The Potential Contribution of Hexavalent Chromium to the Carcinogenicity of Chrysotile Asbestos

Our plain-English summary of The Potential Contribution of Hexavalent Chromium to the Carcinogenicity of Chrysotile Asbestos, by M. Walter, W.D.C. Schenkeveld, M. Tomatis, et al (Chemical Research in Toxicology, 2022).

The study

• Authors: M. Walter, W.D.C. Schenkeveld, M. Tomatis, K. Schelch, B. Peter-Vörösmarty, G. Geroldinger, L. Gille, M.C. Bruzzoniti, F. Turci, S.M. Kraemer, M. Grusch
• Journal: Chemical Research in Toxicology
• Published: 2022;35(12):2335-2347
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Chrysotile asbestos is a carcinogenic mineral that has abundantly been used in industrial and consumer applications. The carcinogenicity of the fibers is partly governed by reactive Fe surface sites that catalyze the generation of highly toxic hydroxyl radicals (HO•) from extracellular hydrogen peroxide (H2O2). Chrysotile also contains Cr, typically in the low mass permille range. In this study, we examined the leaching of Cr from fibers at the physiological lung pH of 7.4 in the presence and absence of H2O2. Furthermore, we investigated the potential of cells from typical asbestos-burdened tissues and cancers to take up Cr leached from chrysotile in PCR expression, immunoblot, and cellular Cr uptake experiments. Finally, the contribution of Cr to fiber-mediated H2O2 decomposition and HO• generation was studied. Chromium readily dissolved from chrysotile fibers in its genotoxic and carcinogenic hexavalent redox state upon oxidation by H2O2. Lung epithelial, mesothelial, lung carcinoma, and mesothelioma cells expressed membrane-bound Cr(VI) transporters and accumulated Cr up to 10-fold relative to the Cr(VI) concentration in the spiked medium. Conversely, anion transporter inhibitors decreased cellular Cr(VI) uptake up to 45-fold. Finally, chromium associated with chrysotile neither decomposed H2O2 nor contributed to fiber-mediated HO• generation. Altogether, our results support the hypothesis that Cr may leach from inhaled chrysotile in its hexavalent state and subsequently accumulate in cells of typically asbestos-burdened tissues, which could contribute to the carcinogenicity of chrysotile fibers. However, unlike Fe, Cr did not significantly contribute to the adverse radical production of chrysotile.

In plain English

This laboratory study tested whether chrysotile asbestos releases its trace chromium as hexavalent Cr(VI) and, in separate experiments using added Cr(VI), whether human cells take it up. The authors used chrysotile from a supplier in China containing 1.3 to 1.4 g of chromium per kg. In buffer at pH 7.4 without hydrogen peroxide or added metal-binding chemicals, chromium release from untreated fibers stayed below detection. With hydrogen peroxide at about 100 mmol per litre, roughly 100 times the highest level the authors expect in diseased tissue, 2.0 to 2.3 µmol per litre of chromium, all Cr(VI), was released after 336 hours. At 1 mmol per litre of peroxide, about 0.4 µmol per litre was released after 168 hours. Cultured lung, mesothelial, lung cancer and mesothelioma cells carried Cr(VI) transporter proteins. When given sodium chromate, cells held up to 10 times the medium's chromium concentration, and a transporter blocker cut uptake by up to 45-fold. Chromium did not appear to add to the fibers' production of hydroxyl radicals. The authors concluded that Cr(VI) leaching should be considered a potential contributor to chrysotile's carcinogenicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study: batch experiments with chrysotile fibers in buffered solutions, plus gene expression (qPCR, microarray), immunoblot and chromium uptake experiments in cultured human cells. Fiber leaching and cell uptake were tested in separate experiments.
• Who was studied: Chrysotile asbestos from a commercial supplier in China (Shijiazhuang). Cultured human cells: immortalized lung epithelial (BEAS-2B), immortalized mesothelial (MeT-5A), lung carcinoma (A549) and malignant pleural mesothelioma (P31) cells. The PCR panel also included primary mesothelial cultures (NP1, NP2) and further mesothelioma cultures (MM05, SPC212, VMC23, VMC40). Microarray data came from MeT-5A, NP2 and mesothelioma cell cultures.
• Exposure: Chrysotile fibers containing 1.3 to 1.4 g per kg chromium, tested untreated and after pre-weathering, with or without hydrogen peroxide or metal-chelating agents (EDTA, DTPA, DFOB). The main peroxide concentration was 3.3 g per litre (about 100 mmol per litre), and 100, 10, 1 and 0.1 mmol per litre were also tested. Cells were exposed to sodium chromate (Cr(VI)) at 0.2 to 2000 µmol per litre, not directly to fiber leachate.
• Main results:
  • In the buffer-only blank treatment, with no peroxide and no chelators, chromium leached from untreated fibers at pH 7.4 stayed below the limit of detection (16.6 nmol per litre).
  • Without peroxide, metal-chelating agents did release chromium from untreated fibers. After 336 h, EDTA released 2.2 µmol per litre, DTPA 2.1 µmol per litre and DFOB 0.7 µmol per litre.
  • With hydrogen peroxide, chromium in solution reached 2.0 to 2.3 µmol per litre after 336 h for untreated, blank-weathered and DFOB-weathered fibers.
  • At a lower hydrogen peroxide concentration of 1 mmol per litre, about 0.4 µmol per litre of chromium was released from untreated chrysotile after 168 h.
  • Chromium released with hydrogen peroxide at pH 7.4 was entirely hexavalent, Cr(VI). Chromium released at pH 3.0 without peroxide was entirely trivalent, Cr(III).
  • The Cr(VI) transporters SLC4A1 and SLC26A1 were detected at the protein level in MeT-5A, P31, BEAS-2B and A549 cells. A549 showed only a faint band for SLC4A1.
  • Four hours after cells were given Cr(VI), chromium concentrations inside the cells were up to 10 times the concentration added to the medium. This effect was greatest at 0.2, 2 and 20 µmol per litre. At 2000 µmol per litre, intracellular chromium in BEAS-2B, MeT-5A and P31 cells was below the added concentration.
  • The anion transporter inhibitor DIDS significantly reduced chromium uptake in all four cell types when 2 µmol per litre Cr(VI) was added. The largest reduction was 45-fold, in MeT-5A mesothelial cells.
  • Hydroxyl radical yield, as a percentage of untreated fibers, was 62% for blank-weathered fibers, 9% for DFOB-treated fibers, 14% for EDTA-treated fibers and 3% for DTPA-treated fibers. DTPA treatment did not remove the fibers' reactive chromium, so the authors judged chromium's contribution to hydroxyl radical production negligible.
• The authors' conclusion: The authors concluded that, together with earlier in vivo leaching studies in rats, their results indicate that leaching of hexavalent chromium should be considered a potential contributor to the genotoxicity and carcinogenicity of chrysotile asbestos. They also concluded that chromium on chrysotile surfaces does not appear to contribute to a relevant extent to the fibers' radical-generating chemistry.
• Limitations the authors state:
  • The starting hydrogen peroxide concentration in the main leaching experiments was about two orders of magnitude (roughly 100 times) higher than the maximum expected in diseased tissue (up to 1 mmol per litre). It stayed higher than expected tissue levels throughout the experiments.
  • The authors state that they do not know why chromium leached differently from the other metals (iron and nickel) after the fibers were pretreated with chelating agents.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile, Lung cancer.

Medical terms in this study, explained in our Lexicon: Chrysotile, Carcinogenic, Hydroxyl Radical, Carcinoma, Mesothelioma.

Related studies

• Identifying the reactive sites of hydrogen peroxide decomposition and hydroxyl radical formation on chrysotile asbestos surfaces — M. Walter, W.D.C. Schenkeveld, et al. (2020)
• Chromium and nickel — G. Kazantzis (1972)
• Chromium and nickel in Pteridium aquilinum from environments with various levels of these metals — K. Kubicka, A. Samecka-Cymerman, et al. (2015)
• The carcinogenicity of chrysotile asbestos--a review — W.J. Nicholson (2001)
• Potential toxicity of nonregulated asbestiform minerals: balangeroite from the western Alps. Part 2: Oxidant activity of the fibers — F. Turci, M. Tomatis, et al. (2005)
• The effect of weathering on ecopersistence, reactivity, and potential toxicity of naturally occurring asbestos and asbestiform minerals — S. Enrico Favero-Longo, F. Turci, et al. (2009)

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