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Toxicology Reflections

How Much Vitamin D is Safe?

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How Much Vitamin D is Safe?

Vitamin D is a hot topic in health research.  Most of the excitement revolves around its potential to prevent and treat chronic diseases.  This reflection will consider the risks and benefits of vitamin D supplementation.  On one hand, a lack of vitamin D can lead to a nutritional deficiency. On the other hand, too much vitamin D can have toxic effects.  In the end, the question I will pose to the reader and answer for myself is: how much vitamin D supplementation should we take?

Vitamin D is a nutrient that regulates the absorption and metabolism of calcium and phosphate.  It is the only vitamin that can be synthesized, but it is still considered a vitamin because the conversion of cholesterol to vitamin D can only take place when the skin is exposed to ultraviolet (UV) light.  Deficiencies are common when people have little sun exposure and little access to vitamin D rich foods.  Severe deficiencies manifest themselves as rickets in children and osteomalacia in adults.  In both of these conditions, the bones become soft because they lack sufficient mineralized calcium and phosphate.

Vitamin D deficiency is a real concern at latitudes associated with long winters because the population is completely dependent on dietary sources of vitamin D for a large portion of the year.  For example, people cannot synthesize vitamin D from November until February in most of Canada.1  In Saskatoon, Saskatchewan, sun exposure is likely inadequate from October until March.  So, where do Canadians get their vitamin D in the winter?  Milk products and alternatives are enriched with enough vitamin D so that the recommended daily intake (RDI) of vitamin D can be acquired if you eat and drink according to the recommendations in the Canadian Food Guide.  However, there are two problems with this policy.  The first (and most obvious) is that not everyone eats and drinks according to the Canadian Food Guide.  Some ethnic groups that have immigrated to Canada do not drink milk or milk substitutes.  The second problem is that the current RDI may not be sufficient for optimal health.  While the current RDI will certainly prevent rickets and osteomalacia, new studies are indicating that higher levels of vitamin D may be required to prevent cancer and heart disease.2  Low vitamin D levels have also been linked with an increased risk of preeclampsia in pregnant women.3

So how can Canadians get more vitamin D?  While there are some vitamin D rich foods such as liver and egg yolks, vitamin D supplements have become much more popular, partially because it is much easier to control the dose.   Vitamin D supplements are now easily accessible at all pharmacies and many grocery stores.  Vitamin D can be part of a multivitamin or by itself in chewable pills, liquid capsules, or liquid droppers.  There is also a wide array of doses available, ranging from 400 – 50 000 International Units (IU) (10 – 1250μg).4

Naturally, when consumers start to read the labels showing different doses, they will be concerned with original question in this reflection.  How much vitamin D is safe?  The answer is not too little and not too much.  Vitamin D has a typical U-shaped dose-response curve where adverse effects increase at both low and high doses.  Hypercalcemia is the first known adverse effect seen with vitamin D toxicity, but the lowest observable adverse effect level (LOAEL) remains unknown.5  Hypercalcemia can lead to calcification of soft tissues and has been linked with cardiovascular disease.6  It is important to note that these toxic effects only occur with excessive dietary intake or direct injection, not sun exposure.  This is because the sun’s UV radiation acts as a negative feedback system by breaking down excess vitamin D under the skin.5  Another common misconception is that vitamin D causes birth defects.  Vitamin D is not a teratogen, but vitamin D induced hypercalcemia may cause birth defects involving vascular stenosis.7  Consumers need to be aware that is important avoid toxicity as well as deficiency.

Hathcock et al. published a risk assessment indicating that the no observable adverse effects level (NOAEL) for vitamin D is 10,000 IU (250 ug)/day.5  This dose is based on two randomized controlled trials that found no adverse effects in healthy men after 8 and 20 weeks.  The authors recommend that an uncertainty factor should be applied to this NOAEL to account for variation in the population.

After a jointly funded investigation in 2010, the Canadian and American governments applied an uncertainty factor of 10 to this NOAEL for infants (0-6 months) to establish a tolerable upper intake level (UL) of 1000 IU/d.  The UL increases with age: 1500 IU/d for infants (7-12 months), 2000 IU/d for children (1-3 years), 3000 IU/d for children (4-8 years), and 4000 IU/d for children (9+ years) and all adults.8,9  The ULs for vitamin D in Europe are based on the same studies and are very similar: 1000 IU/d for infants (0-12 months), 2000 IU/d for children (1-10 years), and 4000 IU/d for children (10+years) and adults.10

In the United Stated and Canada, the RDIs are 400 IU for infants (0-12 months), 600 IU for children and adults (1-70 years), and 800 IU for seniors older than 70.8,9  The Canadian government advises that dietary intake is adequate for most Canadian but seniors over the age of 50 should take daily vitamin D supplements with 400 IU.  These recommendations are comparatively higher than the guidelines set by the World Health Organization (200 IU for adults and 600 IU for seniors) and most European countries (200-400 IU for adults and seniors).11  These differences are due to differences in perceived health benefits and basic assumptions about sun exposure and dietary habits.

The question remains, are these government recommendations adequate for optimal health? Hathcock et al. report that despite many hours of sun exposure, vitamin D levels in outdoor workers at the end of the summer are equivalent to a daily intake of 2800-4000 IU.5  This supports that a UL of 4000 IU is reasonable.  However, considering that humans have worked outdoors for the vast majority of their existence, it seems reasonable to me that our biological systems are best adapted to sunshine abundant conditions and a higher RDI may be warranted.  While there is no decisive evidence that daily doses higher than the RDIs are beneficial, there is strong evidence that daily doses below 4000 IU pose no harm.  The most reasonable safe solution that I have formulated for myself is to spend time outdoors in the summer and to take a daily vitamin supplement of 1000-2000 IU in the winter (October-March).

In summary, this reflection has looked at the risks and benefits of vitamin D supplementation. I believe that dietary sources of vitamin D and sunlight exposure are adequate for me in the summer, but taking vitamin D supplements of 1000-2000 IU/d in the winter is warranted.  What do you think is an appropriate amount of supplementation for optimum health?

References

  1. Sharma, S., Barr, A. B., Macdonald, H. M., Sheehy, T., Novotny, R., & Corriveau, A. (2011). Vitamin D deficiency and disease risk among aboriginal Arctic populations. Nutr Rev, 69(8), 468-478. doi: 10.1111/j.1753-4887.2011.00406.x
  2. Holick, M. F. (2007). Vitamin D deficiency. N Engl J Med, 357(3), 266-281. doi: 10.1056/NEJMra070553
  3. Marya, R. K., Rathee, S., Manrow M. (1987). Effect of calcium and vitamin D supplementation on toxaemia of pregnancy. Gynecol Obstet Invest, 24:38–42. doi: 10.1159/000298772
  4. Haines, S. T., & Park, S. K. (2012). Vitamin D supplementation: what’s known, what to do, and what’s needed. Pharmacotherapy, 32(4), 354-382. doi: 10.1002/phar.1037
  5. Hathcock, J. N., Shao, A., Vieth, R., & Heaney, R. (2007). Risk assessment for vitamin D. American Journal of Clinical Nutrition, 85(1), 6-18. hyperlink
  6. Brandenburg, V. M., Vervloet, M. G., & Marx, N. (2012). The role of vitamin D in cardiovascular disease: From present evidence to future perspectives. Atherosclerosis, 225(2), 253-263. doi: 10.1016/j.atherosclerosis.2012.08.005
  7. Kaushal, M. and Magon N. (2013). Vitamin D in pregnancy: A metabolic outlook. Indian J Endocrinol Metab, 17(1): 76–82. doi: 10.4103/2230-8210.107862
  8. The United State Office of Dietary Suppliments. http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
  9. Health Canada. http://www.hc-sc.gc.ca/fn-an/nutrition/vitamin/vita-d-eng.php
  10. EFSA Panel on Dietetic Products, Nutrition and Allergies (2012). Scientific Opinion on the Tolerable Upper Intake Level of vitamin D. EFSA Journal, 10(7):2813 doi: 10.2903/j.efsa.2012.2813
  11. Doets, E. L., et al. (2008) Current micronutrient recommendations in Europe: towards understanding their differences and similarities. European Journal of Nutrition. 47(1):17-40. doi: 10.1007/s00394-008-1003-5

 

 

13 thoughts on “How Much Vitamin D is Safe?

  1. Great topic! I was especially interested in the RDI of 400 IU of vitamin D for infants (1-12 months) here in Canada. Although it may be difficult for an adult to over-dose on vitamin D, given the delivery of concentrated vitamin D drops for infants, it is much easier to over-dose a baby, especially with the large number of variables (e.g. how much vitamin D is in breast milk, formula, or absorbed from the sun). Rajakumar et al. (2013) case study an incident of vitamin D over-dose involving a 3-month old which brings to light the possibility and likelihood of over-dosing infants if parents are not properly educated. One could see how it wouldn’t be difficult to exceed the upper limit of 1000 IU/day when administering the 400 IU/drop infant supplement.

    Rajakumar, K, E.C. Reis and M.F. Holick. 2013. Dosing error with over-the-counter vitamin D supplement: a risk for vitamin D toxicity in infants. Clinical Pediatrics. 52(1):82-85

  2. I found this a really interesting and relevant topic for Canadian’s because our sun-time is limited and many Canadians turn to supplementation in the winter to maintain “healthy” Vitamin D levels. You discussed uncertainty surrounding the safe range of Vitamin D intake. This is an important point in estimating risk but another uncertainty that exists in estimating a safe dose for Vitamin D is the form of vitamin D (eg. Ergocalciferol or cholecalciferol) that provides the most benefit. Houghton and Vieth point out that Vitamin D isoforms differ between natural and synthetic sources and that the two may not be interchanged1. In their research, they found that Vitamin D3 is produced during sun exposure and fish consumption but D2 is the form prescribed in supplements1. Multivitamins, however, may contain both forms. If the supplements being consumed consist of mainly Vitamin D2 the consumers may still be deficient in Vitamin D. This may be an area that is worth exploring further in the risk assessment of Vitamin D.

    1. Houghtan L.A., Vieth R. (2006). The case against ergocalciferol (vitamin D2) as a vitamin supplement. American Society for Clinical Nutrition. 84: 694 – 697

  3. Great topic. What I find interesting is the number of studies investigating Vitamin D (25-hydroxyvitamin D) supplementation and cancer risk. For example, Garland (1) et a. did a review of epidemiological studies to examine the relationship between serum levels of vitamin D and incidence rates of cancers (e.g., colon, breat, ovarian, renal, pancreatic, aggressive protostate). They approximate that raising the minimum serum vitamin D to 40 to 60 ng/mL would prevent 58,000 and 49,000 new cases of breast and colorectal cancer per year in North America, respectively (1). It is also proposed that these serum levels could reduce case-fatatlity rates of patients that have breats, colorectal, or prostate cancer by 50% (1). Studies have also shown that supplementation at 2000 IU/day of vitamin D3 causes no adverse effects (2). To answer Steven’s questions, I would take 2000 IU/day all year regardless of where I live due to the literature on the relationship of vitamin D serum levels and incidence rates of cancer.

    (1) Garland et al. 2009. Vitamin D for cancer prevention: global perspectives. Annals of Epidemiology, 19, 468-483. http://www.sciencedirect.com/science/article/pii/S1047279709001057

    (2) National Academy of Science, Institute of Medicine, Food and Nutrition Board. 1997. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington (DC), National Academy Press. http://www.ncbi.nlm.nih.gov/books/NBK109825/

  4. I agree, a very interesting topic. I too take a supplement of 2000 IU on the recommendation of my physician who checked my blood levels last fall and found them to be deficient. I didn’t think to ask what my levels were and whether my levels were just borderline (insufficient) or truly deficient. I also only take supplements in the winter, but perhaps I should reconsider that, and I should also check the form of my supplements. It is interesting to see that Stats Canada study estimated that 2/3 of the Canadian population have sufficient blood levels (Statistics Canada, 2013), although it appears sufficient levels are defined in relation to bone health. This is in contrast to an article by Dawson-Hughes et al (2010) who found that globally, insufficiency ranged from 50-90% of the population. It appears there is much debate over what levels are sufficient and what level of supplementation is recommended (both of which appear to be quite depends on the endpoints of interest) and presumably there is debate over toxicity as well, so I am very interested in hearing more on this topic.

  5. Author –
    In this post I would like to address some of the comments raised on the discussion board about vitamin D. Specifically, I will reflect on the different forms of vitamin D and the controversy surrounding vitamin D insufficiency. Insufficiency refers to levels of vitamin D which are not detrimental to bone health (as seen in deficiency) but increase risks to developing chronic diseases including atherosclerosis and cancer.

    Vitamin D has is converted to many different forms during synthesis. First cholesterol is converted into previtamin D under the skin when exposed to sunlight. It is then hydroxylated in the liver to form 25-hydroxyvitamin D. The final step is hydroxylation in the kidney to form 1,25-hydroxyvitamin D, the active hormone. These forms of vitamin D are also called cholecalciferol (D3). The other form of vitamin D can be found in plants and is called ergosterol (D2). A detailed pathway for D3 and D2 can be found here. Studies have shown that D3 is a more effective supplement (Tripkovic et al., 2012).

    Vitamin D levels are typically measured in the blood, but because the active form of vitamin D is a hormone, it is only found at very low concentrations. It is much easier to detect the transport form of vitamin D, 25-hydroxyvitamin D (25-OH-D). 25-OH-D blood serum levels have become the standard biomarker for evaluating vitamin D status. As many people mentioned in the comments, the level of 25-OH-D indicating ideal health remains controversial. The Canadian and American clinical definition of insufficiency is <30 ng/ml (75 nmol/L) but definitions in the scientific community range from <16 ng/mL (Hanley & Davison, 2005) to <40 ng/mL (Garland et al., 2009). Hanley and Davison defined vitamin D insufficiency at a low range to make the most conservative estimate of the prevalence vitamin D insufficiency in North America. The highest recommendation is intended to be protective against many types of cancer.

    To summarize, people supplementing with vitamin D should try to acquire D3 because it is more effective at raising 25-OH-D blood serum levels. There continues to be little consensus on how high 25-OH-D levels should be, but the official recommendation from national medical organizations is 30 ng/mL and the highest recommendation is 40 ng/mL.

    References:

    Lanteria, P, et al. (2013). Vitamin D in Exercise: Physiological and Analytical Concerns. Clinica Chimica Acta. 415(16): 45-53. http://origin-ars.els-cdn.com/content/image/1-s2.0-S0009898112004391-gr1.jpg

    Tripkovic, L, et al. (2012). Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 95:1357–64. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349454/

    Hanley, D. A., & Davison, K. S. (2005). Vitamin D insufficiency in North America. J Nutr, 135(2), 332-337.

    Garland et al. 2009. Vitamin D for cancer prevention: global perspectives. Annals of Epidemiology, 19, 468-483.

  6. I find your topic really interesting from a public perception point of view. Specially when you compare it with the topic that i am working with: water fluoridation. In my opinion the reaction of the community to vitamin D supplements in products such as milk, has not been taken with the same reactive approach as water fluoridation did. Based on the data you are handling, do you think there is any toxicological reasoning for this difference (e.g. lower effect levels for fluoride or more significant effects) or is it merely a perception issue based on the higher freedom that choosing your own brand of milk brings compared to the rigid water supply system?

  7. Author –
    Risk perception was one of the major concepts we talked about in class. This week’s reflection will take a closer look risk perception in relation to vitamin D.

    Last week someone commented on the similarities between the fortification of dairy products with vitamin D and the fluoridation of water. While fluoridation of drinking water has encountered plenty of resistance from various stakeholders, there has been little opposition to fortifying staple foods with vitamin D. Chlorination of water is perhaps less controversial than fluoridation, but it represents another public health decision that has gathered much criticism. Why is the perceived risk of chlorination and fluoridation of drinking water so much greater than perceived risks concerning vitamin D?

    Vitamin D is unique from the chemicals being discussed by other students in this class because unlike caffeine, trihalomethanes, etc. some vitamin D is actually necessary for human health. (Arguably, small amounts of fluoride are beneficial but it is not necessary to prevent dental caries if one practices good dental hygiene.) Vitamin D can naturally be found in the foods that are fortified and is synthesized in the body, so it is considered a natural biochemical. This likely contributes to why people are less concerned with being exposed to high levels of vitamin D. There is a common misconception that all natural biochemicals are safe. In reality, an excess of natural biochemicals can be harmful, espectially potent effectors such as hormones. For example, excess estrogen increases the risk of breast and endometrial cancer (Liang and Shang, 2013). Like estrogen, vitamin D acts like a hormone. Only very low concentrations are needed to control calcium and phosphate levels.

    Another factor to consider is the route of exposure. Vitamin D is added to milk, butter, margarine, and milk substitutes. As noted in my first reflection, it is possible (even preferable for some people) to avoid all of these foods, whereas everyone needs to consume water (increasing exposure to fluoride and trihalomethanes). It is also important to note that vitamin D supplimentation is completely voluntary and represents a much greater exposure than dietary sources in most cases. One exception is cases where there has been a mistake in the fortification process but these events are very rare (Hathcock et al, 2007).

    In conclusion, the perceived risk of vitamin D intoxication is low in the general public.

    Liang, J., Shang, Y. (2013) Estrogen and Cancer. Annual Review of Physiology. 75: 225-240

    Hathcock, J. N., Shao, A., Vieth, R., & Heaney, R. (2007). Risk assessment for vitamin D. American Journal of Clinical Nutrition, 85(1), 6-18

  8. As you mentioned above there are many factors that contribute to the risk perception of Vitamin D among the public. I recall reading an article in 2012, after the absent winter we had, that stated that one of the possible reasons for the lowest flu rate in 30 years that winter was the high amount of sunny-days that upped Vitamin D levels. They suggested that this was because Vitamin D increases the immune function and helped to fight influenza.

    I know that among my own family whenever a cold comes along my mother always suggests taking high doses of Vitamin D twice a day to “boost the immune system.” The general perception of risk towards vitamin D is therefore relatively low in my family. The literature has also explored this topic 2,3 and I am wondering if there is any basis for the assumption that Vitamin D might also help to fight acute illnesses (such as the common cold) as well as chronic illnesses? In addition, is there any evidence to suggest that high rates of Vitamin D consumption associated with fighting influenza in the general population results in hypercalcemia?

    CBC News. (2012). 5 reasons why flu season is MIA this year. http://www.cbc.ca/news/canada/5-reasons-why-flu-season-is-m-i-a-this-year-1.1159618 (accessed September 30, 2013)
    Sundaram M.E., Coleman L.A. (2012). Vitamin D and Influenza. Adv. Nut. 3: 517 – 525
    Urashima M., Segawa T., Okazaki M., Kurihara M., Wada Y., Ida H. (2010). Randomized trial of Vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Amer. Soc. Nut. 91: 1255 – 1260

  9. I have often heard about bodybuilding in relation to vitamin supplements and their potential dangers. Daher et al 2009 provides a couple of case studies where bodybuilders essentially overdosed on Vit D and had renal failure. Are there warnings provided on products containing excessive amounts of vitamins? I imagine one wouldn’t have to look to hard in a “natural health” store to find supplements containing excessive levels. I think it is also interesting that there is almost no public reaction to this (like you stated above – no one seems to care about Vit D supplementation). One reason could be that it is a personal choice to buy supplements or milk but city supplied drinking water that is flourinated, etc is not a choice for most people.

  10. Thanks for following up on the topic of risk perception. You mentioned that perhaps part of the reason why Vitamin D additions are better taken by the public that those of fluoride and other compounds could be the “natural” origin of the vitamin.

    On this note, i am aware that a decent amount of discussion has been happening in recent years about the risk of synthetically produced Ascorbic acid Vs natural vitamin C. I have not been able to find much scientific data backing up the claims of those claiming the awefulness of the synthetic version, but for sure there is a group of the public that believes this is the case.

    In the case of vitamin D, how is the compound added to milk and other products synthesize? is it in any way different from natural versions of vitamin D? has there been any public concerns in this respect?

  11. Author –
    This week I would like to focus on the topic of critical receptors (a.k.a. sensitive populations) for vitamin D. As we discussed in class, it is important during a risk assessment to identify which demographics are most at risk for a given chemical. Toddlers are often considered critical receptors because they like to put everything in their mouths and similar exposures are higher relative to their small body mass. I will identify key factors that can increase risk of vitamin D deficiency and toxicity.

    As discussed in my first reflection, vitamin D deficiency is most common in demographics linked to reduced ultraviolet (UV) light exposure. Enduring long winters, staying indoors, wearing body coverings or sunscreen, and having dark skin pigmentation all contribute to reducing UV light exposure (Motiwala & Wang, 2012). These demographics are at the most risk of having vitamin D deficiency. Another important critical receptor is people older than 50 years. Older adults are less efficient at synthesizing vitamin D from cholesterol when exposed to UV light. This limitation is reflected government recommendations. The recommended daily intakes for older adults is consistently higher in most countries. Health Canada recommends that people over the age of 50 should take a daily supplement containing 400 International Units (IU) of vitamin D per day.

    Vitamin D toxicity is less common than vitamin D deficiency but there are a few factors that can increase risk. As mentioned earlier, having a small bodymass results in a higher dose relative to bodyweight. Therefore, children represent an important sensitive population, especially infants with Down syndrome or hypothyroidism because they may have increased absorption or decreased metabolism of vitamin D (Ozkan et al., 2012). A few other medical conditions have also been linked to increased vitamin D sensitivity. Some studies suggest that patients with sarcoidosis or mycobacterium infections and patients treated with thiazide diuretics are more sensitive to vitamin D toxicity. These studies have only considered doses much higher than the tolerable upper limit (UL) for adults (4000 IU/d). The lowest daily dose associated with hypercalcima was 77,000 UI in a patient with sarcoidosis. Results from these studies support that doses as high as 10,000 IU/d do not cause adverse effects (Hathcock et al., 2007). The best evidence suggests that 4000 IU is a very conservative UL, but there are only a few small studies involving these sensitive subpopulation so there is still some uncertainty remaining.

    There are sensitive populations for both vitamin D deficiency and toxicity. Considering age, older adults are at highest risk of vitamin D deficiency whereas infants are at highest risk of toxicity. However, there are a number of other factors influencing risk. For vitamin D deficiency, behavioural or regional differences that decrease sun exposure are significant risk factors. For vitamin D toxicity, there are a number of medical conditions that may increase vitamin D sensitivity.

    References:

    Hathcock, J. N., Shao, A., Vieth, R., & Heaney, R. (2007). Risk assessment for vitamin D. American Journal of Clinical Nutrition, 85(1), 6-18.

    Health Canada. http://www.hc-sc.gc.ca/fn-an/nutrition/vitamin/vita-d-eng.php

    Motiwala, S. R., & Wang, T. J. (2012). Vitamin D and cardiovascular risk. Curr Hypertens Rep, 14(3), 209-218. doi: 10.1007/s11906-012-0262-y

    Ozkan, B., Hatun, S., & Bereket, A. (2012). Vitamin D intoxication. Turk J Pediatr, 54(2), 93-98.

  12. I see that Health Canada states that there is no benefit of taking more than the RDA of 400 IU yet you state here that 4000 IU is very conservative. Why is the Health Canada RDA so low? I would think that older women in particular would need more?

  13. Author –
    Some people have brought up the issue of vitamin D and its association with the immune system. There have been studies coorelating vitamin D deficiency (and insufficiency) to increased susceptibility to infectious disease as well as an increased risk of autoimmune diseases such as Chrohn’s disease and multiple sclerosis (White, 2008). This correlation has been shown in epidemiological studies measuring vitamin D levels in the blood. These diseases are also associated with reduced sun exposure and long winters. Polymorphisms of the vitamin D receptor also support this hypothesis as it is also associated with increased risk of infectious and autoimmune diesease.

    References:

    White, J. H. (2008). Vitamin D signaling, infectious diseases, and regulation of innate immunity. Infect Immun, 76(9), 3837-3843. doi: 10.1128/IAI.00353-08

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