Abstract

Vitamin D synthesis by exposure of skin to solar ultraviolet radiation (UVR) provides the majority of this hormone that is essential for bone development and maintenance but may be important for many other health outcomes. This process, which is the only well-established benefit of solar UVR exposure, depends on many factors including genetics, age, health, and behavior. However, the most important factor is the quantity and quality of UVR reaching the skin. Vitamin D synthesis specifically requires ultraviolet B (UVB) radiation that is the minority component (<5%) of solar UVR. This waveband is also the most important for the adverse effects of solar exposure. The most obvious of which is sunburn (erythema), but UVB is also the main cause of DNA damage to the skin that is a prerequisite for most skin cancers. UVB at the Earth's surface depends on many physical and temporal factors such as latitude, altitude, season, and weather. Personal, cultural, and behavioral factors are also important. These include skin melanin, clothing, body surface area exposed, holiday habits, and sunscreen use. There is considerable disagreement in the literature about the role of some of these factors, possibly because some studies have been done by researchers with little understanding of photobiology. It can be argued that vitamin D supplementation obviates the need for solar exposure, but many studies have shown little benefit from this approach for a wide range of health outcomes. There is also increasing evidence that such exposure offers health benefits independently of vitamin D: the most important of which is blood-pressure reduction. In any case, public health advice must optimize risk versus benefit for solar exposure. It is fortunate that the individual UVB doses necessary for maintaining optimal vitamin D status are lower than those for sunburn, irrespective of skin melanin. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.


Authors

Neville, Jonathan J;  Palmieri, Tommaso;  Young, Antony R

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  • pre-publication peer review (FINAL ROUND)
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    2020/12/17

    17-Dec-2020

    Dear Antony:

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    2020/12/02

    02-Dec-2020

    RE: JBMR Plus MS# JBM4-08-20-0098 : Physical Determinants of Vitamin D Status

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    Deputy Editor Comments to Author:

    Thanks for submitting an interesting Ms -- the referees have major comments and questions and we hope you will be able to address these points and correct what is needed and formulate a rebuttal if you have good arguments to do so

    we look forward to a revised Ms in one week if possible

    Reviewer(s)' Comments to Author:

    Reviewer: 1

    Comments to the Author
    This is a useful review of current understanding of the factors that affect vitamin D synthesis. It is submitted as an Original Article, but is effectively a review and contains no new experimental research by the authors. It is not entirely clear how it should be evaluated, but it would be misleading not to put ‘Review’ or ‘Overview’ in the title. The article covers the salient points, but does not reveal anything particularly new. It is helpful in pointing out where there are still uncertainties with opposing results in the literature, or unknowns.
    The broad structure is well organised. However, there are many instances of careless or imprecise expression that at best reduces clarity and at worst means the sentence is incorrect, or could at least be interpreted incorrectly.
    There are also too many examples of sudden change in subject or direction, and disconnects between statements that are presumably meant to be supportive of each other.
    These confusions need to be removed before the paper can be published.
    Abstract – ‘Vitamin D synthesis specifically requires UVB (wavelengths from ~295-315nm) in sunlight that is the minority component (<5%) solar UVR.’ This is an awkward sentence and incorrect. The UVB does not have to come from sunlight. Split into two sentences, after the first parentheses.
    Intro, first paragraph – ‘many effects on human health’; ‘such as reduced blood pressure’
    ‘This dose, in physical terms, is very dependent on the UVR source used.’ This sentence needs further explanation. What ‘physical terms’ are referred to here? The erythema effective UV dose as defined previously is not source dependent. There is also a contradiction with the second paragraph on Action Spectrum.
    Vitamin D deficiency – this section is contradictory and unsatisfactory. It highlights Africa as having particularly poor vitamin D status even though better than the global average, and the UK (the only two comparators). This section needs to be more thorough and consistent.
    Action spectra – it should be noted that the CIE action spectrum is only truly applicable for initial irradiations and the first step in vitamin D synthesis (7DHC to previtamin D). Prolonged exposure (at least in sunlight) will initiate other reactions. Use with care – as discussed in the CIE document! It is disingenuous to say the CIE action spectrum should be shifted to match the unpublished Young action spectrum that has a different endpoint. They are assessing two different outcomes. Which outcome is the better one to use is a different debate.
    Paragraph on reciprocity and pig skin. What is the point of this within the context of determining an action spectrum for pre vitamin D / vitamin D / 25OHD (which one, not stated)? Yes, reciprocity is important, but seems a distraction from the fact of having a peak very similar to the CIE action spectrum for previtamin D synthesis.
    UVR Dose – end first paragraph – there are other publications that show the plateau effect after repeated exposures occurs also with low starting status of 25OHD (eg Farrar et al.)
    Second paragraph – sudden change from human to pig skin. On the human study, given the previous discussions can this be qualified with source and dose given.
    Neither constitutive pigmentation…. It is not clear which study this comment refers to, please clarify. If it is a general statement then it is unreferenced and there are other studies that do show a clear impact of constitutive pigmentation and these should also be mentioned. In fact they should be mentioned anyway to provide a balanced view.
    Atmosphere – not exposed to the health effects of UVB, but exposed to UVB with consequent health effects.
    The limited evidence for decreasing UVB is unsurprising as neither ozone nor UVB changed enormously outside polar regions – and other atmospheric factors also play a role.
    End second paragraph – UVB scattering is always greater than for UVA, not just when the pathlength is long.
    Next paragraph – very confused, sudden switch to UVI and the paragraph ends with talking about ODSs. Rewrite. At the start: effect of clouds is smaller than what? Clouds do not contribute to UVI, they contribute to attenuation of UV radiation in the atmosphere and therefore modify the incident UVR / UVI.
    Altitude – in keeping with previous paragraphs there is scope for more discussion of the physical changes to UV irradiance at altitude, rather than, or as well as the vitamin d studies that are confounded by multiple factors not yet discussed. See eg papers by Blumthaler and others.
    Temporal factors - Seasonal changes can be modelled to agree with observational data(105) – what does this mean, or prove?
    Second paragraph – another disconnect between the two parts of this paragraph.
    Body site and surface area – ‘The increase with abdominal exposure was 4nmol/L.’ Clarify this was increase in 25OHD after abdominal exposure, rather than increase relative to exposing other body parts.
    Odd comparison of 4, 11 and 3.8, with 11 stated as similar to 4, but 3.8 as less than both. Rephrase.
    Top of P7 – disconnect with chicken information. How is this relevant? Back skin is usually feather covered. Please remove. The next sentence also flips back to humans without any warning.
    Sunscreen use – first paragraph – mainly but not exclusively
    Conclusion – ‘Vitamin D production is dependent on dose, but not dose rate, meaning longer periods of lower irradiance sun exposure are as effective, and safer, than short periods of high intensity exposure’ This could be misleading and should be rephrased or qualified.
    Using CIE action spectra (and accepting there are uncertainties) then technically short periods of higher intensity UV are safest (less erythema dose per vitamin D dose). In practice, at the extremes, both statements might be considered correct or incorrect. Solar irradiance is constantly changing and low/high irradiance has not been defined. When solar irradiance is moderate/limited then (locally) high irradiance periods are best; when solar irradiance is very high, then exposure at (locally) lower irradiance periods would be preferable and reduce the risk of damage from even short exposures at peak UV.

    References:
    Farrar MD, Webb AR, Kift R, Durkin MT, Allan D, Herbert A, Berry JL and Rhodes LE.(2013) Efficacy of a dose-range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure. Am J Clin Nutr. 97(6): 1210-1216
    Blumthaler,M., Webb, A.R.,Seckmeyer,G.,Bais,A.F.,Huber,M.,Mayer,B. (1994) Simultaneous Spectroradiometry:a study of solar UV Irradiance at two altitudes. Geophys. Res. Letts. 21(25): 2805-2808
    Wagner,Jochen, E., Federico Angelini ,AnttiArola, Mario Blumthaler , Michael Fitzka , Gian Paolo Gobbi, Richard Kift, Axel Kreuter , Harald E. Rieder , StanaSimic , Ann Webb and Philipp Weihs(2010) Comparison of surface UV irradiance in mountainous regions derived from satellite observations and model calculations with ground-based measurements. MeteorologischeZeitschrift19, No. 5, 481-490

    Reviewer: 2

    Comments to the Author
    The manuscript seems to be making the case that solar UVB exposure is a good source of vitamin D. That is correct. However, there are important limitations such as the seasonality of adequate solar UVB to produce vitamin D, whether optimal 25OHD concentrations can be reached, the effect of skin pigmentation, current lifestyles with people spending more time indoors, the fact that cosmetics now contain significant amounts of sunscreen, etc. In the opinion of the reviewer, solar UVB might now be better considered as a minor source of vitamin D in summer, and that supplements be considered the more important source. A number of additional references to consider in developing the arguments are suggested in this review.

    UVB wavelengths: stated as 295-315 nm
    Comment: others say 290-315 nm
    A search of pubmed.gov with “solar UVB 290” finds 146 results
    A search of pubmed.gov with “solar UVB 295” finds 28 results
    Suggest changing to 290-

    It can be argued that vitamin D supplementation obviates the need for solar
    exposure, but many studies have shown little benefit from this approach for a wide range of health outcomes.
    Comment: This point should be developed in the text. However, the primary reason for lack of benefits being found is that most of the vitamin D RCTs were based on guidelines for pharmaceutical drugs, not nutrients.
    Guidelines for optimizing design and analysis of clinical studies of nutrient effects.
    Heaney RP.Nutr Rev. 2014 Jan;72(1):48-54. doi: 10.1111/nure.12090. Epub 2013 Dec 13.

    When based on 25(OH)D, which is related to health outcomes (vitamin D dose is not), beneficial effects are often found:
    Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study.
    Dawson-Hughes B, Staten MA, Knowler WC, Nelson J, Vickery EM, LeBlanc ES, Neff LM, Park J, Pittas AG; D2d Research Group.Diabetes Care. 2020 Dec;43(12):2916-2922. doi: 10.2337/dc20-1765. Epub 2020 Oct 5.

    Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations 60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort.
    McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF, Gorham ED, Hollis BW, Trump DL, Lappe JM.PLoS One. 2018 Jun 15;13(6):e0199265. doi: 10.1371/journal.pone.0199265.

    Maternal 25(OH)D concentrations 40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center.
    McDonnell SL, Baggerly KA, Baggerly CA, Aliano JL, French CB, Baggerly LL, Ebeling MD, Rittenberg CS, Goodier CG, Mateus Niño JF, Wineland RJ, Newman RB, Hollis BW, Wagner CL.PLoS One. 2017 Jul 24;12(7):e0180483. doi: 10.1371/journal.pone.0180483. eCollection 2017.

    Serum 25-Hydroxyvitamin D Concentrations 40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study.
    McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, Lappe JM, Heaney RP.PLoS One. 2016 Apr 6;11(4):e0152441. doi: 10.1371/journal.pone.0152441. eCollection 2016.

    Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial.
    Chandler PD, Chen WY, Ajala ON, Hazra A, Cook N, Bubes V, Lee IM, Giovannucci EL, Willett W, Buring JE, Manson JE; VITAL Research Group.JAMA Netw Open. 2020 Nov 2;3(11):e2025850. doi: 10.1001/jamanetworkopen.2020.25850.

    Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.
    Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Janssens W, Jensen ME, Kerley CP, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S, Stelmach I, Trilok Kumar G, Urashima M, Camargo CA, Griffiths CJ, Hooper RL.Health Technol Assess. 2019 Jan;23(2):1-44. doi: 10.3310/hta23020.

    Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study).
    Rastogi A, Bhansali A, Khare N, Suri V, Yaddanapudi N, Sachdeva N, Puri GD, Malhotra P.Postgrad Med J. 2020 Nov 12:postgradmedj-2020-139065.

    "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study".
    Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, Quesada Gomez JM.J Steroid Biochem Mol Biol. 2020 Oct;203:105751. doi: 10.1016/j.jsbmb.2020.105751. Epub 2020 Aug 29.
    (calcifediol is 25(OH)D2 and the patients were given the equivalent of 130,000 IU of vitamin D2 in the first week.

    “Supplementation may provide a safer means
    of obtaining an adequate vitamin D status in those who are
    sub-optimal. However, this approach may avoid benefits of
    solar exposure that are independent of vitamin D and there
    are reports of increasing toxicity(41).”
    Taylor PN, Davies JS. A review of the
    growing risk of vitamin D toxicity from
    inappropriate practice. Br J Clin
    Pharmacol. Jun 2018;84(6):1121-7. Epub
    2018/03/03
    Comment: The risk of toxicity is very small.
    Development of Vitamin D Toxicity from Overcorrection of Vitamin D Deficiency: A Review of Case Reports.
    Galior K, Grebe S, Singh R.Nutrients. 2018 Jul 24;10(8):953. doi: 10.3390/nu10080953.
    And can be overcome easily

    Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States.
    Araki T, Holick MF, Alfonso BD, Charlap E, Romero CM, Rizk D, Newman LG.J Clin Endocrinol Metab. 2011 Dec;96(12):3603-8. doi: 10.1210/jc.2011-1443.

    UV exposure also entails a reduction in folate concentrations, an important factor for pregnant women.
    UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes.
    Lucock M, Beckett E, Martin C, Jones P, Furst J, Yates Z, Jablonski NG, Chaplin G, Veysey M.Am J Hum Biol. 2017 Mar;29(2). doi: 10.1002/ajhb.22929.

    Folate and phototherapy: What should we inform our patients?
    Zhang M, Goyert G, Lim HW.J Am Acad Dermatol. 2017 Nov;77(5):958-964. doi: 10.1016/j.jaad.2016.10.016.

    It is fortunate that the individual UVB doses necessary for maintaining optimal vitamin D status are lower than those for sunburn, irrespective of skin melanin.
    Comment: Perhaps, but it depends on the amount of skin exposed and how optimal vitamin D status is defined. The definition of optimal 25OHD concentration does not seem to be given in the manuscript.
    What is given is: Serum 25(OH)D concentration gives the most accurate
    estimate of vitamin D status(19). There are different definitions of vitamin D insufficiency/deficiency but serum 25(OH)D <50nmol/L is widely used for insufficiency(20)
    That is not a good reference. The definition of optimal 25OHD should be based on health outcomes, not population mean values. The findings from some of the studies listed earlier indicate that health benefits related to 25OHD continue to increase to and above 100 nmol/l.
    Speaking of Africa, these references are useful:

    Vitamin D status indicators in indigenous populations in East Africa.
    Luxwolda MF, Kuipers RS, Kema IP, van der Veer E, Dijck-Brouwer DA, Muskiet FA.Eur J Nutr. 2013 Apr;52(3):1115-25. doi: 10.1007/s00394-012-0421-6. Epub 2012 Aug 10.PMID: 22878781

    Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l.
    Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA.Br J Nutr. 2012 Nov 14;108(9):1557-61. doi: 10.1017/S0007114511007161. Epub 2012 Jan 23.PMID: 22264449

    Ref. 116, Powe, is in dispute since it used monoclonal assay. See
    Free 25(OH)D and the Vitamin D Paradox in African Americans.
    Aloia J, Mikhail M, Dhaliwal R, Shieh A, Usera G, Stolberg A, Ragolia L, Islam S.J Clin Endocrinol Metab. 2015 Sep;100(9):3356-63. doi: 10.1210/JC.2015-2066.

    Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations.
    Nielson CM, Jones KS, Chun RF, Jacobs JM, Wang Y, Hewison M, Adams JS, Swanson CM, Lee CG, Vanderschueren D, Pauwels S, Prentice A, Smith RD, Shi T, Gao Y, Schepmoes AA, Zmuda JM, Lapidus J, Cauley JA, Bouillon R, Schoenmakers I, Orwoll ES; Osteoporotic Fractures in Men (MrOS) Research Group.J Clin Endocrinol Metab. 2016 May;101(5):2226-34. doi: 10.1210/jc.2016-1104.

    Figure 5 needs units for 25(OH)D3 on the y-axis

    Regarding the abstract “It is fortunate that the individual UVB doses necessary for maintaining optimal vitamin D status are lower than those for sunburn, irrespective of skin
    melanin” and FST, papers such as this should also be cited
    Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004.
    Ginde AA, Liu MC, Camargo CA Jr.Arch Intern Med. 2009 Mar 23;169(6):626-32. doi: 10.1001/archinternmed.2008.604.

    The vitamin D status of the US population from 1988 to 2010 using standardized serum concentrations of 25-hydroxyvitamin D shows recent modest increases.
    Schleicher RL, Sternberg MR, Lacher DA, Sempos CT, Looker AC, Durazo-Arvizu RA, Yetley EA, Chaudhary-Webb M, Maw KL, Pfeiffer CM, Johnson CL.Am J Clin Nutr. 2016 Aug;104(2):454-61. doi: 10.3945/ajcn.115.127985.

    Since it can be assumed to first order that Blacks, Hispanics, and Whites in the U.S. get about the same UVB exposure, the final statement in the abstract seems to be incorrect.

    Also, solar UVB is only a good source of vitamin D when the solar elevation angle is above 45 deg., both in season and during the day. Thus, at higher northern latitudes, reasonable amounts of vitamin D can be produced for 2-3 months a year. These papers might be cited
    The relationship between ultraviolet radiation exposure and vitamin D status.
    Engelsen O.Nutrients. 2010 May;2(5):482-95. doi: 10.3390/nu2050482. Epub 2010 May 4.

    Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors.
    Hyppönen E, Power C.Am J Clin Nutr. 2007 Mar;85(3):860-8. doi: 10.1093/ajcn/85.3.860.

    Temporal relationship between vitamin D status and parathyroid hormone in the United States.
    Kroll MH, Bi C, Garber CC, Kaufman HW, Liu D, Caston-Balderrama A, Zhang K, Clarke N, Xie M, Reitz RE, Suffin SC, Holick MF.PLoS One. 2015 Mar 4;10(3):e0118108

    This commentary might be cited along with Ref. 3, Weller
    Solar UV Radiation: A Potential Modifiable Risk Factor for Hypertension.
    Kapil V, Gupta AK.J Am Heart Assoc. 2020 Mar 3;9(5):e015627. doi: 10.1161/JAHA.120.015627.
    As well as this one
    Ultraviolet light may contribute to geographic and racial blood pressure differences.
    Rostand SG.Hypertension. 1997 Aug;30(2 Pt 1):150-6. doi: 10.1161/01.hyp.30.2.150.

    Diet also plays an important role regarding 25OHD:
    Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study.
    Crowe FL, Steur M, Allen NE, Appleby PN, Travis RC, Key TJ.Public Health Nutr. 2011 Feb;14(2):340-6.

    Decision letter by
    Cite this decision letter
    Reviewer report
    2020/12/02

    The manuscript seems to be making the case that solar UVB exposure is a good source of vitamin D. That is correct. However, there are important limitations such as the seasonality of adequate solar UVB to produce vitamin D, whether optimal 25OHD concentrations can be reached, the effect of skin pigmentation, current lifestyles with people spending more time indoors, the fact that cosmetics now contain significant amounts of sunscreen, etc. In the opinion of the reviewer, solar UVB might now be better considered as a minor source of vitamin D in summer, and that supplements be considered the more important source. A number of additional references to consider in developing the arguments are suggested in this review.

    UVB wavelengths: stated as 295-315 nm
    Comment: others say 290-315 nm
    A search of pubmed.gov with “solar UVB 290” finds 146 results
    A search of pubmed.gov with “solar UVB 295” finds 28 results
    Suggest changing to 290-

    It can be argued that vitamin D supplementation obviates the need for solar
    exposure, but many studies have shown little benefit from this approach for a wide range of health outcomes.
    Comment: This point should be developed in the text. However, the primary reason for lack of benefits being found is that most of the vitamin D RCTs were based on guidelines for pharmaceutical drugs, not nutrients.
    Guidelines for optimizing design and analysis of clinical studies of nutrient effects.
    Heaney RP.Nutr Rev. 2014 Jan;72(1):48-54. doi: 10.1111/nure.12090. Epub 2013 Dec 13.

    When based on 25(OH)D, which is related to health outcomes (vitamin D dose is not), beneficial effects are often found:
    Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study.
    Dawson-Hughes B, Staten MA, Knowler WC, Nelson J, Vickery EM, LeBlanc ES, Neff LM, Park J, Pittas AG; D2d Research Group.Diabetes Care. 2020 Dec;43(12):2916-2922. doi: 10.2337/dc20-1765. Epub 2020 Oct 5.

    Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations 60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort.
    McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF, Gorham ED, Hollis BW, Trump DL, Lappe JM.PLoS One. 2018 Jun 15;13(6):e0199265. doi: 10.1371/journal.pone.0199265.

    Maternal 25(OH)D concentrations 40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center.
    McDonnell SL, Baggerly KA, Baggerly CA, Aliano JL, French CB, Baggerly LL, Ebeling MD, Rittenberg CS, Goodier CG, Mateus Niño JF, Wineland RJ, Newman RB, Hollis BW, Wagner CL.PLoS One. 2017 Jul 24;12(7):e0180483. doi: 10.1371/journal.pone.0180483. eCollection 2017.

    Serum 25-Hydroxyvitamin D Concentrations 40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study.
    McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, Lappe JM, Heaney RP.PLoS One. 2016 Apr 6;11(4):e0152441. doi: 10.1371/journal.pone.0152441. eCollection 2016.

    Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial.
    Chandler PD, Chen WY, Ajala ON, Hazra A, Cook N, Bubes V, Lee IM, Giovannucci EL, Willett W, Buring JE, Manson JE; VITAL Research Group.JAMA Netw Open. 2020 Nov 2;3(11):e2025850. doi: 10.1001/jamanetworkopen.2020.25850.

    Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.
    Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Janssens W, Jensen ME, Kerley CP, Laaksi I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S, Stelmach I, Trilok Kumar G, Urashima M, Camargo CA, Griffiths CJ, Hooper RL.Health Technol Assess. 2019 Jan;23(2):1-44. doi: 10.3310/hta23020.

    Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study).
    Rastogi A, Bhansali A, Khare N, Suri V, Yaddanapudi N, Sachdeva N, Puri GD, Malhotra P.Postgrad Med J. 2020 Nov 12:postgradmedj-2020-139065.

    "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study".
    Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, Quesada Gomez JM.J Steroid Biochem Mol Biol. 2020 Oct;203:105751. doi: 10.1016/j.jsbmb.2020.105751. Epub 2020 Aug 29.
    (calcifediol is 25(OH)D2 and the patients were given the equivalent of 130,000 IU of vitamin D2 in the first week.

    “Supplementation may provide a safer means
    of obtaining an adequate vitamin D status in those who are
    sub-optimal. However, this approach may avoid benefits of
    solar exposure that are independent of vitamin D and there
    are reports of increasing toxicity(41).”
    Taylor PN, Davies JS. A review of the
    growing risk of vitamin D toxicity from
    inappropriate practice. Br J Clin
    Pharmacol. Jun 2018;84(6):1121-7. Epub
    2018/03/03
    Comment: The risk of toxicity is very small.
    Development of Vitamin D Toxicity from Overcorrection of Vitamin D Deficiency: A Review of Case Reports.
    Galior K, Grebe S, Singh R.Nutrients. 2018 Jul 24;10(8):953. doi: 10.3390/nu10080953.
    And can be overcome easily

    Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States.
    Araki T, Holick MF, Alfonso BD, Charlap E, Romero CM, Rizk D, Newman LG.J Clin Endocrinol Metab. 2011 Dec;96(12):3603-8. doi: 10.1210/jc.2011-1443.

    UV exposure also entails a reduction in folate concentrations, an important factor for pregnant women.
    UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes.
    Lucock M, Beckett E, Martin C, Jones P, Furst J, Yates Z, Jablonski NG, Chaplin G, Veysey M.Am J Hum Biol. 2017 Mar;29(2). doi: 10.1002/ajhb.22929.

    Folate and phototherapy: What should we inform our patients?
    Zhang M, Goyert G, Lim HW.J Am Acad Dermatol. 2017 Nov;77(5):958-964. doi: 10.1016/j.jaad.2016.10.016.

    It is fortunate that the individual UVB doses necessary for maintaining optimal vitamin D status are lower than those for sunburn, irrespective of skin melanin.
    Comment: Perhaps, but it depends on the amount of skin exposed and how optimal vitamin D status is defined. The definition of optimal 25OHD concentration does not seem to be given in the manuscript.
    What is given is: Serum 25(OH)D concentration gives the most accurate
    estimate of vitamin D status(19). There are different definitions of vitamin D insufficiency/deficiency but serum 25(OH)D <50nmol/L is widely used for insufficiency(20)
    That is not a good reference. The definition of optimal 25OHD should be based on health outcomes, not population mean values. The findings from some of the studies listed earlier indicate that health benefits related to 25OHD continue to increase to and above 100 nmol/l.
    Speaking of Africa, these references are useful:

    Vitamin D status indicators in indigenous populations in East Africa.
    Luxwolda MF, Kuipers RS, Kema IP, van der Veer E, Dijck-Brouwer DA, Muskiet FA.Eur J Nutr. 2013 Apr;52(3):1115-25. doi: 10.1007/s00394-012-0421-6. Epub 2012 Aug 10.PMID: 22878781

    Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l.
    Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA.Br J Nutr. 2012 Nov 14;108(9):1557-61. doi: 10.1017/S0007114511007161. Epub 2012 Jan 23.PMID: 22264449

    Ref. 116, Powe, is in dispute since it used monoclonal assay. See
    Free 25(OH)D and the Vitamin D Paradox in African Americans.
    Aloia J, Mikhail M, Dhaliwal R, Shieh A, Usera G, Stolberg A, Ragolia L, Islam S.J Clin Endocrinol Metab. 2015 Sep;100(9):3356-63. doi: 10.1210/JC.2015-2066.

    Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations.
    Nielson CM, Jones KS, Chun RF, Jacobs JM, Wang Y, Hewison M, Adams JS, Swanson CM, Lee CG, Vanderschueren D, Pauwels S, Prentice A, Smith RD, Shi T, Gao Y, Schepmoes AA, Zmuda JM, Lapidus J, Cauley JA, Bouillon R, Schoenmakers I, Orwoll ES; Osteoporotic Fractures in Men (MrOS) Research Group.J Clin Endocrinol Metab. 2016 May;101(5):2226-34. doi: 10.1210/jc.2016-1104.

    Figure 5 needs units for 25(OH)D3 on the y-axis

    Regarding the abstract “It is fortunate that the individual UVB doses necessary for maintaining optimal vitamin D status are lower than those for sunburn, irrespective of skin
    melanin” and FST, papers such as this should also be cited
    Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004.
    Ginde AA, Liu MC, Camargo CA Jr.Arch Intern Med. 2009 Mar 23;169(6):626-32. doi: 10.1001/archinternmed.2008.604.

    The vitamin D status of the US population from 1988 to 2010 using standardized serum concentrations of 25-hydroxyvitamin D shows recent modest increases.
    Schleicher RL, Sternberg MR, Lacher DA, Sempos CT, Looker AC, Durazo-Arvizu RA, Yetley EA, Chaudhary-Webb M, Maw KL, Pfeiffer CM, Johnson CL.Am J Clin Nutr. 2016 Aug;104(2):454-61. doi: 10.3945/ajcn.115.127985.

    Since it can be assumed to first order that Blacks, Hispanics, and Whites in the U.S. get about the same UVB exposure, the final statement in the abstract seems to be incorrect.

    Also, solar UVB is only a good source of vitamin D when the solar elevation angle is above 45 deg., both in season and during the day. Thus, at higher northern latitudes, reasonable amounts of vitamin D can be produced for 2-3 months a year. These papers might be cited
    The relationship between ultraviolet radiation exposure and vitamin D status.
    Engelsen O.Nutrients. 2010 May;2(5):482-95. doi: 10.3390/nu2050482. Epub 2010 May 4.

    Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors.
    Hyppönen E, Power C.Am J Clin Nutr. 2007 Mar;85(3):860-8. doi: 10.1093/ajcn/85.3.860.

    Temporal relationship between vitamin D status and parathyroid hormone in the United States.
    Kroll MH, Bi C, Garber CC, Kaufman HW, Liu D, Caston-Balderrama A, Zhang K, Clarke N, Xie M, Reitz RE, Suffin SC, Holick MF.PLoS One. 2015 Mar 4;10(3):e0118108

    This commentary might be cited along with Ref. 3, Weller
    Solar UV Radiation: A Potential Modifiable Risk Factor for Hypertension.
    Kapil V, Gupta AK.J Am Heart Assoc. 2020 Mar 3;9(5):e015627. doi: 10.1161/JAHA.120.015627.
    As well as this one
    Ultraviolet light may contribute to geographic and racial blood pressure differences.
    Rostand SG.Hypertension. 1997 Aug;30(2 Pt 1):150-6. doi: 10.1161/01.hyp.30.2.150.

    Diet also plays an important role regarding 25OHD:
    Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study.
    Crowe FL, Steur M, Allen NE, Appleby PN, Travis RC, Key TJ.Public Health Nutr. 2011 Feb;14(2):340-6.

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    Cite this review
    Reviewer report
    2020/10/24

    This is a useful review of current understanding of the factors that affect vitamin D synthesis. It is submitted as an Original Article, but is effectively a review and contains no new experimental research by the authors. It is not entirely clear how it should be evaluated, but it would be misleading not to put ‘Review’ or ‘Overview’ in the title. The article covers the salient points, but does not reveal anything particularly new. It is helpful in pointing out where there are still uncertainties with opposing results in the literature, or unknowns.
    The broad structure is well organised. However, there are many instances of careless or imprecise expression that at best reduces clarity and at worst means the sentence is incorrect, or could at least be interpreted incorrectly.
    There are also too many examples of sudden change in subject or direction, and disconnects between statements that are presumably meant to be supportive of each other.
    These confusions need to be removed before the paper can be published.
    Abstract – ‘Vitamin D synthesis specifically requires UVB (wavelengths from ~295-315nm) in sunlight that is the minority component (<5%) solar UVR.’ This is an awkward sentence and incorrect. The UVB does not have to come from sunlight. Split into two sentences, after the first parentheses.
    Intro, first paragraph – ‘many effects on human health’; ‘such as reduced blood pressure’
    ‘This dose, in physical terms, is very dependent on the UVR source used.’ This sentence needs further explanation. What ‘physical terms’ are referred to here? The erythema effective UV dose as defined previously is not source dependent. There is also a contradiction with the second paragraph on Action Spectrum.
    Vitamin D deficiency – this section is contradictory and unsatisfactory. It highlights Africa as having particularly poor vitamin D status even though better than the global average, and the UK (the only two comparators). This section needs to be more thorough and consistent.
    Action spectra – it should be noted that the CIE action spectrum is only truly applicable for initial irradiations and the first step in vitamin D synthesis (7DHC to previtamin D). Prolonged exposure (at least in sunlight) will initiate other reactions. Use with care – as discussed in the CIE document! It is disingenuous to say the CIE action spectrum should be shifted to match the unpublished Young action spectrum that has a different endpoint. They are assessing two different outcomes. Which outcome is the better one to use is a different debate.
    Paragraph on reciprocity and pig skin. What is the point of this within the context of determining an action spectrum for pre vitamin D / vitamin D / 25OHD (which one, not stated)? Yes, reciprocity is important, but seems a distraction from the fact of having a peak very similar to the CIE action spectrum for previtamin D synthesis.
    UVR Dose – end first paragraph – there are other publications that show the plateau effect after repeated exposures occurs also with low starting status of 25OHD (eg Farrar et al.)
    Second paragraph – sudden change from human to pig skin. On the human study, given the previous discussions can this be qualified with source and dose given.
    Neither constitutive pigmentation…. It is not clear which study this comment refers to, please clarify. If it is a general statement then it is unreferenced and there are other studies that do show a clear impact of constitutive pigmentation and these should also be mentioned. In fact they should be mentioned anyway to provide a balanced view.
    Atmosphere – not exposed to the health effects of UVB, but exposed to UVB with consequent health effects.
    The limited evidence for decreasing UVB is unsurprising as neither ozone nor UVB changed enormously outside polar regions – and other atmospheric factors also play a role.
    End second paragraph – UVB scattering is always greater than for UVA, not just when the pathlength is long.
    Next paragraph – very confused, sudden switch to UVI and the paragraph ends with talking about ODSs. Rewrite. At the start: effect of clouds is smaller than what? Clouds do not contribute to UVI, they contribute to attenuation of UV radiation in the atmosphere and therefore modify the incident UVR / UVI.
    Altitude – in keeping with previous paragraphs there is scope for more discussion of the physical changes to UV irradiance at altitude, rather than, or as well as the vitamin d studies that are confounded by multiple factors not yet discussed. See eg papers by Blumthaler and others.
    Temporal factors - Seasonal changes can be modelled to agree with observational data(105) – what does this mean, or prove?
    Second paragraph – another disconnect between the two parts of this paragraph.
    Body site and surface area – ‘The increase with abdominal exposure was 4nmol/L.’ Clarify this was increase in 25OHD after abdominal exposure, rather than increase relative to exposing other body parts.
    Odd comparison of 4, 11 and 3.8, with 11 stated as similar to 4, but 3.8 as less than both. Rephrase.
    Top of P7 – disconnect with chicken information. How is this relevant? Back skin is usually feather covered. Please remove. The next sentence also flips back to humans without any warning.
    Sunscreen use – first paragraph – mainly but not exclusively
    Conclusion – ‘Vitamin D production is dependent on dose, but not dose rate, meaning longer periods of lower irradiance sun exposure are as effective, and safer, than short periods of high intensity exposure’ This could be misleading and should be rephrased or qualified.
    Using CIE action spectra (and accepting there are uncertainties) then technically short periods of higher intensity UV are safest (less erythema dose per vitamin D dose). In practice, at the extremes, both statements might be considered correct or incorrect. Solar irradiance is constantly changing and low/high irradiance has not been defined. When solar irradiance is moderate/limited then (locally) high irradiance periods are best; when solar irradiance is very high, then exposure at (locally) lower irradiance periods would be preferable and reduce the risk of damage from even short exposures at peak UV.

    References:
    Farrar MD, Webb AR, Kift R, Durkin MT, Allan D, Herbert A, Berry JL and Rhodes LE.(2013) Efficacy of a dose-range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure. Am J Clin Nutr. 97(6): 1210-1216
    Blumthaler,M., Webb, A.R.,Seckmeyer,G.,Bais,A.F.,Huber,M.,Mayer,B. (1994) Simultaneous Spectroradiometry:a study of solar UV Irradiance at two altitudes. Geophys. Res. Letts. 21(25): 2805-2808
    Wagner,Jochen, E., Federico Angelini ,AnttiArola, Mario Blumthaler , Michael Fitzka , Gian Paolo Gobbi, Richard Kift, Axel Kreuter , Harald E. Rieder , StanaSimic , Ann Webb and Philipp Weihs(2010) Comparison of surface UV irradiance in mountainous regions derived from satellite observations and model calculations with ground-based measurements. MeteorologischeZeitschrift19, No. 5, 481-490

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