Analytic comparison of talc in commercially available baby powder and in pelvic tissues resected from ovarian carcinoma patients.

OBJECTIVE: Measure the size and shape of talc particles in talcum powder and compare this data to the size and shape of talc particles found in surgically resected tissues from patients with ovarian carcinoma. METHODS: Using polarized light microscopy (PLM) and scanning electron microscopy (SEM), we measured the size and shape of talc particles in samples of talc-containing baby powder (TCBP) and surgically resected pelvic tissues (hysterectomies) from talc-exposed patients with ovarian carcinoma. RESULTS: The most frequent class of particles in TCBP can be unequivocally identified as talc, using both polarized light microscopy and scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDX). The talc particles found in resected tissues from ovarian carcinoma patients are similar in size and shape to the most abundant morphological class of particles in TCBP. CONCLUSIONS: This finding, combined with previous epidemiological literature and tissue-based analytical studies, provides further evidence that the small, isodiametric particles that dominate TCBP can migrate from the perineum and become lodged in distal structures in the female reproductive tract, where they may lead to an increased risk of developing ovarian carcinoma.

Analysis of particles from hamster lungs following pulmonary talc exposures: implications for pathogenicity.

BACKGROUND: Talc, a hydrous magnesium silicate, often used for genital hygiene purposes, is associated with ovarian carcinoma in case-control studies. Its potential to cause inflammation, injury, and functional changes in cells has been described. A complication of such studies is that talc preparations may be contaminated with other materials. A previous study by (Beck et al. Toxicol Appl Pharmacol 87:222-34, 1987) used a hamster model to study talc and granite dust exposure effects on various biochemical and cellular inflammatory markers. Our current study accessed key materials used in that 1987 study; we re-analyzed the original talc dust with contemporary scanning electron microscopy and energy dispersive x-ray analysis (SEM/EDX) for contaminants. We also examined the original bronchoalveolar lavage (BAL) cells with polarized light microscopy to quantify cell-associated birefringent particles to gain insight into the talc used. RESULTS: SEM/EDX analyses showed that asbestos fibers, quartz, and toxic metal particulates were below the limits of detection in the original talc powder. However, fibers with aspect ratios ≥3:1 accounted for 22% of instilled material, mostly as fibrous talc. Talc (based on Mg/Si atomic weight % ratio) was the most abundant chemical signature, and magnesium silicates with various other elements made up the remainder. BAL cell counts confirmed the presence of acute inflammation, which followed intratracheal instillation. Measurements of cell associated birefringent particles phagocytosis revealed significant differences among talc, granite, and control exposures with high initial uptake of talc compared to granite, but over the 14-day experiment, talc phagocytosis by lavaged cells was significantly less than that of granite. Phagocytosis of talc fibers by macrophages was observed, and birefringent particles were found in macrophages, neutrophils, and multinucleate giant cells in lavaged cells from talc-exposed animals. CONCLUSION: Our data support the contention that talc, even without asbestos and other known toxic contaminants, may elicit inflammation and contribute to lung disease. Our findings support the conclusions of (Beck et al. Toxicol Appl Pharmacol 87:222-34, 1987) study. By analyzing particulate exposures with polarized light microscopy and SEM/EDX, fibrous talc was identified and a distinctive pattern of impaired particulate ingestion was demonstrated.

Migration of Talc From the Perineum to Multiple Pelvic Organ Sites.

OBJECTIVES: Genital talc use is associated with increased risk for ovarian carcinoma in epidemiologic studies. Finding talc in pelvic tissues in women with ovarian carcinoma who have used talc is important in documenting exposure and assessing talc's biologic potential, but tissue-based morphology studies have been rarely reported. METHODS: We report five patient cases with documented perineal talc use, each of whom had talc (by both polarized light and scanning electron microscopy) in multiple pelvic sites distant from the perineum. Six negative-exposure control patients were also analyzed. RESULTS: Talc particles were found in exposed patients, typically within two or more of the following locations: pelvic region lymph nodes, cervix, uterine corpus, fallopian tubes, and ovaries. CONCLUSIONS: Our report adds new insights into the biologic potential of talc and suggests additional anatomic sites that should be closely examined for talc by oncologic surgical pathologists in the setting of perineal talc use.

Development of High-Strength Extended-Release Multiparticulate System by Crystallo-co-agglomeration Technique with Integration of Central Composite Design.

The number of unit operations to be followed in the preparation of tablets was cumbersome and may introduce material as well as process-related critical parameters which may negatively affect the quality of final formulation. The hypothesis of the present research was to develop directly compressible, high-strength extended-release spherical agglomerates of talc containing indapamide by crystallo-co-agglomeration technique. Hydroxypropyl methylcellulose 15 cps and polyethylene glycol 6000 were used to impart the desired sphericity, strength, and deformability to agglomerates, respectively. Ethyl cellulose 10 cps was used to improve the strength of agglomerates and achieve extended release. Design of experiment (rotatable central composite design) was implemented for the elucidation of the effect of type and quantity of polymers on quality attributes of agglomerates. Prepared agglomerates were evaluated for morphological, micromeritic, mechanical, and drug release properties. A satisfactory yield (> 97%, wt/wt), better crushing strength, and low friability of agglomerates indicated good processing and handling characteristics. Compatibility and reduced crystallinity of indapamide in agglomerates were confirmed by spectroscopic and X-ray diffraction studies. Formation of the miniscular dosage form and hydrophobicity of talc were the key factors observed in controlling and extending the drug release (up to 6 h) from agglomerates. Hence, the developed crystallo-co-agglomeration technique could be successfully used for the preparation of directly compressible high-strength extended-release spherical agglomerates of indapamide.

Safety Assessment of Talc as Used in Cosmetics.

The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of talc for use in cosmetics. The safety of talc has been the subject of much debate through the years, partly because the relationship between talc and asbestos is commonly misunderstood. Industry specifications state that cosmetic-grade talc must contain no detectable fibrous, asbestos minerals. Therefore, the large amount of available animal and clinical data the Panel relied on in assessing the safety of talc only included those studies on talc that did not contain asbestos. The Panel concluded that talc is safe for use in cosmetics in the present practices of use and concentration (some cosmetic products are entirely composed of talc). Talc should not be applied to the skin when the epidermal barrier is missing or significantly disrupted.

Effect of drug content and agglomerate size on tabletability and drug release characteristics of bromhexine hydrochloridetalc agglomerates prepared by crystallo-co-agglomeration.

The objective of the investigation was to study the effect of bromhexine hydrochloride (BXH) content and agglomerate size on mechanical, compressional and drug release properties of agglomerates prepared by crystallo-co-agglomeration (CCA). Studies on optimized batches of agglomerates (BXT1 and BXT2) prepared by CCA have showed adequate sphericity and strength required for efficient tabletting. Trend of strength reduction with a decrease in the size of agglomerates was noted for both batches, irrespective of drug loading. However, an increase in mean yield pressure (14.189 to 19.481) with an increase in size was observed for BXT2 having BXH-talc (1:15.7). Surprisingly, improvement in tensile strength was demonstrated by compacts prepared from BXT2, due to high BXH load, whereas BXT1, having a low amount of BXH (BXH-talc, 1:24), showed low tensile strength. Consequently, increased tensile strength was reflected in extended drug release from BXT2 compacts (Higuchi model, R(2) = 0.9506 to 0.9981). Thus, it can be concluded that interparticulate bridges formed by BXH and agglomerate size affect their mechanical, compressional and drug release properties.

Influence of talc dose on extrapleural talc dissemination after talc pleurodesis.

This study was designed to ascertain, in a rabbit model, extrapleural talc deposition and the related inflammatory response after talc slurry pleurodesis with two clinical doses, 200 and 50 mg/kg. Histopathologic evaluations revealed that whereas numerous rabbits receiving a high dose had talc in the ipsilateral (70%) and contralateral (55%) lung, mediastinum (90%), pericardium (30%), and liver (25%), a small number of animals treated with a low dose showed talc in the ipsilateral lung (10%) and mediastinum (20%) and none in the contralateral lung, pericardium, or liver. Hematologic and immunocytochemical analyses showed that a systemic inflammatory response develops shortly after pleurodesis with a high talc dose involving massive accumulation of neutrophils and macrophages in lung tissue. Zymography also revealed that the pulmonary expression of matrix metalloproteinases 2 and 9 was up-regulated in both lungs in a dose-dependent manner soon after talc instillation. Furthermore, microscopic examination of lung specimens revealed that the higher the dose of talc, the greater the development of both fibrotic visceral pleural thickening and foreign-body granulomas. These findings show pleurodesis with a high talc dose to be associated with an increased risk of extrapleural talc deposition, which may originate undesirable acute and chronic inflammatory responses.

[An experimental study on the systemic distribution of calibrated talc after intra-pleural injection]. / Etude expérimentale de la distribution systémique de talc calibré après injection intrapleurale.

INTRODUCTION: Among the agents used to produce pleural symphysis talc is the most effective and least expensive. However, its use is controversial on account of the description of respiratory complications associated with subsequent systemic spread of the talc particles. This hypothesis rests on clinical and experimental observations of talc particles in the viscera. However, all talc preparations are not identical and this extra-pleural spread could be dependent on particle size. This experimental study was undertaken to determine whether there was systemic spread of a calibrated talc preparation used routinely in clinical practice following intra-pleural administration in rats. METHODS: 48 rats received 20 mg (11 rats) and 40 mg (33 rats) of calibrated talc suspended in 1 ml of physiological saline by intra-pleural injection. The animals were randomised for sacrifice at 24 hours (22 rats) and 72 hours (22 rats) after the injection. The lungs, parietal pleura, diaphragm, liver, spleen, pericardium, brain and blood were examined by light microscopy and polarised light to search for bi-refringent particles. RESULTS: No deaths occurred during the procedure. At the time of sacrifice no pleural symphysis was seen. In 5 animals some talc particles were seen in the extra-thoracic organs: in the liver in 3 in the spleen in 1 and one particle in the brain of one animal examined by electron microscopy. No talc particles were found in the blood. CONCLUSIONS: Intra-pleural injection of calibrated talc, (Steritalc-Novatech-Plan de Grasse-France) has a weak systemic spread in > small animals. These results may be related to the diameter of the talc particles used (mean 33.6 microns; median 31.3 microns). The hypothesis that systemic spread is influenced by the diameter of the talc particles needs to be supported by experimental studies using talc particles of smaller diameter in order to compare the systemic distribution of the different preparations.

Distribution of calibrated talc after intrapleural administration: an experimental study in rats.

STUDY OBJECTIVE: Many reports have shown that talc is the most effective and least expensive agent for the creation of a pleural symphysis. However, its use still remains controversial due to severe acute respiratory side effects possibly related to the systemic dissemination of talc particles. The purpose of this study was to assess the distribution of calibrated talc after intrapleural administration in rats. MATERIAL AMD METHODS: Thirty-seven Wistar male rats were randomly assigned to undergo pleurodesis by talc slurry (33 rats) or by simple chest tube drainage (control group; 4 rats). Forty milligrams of calibrated talc suspended in 1 mL sterile saline solution was injected into rats in the treated group. The animals were randomly assigned for autopsy at 24 or 72 h after pleural injection. Lungs, parietal pleura, diaphragm, liver, kidneys, spleen, pericardium, brain, and blood were assessed by polarized light for birefringent talc particle detection and counting. RESULTS: No deaths were observed. The autopsies showed no pleurodesis at 24 and 72 h. Despite high doses of talc (extrapolated from the dose of 10 g in a 70-kg adult man), few talc particles were found in the liver of two rats, in the spleen of one rat, and only one particle of talc was observed at the brain surface of the rat studied by scanning electron microscopy. No particles were found in the other organs, in particular in the contralateral lung and blood, contrasting with previously published results using noncalibrated talc particles. CONCLUSIONS: The lack of systemic dispersion of talc particles, with the packaging talc we currently use in our clinical practice, is probably due to the size of the talc particles, which are larger than the other talc preparations. Calibrated talc is required in case of intrapleural administration for pleurodesis to avoid systemic dissemination and potential secondary acute respiratory failures.

Influence of particle size on extrapleural talc dissemination after talc slurry pleurodesis.

BACKGROUND: Cases of acute respiratory failure reported after talc pleurodesis have raised concerns about its safety. It has been speculated that this pulmonary inflammatory syndrome is secondary to the extrapleural dissemination of the talc particles. STUDY OBJECTIVES: To test the hypothesis that particle size influences extrapleural talc deposition and pleural inflammation after talc slurry pleurodesis. DESIGN: Thirty rabbits underwent pleurodesis as follows: 10 rabbits received 200 mg/kg of the talc used for human pleurodesis, normal talc (NT); 10 rabbits received 200 mg/kg of talc with particles of larger size, large talc (LT); and 10 rabbits received saline solution. Samples from the ipsilateral lung, chest wall, diaphragm, mediastinal pleura, heart, liver, spleen, and right kidney were obtained at 24 h and 7 days and processed for optic and electron microscopy and energy-dispersive x-ray analysis. RESULTS: Visceral pleural thickening was greater with NT than with LT, but no differences were observed in the macroscopic score of adhesions. There was more talc in the lungs of the rabbits that received NT than in those that received LT. Talc particles were detected in mediastinum (100%) and pericardium (20%), irrespective of the talc used. Three animals, all receiving NT, had talc particles in the liver. CONCLUSIONS: Our study shows that while both talcs were equally effective in achieving pleurodesis, the intrapleural injection of NT elicits greater pulmonary and systemic talc particle deposition than LT. Moreover, pleural inflammation was greater with NT than with LT.

Distribution of talc suspension during treatment of malignant pleural effusion with talc pleurodesis.

Talc pleurodesis is an effective technique for the management of symptomatic malignant pleural effusions. It is assumed that a good dispersion of talc suspension contributes to the final success of this treatment. For this purpose, guidelines often advise to rotate the patient after intra-pleural instillation of the sclerosant. This prospective, randomized study analyses the dispersion of talc suspension and the overall success rate in patients with malignant effusions. After instillation of 99mTc-sestamibi-labeled talc suspension ten subjects were rotated for 1 h, while the ten other patients remained in a stable supine body position. Scintigraphic imaging was done in two directions immediately after instillation and after 1 h with a clamped drain. The overall success of the treatment was assessed 1 month after the pleurodesis. The dispersion of talc was limited and unequal in 75% of the subjects. In two patients with apparently good distribution on anterior views, the lateral views of the scintigraphy showed only limited distribution. Rotation of the patients did not influence the dispersion of sludge after 1 min or 1 h. Pleurodesis was successful in 85% of the patients after 1-month follow-up. Standard rotation protocols for patients with malignant pleural effusion do not affect the overall dispersion of talc suspension and should be abolished because of the discomfort caused to the patients.

Systemic distribution of talc after intrapleural administration in rats.

STUDY OBJECTIVES: Many reports have shown the efficacy of talc to induce an effective pleurodesis. However, there is little information about the side effects related to this sclerosing agent. The objective of this experimental study is to recognize the systemic distribution of talc after its instillation into the pleural space of rats. DESIGN: Forty animals were assigned to receive talc through a catheter placed in a left minimal thoracotomy. They were randomly divided in two groups: group 1 received 20 mg of talc and group 2 received 10 mg in the same total volume of 1 mL of saline solution. Half of the animals in each group were killed 24 h and the other half 48 h after the procedure. BAL was collected and histologic sections of both lungs, chest wall, liver, kidneys, spleen, heart, and brain were examined. Crystals were tracked using polarized light and we have used a "birefringent particles index of deposition" in an attempt to quantify the amount or talc encountered in different organs. RESULTS: Talc crystals were found in every organ of all animals studied (100%). There was no statistical difference either on the dose of talc used or in the time of death. The amount of talc was statistically different in the organs, which made us divagate about a route of absorption. CONCLUSIONS: We conclude that there is a progressive deposition of talc particles in the organs examined after its administration into the pleural space of normal rats. This report suggests that there is a rapid absorption of talc through the pleural surface and that the systemic distribution thereafter is not dose related. Further studies are necessary to assess the amount of crystals and the clinical correlation to these findings.

The NTP talc inhalation study: a critical appraisal focused on lung particle overload.

Recently published results in a NTP report of a 2-year inhalation study with talc in rats and mice seem to fit the category of being associated with particle overload quite well: Exposure concentrations of 6 and 18 mg/m3 induced pulmonary inflammation and fibrosis in male and female rats and induction of lung tumors (in female rats only) of the high exposure group; mice of either sex showed an inflammatory response but did not show pulmonary fibrosis or lung tumors. Analysis of the particle accumulation kinetics in lungs of both rats and mice indeed shows that lung overload had been reached at both exposure concentrations in both species resulting in increased talc accumulation of high lung burdens. This and the chronic inflammatory response indicate that the maximum tolerated dose (MTD) had been exceeded at both exposure levels. This result was predictable based on the outcome of a 4-week range-finding study prior to initiation of the chronic talc study; however, the short duration of the range-finding study may have been inadequate to give great confidence in the prediction and therefore may have accounted for the failure to include a concentration below the MTD in the chronic study. Further analysis of the results of the chronic talc study show that talc particles behave like other low-toxicity particles such as TiO2 and toner with respect to effects on lung clearance and chronic pulmonary inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Unusual intestinal talcosis.

A case of intestinal talcosis in a 46-year-old man is reported. At the age of 27, the patient was treated for pulmonary tuberculosis with tablets containing talc (183 g talc per 2,670 g total drug intake) over a period of 28 months. Eighteen years later, the patient was hospitalized for abdominal pain that remained refractory to antacids; he subsequently underwent a right hemicolectomy. Light-microscopic examination revealed a prominent fibrosis of the intestinal wall in which birefringent particles were demonstrated by polarized light. Using energy-dispersive spectroscopy, an analysis of these particles showed that they were predominantly composed of silicon and magnesium as well as small amounts of phosphorus, sulphur, calcium, and iron--the spectrum typically associated with talc. We believe that the source of this talc is the tablets ingested by the patient during prior antituberculosis therapy.