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Department of Nutritional Sciences and Department of Laboratory Medicine and Pathology, University of Toronto, and Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada M5G 1L5
2 To whom correspondence should be addressed. E-mail: rvieth{at}mtsinai.on.ca.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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1 nmol/L (0.4 µg/L). Published reports suggest toxicity may occur with 25(OH)D concentrations beyond 500 nmol/L (200 µg/L). Older adults are advised to maintain serum 25(OH)D concentrations >75 nmol/L. The preceding numbers indicate that vitamin D3 intake at the UL raises 25(OH)D by 50 nmol/L and that this may be more desirable than harmful. The past decade has produced separate North American, European, and U.K. reports that address UL or guidance-level values for vitamin D. Despite similar well-defined models for risk assessment, each report has failed to adapt its message to new evidence of no adverse effects at higher doses. Inappropriately low UL values, or guidance values, for vitamin D have hindered objective clinical research on vitamin D nutrition, they have hindered our understanding of its role in disease prevention, and restricted the amount of vitamin D in multivitamins and foods to doses too low to benefit public health.
KEY WORDS: • vitamin D • cholecalciferol • hypercalcemia • tolerable upper intake level • 25-hydroxyvitamin D • toxicology
The following discussion focuses on the inadequacies of the current upper intake level (UL)3 value for vitamin D and the potential public health benefits of a proposed higher tolerable upper-intake level for this unique fat-soluble vitamin. Unlike the slow, subtle effects of most vitamin excess, vitamin D overdose is unambiguously evident by hypercalcemia, dehydration, and tissue calcification (1–4). Furthermore, no other nutrient has a long history of use as a rodenticide (5). These features combine to make vitamin D a good example of why care should be taken to avoid excessive intake of vitamins. While safety is, of course, an important issue, the definition of what constitutes an "excessive intake" of vitamin D remains so ambiguous that it may affect the ability of the public to obtain supplements with doses of vitamin D that are appropriate for health.
The vague terminology of vitamin D safety. The Institute of Medicine, through a Canadian/United States Subcommittee on Upper Reference Levels of Nutrients and the European Commission's Health and Consumer Protection Directorate-General, defines a tolerable upper intake level as the highest daily level of chronic nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population (6,7). The United Kingdom's EVM (Expert Group on Vitamins and Minerals) may specify a "safe upper limit," but it did not establish such a value for vitamin D. Instead, the EVM offered a guidance level for vitamin D, defined as "doses of vitamins and minerals that potentially susceptible individuals could take daily on a life-long basis, without medical supervision in reasonable safety" (8; p. 6).
The UL is important because its purpose is to ensure public safety, but one might question whether the UL value established for vitamin D fulfills this purpose. Over the past decade, an "excessive intake" of vitamin D has come to be defined for most people by the UL; however, this has never been the meaning intended for the UL. The definition of the UL is ambiguous, based more on what it is not, than on what it is. A better alternative, applied to some nutrients in the U.K., is the safe upper limit (SUL). "SULs or Guidance Levels are the doses of vitamins and minerals that susceptible individuals could take daily on a life-long basis, without medical supervision. The levels have been derived so that the consumer can have confidence that harm should not ensue from daily intake up to that level" (8; p. 23). The SUL is an assurance of safety. Remarkably, the EVM does not define a safe level for vitamin D, and has offered a "guidance level" instead. For vitamin D, the EVM document explains the guidance level with terminology similar to the way the UL is defined, where the intake of 25 mcg/d (1000 IU/d) "would not be expected to cause adverse effects in the general population" (8). In the EVM document, the guidance level is an assurance of safety, but it is this way with less certainty than the criteria needed for an SUL [this would account for why its uncertainty factor is so large, as discussed later]. The UL, SUL and guidance level are all well-intentioned guides for the general public. Unfortunately, they are not straight forward, and for vitamin D in particular, they hinder the implementation of scientific evidence that adults require more vitamin D than previously thought.
Nutritional adequacy for vitamin D is measured, based not on intake from food or supplements, but rather upon serum 25-hydroxyvitamin D [25(OH)D] concentrations. In Europe, the Scientific Committee on Food based its UL upon the 100 mcg/d dose of vitamin D3 that produced 25(OH)D levels as high as 150 nmol/L (9,10). It then applied an uncertainty factor (UF; a factor divided into the no-observed-adverse-effect-level to obtain the UL) of 2, ending up with a UL of 50 mcg/d (7). All bodies that have specified a UL for vitamin D specifically avoid the question of whether an intake more than the UL is safe or harmful.
The UL has taken on implications beyond its intended purpose "to assist in dietary planning and counseling for free-living (nonmedically supervised), apparently healthy individuals" (11; p. 865). Whether intended or not, at least 5 interest groups are affected by the UL (Table 1). Each group draws different implications from the UL for vitamin D. One implication is that the UL for vitamin D plays a major role in determining the dosage suitable for nutrition research. There are several examples of this limitation on research (12–14). In theory, the UL is based upon knowledge gained through research. However, the UL does affect the kind of research that helps to determine the UL.
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To date, committees that address the issue of vitamin D safety have failed to address the possibility that a narrower minimum risk zone (as is hypothetically represented by the middle panel of Fig. 1) might be appropriate. The current dilemma with respect to vitamin D is how to deal with a UL that is 50 mcg/d in light of accumulating evidence that the total daily adult requirement may be 100 mcg/d (16).
Failure to define what is a physiologic "intake" of vitamin D.
For vitamin D, the nutritional value is not straightforward. For example, the British EVM document does not define the nutritional value for any nutrient, let alone for vitamin D (8). Because very few foods naturally contain vitamin D, the conventional definition of the term nutrient can be challenged. The definition of adequate intake is an "observed or experimentally derived intake by a defined population or subgroup that, in the judgment of the DRI Committee, appears to sustain a defined nutritional state, such as normal circulating nutrient values, growth, or other functional indicators of health". Adequate intake is a "judgment" made necessary by the lack (6; p. 315) or absence of the quality of evidence necessary for establishing a recommended dietary requirement (RDA) (6). This adds another dimension of complexity to the dilemma from the preceding paragraph. As long as the UL prevents healthy adults from consuming an amount of vitamin D that can produce the serum 25(OH)D concentrations (associated with health benefits in epidemiologic studies of vitamin D-deficient adults), it will be difficult to design studies of a quality suitable for establishing RDA levels for vitamin D. The objective index for vitamin D adequacy is the serum concentration of 25(OH)D (6). A recent consensus suggests that desirable 25(OH)D values exceed 75 nmol/L (17). An adult who regularly consumes the UL for vitamin D will increase serum 25(OH)D by 50 nmol/L (18). The arithmetic suggests that the UL and the U.K.'s guidance level for vitamin D are too low, possibly even too low for the criteria for an RDA. This field begs for a reassessment by the Food and Nutrition Board. An argument for raising the RDA for elderly adults has been presented in this symposium (19).
The nutritional value for vitamin D should be defined as an amount of vitamin D equivalent to what an adult can acquire through exposing full skin surface to summer sunshine. That is, a physiologic intake of vitamin D for an adult might range upward to 250 mcg/d (20–22).
For every other nutrient, a physiologic amount is the quantity acquired by eating a normal diet. What makes vitamin D different is that supplementation or fortification is intended to compensate for a deficiency of sunshine (23,24). Furthermore, "pharmacologic" is not necessarily "toxic." The effects of higher doses of vitamin D3 (in contrast to vitamin D2) need to be characterized far better than they are now.
To date, most preparations of prescriptions for high-dose vitamin D have been in the form of vitamin D2, a compound that is not commonly present in foods or in primate circulation, and which has been shown to be less effective in raising serum 25(OH)D than vitamin D3 when tested in humans (25–27). Vitamin D3 is now the most common form used in over-the-counter dietary supplements and in food fortification in the U.S. and Canada. Food-related deliberations about the safety of vitamin D supplementation should focus specifically on evidence pertaining to vitamin D3 as the natural, physiologic product.
UL considerations: hazard identification. Hypercalcemia is the classic criterion for determining vitamin D excess. Hypercalciuria can occur at lower doses of vitamin D than those that cause hypercalcemia (28). The cause of hypercalciuria is difficult to address. Although a higher serum 25(OH)D is associated with higher intestinal calcium absorption, this effect reaches a plateau at 75 nmol/L (19). Furthermore, according to epidemiologic evidence, there is no relation between vitamin D intake and the incidence of hypercalciuria (29).
The mechanisms by which vitamin D is toxic at the molecular level have been reviewed (30). In short, the mechanisms of toxic action for vitamin D, the nutrient, are probably due to saturation of the binding sites on vitamin D-binding protein in plasma, which has a total capacity for vitamin D metabolites of 4700 nmol/L (31). Furthermore, it is impossible to turn off completely the 1-hydroxylase enzyme that is driven through mass action by 25(OH)D. The high concentration of "free" 1,25(OH)2D, despite a normal total 1,25(OH)2D concentration, is the mechanism by which the hypercalcemia of sarcoidosis is achieved (2). Another mechanism of toxicity involves the limited capacity to adapt metabolic clearance of vitamin D to eliminate metabolites from the body.
The quality and completeness of the data that support the current NOAEL and LOAEL are highly questionable. Official reports tend to focus on studies by Narang et al. (32) and Johnson et al. (33), which support the risk of harm at intakes around the current UL. The problems with the study by Narang et al. have been thoroughly dealt with elsewhere (10,34). The Johnson et al. (33) abstract mentions that 2 of 63 vitamin D-supplemented patients developed hypercalcemia, but none of the 40 placebo patients developed hypercalcemia. Although the difference in incidence of hypercalcemia is certainly not significant (P = 0.52), the Johnson publication is the main justification for British conservatism about vitamin D UL(8). Another article highlighted by the EVM is by Honkanen et al. (35), who supplemented free-living adults and institutionalized elderly with 45 mcg/d (1800 IU/d) of vitamin D. Honkanen et al. did not detect a change in serum calcium, yet they present their study as if there were potential for harm with vitamin D. This is despite the fact that the only 3 hypercalcemic subjects in their study were in the placebo group! This aspect of the Honkanen report was overlooked by the EVM (8). If one combines the 2 hypercalcemic patients taking vitamin D from the Johnson et al. study with the 3 hypercalcemic patients in the placebo group from the Honkanen et al. study, it becomes clear that consumption of vitamin D at 50 mcg/d (2000 IU/d) contributes no adverse effect whatsoever. The traditional definition of hypercalcemia is a serum- or plasma-calcium level that is higher than the 97.5th percentile of levels in a normal population. Because the studies of both Johnson et al. and Honkanen et al. involved >100 patients, the number of subjects whose calcium bounced into hypercalcemic levels agrees with what could be expected for any population, especially an older one. There are well-described studies that confirm safety of vitamin D3 intakes at 100 mcg/d (10,36) and at 250 mcg/d (37,38).
Probably the most helpful publications from a public-health perspective about the risks of vitamin D intake are those concerning the case of a home-delivery dairy in Boston that served 11,000 households with over-fortified milk containing highly variable amounts of vitamin D (39,40). Based on the dairy's purchase records of vitamin D, the average quart of milk contained 300 mcg/quart (12,000 IU/quart) between 1985 and 1991. However, the error, due to bad dispensing equipment for vitamin D, ranged upward as high as 6000 mcg/quart (while normal is 10 mcg/quart). Blank et al. reported that there were 56 cases of suspected or confirmed vitamin D intoxication (40). The most susceptible members of the population were women over the age of 69, infants, and children. If the current UL or the LOAEL for vitamin D were true, there have been far more cases of hypercalcemia.
UL considerations: the dose-response relation
Human studies. Several reports of industrial-scale mishaps have resulted in hypercalcemia (1–4). In the iatrogenic context, the lowest intake of vitamin D associated with hypercalcemia has been with a dose of vitamin D2 of at least 40,000 IU/d (1000 mcg/d) for several months (20). Patients given regular bolus doses of vitamin D3 [7500 mcg/wk (300,000 IU/wk)] can also develop hypercalcemia (41). This hypercalcemia was associated with 25(OH)D levels >1000 nmol/L. However, hypercalcemia can occur with 25(OH)D levels as low as 355 nmol/L (42).
Heaney et al. (38) studied the effects of increasing doses of vitamin D. He found that an incremental increase in vitamin D3 increases the serum 25(OH)D by 1.0 nmol/L when 25(OH)D levels are low, but this increment of mcg/d declines as the 25(OH)D increases beyond 100 nmol/L (18).
Animal studies.
The most complete dose-response study published is that of Shepard and DeLuca (43). They gave groups of rats 10-fold increments of vitamin D3 dosages. The highest dose that did not produce hypercalcemia was 65 nmol/d · rat–1, this works out to 25 mcg/rat (1000 IU/rat). If we assume that they used relatively large rats, this becomes 50 mcg/kg (2000 IU/kg). If one then uses the 10-fold uncertainty factor for between-species comparisons, these rat data imply that, for an adult human, the NOAEL is 250 mcg/d (10,000 IU/d). Using the same comparison, Shepard and DeLuca's study (43) suggests that adult human LOAEL may be 10 times more than that.
High-vitamin D dosage studies have recently been reported for Great Dane dogs. Nineteen weeks of supplementation at 1350 µg/kg did not change serum-calcium levels (44). The resulting serum 25(OH)D concentration was 1255 nmol/L. By dividing the dog dose by 10, to account for the different species, this translates to a NOAEL human equivalent of 135 mcg/kg. This value suggests a wide margin of safety in dogs, but such a dose is implausibly high in the human context.
UL considerations: use of judgment
The concept of a UL for nutrient intakes has been implemented formally for only a decade. However, RDA reports before the 1990s did address the issue of vitamin D safety. The progression of historical statements relating to safe and toxic vitamin D intakes are summarized in Table 3. The first mention of the value that is the current North American/European UL of 50 mcg/d (2000 IU/d) was the statement in the RDA of 1964, that 50 mcg/d (2000 IU/d) may be a limit for infants (45). Because of a lack of evidence to the contrary, this same value was later extended to adults (46). That value, 50 mcg/d (2000 IU/d), has remained the focus of vitamin D safety committees ever since.
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The concern that harm can result from combining a high intake of vitamin D with abundant sun exposure must be addressed. Based upon reports of patients intoxicated with vitamin D3, we know that it requires 25(OH)D levels of >700 nmol/L to cause an undesirable change in calcium homeostasis (2,4,20,39). There is a potential risk of vitamin D intoxication in adults receiving abundant sunshine that, by itself, provides a safe amount of vitamin D (6–8). These adults may be theoretically more susceptible to toxicity when taking vitamin D supplements because of the cumulative effect from supplements and sun. American outdoor workers acquire a sun-derived vitamin D equivalent to consuming 100 mcg/d (21). Although sun exposure delivers a moderate dose compared with doses safely used clinically, judgment in relation to a UL for vitamin D should account for sunshine.
There are rare individuals, such as those with sarcoidosis or tuberculosis, who should avoid both sunshine and vitamin D (48). However, this should be balanced against the possibility that the incidence of these diseases may be higher because of prevailing vitamin D insufficiency. One should ask whether the upregulation of 1-hydroxylase within tissues represents a form of vitamin D hunger (49), and that with chronic upregulation of 1-hydroxylase, some cells lose the ability to downregulate 1,25(OH)2D production once the substrate becomes available. There has also been a long-standing assumption that patients with primary hyperparathyroidism may be hypersensitive to vitamin D (8,50). However, recent work indicates that administering vitamin D to patients with primary hyperparathyroidism is noncalcemic, and that it suppresses PTH secretion and bone turnover (51).
Effect of committee psychology on the uncertainty factor
The analysis in Table 3 can only be explained as a psychological barrier that historic safety limits for vitamin D impose on the judgment of subsequent committees. In a group setting, the easiest way for anyone with good intention to exhibit good judgment is to be conservative. Anyone who proposes an increase in the UL will have to face others who see this as a move in the direction of greater danger (54). The path of least resistance is to avoid a change to the UL. This becomes very easy for a group to accept because the considerations and guidelines that UL committees must follow explicitly ignore any possibility that a low UL might be a problem in itself. The wide, flat gap in classic figures that illustrate risk-of-deficiency and risk-of-excess curves makes it easy to imagine that a UL will have no consequence for setting an eventual RDA (Fig. 1, top). The British report explicitly states that the "EVM has not conducted risk/benefit analyses of the nutrients since beneficial effects in excess of the nutritional value of the vitamins and minerals are not within its remit" (8; p. 130). The psychology and the evidence in Table 3 indicate that committees who are considering the safety of vitamin D adapt to new knowledge that higher doses are safe by raising the uncertainty factor instead of raising the UL.
The process of ignoring evidence of the true nutrient requirement has resulted in an unrealistically low UL for vitamin D. This low UL is itself harmful. The low UL has been, and continues to be, the major hindrance to solving the problem of vitamin D insufficiency in adults.
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FOOTNOTES |
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3 Abbreviations used: LOAEL, lowest-observed-adverse-effect-level; NOAEL, no-observed-adverse-effect-level; RDA, recommended dietary allowance; SUL, safe upper limit; UL, tolerable upper limit; UF, uncertainty factor; 25(OH)D, 25-hydroxyvitamin D.
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S. J. Whiting and M. S. Calvo Overview of the Proceedings from Experimental Biology 2005 Symposium: Optimizing Vitamin D Intake for Populations with Special Needs: Barriers to Effective Food Fortification and Supplementation J. Nutr., April 1, 2006; 136(4): 1114 - 1116. [Full Text] [PDF]
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R. P. Heaney Barriers to Optimizing Vitamin D3 Intake for the Elderly J. Nutr., April 1, 2006; 136(4): 1123 - 1125. [Abstract] [Full Text] [PDF]
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M. S. Calvo and S. J. Whiting Public Health Strategies to Overcome Barriers to Optimal Vitamin D Status in Populations with Special Needs J. Nutr., April 1, 2006; 136(4): 1135 - 1139. [Abstract] [Full Text] [PDF]
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