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What is the upper limit and NOAEL and are they justified?

Posted on: February 26, 2013   by  John Cannell, MD

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The upper limit (UL) for vitamin D, set by the 2011 Food and Nutrition Board, is 4,000 IU per day. This is defined as the highest level of daily consumption that causes no side effects in humans when used indefinitely without medical supervision.

The same board set the No Observed Adverse Effects Level (NOAEL) at 10,000 IU/day. The NOAEL is the dose at which there are no published studies showing any adverse effects of that dosage. As an aside, if there are any studies showing 20,000 IU/day is unsafe, I would like to see them.

Anyway, the Upper Limit is simply calculated from the NOAEL by dividing by a safety factor.  In vitamin D’s case, they divided the NOAEL of 10,000 IU/day by 2.5 to get the Upper Limit of 4,000 IU/day.

At the Vitamin D Council, we recommend that patients exceed the Upper Limit, but not exceed the NOAEL of 10,000 IU/day, unless they are under medical supervision or know what they are doing. But why do we recommend more than the Food and Nutrition Board’s Upper Limit?

Because the question is, will 4,000 IU/day get 97.5% of the population above a certain 25(OH)D threshold, such as 30 ng/ml? Or are doses higher than 4,000 IU/day needed to achieve blood levels above 30 ng/ml, 30 ng/ml still being much lower than average 25(OH)D levels found in hunter gatherers living around the equator, which are about 46 ng/ml.

Vitamin D status in indigenous populations: Part 1 Posted on August 27, 2012 by John Cannell, MD

Doctor Etienne Cavalier and colleagues of the University of Liège in Belgium recently tried to find out if 4,000 IU/day is enough by giving large or stoss doses to a total of 140 subjects.

Cavalier E, Faché W, Souberbielle JC. A Randomised, Double-Blinded, Placebo-Controlled, Parallel Study of Vitamin D3 Supplementation with Different Schemes Based on Multiples of 25,000 IU Doses. Int J Endocrinol. 2013;2013:327265.

The study took place in Belgium between January and July of 2011 and included only healthy patients above the age of 50. In Belgium, the only vitamin D available to doctors is a 25,000 IU capsule of vitamin D3, so that is what they used. They used twice monthly dosing schedules, giving a dose in their office every two weeks to ensure 100% compliance. Here were their dosing groups:

  • They gave the equivalent of about 4,200 IU/day to the first group of 40 patients whose initial 25(OH)D levels were below 10 ng/ml.
  • They gave about 3,000 IU/day to a second group of 40 patients, whose initial levels were between 10 and 20 ng/ml.
  • They gave about 2,000 IU/day to a third group whose initial levels were between 20 and 30 ng/ml.
  • They gave about 1,600 IU/day to a fourth group whose initial levels were over 30 ng/ml
  • They gave a placebo to a fifth group whose mean levels were 18 ng/ml.

Keep in mind the above doses are calculated from the “stoss” or large doses the patients were actually getting every two weeks. They tested 25(OH)D levels during the study including the final level which was drawn 30 days after the four groups completed their dosing schedules.

The first remarkable thing the authors found was that the placebo group’s levels did not rise in spite of the study ending in July. Apparently, older Belgium adults get little sunshine.

Next, they were surprised at how many of the subject still had final levels less than 30 ng/ml, despite what they considered large doses of vitamin D. The percentages of patients failing to achieve a final 25(OH)D of at least 30 ng/ml were 62% in group 1, 60% in group 2, 25% in group 3, 45% in group 4, and 86% in the placebo group. However, these final levels were drawn one month after the final dose of vitamin D, so they would have been higher if they were tested a week after the final dose.

Nevertheless, the authors wrote,

“Overall, this suggests that the doses of vitamin D3 administered in the present study were insufficient to achieve or maintain the 30 ng/mL target in a significant proportion of the included subjects. It must be underlined that the dose administered to the subjects with a baseline serum level ≤10 ng/mL was already very close (slightly above in fact) to the upper safety limit of 4,000 IU/day defined by the IOM. Thus, if a 25(OH)D level of 30 ng/mL or more is targeted in future studies, higher doses than the IOM Upper Limit should be used.”

I like it when academics contradict the Food and Nutrition Board’s recommendations. First, this study makes the Vitamin D Council’s recommendations (5,000 IU/day) seem reasonable, if not conservative. Second, it legitimizes what any practitioner who gives vitamin D and subsequently tests 25(OH)D levels will tell you; 4,000 IU/day is simply not enough for some people. In fact, 5,000 IU/day is not enough for some people. However, we recommend that anyone who exceeds 5,000 IU/day have a 25(OH)D test three months after taking such a dose to be sure that it achieves the desired effect, which is natural blood levels.

17 Responses to What is the upper limit and NOAEL and are they justified?

  1. roger.rolfe@sympatico.ca

    Dr. Cannell:
    This is a very interesting study, and it prompts me to ask you a question. What level of daily supplementation is required to get 97.5% of the population up to a target of 50 ng/ml (natural levels)? What’s your guess?

    I know what I need (5000IU in the summer, 6000-7000IU in the winter) since I’ve tested and monitor my blood levels regularly. And I know what my wife needs (5000IU in summer, 6000IU in winter) since we test and monitor her also.

    But what do you think is required for the population to achieve natural levels?

    Regards,
    Roger Rolfe
    Toronto Canada.

    • Brant Cebulla

      Roger, good question.

      • GrassrootsHealth studied this from their testing participants and they found that a dose of 14,100 IU/day is needed to ensure 97.5% of the population meet a level of 50 ng/ml. The problem, however, is that this dosage gave the population a mean level of 85 ng/ml, which is definitely high on a population level.
      • 9,600 IU/day ensured 97.5% hit a level of at least 40 ng/ml.
      • 6,100 IU/day to ensure 97.5% hit a level of at least 30 ng/ml.

      I might guess their population is a little biased, might not represent the general public very well and subsequently exaggerates dosing requirements a pinch, but I’m just speculating. Some of their participants may be enrolled because they are hyper-aware of vitamin D for a reason, like they are prone to low levels of vitamin D, suffer from malabsorption issues, etc…

      Just shows how variant vitamin D requirements are for an entire population and that it’s going to take a very comprehensive strategy to ensure a majority of the population hits certain thresholds. Part of the reason the IOM didn’t raise requirements higher is because they didn’t want to deal with strategy at this time. While research hints we need higher levels, IOM wants near perfect research before they “deal with it.”

      Cheers,
      Brant

    • Brant Cebulla
  2. RufusG

    I have taken 5,000 IU each day for the past 3 years and my 25(OH)D blood level is typically 143 nmol/L (57 ng/mL). My weight is 70kg (154 lbs)

  3. hlahore@gmail.com

    Yes, many people need >4,000 IU of vitamin D
    Study of 3000 HEALTHY, non-obese men aged 50 in 2011 showed
    – 9600 IU was needed to get 97.5% to 40 ng
    – 14,100 IU needed to get 97.5% to 50 ng/ml
    – And concluded that 40,000 IU unlikely to result in vitamin D toxicity.
    http://is.gd/doseresponse
    Notes also:
    1) You can 2X your response to vitamin D: http://is.gd/2xvitd
    2) There are many reasons for low response http://is.gd/lowresponse

  4. kenmerrimanmd

    it certainly seems to depend on pt size but other factors are at play also

    my bigger pts seem to require 20,000 IU/day to break thru 50

    occasionally run across somebody who takes only a little vit D or none who has a good vit D level without other obvious sources this I have no answer for??? certainly monitoring seems to be a very good idea

  5. allometric24

    Surely the best way to resolve these variability issues is for studies to focus on individuals who require higher then average intake of Vit D. Are they obese? What is their skin colour?
    What is their ethnicity? Are they old or infirm?
    At some point we have to look at the individual. Epidemiology is a limited science.

  6. kenmerrimanmd

    I was very interested in the results of the Belgium study
    in group 4 the pts started out with 30 ng/ml and were given~ 1600 IU vitD per day

    at the end point only 45% had vit level of 30 so >50% lowered their vit D level while taking 1600 IU vit/day kind of interesting

  7. John Cannell, MD

    How much would it take to get 97.5% of the population above 50 ng/ml?

    I would guess, and it is a guess, about 10,000 IU/day.

  8. Rebecca Oshiro

    allometric24, Robert Heaney says “25(OH)D response to therapeutic doses of vitamin D varies over a six-fold range, and is hence difficult to predict.”

    http://www.grassrootshealth.net/webinars

    In my little n=2 experiment of my husband and I, 4,000 IU of D per day gave him a 25(OH)D blood level of 32 ng/mL and me one of 61 ng/mL.

  9. edieeyes

    I’ve been wondering as well, have there been any studies done on individuals using sunscreen
    all the time> are their vitamin D levels lower as a result of blocking the sun?
    Many women use make-up that has sunscreen protection in it all the time!

  10. bacullen@gmail.com

    In this and other reviews we see blood levels of 25-HO-D3 quoted. Several yrs ago there was up to a 30% overestimation of D by some (most?) labs. Have these differences been resolved, i.e. what are the real numbers?

  11. cowman91710

    My wife has been taking slightly more than 5000 IU per day for a few years, and a recent test revealed that she is at 32 ng/mL, so she has increased it to 10,000 IU in hopes that she will exceed 50 ng/mL. We’ll let you know.

    Kent

  12. jpmck@sbcglobal.net

    I have been taking 50,000 units of Vit. D3 every 10 days for a year or so now and my Primary Care Physician tested me for Vitamin D Level and just called me to report that at present my blood level
    is 76 ng/ml, and seemed by pleased with that level.

    Jim McKinley, BS, MS, RPh in Texas (age 89)

  13. pcolquet

    Dr. Cannell,

    My autistic son’s serum 25(OH)D level is 23 ng/mL. What should the target level be and for how long? I ask, because it seems that FNB suggest long term levels above 50-60 ng/mL are related to negative health effects, that even lower serum levels (approximately 75–120 nmol/L or 30–48 ng/mL) are associated with increases in all-cause mortality. Any thoughts?

    “Long-term intakes above the UL (4000 iu) increase the risk of adverse health effects. Most reports suggest a toxicity threshold for vitamin D of 10,000 to 40,000 IU/day and serum 25(OH)D levels of 500–600 nmol/L (200–240 ng/mL). While symptoms of toxicity are unlikely at daily intakes below 10,000 IU/day, the FNB pointed to emerging science from national survey data, observational studies, and clinical trials suggesting that even lower vitamin D intakes and serum 25(OH)D levels might have adverse health effects over time. The FNB concluded that serum 25(OH)D levels above approximately 125–150 nmol/L (50–60 ng/mL) should be avoided, as even lower serum levels (approximately 75–120 nmol/L or 30–48 ng/mL) are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly. The FNB committee cited research which found that vitamin D intakes of 5,000 IU/day achieved serum 25(OH)D concentrations between 100–150 nmol/L (40–60 ng/mL), but no greater. Applying an uncertainty factor of 20% to this intake value gave a UL of 4,000 IU which the FNB applied to children aged 9 and older, with corresponding lower amounts for younger children.”

  14. Rita and Misty

    Dear pcolquet,

    Certainly, I’m not a physician nor am I a scientific researcher. However, I sit exactly halfway between neurotypical and Aspergers syndrome. My personality and emotional fortitude has vastly improved with high dose vitamin D. I keep my level at the highest end of optimal. I can easily masquerade as a neurotypical extrovert for a full 8 hours per day.

    In winter I take 20,000 iu D3 daily. In summer I take 16,000 iu D3 daily. I need to invest in a sunlamp, and I am foolish not to have done so already. There are additional benefits to sunshine and UV rays. We evolved as creatures requiring the sun.

    Be well,
    Rita

  15. Rita and Misty

    Regarding this statement: “The FNB concluded that serum 25(OH)D levels above approximately 125–150 nmol/L (50–60 ng/mL) should be avoided, as even lower serum levels (approximately 75–120 nmol/L or 30–48 ng/mL) are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly.”

    I wonder how many folks were supplementing with Cod Liver Oil, which contains toxic amount of vitamin A. Too much A hinders the body’s ability to utilize D.

    Additionally, sometimes folks who are critically ill may look to raising their vitamin D blood serum levels in an attempt to stave off impending death. Unfortunately, there is no cure for death.

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