Response of Jugdaohsingh et al. (Nutrition & Metabolism 2013, 10:65) is not convincing concerning the safety of MMST. Dirk Vanden Berghe, University of Antwerp 29 November 2013 It is correct that I was involved in clinical and pre-clinical studies on choline-stabilized orthosilicic acid (ch-OSA) and in the galenic formulation of ch-OSA containing food supplements. As indicated in my letter, my work on silicon was partly funded by research funds from the industry. I have received such funds not only from Bio Minerals but also from other companies and only until September 2009 which is more than 4 years ago. Sponsoring of research by the industry is common practice, in fact the study of the authors on MMST was also sponsored by the manufacturer of MMST (LLR-G5 Ltd.). The authors distract the reader by bringing the subject to ch-OSA instead of the topic of my letter which is the safety issue of monomethylsilanetriol (MMST). The authors erratically refer to ch-OSA as "nanosilica". ch-OSA is a liquid which is diluted in a beverage when it is used as a food supplement. A 29Si-speciation study of which I was the co-investigator and professor Kinrade the investigator clearly demonstrated that the majority of the silicon in the ch-OSA dilute is present in the form of orthosilicic acid. Analysis of serum and urine of healthy subjects who took ch-OSA, demonstrated that only orthosilicic was present. This study was part of a technical dossier on ch-OSA which was submitted to the European Food Safety Authority (EFSA) and is referenced in the EFSA opinion on ch-OSA (see reference 8 of my letter). The EFSA's panel of experts describes the following in their published EFSA opinion " NMR analysis, after dilution of a 2 % silicon containing 29Si-ch-OSA sample in water, demonstrates that the majority of silicon is present as orthosilicic acid " and " 29 Si-NMR analysis of serum, collected 2 h after administration of ch-OSA, demonstrated that only orthosilicic acid was present. 29Si-NMR analysis of urine also indicated the presence of orthosilicic acid in a sample collected during the first 3 h after intake of ch-OSA " (see also: http://www.efsa.europa.eu/de/efsajournal/doc/948.pdf) . Typically, " nanosilica" are very small, solid particles of amorphous silica. Inhalation of these dry nano particles was found to induce lung inflammation and intravenous administration was found to cause liver injury in rodents. It is not clear to which extend the particles dissolve into ortosilicic acid when orally administrated. Clearly, such nanosilica are very different from ch-OSA. The authors refer to a textbook of Iler. In this textbook it is explained (page 175) that nanoparticles are formed by polymerization of orthosilicic acid, but only in basic (i.e. pH > 7) solution. According to Iler such nanoparticles will not form in ch-OSA since ch-OSA is a liquid with a very low pH (1.2) i.e. very acid. I share the authors' concern about the safety of nanosilica, but this has no relation with ch-OSA for the reasons explained above. Surprisingly, the authors mention that "MMST is used widely in continental Europe without any reported adverse effects". It should be clear however that since 2009, MMST cannot legally be used in food supplements in the European Union, since it is not in the list of authorized ingredients. EFSA concluded in her opinion on MMST (see: http://www.efsa.europa.eu/en/efsajournal/doc/950.pdf) that " given the absence of adequate data on the bioavailability of silicon from monomethylsilanetriol and the toxicity of monomethylsilanetriol, the panel could not assess the safety of the source " which resulted in a "negative" EFSA opinion. Any use of MMST in food supplements is forbidden in the EU since 2009. The authors minimize the importance of toxicology studies. MMST has not been studied in core toxicology studies nor has it been studied in long term animal and/or human supplementation studies. The latter studies could be used to justify the absence of core toxicology studies. If such studies exist we invite the authors to cite these as I have not been able to find these and neither has EFSA in 2009. The authors do not agree to use primitive organisms such as diatoms or plants as indicator species for human safety. I find this a bizarre statement since the AMES test, a generally accepted test for mutagenicity, is done with bacteria and is part of core toxicology studies. Plants are as humans, eukaryotic organisms with a similar complexity in biochemical pathways. At the very least, when proof of toxicity is found in these organisms more careful investigation is needed to document human safety, moreover when core toxicology studies or long term supplementation studies in animals and humans cannot be found. I am happy to see that the authors agree with my remark that their study in pre-menopausal women should be expanded to other population groups. With respect to the study design the authors minimize the absence of both a wash-out period and information on the diet of the participants although this is standard procedure in good clinical practice of such studies. The authors also minimize the fact that in their study they have not taken into account the glomerular filtration rate and give a non-convincing answer. Fact is that we have no information on the dietary intake of the study subjects including on differences in beverage consumption between subjects and between sessions for the same subject (cross-over !). Such differences will impact urine concentrations when it is reported in mg/l and make the obtained results unreliable. My remark that tissue loading of MMST cannot be excluded, remains valid even when 10 % of the measured increase in urinary silicon is found as MMST. It is not known for sure what has caused the total increase in urinary silicon since this can be a result of differences in glomerular filtration rate or differences in dietary silicon intake. The fact that a large quantity of MMST is detected in serum is completely contradictory to the authors' general statement in their article that "MMST is converted to orthosilicic acid". Such statement is simply not supported by their data. The authors claim that indications are found in work of Côté-Beaulieu et al. (2009) and Arkles et al. (2013), which I have cited in my letter, for the "in vivo bioconversion of methylsilanetriols to silicic acid". The work of Côté-Beaulieu, shows that organic silanols are phytotoxic and cannot be considered as substitutes for silicic acid. These authors suggest that monomethyl silicic acid remains in soluble form in planta and that deposits are formed directly on the leaf surface following the hydrolysis to silicic acid or alternatively, by polymerization to polydimethylsiloxane, i.e. hydrolysis to silicic acid remains purely hypothetical and the observed deposits can also be explained by polymerization to polydimethylsiloxane. In the work of Arkles et al. the 29Si- NMR spectrum of a hydrolysate of hydroxymethyltriethoxysilane shows a multiplicity of resonances which does not refer to orthosilicic acid. In the same work, studies with diatoms show that the growth rate is reduced with 25-30 % when hydroxymethylsilanetriol is used in the culture medium instead of silicic acid. When the culture medium is aged over 6 days the difference in growth rate is no longer observed which leads the authors to suggest that a conversion to silicic acid could have happened. This remains hypothetical as no proof is given by these authors of such a conversion. Fact is, that a significant growth inhibitory effect is observed for hydroxymethylsilanetriol in diatoms. The authors refer to a 29Si speciation study as "extremely expensive", "time consuming" and " insufficient 29Si for quantitation by the world's most sensitive 29Si NMR spectrometer". The first two statements are in part correct i.e. such a study is expensive and time consuming but of the same order as any other well designed clinical study with proper analytical testing. However this should not pose any problems when human safety is to be documented. The last statement is incorrect since the authors themselves, confirm that they have done such a study (see endnotes, page 8: " In practice, however the best experimental LOD that the same authors have ever achieved in blood, for example, is just under 1 ppm (manuscript in preparation, Kinrade et al.) ". Since the authors have previously published that MMST has a high bioavailability, it should not be problematic to obtain such silicon concentrations in serum and urine, it is more a question of adjusting the supplementation dosage. A 29Si speciation study is the only objective method to investigate if MMST is to a great extent converted to OSA in vivo. In conclusion, I firmly stand with the remarks I made in my letter. The fact that organic silanols are widely used and that core toxicology or long term studies in animals or humans are not available for these compounds, should make us alert and justify the need for more studies prior of making bold statements such as "The silicon supplement MMST is safe". Moreover since silicon and in particular silicic acid has been suggested as the natural antagonist to the toxicity of aluminum, the application of orthosilicic acid's organic analog MMST should be carefully evaluated. This remains my major concern. Competing interests DVB has received in the past 5 years research funds from the silicon supplement industry until September 2009.