pleural thickening was 31 per cent in those who worked more than 15 years and was significantly increased as compared to that in potash miners. Workers with pleural thickening had decreased pulmonary function in comparison to those who did not. Decreased one-sec forced expiratory volume and forced vital capacity were associated with exposure to respirable particulate and asbestiform fibers.

Adult

Identification and quantitation of asbestos in talc.

The currently used analytical methods for identification, characterization and quantitation of asbestos fiber in consumer talcum products include polarized light microscopy, x-ray diffraction analysis, transmission electron microscopy with selected area electron diffraction and electron microprobe techniques. Light microscope methods have severe limitations imposed by the ultimate size resolution of the light-optical system. Small particles go unresolved; those marginally resolved may possess optical properties different from those properties cited in the literature; most optical properties, e.g., indices of refraction, are difficult to measure on small particles. In addition to these difficulties, talc fibers often possess optical properties different from those of talc plates, which further confound analysis. Light microscopy is recommended for use only as a preliminary tool on limited, large-sized, samples. Transmission electron microscopy is a good standard technique for visualization of contaminant asbestos fibers. Together with selected area electron diffraction, talc fibers may be easily differentiated from amphibole asbestos fibers on the basis of both morphological and structural characterization. Chrysotile fibers are easily distinguished on this basis as well. The amphibole asbestos minerals require chemical characterization to differentiate among the different fiber types. Probe analysis is mandatory for such fibers. The major drawbacks to electron beam instrumentation for the mineralogical characterization of talcum products are the time and effort required for data acquisition. These techniques do not lend themselves to routine study.X-ray diffraction analysis, utilizing the step-scan method, offers a relatively rapid, quantitative technique for gross fiber analysis. Based on comparison with standard specimens the fiber content of talcs may be quantitatively determined. It is essential to employ a specimen preparation technique which yields homogeneously dispersed particles. Tremolite may be determined at levels as low as 0.10% by weight, chrysotile 0.25%, and anthophyllite at 2.0% by weight occurrence in talc. The variance of these values depends upon many factors, including the mass absorption coefficient of the fiber types as compared to talc and selected diagnostic reflections and their relative intensities. Each of the above techniques is described in detail. A method for routine analysis of consumer talcum products is suggested.

Asbestos