Anderson, Simon Hc

Jugdaohsingh, Ravin

Kinrade, Stephen D

Powell, Jonathan J

Nutrition & Metabolism

PubMed

Ravin Jugdaohsingh

Simon HC Anderson

Stephen D Kinrade

Jonathan J Powell

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Response to Prof D. Vanden Berghe letter: 'There are not enough data to conclude that Monomethylsilanetriol is safe’

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Apollo (Cambridge)

Jugdaohsingh et al. Nutrition & Metabolism 2013, 10:65http://www.nutritionandmetabolism.com/content/10/1/65LETTER TO THE EDITOR Open AccessResponse to Prof D. Vanden Berghe letter: ‘Thereare not enough data to conclude thatMonomethylsilanetriol is safe’Ravin Jugdaohsingh1,2*, Simon HC Anderson2, Stephen D Kinrade3 and Jonathan J Powell1This article is in response to Vanden Berghe: There are not enough data to conclude that Monomethylsilanetriol is safe. Nutrition & Metabolism 201310:66: www.nutritionandmetabolism.com/content/10/1/66Keywords: Monomethylsilanetriol, Choline-stabilised orthosilicic acid, Nanoparticles, Orthosilicic acid, Proton nuclearmagnetic resonance spectroscopyBackground & discussionThe silicon supplement “ch-OSA [choline stabilized‘orthosilicic’ acid] was developed by Dirk Vanden Berghefor Bio Minerals n.v.” [1-4]. Here, Dirk Vanden Bergheprovides a list of comments/questions on our recentpublication [5] concerning a different form of supplemen-tal silicon, namely ‘Monomethylsilanetriol’ (MMST; Si(OH)3CH3).We entirely disagree with his concerns but beforeaddressing these directly, we wish to re-emphasiseimportant background information. Germane to this isthe understanding of the limitations and concernsover current supplemental forms of silicon, as dictatedby their aqueous chemistry.From the diet silicon is absorbed as Si(OH)4(orthosilicic acid) [6-8]. Any effort to concentrate thisform of silicon leads to self-association, polymerisationand (nano) silica formation. In ch-OSA, for example, ahigh dose quaternary ammonium compound stabilisesthese very small nanoparticles of silica to prevent theiraggregation [9] as, for example, is discussed by Iler[10]. However, in the case of silicon dioxide/silicic acid,no stabilisers are used and aggregation may proceedwith mixed soluble, nano and micron sized silica species(note, in this case, silicic acid is used as a ‘catch-all’ formonomeric and varying degrees of polymeric silica). For* Correspondence: ravin.jugdaohsingh@mrc-hnr.cam.ac.uk1MRC Human Nutrition Research, Elsie Widdowson Laboratory, FulbournRoad, Cambridge CB1 9NL, UK2Gastrointestinal Laboratory, Rayne Institute, St Thomas’ Hospital, London, UKFull list of author information is available at the end of the article© 2013 Jugdaohsingh et al.; licensee BioMedCreative Commons Attribution License (http:/distribution, and reproduction in any mediumDomain Dedication waiver (http://creativecomarticle, unless otherwise stated.all of these supplemental forms, bioavailability is limited(absorption less than 20% and as low as 1%) [8]. Moreover,there are currently significant concerns over nanosilicaand more careful evaluation is required for its safeingestion [11,12]. We thus reported on the metabolismand human safety of a soluble silicon form (MMST)that is very well absorbed (i.e. equivalent to dietaryorthosilicic acid [8,13]).Direct responsesOverall, our intention was not to provide a full toxico-logical report of MMST but, rather, and as stated in ourpaper [5], to establish if it contributes to the body poolof silicon in humans and, if so, whether it was safe inthat setting. We stand firmly by our conclusions that, inboth cases, the answers are “yes”: MMST provided amarked increase in the body pool of Si according tostate-of-art measures and was safe throughout thestudy. Nonetheless, we fully agree that for a formalsafety assessment of MMST, or any (silicon) supplement,human safety data should be accompanied by specific,preclinical toxicological data and, as Professor VandenBerghe notes, be judged in Europe by the EFSA ratherthan by individual academics. Our following responses dealwith the points of his main letter in chronological order:1. We do not agree that EFSA previously gave a“negative” opinion on the use of MMST as asupplement. They were unable to reach a conclusionas insufficient data were provided [14]. TheCentral Ltd. This is an Open Access article distributed under the terms of the/creativecommons.org/licenses/by/2.0), which permits unrestricted use,, provided the original work is properly cited. The Creative Commons Publicmons.org/publicdomain/zero/1.0/) applies to the data made available in thisJugdaohsingh et al. Nutrition & Metabolism 2013, 10:65 Page 2 of 4http://www.nutritionandmetabolism.com/content/10/1/65assessment process appears, nonetheless, ongoing,underpinning the importance of new findings suchas those provided in our manuscript [5].2. In the introduction of our paper, previous studies,when taken together, help to provide a rationale forour study: they add weight to arguments over thehuman safety of MMST rather than beingconclusive in their own right. Indeed, this is partlywhy we undertook a more direct human safetystudy. As stated in the introduction of our paper,MMST is used widely in continental Europe withoutany reported adverse effects.3. We concur with EFSA guidance that long termhuman safety studies are not required for safetyassessment of food supplements. However, as notedabove, at least some appropriate pre-clinicaltoxicological data should be provided. In the contextof diet and dietary supplement assessment, the studyof 22 human subjects over 4 weeks providessignificant and relevant added value to toxicologicalassessment in rodents. Indeed, again using ch-OSAas an example of one of the approved Europeansilicon supplements, we note the EFSA’s actualcomments of Section 3.3 in their report [15]; “Thepetitioner states that no complete toxicologicalevaluation was carried out for ch-OSA since itcontains choline and a stabilised form of a naturaloccurring silicon compound (orthosilicic acid). Instead,the petitioner provided the results of a large number ofanimal and human supplementation studies”.Notwithstanding that orthosilicic acid should readnanosilica, it makes the valid and important pointthat dietary supplements do not carry the same onusof toxicological assessment as therapeutics. Datamay, more commonly, be bridged and evidence isusually drawn from both direct rodent studies andhuman supplementation studies. The process isrobust but, equally, recognises the distinctionbetween a “food” and a “therapeutic”.4. We do not support Professor Vanden Berghe’simplication that “plants” (nor primitive organisms suchas diatoms) should now be used as indicator species forhuman safety assessment and, rather, support thecurrent processes in place. In fact two studies thatProfessor Vanden Berghe cites (Blunder et al., 2011 &Arkles et al., 2013) did not investigate MMST.5. Data sheets and analytical reports confirmed thepurity of the MMST in aqueous solution with onlybackground potassium and phosphate ions: no othercomponents were present when assessed againststringent analytical criteria.6. Page 2, line 53 to line 57 of our manuscript [5]explains why pre-menopausal women may be animportant target population for Si supplementation.We agree that similar investigations could beundertaken in men and older women, but it is highlyunlikely that any potential detrimental effects wouldbe seen in these populations and not in youngwomen. Indeed, we previously reported nodifference in the metabolism of MMST or OSA inthese different populations [8,16].7. We disagree with Professor Vanden Berghe’sconcerns over our study design. Subjects were usedas their own controls against placebo, in arandomised and blinded fashion: this is a standard,robust trial design that allows conclusions to bedrawn in comparing the “active” to “placebo” andboth against baseline. Given that only the active(MMST), and not placebo, differed from baselineand there were no effects of order (MMST beforeplacebo or placebo before MMST), then clearly thediet over the eight weeks played no significant role.Secondly, previous work, as we have referenced[8,13], characterised the acute urinary excretion ofMMST: the ten-hour fast of subjects in our just-published study [5] was well outside of this period.Indeed, that only 10% of the increase in total urinarysilicon post supplementation could be accounted forby MMST proves that there was little carry over.Thirdly, the finding of very low urinary levels ofMMST in a few volunteers at baseline or afteringesting only placebo indicates some normalbackground environmental exposure. Whilst thesource would be of interest, in the context of thisstudy the levels were tiny (21 ± 7 μg/L MMST versus8.5 ± 5 mg/L total Si in the same urine samples) andin no way could therefore contribute to our findings.Fourthly, there was no wash out period (see‘Subjects and methods’ section [5]), and the fact thatthere was no effect of treatment order on theanalytical results justifies this decision.8. Professor Vanden Berghe refers to a comment onour study that was posted on line by Dr C Exley,who proposes that valid interpretation of ourfindings would require GFR measures. For three ofthe outcomes of interest in our publication, namelyraised fasting serum Si as a marker of Si stores,serum Si:MMST ratios and the safety of MMST,there is little to be added by such a measure.However, for the fourth outcome, namely Si:MMSTratio in urine following supplementation, additionalurinary creatinine measures may have a role-at leastto ward off improbable theories of the data beingerroneous due to alterations in renal handling. Ourlong experience with dietary silicon metabolismstudies has taught us that inter-individual variationleads to far greater variance than intra-individualurinary Si excretion. Thus we controlled for this1Jugdaohsingh et al. Nutrition & Metabolism 2013, 10:65 Page 3 of 4http://www.nutritionandmetabolism.com/content/10/1/65variance using a cross over design, such that thesame volunteers emptied their bladders at the sametime of day on three separate occasions. As notedabove we used the robust design of double bind,placebo-controlled intervention: the baseline andplacebo intervention yielded no difference in urinarysilicon concentrations. As such, for MMSTintervention to increase the urinary siliconconcentration as an artefact, the supplement wouldneed to cause an unexpected concentration ofdissolved urinary solids. Our prior work on MMSTabsorption and excretion in volunteers has notrevealed changes in urinary volume and, as ouroverall objective was to seek Si:MMST ratiosfollowing supplementation, arguments aroundimprovement of GFR would also need to includedisproportionate concentration of one form ofsilicon over the other. The increase in fastingurinary silicon levels mirrored increases in fastingserum silicon levels and we stand fully by theinterpretation of these findings.9. It is not possible that tissue uptake of MMST explainsour data. Ingested MMSTcould not increase totalurinary silicon by the amounts shown ANDsimultaneously be partitioned into tissue. The pointwe made, that appears to have been missed, is asfollows: of the measured increase in urinary silicon,only 10% exists in the form of MMST (either as thetail of the acute excretion or a slower secondarypathway of excretion). Either way, MMST is clearlybeing converted to inorganic silicon since no otherorganic form was detected by proton NMR. At theseconcentrations inorganic silicon only exists as Si(OH)4.0. Regarding the use of 29Si NMR for speciation,Professor Vanden Berghe quotes some idealised,non-aqueous limit of detection (LOD) work. Underaqueous conditions in biological samples the limitof quantitation is greatly compromised. An entirestudy with pure 29Si-supplement would not onlybe extremely expensive and time consuming butwould still provide samples with insufficient 29Sifor quantitation by the world’s most sensitive 29SiNMR spectrometera. We took a pragmatic and robustapproach to the problem and used differential analysis(1H-NMR versus ICPOES) to demonstrate, albeitindirectly, bioconversion. Coupled with the publisheddirect metabolism data that we reference we firmlyconclude that supplemental MMST undergoesmetabolism (demethylation and hydroxylation) andforms Si(OH)4 in vivo in humans. Interestingly, thework of Côté-Beaulieu et al., (2009) and Arkles et al.,(2013) that Professor Vanden Berghe cites, alsoindicate the in vivo bioconversion of methylsilanetriolsto silicic acid.ConclusionWe fully stand by our statements over the safety and meta-bolism of MMST in the human setting of our study. Weurge that with the spotlight on nanosilica safety, other formsof supplemental silicon now provide similar direct safety data.EndnotesaIn the 1999 paper referred to by Professor VandenBerghe (Knight CTG, Kinrade SD. Silicon-29 nuclearmagnetic resonance spectroscopy detection limits. AnalChem 1999, 71:265-267), the authors reported optimal29Si NMR limits of detection (LOD), based on a 2:1signal-to-noise ratio (S/N) and using the highest-fieldcommercial spectrometer available for 29Si NMR, forhexamethyldisiloxane dissolved in chloroform. Using anormal one-pulse sequence with a 17 h total run time(6784 90° pulses with a recycle period of 10 s, attenuatedby the addition of Cr(acac)3 relaxation agent), theyachieved a 2 ppm LOD. They managed to reduce theLOD to 0.3 ppm by using a DEPT-45 pulse sequencewhich transfers polarization to 29Si nuclei from coupledmethyl protons and also permits much faster pulserecycling. This technique, however, is not possible fororthosilicic acid, owing to rapid exchange of silanolprotons with water. Moreover, the T1 relaxation timefor dilute orthosilicic acid in blood or urine exceeds30-40 s (Kinrade SD, Marat K, Knight CTG. Longitu-dinal 29Si nuclear magnetic relaxation in aqueous alkali-metal silicate solutions revisited. J Phys Chem 1996,100:18351-18356). Based on the numbers presented above,the theoretical LOD for orthosilicic acid in a biofluidwould be approximately 7 ppm (612 90° pulses with arecycle period of 100 s over 17 h). This would be expectedto decrease to 0.4 ppm if the orthosilicic acid was 100%enriched in 29Si isotope. In practise, however, the best ex-perimental LOD that the same authors have ever achievedin blood, for example, is just under 1 ppm (manuscript inpreparation, Kinrade et al). Unfortunately, the aboveLODs are not sufficient for semi-quantitative NMR. Highprecision (standard deviation <1%) NMR peak integra-tion requires at least a 250:1 S/N (Holzgrabe U. Quantita-tive NMR spectroscopy in pharmaceutical applications.Progr Nucl Magn Reson Spectr 2010, 57:229-240). Even aminimal level of precision would require at least a 25:1 S/Nor a biofluid concentration of 25 ppm 29Si.Competing interestsThe authors’ laboratories have received research funding from the siliconsupplement and food industry. For the work presented in the just-publishedpaper [5] the MMST and placebo solutions and costs of 1H-NMR analysiswere provided by LLR-G5 Ltd (Castlebar, Ireland) and all other research costswere met by the author’s laboratories. The research was designed, executed,analysed and communicated only by the authors. J. J. P. and S. D. K. haveconsulted to BioMinerals NV (Ch-OSA company) and/or LLR-G5 Ltd (MMSTcompany) and others in the silicon supplement industry. All other authorshave no competing interest.Jugdaohsingh et al. Nutrition & Metabolism 2013, 10:65 Page 4 of 4http://www.nutritionandmetabolism.com/content/10/1/65Author details1MRC Human Nutrition Research, Elsie Widdowson Laboratory, FulbournRoad, Cambridge CB1 9NL, UK. 2Gastrointestinal Laboratory, Rayne Institute,St Thomas’ Hospital, London, UK. 3Department of Chemistry, LakeheadUniversity, Thunder Bay, ON, Canada.Received: 18 October 2013 Accepted: 19 October 2013Published: 22 October 2013References1. Calomme M, Geusens P, Demeester N, Behets GJ, D’Haese P, SindambiweJB, Vanden Berghe D, Van H: Partial prevention of long-term femoralbone loss in aged ovariectomized rats supplemented with cholinestabilized orthosilicic acid. Calcif Tissue Int 2006, 78:227.2. Barel A, Calomme M, Timchenko A, De Paepe K, Demeester N, Rogiers V,Clarys P, Vanden Berghe H: Effect of oral intake of choline-stabilizedorthosilicic acid on skin, nails, hair in women with photodamaged skin.Arch Dermatol Res 2005, 297:147.3. Wickett RR, Kossman E, Barel A, Demeester N, Clarys P, Vanden Berghe D,Calomme M: Effect of oral intake of choline-stabilized orthosilicic acid on hairtensile strength and morphology in women with fine hair. Arch Dermatol Res2007, 299:499.4. Spector TD, Calomme MR, Anderson SHC, Clement G, Bevan L, Demeester N,Swaminathan R, Jugdaohsingh R, Berghe DA, Powell JJ: Choline-stabilizedorthosilicic acid supplementation as an adjunct to calcium/vitamin D3stimulates markers of bone formation in osteopenic females: a randomised,placebo-controlled trial. BMC Musculoskelet Disord 2008, 9:85–95.5. Jugdaohsingh R, Hui M, Anderson SH, Kinrade SD, Powell JJ: The siliconsupplement ‘Monomethyl silanetriol’ is safe and increases the body pool ofsilicon in healthy pre-menopausal women. Nutr Metab (Lond) 2013, 10:37.6. Jugdaohsingh R, Anderson SH, Tucker KL, Elliott H, Kiel DP, Thompson RP, PowellJJ: Dietary silicon intake and absorption. Am J Clin Nutr 2002, 75:887–893.7. Jugdaohsingh R, Reffitt DM, Oldham C, Day JP, Fifield LK, Thompson RP,Powell JJ: Oligomeric but not monomeric silica prevents aluminumabsorption in humans. Am J Clin Nutr 2000, 71:944–949.8. Sripanyakorn S, Jugdaohsingh R, Dissayabutr W, Anderson SH, ThompsonRP, Powell JJ: The comparative absorption of silicon from different foodsand food supplements. Bri J Nutr 2009, 102:825–834.9. Jugdaohsingh R, McCrohan CR, White KN, Thompson RPH, Powell JJ: Rapidnon-equilibrium aluminium-ligand interactions: studies on theprecipitation of aluminium by laser light scattering, ultrafiltration andcentrifugation. J Inorg Biochem 2001, 87:29–35.10. Iler RK: The chemistry of silica: solubility, polymerisation, colloid and surfaceproperties, and biochemistry. New York: John Wiley & Sons; 1979.11. Gehrke H, Frühmesser A, Pelka J, Esselen M, Hecht LL, Blank H, Schuchmann HP,Gerthsen D, Marquardt C, Diabate S, Weiss C, Marko D: In vitro toxicity ofamorphous silica nanoparticles in human colon carcinoma cells.Nanotoxicology 2012, 7:274–293. Epub ahead of print.12. Napierska D, Thomassen LCJ, Lison D, Martens JA, Hoet PH: The nanosilicahazard: another variable entity. Part Fibre Toxicol 2010, 7:39.13. Allain P, Cailleux A, Mauras Y, Renier JC: Digestive absorption of siliconafter a single administration in man in the form of methylsilanetriolsalicylate. Therapie 1983, 38:171–174.14. European Food Safety Authority. Scientific Opinion: Monomethylsilanetrioladded for nutritional purposes to food supplements: scientific opinionof the panel on food additives and nutrient sources added to food(EFSA-Q-2006-198, EFSA-Q-2006-296). EFSA J 2009, 950:1–12.15. European Food Safety Authority: Scientific opinion of the panel on foodadditives and nutrient sources added to food on cholinestabilisedorthosilicic acid added for nutritional purposes to food supplementsfollowing a request from the European commission. EFSA J 2009, 948:1–23.16. Jugdaohsingh R, Sripanyakorn S, Powell JJ: Silicon absorption andexcretion is independent of age and sex in adults. Bri J Nutr 2013,110:1024–1030.doi:10.1186/1743-7075-10-65Cite this article as: Jugdaohsingh et al.: Response to Prof D. VandenBerghe letter: ‘There are not enough data to conclude thatMonomethylsilanetriol is safe’. 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Response to Prof D. Vanden Berghe letter: 'There are not enough data to conclude that Monomethylsilanetriol is safe'.

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Response to Prof D. Vanden Berghe letter: 'There are not enough data to conclude that Monomethylsilanetriol is safe'.

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