Contents - IARC

Vitamin D and Cancer
Chapter 5 – Toxicity of vitamin D and long term health effects
The toxic effects of vitamin D are associated with the role of free serum 1α,25-dihydroxyvitamin
D in the regulation of plasma calcium via increased intestinal absorption or increased mobilisation of
bone calcium. Excessive serum concentration of 1α,25-dihydroxyvitamin D may be due to excess
production (e.g., in certain diseases like sarcoïdosis) or by displacement from the Vitamin D Binding
Protein (DBP) because of excess intakes of vitamin D.
Knowledge of non-bone, non-calcium adverse effects that could be associated with the
maintenance of high vitamin D status is currently very limited and needs further investigation.
5.1 Acute toxicity of vitamin D
Since 1928, it has been known that excessive daily vitamin D ingestion (200,000 – 300,000 IU,
i.e., 5,000 – 7,500 µg) produces toxic effects in humans (Hess, 1928). Anecdotal case reports on
vitamin intoxication are generally associated with over-the counter-supplements (Koutkia, Chen et
al.,2001; Propp and Scharfman, 1956; Hoff, 1980; Marriott, 1997) but also with drinking fortified milk
(Jacobus et al.,1992) and dermatological preparations containing high amounts of vitamin D
(Gottswinter et al.,1983).
Acute vitamin D intoxication with hypercalcemia may clinically evoke a myocardial infarction
(Linden, 1974; Ashizawa et al.,2003). Hypercalcemia could also lead to an increased calcium
excretion into urine. Prolonged hypercalcemia can cause kidney damage (kidney stones and renal
dysfunction), calcification of soft tissues, including kidney, blood vessels, heart and lungs.
5.2 Long-term use of less than 25 µg vitamin D supplements per day
A review of nineteen earlier studies on continuous low dose supplementation (or higher doses
given intermittently) concluded that hypercalcemia was a rare event and usually associated with a
predisposing cause (Byrne et al.,1995).
The Cochrane review of vitamin D and calcium supplements for fracture prevention (Avenell et
al.,2005) concluded that hypercalcemia risk was 2.4 times higher (95%CI 1.52 to 3.71) when vitamin
D or its analogues were used compared to a placebo or calcium. The risk of hypercalcemia was
particularly high for the use of 1α,25 dihydroxyvitamin D (RR 14.94, 95% CI 2.95 to 75.61). A review of
the same topic done by the University of Ottawa (Canada) for the US Department of Health and
Human Services (Cranney et al.,2007) 2 also concluded that there is little evidence from trials that longterm
vitamin D supplementation of between 10 and 25 µg per day would be harmful.
A meta-analysis of randomised trials of vitamin D and calcium supplements found a 7% (-
1%;13%) reduction in all-cause mortality (Autier and Gandini, 2007) in elderly people with low vitamin
D status. This result indicates that fatal adverse events are not likely with long-term use of
supplements containing 10 to 20 µg of vitamin D and 0.5 to 1.2 g of elementary calcium.
A randomised trial in France including 192 women aged 65 years and over with serum 25hydroxyvitamin
D levels less than 12 ng/mL tested daily with 10 µg of vitamin D and 0.5 g elementary
calcium against a placebo (Brazier et al.,2005). This trial made a systematic assessment of a number
of a-priori defined clinical and biological endpoints for all key body systems. After 12 months, no
difference in adverse events was noticed between the intervention and the control groups, apart from
greater uric acid concentrations in the intervention group.
5.3 Use of high doses of vitamin D supplements over several weeks or months
Studies on the safety intakes of high dose vitamin D (i.e., 100 µg up to 1,250 µg per day) were
done over short periods, from a few weeks to 6 months, and rarely for one year or more (Vieth, 1999;
SCF, 2002; Heaney et al.,2003; Kimball et al.,2007; Vieth et al.,2004). Hypercalcemia was not found
in these studies despite 25-hydroxyvitamin D levels that could reach 155 ng/mL over 6 months
(Kimball et al.,2007). Anecdotal reports on subjects taking very high doses (i.e., 100 to 200 µg per
day) of vitamin D supplements during several years were not associated with hypercalcemia (Kimball
and Vieth, 2008). These studies illustrate the tight regulation of calcium balance.
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