Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards.
ABSTRACT The tolerable upper intake level (UL) for vitamin D is 50 mcg/d (2000 iu/d) in North America and in Europe. In the United Kingdom a guidance level exists for vitamin D, 25 mcg/d (1000 iu/d), defined as the dose "of vitamins and minerals that potentially susceptible individuals could take daily on a life-long basis, without medical supervision in reasonable safety." Exposure of skin to sunshine can safely provide an adult with vitamin D in an amount equivalent to an oral dose of 250 mcg/d. The incremental consumption of 1 mcg/d of vitamin D3 raises serum 25-hydroxyvitamin D [25(OH)D ] by approximately 1 nmol/L (0.4 microg/L). Published reports suggest toxicity may occur with 25(OH)D concentrations beyond 500 nmol/L (200 microg/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 approximately 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.
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ABSTRACT: Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001). We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets.PLoS ONE 11/2014; 9(11):e111265. · 3.53 Impact Factor
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ABSTRACT: In recent years, there have been reports suggesting a high prevalence of low vitamin D intakes and vitamin D deficiency or inadequate vitamin D status in Europe. Coupled with growing concern about the health risks associated with low vitamin D status, this has resulted in increased interest in the topic of vitamin D from healthcare professionals, the media and the public. Adequate vitamin D status has a key role in skeletal health. Prevention of the well-described vitamin D deficiency disorders of rickets and osteomalacia are clearly important, but there may also be an implication of low vitamin D status in bone loss, muscle weakness and falls and fragility fractures in older people, and these are highly significant public health issues in terms of morbidity, quality of life and costs to health services in Europe.Although there is no agreement on optimal plasma levels of vitamin D, it is apparent that blood 25-hydroxyvitamin D [25(OH)D] levels are often below recommended ranges for the general population and are particularly low in some subgroups of the population, such as those in institutions or who are housebound and non-Western immigrants. Reported estimates of vitamin D status within different European countries show large variation. However, comparison of studies across Europe is limited by their use of different methodologies. The prevalence of vitamin D deficiency [often defined as plasma 25(OH)D <25 nmol/l] may be more common in populations with a higher proportion of at-risk groups, and/or that have low consumption of foods rich in vitamin D (naturally rich or fortified) and low use of vitamin D supplements.The definition of an adequate or optimal vitamin D status is key in determining recommendations for a vitamin D intake that will enable satisfactory status to be maintained all year round, including the winter months. In most European countries, there seems to be a shortfall in achieving current vitamin D recommendations. An exception is Finland, where dietary survey data indicate that recent national policies that include fortification and supplementation, coupled with a high habitual intake of oil-rich fish, have resulted in an increase in vitamin D intakes, but this may not be a suitable strategy for all European populations. The ongoing standardisation of measurements in vitamin D research will facilitate a stronger evidence base on which policies can be determined. These policies may include promotion of dietary recommendations, food fortification, vitamin D supplementation and judicious sun exposure, but should take into account national, cultural and dietary habits. For European nations with supplementation policies, it is important that relevant parties ensure satisfactory uptake of these particularly in the most vulnerable groups of the population.Nutrition Bulletin 10/2014; 39(4).
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ABSTRACT: Vitamin D is unique among the essential nutrients in that it can be made in the body via exposure of the skin to sunlight. There are few rich sources of vitamin D in the diet. Vitamin D is essential for maintaining healthy bones and deficiency of vitamin D causes rickets in children and osteomalacia in adults. In the UK, there is evidence that low vitamin D status is prevalent in the population and older adults living in institutions are particularly at risk.There are two forms of vitamin D that can be added to foods and drinks: vitamin D2 and D3. They have somewhat different structures, and there are some differences in the way they are metabolised by the body. Overall, the evidence for the relative effectiveness of vitamin D2 vs. D3 is mixed, and more studies are needed to provide a clearer picture. However, there does seem to be some indication that D3 is more effective than D2 in raising vitamin D status.Nutrition Bulletin 09/2011; 36(3).
Symposium: Optimizing Vitamin D Intake for Populations
with Special Needs: Barriers to Effective Food
Fortification and Supplementation
Critique of the Considerations for Establishing the Tolerable Upper Intake
Level for Vitamin D: Critical Need for Revision Upwards1
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
Europe. In the United Kingdom a guidance level exists for vitamin D, 25 mcg/d (1000 IU/d), defined as the dose ‘‘of
vitamins and minerals that potentially susceptible individuals could take daily on a life-long basis, without medical
supervision in reasonable safety.’’ Exposure of skin to sunshine can safely provide an adult with vitamin D in an
amount equivalent to an oral dose of 250 mcg/d. The incremental consumption of 1 mcg/d of vitamin D3raises serum
25-hydroxyvitamin D [ 25(OH)D ] by ;1 nmol/L (0.4 mg/L). Published reports suggest toxicity may occur with 25(OH)D
concentrations beyond 500 nmol/L (200 mg/L). Older adults are advised to maintain serum 25(OH)D concentrations
.75 nmol/L. The preceding numbers indicate that vitamin D3intake 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.
The tolerable upper intake level (UL) for vitamin D is 50 mcg/d (2000 IU/d) in North America and in
J. Nutr. 136: 1117–1122, 2006.
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)3value 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, dehydra-
tion, and tissue calcification (1–4). Furthermore, no other nu-
trient 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
The vague terminology of vitamin D safety.
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
but it did not establish such a value for vitamin D. Instead, the
EVM offered a guidance level for vitamin D, defined as ‘‘doses
1Presented as part of the symposium ‘‘Optimizing Vitamin D Intake for
Populations with Special Needs: Barriers to Effective Mechanisms of Food
Fortification and Supplementation’’ given at the 2005 Experimental Biology
meeting on April 4, 2005, San Diego, CA. The symposium was sponsored by
the American Society for Nutrition and supported, in part, by educational grants
from the Centrum Foundation of Canada, the Coca-Cola Company, and the
Natural Ovens Bakery, Inc. The proceedings are published as a supplement to The
Journal of Nutrition. This supplement is the responsibility of the guest editors to
whom the Editor of The Journal of Nutrition has delegated supervision of both
technical conformity to the published regulations of The Journal of Nutrition and
general oversight of the scientific merit of each article. The opinions expressed in
this publication are those of the authors and are not attributable to the sponsors or
the publishers, editor, or editorial board of The Journal of Nutrition, and do not
necessarily reflect those of the Food and Drug Administration. The guest editors for
this symposium publication are Susan J. Whiting, College of Pharmacy and
Nutrition, University of Saskatchewan, SK, Canada and Mona S. Calvo, Center for
Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD,
2To whom correspondence should be addressed. E-mail: email@example.com.
3Abbreviations 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-
0022-3166/06 $8.00 ? 2006 American Society for Nutrition.
by guest on June 1, 2013
of vitamins and minerals that potentially susceptible individuals
could take daily on a life-long basis, without medical supervi-
sion 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 estab-
lished 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 termi-
nology 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 D3that 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 ob-
tain 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
The UL has taken on implications beyond its intended
purpose ‘‘to assist in dietary planning and counseling for free-
living (nonmedically supervised), apparently healthy individ-
uals’’ (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.
The top panel of Figure 1 summarizes the classic concepts
behind dietary recommendations. For this, the risk of harm is
represented by the height of the curved lines above the hori-
zontal axis. The left vertical axis represents risk of harm from
insufficiency, the right axis represents risk of harm due to excess.
The UL is obtained by adjusting the no-observed-adverse-effect-
level (NOAEL) downward by dividing by a UF. The UF is in-
tended to reflect a conservative approach, to compensate for
possible inadequacy of data. In theory, as more data become
available, uncertainty should decrease. The NOAEL is usually
A summary of the considerations for safe upper limits of
nutrients as outlined by the relevant bodies (Table 2) (6–8), is
further explained by Walter (15).
Unrealistic hypothetical curves for risk of vitamin D
deficiency and excess.
The fundamental assumption is that,
for all nutrients, there is a wide gap between risk of nutrient
inadequacy and the risk of nutrient excess (Fig. 1). The flat
section of the graph is entirely hypothetical and may or may not
be relevant to vitamin D. A wide gap between adequate and
excessive intake is used to justify why committees that evaluate
nutrient requirements are usually different and separate from
the committees that evaluate excess (6–8). A narrow gap (like
that represented by the middle panel of Fig. 1) would force
committees to balance risks and benefits, instead of addressing
each without regard for the other.
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 di-
lemma 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
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 con-
ventional definition of the term nutrient can be challenged.
The definition of adequate intake is an ‘‘observed or experi-
mentally 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
Influence of the UL on actions and policies of key interest groups
Medical and health advisors,
and the general public.
Dietary supplement industry.
The UL plays a major role in determining what the public can be advised to take without a prescription. It specifies
the point beyond which pharmacists advise customers that vitamin D can be toxic.
The UL limits the amount of vitamin D that manufacturers may provide in a daily dose to the general public in
The UL defines the vitamin D level beyond which legal counsel can argue that a product is unsafe or substantiate
that the product has the potential to cause harm due to excessive vitamin D content.
Clinical nutrition researchers. The UL plays a powerful role in the dosage that can be used for nutrition research even though ‘‘physiologic’’
supplies of vitamin D via the skin reach above 250 mcg/d. Vitamin D is classified as a drug in Europe if the dose
is over 10 mcg/d, and in North America if the dose is over 25 mcg/d.
Research ethics committees
and government oversight.studies at doses higher than the UL. Consequently, the UL defines and limits the dose of vitamin D that is
feasible for clinical nutrition research.
For ‘‘drug’’ studies, additional monitoring is mandated that limits enrollment and increases cost of clinical
by guest on June 1, 2013
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 concen-
tration 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 up-
ward to 250 mcg/d (20–22).
For every other nutrient, a physiologic amount is the quan-
tity 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 D3when tested in humans (25–27).
Vitamin D3is 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 D3as the natural, physiologic
UL considerations: hazard identification. Hypercalcemia
is the classic criterion for determining vitamin D excess. Hy-
percalciuria 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 as-
sociated 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).
of the binding sites on vitamin D-binding protein in plasma,
which has a total capacity for vitamin D metabolites of ;4700
the 1-hydroxylase enzyme that is driven through mass action
by 25(OH)D. The high concentration of ‘‘free’’ 1,25(OH)2D,
anismbywhichthehypercalcemia ofsarcoidosis isachieved(2).
Another mechanism of toxicity involves the limited capacity to
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 5 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 with45mcg/d(1800 IU/d)ofvitaminD.Honkanenetal.
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
vitamin D according to Yates et al. (53). The abbreviations represented
are: EAR, estimated average requirement (for vitamin D); AI, adequate
intake; UL,upper level (calculated by dividingNOAELbyUF); NOAEL,no
observed adverse effect level; UF, uncertainty factor; LOAEL, lowest
observed adverse level. (Middle) The middle panel represents a different
set of relations for deficiency and excess. The graph illustrates a
hypothetical situation implied by combining the current UL with some of
the recent evidence of adult requirements (16). This relation implies that
some healthyadults require vitamin D in an amount that might be adverse
to others. For health policy, the overlapping curves for deficiency and
excess complicate decisions by making it necessary to balance risks and
benefits. The possibility of this scenario has not been addressed in
assessments of vitamin D safety (6–8). (Bottom) Represents what the
author proposes may be the accepted reality for vitamin D in the future,
based on an RDA that reflects the vitamin D supply from physiologic sun
exposure of adults, and data on dose tolerability.
(Top) Representation of nutrition terms relevant to
CRITIQUE OF THE VITAMIN D UL
by guest on June 1, 2013
report was overlooked by the EVM (8). If one combines the 2
study with the 3 hypercalcemic patients in the placebo group
from the Honkanen et al. study, it becomes clear that con-
sumption 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 D3intakes
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
have resulted in hypercalcemia (1–4). In the iatrogenic con-
text, the lowest intake of vitamin D associated with hypercal-
cemia has been with a dose of vitamin D2of 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 asso-
ciated with 25(OH)D levels .1000 nmol/L. However, hyper-
Several reports of industrial-scale mishaps
calcemia can occur with 25(OH)D levels as low as 355 nmol/L
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).
The most complete dose-response study
published is that of Shepard and DeLuca (43). They gave
groups of rats 10-fold increments of vitamin D3dosages. The
highest dose that did not produce hypercalcemia was 65 nmol/d
? rat21, 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) sug-
gests that adult human LOAEL may be ;10 times more than
High-vitamin D dosage studies have recently been reported
for Great Dane dogs. Nineteen weeks of supplementation at
1350 mg/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 im-
plemented 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 men-
tion 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
Process for establishing the safe upper limits for nutrients
1. Hazard identification through the collection, organization, and evaluation of all information pertaining to the adverse effects of a given nutrient.
Animal studies may be of importance, but the key issue is evidence of adverse effects in humans.
a) proof of causality
b) route of exposure (oral, dermal exposure, etc.)
c) duration of exposure (acute vs. chronic)
d) mechanisms of toxic action
e) the quality and completeness of the database
f) identification of highly sensitive subpopulations
2. Characterizing the dose-response between nutrient intake and adverse effect:
a) human data are preferable, but animal data are relevant
b) estimate the highest intake at which no adverse effect has been observed (NOAEL)
c) estimate the lowest intake at which an adverse effect has been identified (LOAEL)
d) take into account the range of nutrient intakes among members of a healthy population
3. Use judgment for setting the uncertainty factor (UF). Estimate the uncertainties and establish the UF for extrapolating the observed data and applying
it to the risk for the general population:
a) the larger the uncertainty, the larger the UF and the smaller the UL (the corollary is that UF should become less over time as more data become
b) if most data are from human studies, the UF will be lower than five
c) if animal studies are the main source of evidence, the UF value may go up to ten
d) if a NOAEL value cannot be established, the UF may also be applied to a LOAEL value (a general observation is that estimated NOAELs are
approximately one-third the LOAEL)
by guest on June 1, 2013
IU/d), has remained the focus of vitamin D safety committees
Since 1968, the adult safety limits for vitamin D, be they
general comments, guidance levels, or UL values, have re-
mained in the range of 25–50 mcg/d (6–8,46,47). In theory, the
UF should become smaller as evidence accumulates. However,
looking at Table 3, it is evident that, rather than raising the UL
for vitamin D in accordance with data that shows higher
intakes are safe, the UL has remained the same, and the change
in response to this new evidence has been to raise the UF.
Hence, the message the public has received concerning the UL
or the guidance level for vitamin D has not been affected by new
knowledge in the field for close to 40 years.
The concern that harm can result from combining a high
intake of vitamin D with abundant sun exposure must be ad-
dressed. 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 admin-
istering vitamin D to patients with primary hyperparathyroid-
ism is noncalcemic, and that it suppresses PTH secretion and
bone turnover (51).
Effect of committee psychology on the
The analysis in Table 3 can only be explained as a psy-
chological 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 in-
stead of raising the UL.
The process of ignoring evidence of the true nutrient re-
quirement 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.
1. Vieth R, Pinto T, Reen BS, Wong MM. Vitamin D poisoning by table sugar.
2. Pettifor JM, Bikle DD, Cavaleros M, Zachen D, Kamdar MC, Ross FP.
Serum levels of free 1,25-dihydroxyvitamin D in vitamin D toxicity. Ann Intern Med.
3. Nordt SP, Williams SR, Clark RF. Pharmacologic misadventure resulting
in hypercalcemia from vitamin d intoxication. J Emerg Med. 2002;22:302–3.
4. Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an
over-the-counter supplement. N Engl J Med. 2001;345:66–7.
5. Murphy MJ. Rodenticides. Vet Clin North Am Small Anim Pract.
6. Standing Committee on the Scientific Evaluation of Dietary Reference
Intakes. Dietary reference intakes: calcium, phosphorus, magnesium, vitamin D,
and fluoride. Washington, DC: National Academy Press; 1997.
7. European Commission Scientific Committee on Food. Opinion of the
scientific committee on food on the tolerable upper intake level of vitamin D. 2002
December [cited Aug. 11]. Available from: http://europa.eu.int/comm/food/fs/sc/scf/
8. Expert Group onVitamins and Minerals. Safe upper levels for vitamins and
minerals. Great Britain: Food Standards Agency; 2003.
9. Tjellesen L, Hummer L, Christiansen C, Rodbro P. Different metabolism of
vitamin D2/D3 in epileptic patients treated with phenobarbitone/phenytoin. Bone.
10. Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D(3)
intake exceeding the lowest observed adverse effect level. Am J Clin Nutr.
11. Munro I. Derivation of tolerable upper intake levels of nutrients. Am J Clin
Historic review of specific statements about toxic and
tolerable vitamin D intakes for adults
Report yearLOAEL NOAELULUF
NB 1958 (52)
FNB 1964 (45)
FNB 1968 (46)
IOM 1997 (6)
EC 2002 (7)
EVM 2003 (8)
No mention of safety
1Adjusted to 50 kg body wt, according to the statement ‘‘Excessive
quantities of vitamin D (of the order of 1,000 to 3,000 IU/kg/d) are toxic’’
(45; p. 25).
2‘‘There is no evidence that intakes in the order of 2000–3000 IU/d
produce hypercalcemia beyond infancy’’ (46; p. 26) i.e., the historic
precedent in North America that 50 mcg/d (2000 IU/d) may be a safe
3This is a guidance level and not quite a UL. Although the British EVM
group would not specify an uncertainty factor for vitamin D (p. 143 of its
report) (8), the value 4, above, is the de facto uncertainty factor. This is
because 100 mcg/d was the highest dose stated as safe, followed by the
statement, ‘‘a level of 0.025 mg/d supplementary vitamin D would not be
expected to cause adverse effects in the general population.’’ The EVM
group obfuscated the issue of safety by focusing on the mention of 2
hypercalcemic subjects in the vitamin D group of Johnson et al. (33; p. 139),
but they overlooked the 3 hypercalcemic subjects in the placebo group
of Honkanen et al. (35). There is no evidence that vitamin D intake at 50
mcg/d causes hypercalcemia at a higher rate. This lack of evidence now
extends to 275 mcg/d (38).
CRITIQUE OF THE VITAMIN D UL
by guest on June 1, 2013