Talc and Malignant Mesothelioma

Abstract

Malignant mesothelioma is a rare malignancy of serosal-lined tissues. It has been recognized since the last century that the majority of pleural mesotheliomas are caused by exposures to asbestos, a fibrous silicate mineral that was used extensively in the construction trades for its insulating properties. A previously unrecognized source of asbestos exposure is cosmetic talc that has been widely used for personal hygiene and other purposes by adults and children. Since 2014, more than 200 cases of mesothelioma have been reported in individuals, whose only known source of asbestos exposure was cosmetic talc. In this chapter the association of talc with malignant mesothelioma will be reviewed.

1. Introduction

Malignant mesothelioma is a rare malignancy of serosal-lined tissues, including the pleura, peritoneum, tunica vaginalis, and pericardium. The disease was virtually unknown prior to the introduction of asbestos into the workplace and misattributed to metastatic carcinoma. Asbestos is a generic term that has been applied to six naturally occurring fibrous magnesium silicates that were used primarily for their insulating properties in the construction and other trades (Table 1). In 1960, when Wagner described 33 cases in workers and those living in proximity to crocidolite (blue asbestos) mine in South Africa [1]. Subsequent studies demonstrated that all commercially available forms of asbestos were capable of causing malignant mesothelioma (MM), with amphibole (needle-like) forms of asbestos being more carcinogenic on a per fiber basis than chrysotile (serpentine). Due to the strength of association of asbestos and MM in epidemiological studies, the diagnosis of MM should “trigger” inquiry as to whether an individual may have been exposed to asbestos.

Class	Type	Chemical formula
Serpentine	Chrysotile	Mg3(Si2O5)(OH)4
Amphibole	Amosite	Fe7Si8O22(OH)2
	Crocidolite	Na2Fe^II3Fe^III2Si8O22(OH)2
	Tremolite	Ca2Mg5Si8O22(OH)2
	Actinolite	Ca2(Mg,Fe^II)5(Si8O22)(OH)2
	Anthophyllite	(Mg,Fe^II)7Si8O22(OH)2

Table 1.

Regulated asbestos by class, type, and chemical formula.

The prospective risk of developing mesothelioma is directly proportional to the dose (frequency/intensity/duration) of exposure. However, this refers to the a priori risk of developing disease and a low risk should not dissuade one from attributing a mesothelioma to asbestos when there is a history of past exposure. Approximately 10% of heavily exposed insulators have developed mesothelioma so that even heavy exposures do not necessarily lead to the development of disease [2]. At least four epidemiological studies have demonstrated that the risk of developing MM more than doubles following exposures as low as <0.1 f/cc-yr, and cases have been described following brief exposures [3]. Currently, no recognized safe level of occupational or paraoccupational exposure above background (~0.0001 f/cc) has been established. Due to the increased risk of developing MM following low-level exposures, asbestos has been banned by the European Union. However, its use in some products in the U.S. continues to be regulated with a current permissible exposure limit (PEL) of 0.1 f/cc over an 8 h time weighted average. Despite strict controls, regulatory agencies have predicted that even at this level there will be an excess, albeit small, risk of developing MM.

1.1 Clinical features, diagnostics, and treatment

The clinical features of pleural MM are largely stereotypic. Patients complain of cough, shortness of breath, chest pain, and weight loss as common presenting symptoms. Chest imaging generally shows a pleural effusion and nodular pleural thickening that extends circumferentially around the underlying lung. The diagnosis can be established by cytological evidence of malignancy in the pleural fluid or more commonly by pleural biopsy. The spectrum of pathologies include epithelioid and sarcomatoid variants, and the latter has a somewhat more aggressive clinical course. The diagnosis is generally confirmed by immunohistological staining. Positive tumor cell immunostaining for pancytokeratins, calretinin, WT-1, podoplanin (D2–40), CK7, CK5/6, is seen in the majority of cases with epithelioid features, whereas areas of sarcomatoid growth may lack expression of most mesothelial-associated antigens. The majority of epithelioid mesotheliomas also show loss of nuclear expression of BAP-1 and loss of CDKN2A [4].

The disease is virtually always lethal. Complete surgical extirpation is near impossible to achieve due to early invasion of chest wall and mediastinal structures. Current therapeutic interventions include pleurectomy/decortication with combination chemotherapy and/or immunotherapy. Life expectancy is less than two years with or without treatment in most studies [5].

1.2 Pathogenesis

With respect to causation, as individuals are often exposed repeatedly to asbestos, and to multiple sources of asbestos, the specific exposures responsible for the molecular events leading to MM cannot be ascertained. Rather, the cumulative exposure is considered to be the primary determinant of risk for developing MM. Even small amounts of an asbestos-containing material when disrupted can release millions of respirable microscopic asbestos fibers and a gram of asbestos includes more than a trillion fibers. Asbestos fibers are best visualized with transmission electron microscopy and cannot be reliably seen with standard light microscopy. Scanning electron microscopy underestimates asbestos fiber deposition. Fibers that are respirable and deposited in the lung can be transported via lymphatics to other serosal sites where they may cause disease [6, 7]. Fiber-burden analyses, an experimental technique used in an effort to assess asbestos fiber burden and type of fibers deposited is usually based on deposition within the lung, whereas the site of interest is the pleura which is rarely examined. Fiber-burden studies that focus on lung content also underestimate chrysotile content, as this fiber type has a short half-life (days to weeks) in the lung, whereas short fibers of chrysotile appear to persist in the pleura. Some asbestos fibers in the peripheral lung may penetrate the pleura and produce mutations in the lining mesothelial cells directly.

The pathways leading to asbestos-related malignancy are multifactorial. The vast majority of fibers (>90%) are cleared by the host defense mechanism that include nasal hairs, cough, swallowing, muco-ciliary clearance, and phagocytic cells. Nevertheless, those fibers that escape host defenses are capable of causing disease. Pathways leading to injury include direct injury to chromosomal DNA by asbestos fibers and the generation of free-radicals capable of producing genetic injury by inflammatory cells in response to fiber deposition in the pleura.

Much has been learned in recent years concerning the molecular genetics of MM carcinogenesis. Certain genes are frequently somatically mutated in the tumor cells of MM. These include BAP-1, NF2, CDKN2A, p53, mismatch repair genes, and others. In addition, there are families predisposed to developing MM, most notably those with heterozygous germline mutations in BAP-1 [8]. However, biallelic mutations of BAP-1 are seen in MM so that a second non-germline mutation must take place in the path towards malignant transformation [9]. Currently it appears that gene-environmental interactions are required for the development of MM and there is no compelling evidence that germline mutations are sufficient to cause MM in the absence of an environmental mutagen, most often asbestos.

2. Talc

Talc is a naturally occurring mineral mined from the earth. It is a hydrous magnesium silicate with chemical formula Mg3Si4O10(OH)2. Talc dominantly forms from the metamorphism of magnesian minerals such as serpentine, pyroxene, amphibole, and olivine, in the presence of carbon dioxide and water. This is known as “talc carbonation” and produces a suite of rocks known as talc carbonates.

Talc has been used extensively in industrial and pharmaceutical settings as well as in cosmetic powders. Whereas industrial talc varies in composition and may include a mixture of various mineral particles, cosmetic talc consists of platyform particles with only minor impurities (Table 2). Cosmetic talc has been mined throughout the world, with mines located in Italy, Vermont, North Carolina, Montana, Alabama, Korea, and China. Analyses of cosmetic talc from these sources have shown heterogeneous impurities including asbestiform tremolite, anthophyllite, actinolite, and chrysotile. The level of asbestos impurity varies but is usually less than 1% [10].

Mineral group	Name
Carbonate	Dolomite
	Magnesite
	Calcite
	Siderite
Phylosillicate	Chlorite
	Lizardite
	Mica
	Sepiolite
Amphibole	Tremolite
	Actinolite
	Anthophyllite
Tectosilicates	Quartz
	Feldspar
	Magnetite
	Rutile
	Manganese oxide
Sulfides	Pyrite
	Pentlandite
Other	Graphite

Table 2.

Minerals associated with talc.

It is noteworthy that talc is the only commercial product that potentially includes both tremolite and/or anthophyllite and/or actinolite. Actinolite is not found in any commercial product other than talc. Tran et all have suggested that finding talc together with tremolite/actinolite/anthophyllite in fiber burden analyses of tissues is prima facie evidence of cosmetic talc use [11].

The detection of asbestos within samples of cosmetic talc has been controversial and hindered by its presence as a low-level impurity. Identification depends on identifying asbestos fibers (aspect ratio > 3:1) and distinguishing them reliably from talc cleavage fragments. Although the earliest reports showing asbestos in talc were based on X-ray diffraction, accurate identification is optimally carried out by analytical transmission electron microscopy with either electron dispersive spectrometry or selected-area electron diffraction. Blount examined the amphibole content of high-grade cosmetic talc products from deposits in Vermont, Montana, North Carolina and Alabama using a centrifuge/optical method that enriches for amphibole fibers and found a uniformly low amphibole count that included both cleavage fragments and asbestiform fibers with aspect ratios >3:1 [12]. Other investigators have confirmed Blount’s findings using the centrifuge/optical technique, [13] and a recent Federal Drug Administration analysis revealed chrysotile within a popular cosmetic talc product [14].

3. Mesothelioma and talc

Although asbestos was used primarily as an insulating material, it has been identified in other commercial products as well. In 1974, Rohl and Langer showed that 10 of 20 talc products, including baby powders, facial talcums, and pharmaceuticals, contained both tremolite and anthophyllite asbestiform structures [15]. This finding was contested by manufacturers, and went largely unnoticed by the medical community. However, in 2015 Gordon et al identified amphibole asbestos in a cosmetic talcum powder as well as in the lung tissue of a woman with MM who had no other known source of asbestos exposure [16]. The asbestos fibers were confirmed as anthophyllite and tremolite by electron dispersive spectrometry and by selected-area electron diffraction.

In 2019 Moline et al reported 33 cases of MM of the pleura and peritoneum associated with cosmetic talc exposure in subjects referred for medical-legal consultation [17]. In 2020, Emory, Maddox, and Kradin reported 75 additional subjects with MM who had been exposed to cosmetic talc [18]. In 2023, Moline, Patel, and Frank reported 166 additional cases of malignant mesothelioma diagnosed in cosmetic talc users [19]. 44 of these had potential or documented sources of asbestos exposure other than talc. 52/166 of the cases had diffuse peritoneal mesothelioma (DPM), with a similar percentage seen in men and women.

At the present time almost 300 cases of MM have been reported in the medical literature associated at least in part to cosmetic talc usage. Other than a somewhat younger age at time of diagnosis and an increased percentage of women, the clinical features and histology of these tumors has been indistinguishable from mesotheliomas produced by asbestos from other sources. However, due to the widespread availability and application of cosmetic talc in the community, it is possible that an unknown percentage of MM particularly in women previously labeled as “idiopathic” may have been attributable to cosmetic talc use [17].

Until the recent spate of cases of MM, it was thought that cosmetic talc, when used as intended, did not present a health hazard. But this position may not be justified based on the newly recognized cases of MM in talc users, although as will be discussed, it is likely that the prospective risk of developing MM from cosmetic talc use is low. The International Agency for Research on Cancer (IARC) states that asbestos contaminated talc is carcinogenic and should be treated as a potential carcinogen [20].

The argument that cosmetic talc is safe has been based on failure to identify cases of MM in cosmetic talc miners. A recent meta-analysis of six articles that included 5394 miners examined the incidence of MM and showed no increase, although there was a small increase in lung cancer and pneumoconiosis mortality [21]. Clinical trials to examine the risk of developing MM from the use of cosmetic talc have not been conducted and they may not be feasible for the following reasons. It is recognized that ~3000 new cases of mesothelioma occur in the U.S. each year. Although there are currently no data as to how many cases of MM are potentially attributable to cosmetic talc, a liberal “guesstimate” might be 10%, i.e., 300 cases/year. Estimating conservatively that perhaps half of the U.S. population (~150,000,000 individuals) has ever been exposed to cosmetic talc (CT), and assuming 300 new cases of MM potentially attributable to talc per year, one calculates that 0.0002% of the population would be expected to have a CT-associated MM. To detect a single case of malignant mesothelioma, ~500,000 subjects would need to be examined and that number would increase if the true incidence of CT-associated MM is less than 300.

Admittedly, the above calculation is crude, but its order of magnitude is likely approximately correct. While it does not account for the likely higher exposure levels to asbestos in cosmetic talc miners, it does suggest that screening an extremely large number of subjects would be necessary to detect cases of MM and to assess prospective risk. While one can conclude from this estimate that the incidence of MM due to cosmetic talc use is likely low, in a large population, cases can be expected to occur.

Kanarek and Liegel have argued that exposure to cosmetic talc containing asbestos meets the Bradford Hill criteria for causality of MM [22] (Table 3). As the ability of asbestos to cause MM is well established, epidemiological studies are not required to confirm this. Instead, the only justifiable role for an epidemiological study of cosmetic talc would be to establish the prospective risk to those exposed, not causation.

Bradford Hill criteria for assessing causality

1. Strength of association

2. Consistency of association

3. Specificity

4. Temporality

5. Biological gradient

6. Plausibility

7. Coherence

8. Experimental findings

9. Analogy

Table 3.

Criteria suggested by Sir Austin Bradford Hill that should be met in assessing causation.

Hill argued that these were as important as finding statistical significance in an epidemiological study.

4. Cosmetic talc use

Cosmetic talc is a component of body powders, facial and eye makeups, and some animal flea powders [23]. Although asbestos is a trace impurity of cosmetic talc, concentrations of amphibole asbestos during the application of cosmetic talc powders have been measured at ~2.7–4.5 f/cc, which is orders of magnitude greater than current urban background levels (0.0001 f/cc) [13, 16]. It has been used primarily for personal hygiene after bathing but also in the diapering process of infants, as a dry deodorant, and as a dry shampoo. Some subjects report adding it to their shoes to reduce odor. Cosmetic talc is routinely used by barbers in hair salons where it is dusted on the neck area to prevent irritation. Twelve barbers were amongst the reported cases of MM, although a recent meta-analysis of 12 studies of barbers, hair stylists and cosmetologists suggests that their risk of developing disease may be low [24]. Unusual uses of cosmetic talc are occasionally reported. One subject with MM, as a young boy simulated an “ice skating” rink by pouring cosmetic talc over his living room floor. Under conditions like this, exposures to asbestos within talc may be considerable and result in increased risk for developing diseases, including MM, pleural plaques, and talcosis.

5. Demographics

The cases of talc associated MM have included both men and women with female predominance (~70%). The average age for both men and women has been in the early 60s [17, 18, 19]. The majority of MM have been pleural (~60%), but a higher-than-expected percentage have been women with peritoneal mesothelioma (~35%). The underlying genetics of these cases was not consistently available, although a small number of talc-associated MM have shown germline mutations in the BAP-1 gene (unpublished data).

The published cases of talc-associated MM have all been identified through litigation. This may be attributable to the heightened consciousness related to the topic within the legal setting. While an uncertain percentage of all cases of MM are referred for litigation, it is likely high due to the level of publicity that surrounds the topic. In addition, physicians caring for patients with asbestos-related diseases may feel obliged to point out their option of pursuing compensation.

6. Conclusion

The recognition that cosmetic talc may be contaminated with asbestos has raised concerns in the medical community, regulatory agencies, and amongst consumers. Despite sporadic reports dating back to the 1970s, it has only been in the last decade that the potential for cosmetic talc to cause malignancies, including MM and ovarian cancer has been recognized.

Prior to this observation roughly 20% of MM in men and roughly half of MM in women were judged to be “idiopathic,” i.e., it was not possible to identify a source of asbestos exposure. It is noteworthy that cases of talc-associated MM in the past would have been judged “idiopathic.”

The identification of asbestos in cosmetic talc has had substantial economic impact and has triggered contentious ongoing litigation. Although the risk of developing cancer from cosmetic talc is apparently low, as MM is an incurable malignancy, this finding may justify seeking alternatives to its continued use. Increased awareness will require regulatory agencies to reexamine whether cosmetic talc products need to be regulated, labeled as potentially toxic, or banned for consumer usage.

Conflict of interest

The author has served as a compensated expert witness in talc litigation.