Radium toothpaste for teeth that glow
*During the radium craze, which started in 1903 and ran for a decade or so, you could buy radium-enhanced boot polish, chocolates, cocktails – and toothpaste.
People died of course, and Doramad Radioactive Toothpaste, like its users and the radium they ingested, decayed and faded away. Then came fluoride which, unlike radium, enhances dental health. Some think it might be linked to neurodevelopmental issues, but the case does not appear to be a strong one (1). And there also came titanium, mostly in the form of titanium dioxide (TiO2).
While fluoride has one health-positive effect, TiO2 has none. It is used to make toothpaste brighter and whiter; and it is also used to colour paint, paper, cosmetics, pills and food, where it is known as E171. In fact, TiO2 is everywhere. It has been around for a century (it was introduced around the same time as radium), and until recently was considered inert and safe.
About 25 years ago, I first heard that titanium might not be so safe.
At a small meeting of immunologists at the Middlesex Hospital, chaired by the impeccably bow-tied Jonathon Brostoff, I listened as an eminent scientist told the group he had found nano-particles of TiO2 inside M-cells.
Located in the mucosa-associated lymphoid tissues of the intestine, M-cells play a key role in selecting the initiation of immunity or tolerance. They sample the contents of the gut lumen and pick up micro-particles such as calcium phosphate (CaPo4) particles, which influence immune responses due to their ability to carry proteins and other bio-molecules into the MALT. M-cells also swallow particles of TiO2.
Ingested CaPo4 particles dissolve but TiO2 particles do not, and the scientist – to my shame, I do not remember his name – reported that they accumulated over time. He thought it would lead eventually to M-cell dysfunction or death. This idea gathered dust for a quarter century until I stumbled across a paper written by Swedish researchers Fredrik Berglund and Bjorn Carlmark (2). They concluded, ‘Yellow Nail Syndrome is caused by titanium… predominantly from implants’ (2).
YNS is rare and sounds innocuous enough, but the yellow nails are often accompanied by lymphedema and respiratory symptoms such as repeated infection, chronic cough, sinusitis, and bronchiectasis. The Swedes’ evidence and their logic was convincing, and supporting evidence from other researchers started to accumulate.
YNS was linked to titanium in dental amalgam (3), orthopedic implants (4) including a titanium pace-maker (5), and titanium (as TiO2) in toothpaste (6).
Dermatologists at New York Presbyterian found titanium in the nails of YLS patients but not in controls (7), and showed, like Berglund and Carlmark before them, that removal of the source of titanium could lead to resolution in some (but not all) cases.
Evidence emerged that titanium implants could be corroded by salivary acids (8).
A review of titanium toxicology worried about corrosion and abrasion of dental implants creating micro- and nano-particles of titanium and titanium alloys, which if deposited locally could cause local inflammation and implant failure (9). They also considered the deposition of TiO2 particles in remote tissues giving rise to YNS, and listed some previously unrecognized problems; other groups had found the same particles in the bone marrow of humans (10) and the brains of mice (11).
The situation changed again when the chemical industry started to produce large amounts of nano-TiO2. This sexy new material entered the cosmetic industry as an UV-absorbing active in sun-screen products, and once people became aware of nano-technology they realized that even standard TiO2 powder could contain up to 30% nano-particles (12).
This was starting to look like a real problem.
A Dutch group looked at levels of TiO2 ingestion by the general public (13). Major sources were identified as toothpaste (young children only), candy and ice cream, coffee creamer, fine bakery wares and sauces. Mean intakes of TiO2 nano-particles were estimated at 0.19 μg/kg bw/day in the elderly, increasing to 0.55 μg/kg bw/day for middle-aged and younger people and reaching 2.16 μg/kg bw/day in children due to their higher intake of confectionery and their tendency to swallow toothpaste.
In a follow-up paper they identified potential health risks involving the liver, ovaries and testes (14).
In the background, other teams had discovered that not only the size but also the shape of the nano-particles was important (ie 15-17). Inhaled nano-particles of TiO2 exert significant effects on various cell populations but nano-rods turned out to be very much more toxic (18, 19). They cause inflammatory responses similar to those caused by crocidolite, which also has a nano-fibrous structure and is the most virulently carcinogenic form of asbestos. The longer the TiO2 nano-rods, the more toxic they are (19).
This presumably relates to damage caused by nano-fibers to intra-cellular structures because the same pattern of toxicity, with nano-particles being safe and nano-rods being carcinogenic, occurs with carbon (20).
Despite these findings EFSA, which in my view has an excessively pro-industry bias, declared TiO2 safe in 2016 (21). In the following 36 months, however, EFSA’s position was comprehensively undermined by two new pieces of evidence.
An Italian / Belgian group fed large doses of food grade TiO2 to mice, and found accumulation of titanium in the gut mucosa and liver with pronounced inflammatory responses (22).
The icing on the cake, however (and icing, particularly white icing, is chock-full of TiO2), was a report by a very reputable team out of France and Luxembourg showing that rats consuming food grade TiO2 at human dietary levels accumulated TiO2 in their Peyers Patches after a single week (23). After 100 days of a quasi-human diet the rodents developed intestinal pre-cancerous lesions; and there is evidence that these effects are exacerbated by dysbiosis (24, 25), now prevalent in the human population.
In 2020 the French government, cornered by these findings, uncharacteristically hoisted the white flag and banned TiO2 in food sold or manufactured in France (26). They cited ‘possible harmful effects in humans and a lack of scientific data to confirm safety’.
I believe this is the correct approach, and that other nations will probably follow suit.
New evidence showing that nano-TiO2 can penetrate skin and cause damage in the skin and liver (27, 28) raises a question mark over the continued use of TiO2 in sunscreens also.
More speculatively, industrially produced nano-particles of TiO2 in polluted air may well be contributing to the increasing incidence of neurodegenerative disease (29-31). This potential problem, and the possibility that the industrial use of TiO2 nano-particles could be causing wide-spread damage to the ecosystem (32), may eventually lead to further bans.
TiO2 is not a major cause of disease in humans, but it is probably a minor one. If the only cost of banning E171 is off-white cake icing and coffee creamer, that seems like a price worth paying. ‘Green’ forms of nano-TiO2 produced by plants such as Moringa oleifera are claimed to be safer, but that remains to be proven.
The future may be bright (eventually), but it may not be bright white.
Next week: To sleep, to die, and dream of milk. A new approach to cancer.
- Guth S, Hüser S, Roth A, Degen G, Diel P, Edlund K, Eisenbrand G, Engel KH, Epe B, Grune T, Heinz V, Henle T, Humpf HU, Jäger H, Joost HG, Kulling SE, Lampen A, Mally A, Marchan R, Marko D, Mühle E, Nitsche MA, Röhrdanz E, Stadler R, van Thriel C, Vieths S, Vogel RF, Wascher E, Watzl C, Nöthlings U, Hengstler JG. Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses. Arch Toxicol. 2020 May;94(5):1375-1415.
- Berglund F, Carlmark B. Titanium, sinusitis, and the yellow nail syndrome. Biol Trace Elem Res. 2011 Oct;143(1):1-7.
- Ataya A, Kline KP, Cope J, Alnuaimat H. Titanium exposure and yellow nail syndrome. Respir Med Case Rep. 2015 Oct 14;16:146-7.
- Itagaki H, Katuhiko S. Yellow nail syndrome following multiple orthopedic surgeries: a case report. J Med Case Rep. 2019 Jul 1;13(1):200.
- Suzuki T, Tokuda Y, Kobayashi H. The Development of Yellow Nail Syndrome after the Implantation of a Permanent Cardiac Pacemaker. Intern Med. 2017 Oct 1;56(19):2667-2669.
- Hsu TY, Lin CC, Lee MD, Chang BP, Tsai JD. Titanium Dioxide in Toothpaste Causing Yellow Nail Syndrome. Pediatrics. 2017 Jan;139(1):e20160546.
- Decker A, Daly D, Scher RK. Role of titanium in the development of yellow nail syndrome. Skin Appendage Disord. 2015;1:28–30.
- Barbieri M, Mencio F, Papi P, Rosella D, Di Carlo S, Valente T, Pompa G. Corrosion behavior of dental implants immersed into human saliva: preliminary results of an in vitro study. Eur Rev Med Pharmaco. 2017;21:3543–3548.
- Kim KT, Eo MY, Nguyen TTH, Kim SM. General review of titanium toxicity. Int J Implant Dent. 2019 Mar 11;5(1):10.
- Engh CA, Jr, Moore KD, Vinh TN, Engh GA. Titanium prosthetic wear debris in remote bone marrow. A report of two cases. J Bone Joint Surg Am. 1997;79:1721–1725.
- Feng X, Chen A, Zhang Y, Wang J, Shao L, Wei L. Application of dental nanomaterials: potential toxicity to the central nervous system. Int J Nanomedicine. 2015;10:3547–3565.
- Weir A, Westerhoff P, Fabricius L, von Goetz N. Titanium dioxide nanoparticles in food and personal care products. Environ. Sci. Technol. 2012;46:2242–2250.
- Rompelberg C, Heringa MB, van Donkersgoed G, Drijvers J, Roos A, Westenbrink S, Peters R, van Bemmel G, Brand W, Oomen AG. Oral intake of added titanium dioxide and its nanofraction from food products, food supplements and toothpaste by the Dutch population. Nanotoxicology. 2016 Dec;10(10):1404-1414.
- Heringa MB, Geraets L, van Eijkeren JC, Vandebriel RJ, de Jong WH, Oomen AG. Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations. Nanotoxicology. 2016 Dec;10(10):1515-1525.
- Kose O, Tomatis M, Leclerc L, Belblidia NB, Hochepied JF, Turci F, Pourchez J, Forest V. Impact of the Physicochemical Features of TiO2 Nanoparticles on Their In Vitro Toxicity. Chem Res Toxicol. 2020 Sep 21;33(9):2324-2337.
- Katsumiti A, Berhanu D, Howard KT, Arostegui I, Oron M, Reip P, Valsami-Jones E, Cajaraville MP. Cytotoxicity of TiO2 nanoparticles to mussel hemocytes and gill cells in vitro: Influence of synthesis method, crystalline structure, size and additive. Nanotoxicology. 2015;9(5):543-53.
- Wang J, Fan Y. Lung injury induced by TiO2 nanoparticles depends on their structural features: size, shape, crystal phases, and surface coating. Int J Mol Sci. 2014 Dec 3;15(12):22258-78.
- Allegri M, Bianchi MG, Chiu M, Varet J, Costa AL, Ortelli S, Blosi M, Bussolati O, Poland CA, Bergamaschi E. Shape-related toxicity of titanium dioxide nanofibres. PLoS ONE. 2016;11:e0151365.
- Porter D.W, Wu N, Hubbs A.F, Mercer R.R, Funk K, Meng F, Li J, Wolfarth MG, Battelli L, Friend S, Andrew M, Hamilton R Jr, Sriram K, Yang F, Castranova V, Holian A. Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts. Toxicol. Sci. 2013;131:179–193.
- Sakamoto Y, Nakae D, Fukumori N, Tayama K, Maekawa A, Imai K, Hirose A, Nishimura T, Ohashi N, Ogata A. Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fischer 344 rats. J Toxicol Sci. 2009 Feb;34(1):65-76.
- EFSA-European Food Safety Authority Re-evaluation of titanium dioxide (E 171) as a food additive. EFSA J. 2016;14:e04545.
- Talamini L, Gimondi S, Violatto M.B, Fiordaliso F, Pedica F, Tran N.L, Sitia G, Aureli F, Raggi A, Nelissen I, Cubadda F, Bigini P, Diomede L. Repeated administration of the food additive E171 to mice results in accumulation in intestine and liver and promotes an inflammatory status. Nanotoxicology. 2019;13:1087–1101.
- Bettini S, Boutet-Robinet E, Cartier C, Coméra C, Gaultier E, Dupuy J, Naud N, Taché S, Grysan P, Reguer S, Thieriet N, Réfrégiers M, Thiaudière D, Cravedi JP, Carrière M, Audinot JN, Pierre FH, Guzylack-Piriou L, Houdeau E. Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon. Sci. Rep. 2017;7:1–13.
- Bianchi M.G, Allegri M, Chiu M, Costa A.L, Blosi M, Ortelli S, Bussolati O, Bergamaschi E. Lipopolysaccharide adsorbed to the bio-corona of TiO2 nanoparticles powerfully activates selected pro-inflammatory transduction pathways. Front. Immunol. 2017;8:866.
- Ruiz PA, Morón B, Becker H.M, Lang S, Atrott K, Spalinger MR, Scharl M, Wojtal K.A, Fischbeck-Terhalle A, Frey-Wagner I, Hausmann M, Kraemer T, Rogler G. Titanium dioxide nanoparticles exacerbate DSS-induced colitis: Role of the NLRP3 inflammasome. Gut. 2017;66:1216–1224.
- Arrêté du 17 avril 2019 Portant Suspension de la Mise sur le Marché des Denrées Contenant l’Additif E 171 (dioxyde de titane-TiO2) [accessed 24 May 2020]. Available online: https://www.legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000038410047&categorieLien=id.
- Wu J, Liu W, Xue C, Zhou S, Lan F, Bi L, Xu H, Yang X, Zeng F-D. Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol. Lett. 2009;191:1–8.
- Pelclova D, Navratil T, Kacerova T, Zamostna B, Fenclova Z, Vlckova S, Kacer P. NanoTiO2 sunscreen does not prevent systemic oxidative stress caused by UV radiation and a minor amount of nanoTiO2 is absorbed in humans. Nanomaterials. 2019;9:888.
- Calderón-Garcidueñas L, Reed W, Maronpot RR, Henríquez-Roldán C, Delgado-Chavez R, Calderón-Garcidueñas A, Dragustinovis I, Franco-Lira M, Aragón-Flores M, Solt AC, Altenburg M, Torres-Jardón R, Swenberg JA. Brain inflammation and Alzheimer’s-like pathology in individuals exposed to severe air pollution. Toxicol Pathol. 2004 Nov-Dec;32(6):650-8.
- Calderón-Garcidueñas L, Kavanaugh M, Block M, D’Angiulli A, Delgado-Chávez R, Torres-Jardón R, González-Maciel A, Reynoso-Robles R, Osnaya N, Villarreal-Calderon R, Guo R, Hua Z, Zhu H, Perry G, Diaz P. Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. J Alzheimers Dis. 2012;28(1):93-107.
- Shi L, Wu X, Danesh Yazdi M, Braun D, Abu Awad Y, Wei Y, Liu P, Di Q, Wang Y, Schwartz J, Dominici F, Kioumourtzoglou MA, Zanobetti A. Long-term effects of PM2·5 on neurological disorders in the American Medicare population: a longitudinal cohort study. Lancet Planet Health. 2020 Oct 19:S2542-5196(20)30227-8.
- Lee H, Myung W, Kim DK, Kim SE, Kim CT, Kim H. Short-term air pollution exposure aggravates Parkinson’s disease in a population-based cohort. Sci Rep. 2017 Mar 16;7:44741.
- Hou J, Wang L, Wang C, Zhang S, Liu H, Li S, Wang X. Toxicity and mechanisms of action of titanium dioxide nanoparticles in living organisms. J Environ Sci (China). 2019 Jan;75:40-53.