Vitamin D may be one of the most fundamentally
important building blocks available to us for creating
and sustaining vibrant health. In addition to its
classically understood role in bone formation and
calcium absorption, research has uncovered myriad
roles for vitamin D, ranging from increasing muscular
coordination to preventing cancer, heart disease,
autoimmune diseases and radiation-induced tissue
damage.1 Yet vitamin D is also considered
to be "the most toxic of all vitamins."2
It is therefore crucial for us to understand just
how much vitamin D is necessary for optimal health
and just how much can be toxic.
Diseases
against which Vitamin D Is Proven to or Suggested
to Protect1,4
Rickets and osteomalacia
Hypocalcemia
Convulsions, tetany and heart failure
in the newborn
Osteoporosis
Cancer
Heart disease
High blood pressure
Obesity
Arthritis
Mental illness
Chronic pain
Muscular weakness
Radiation poisoning
Diabetes
Multiple sclerosis
Other autoimmune
diseases
Although Weston Price found the foods of primitive
diets to be a full ten times higher in the fat-soluble
vitamins than the "foods of modern commerce"
that displaced them, he did not report the absolute
amount of vitamin D in these diets.3
At the time he wrote, Price did not have a specific
chemical test for vitamin D at his disposal, nor
did he have a way of quantifying the amount of vitamin
D the people he studied obtained from sunlight.
We must therefore turn to modern research to be
able to determine our needs for vitamin D.
A person who wishes to obtain this information
from a natural health perspective, however, is faced
with a number of conflicting recommendations about
both the requirements for and safety of vitamin
D. While the upper limit of vitamin D intake considered
safe by official organizations may be set far too
low to allow most of us to attain optimal levels
of vitamin D, some researchers concerned with the
widely variable responses of individuals to vitamin
D supplementation consider it unsafe to supplement
with even moderate doses of vitamin D without testing
and supervision. Most of these recommendations,
like most of the research on vitamin toxicity, fail
to take into account the interaction between vitamins
A, D and K, which may be the most critical point
to address in a discussion of vitamin D's toxicity.
In fact there is compelling evidence to support
the premise that vitamin D toxicity results from
a relative deficiency of vitamins A and K.
It is not the purpose of this article to establish
which intake of vitamin D is safe to consume without
testing one's vitamin D levels or at which intake
of vitamin D one must begin testing. This article
instead presents the facts, probabilities and uncertainties
about vitamin D requirements and safety, the importance
of the form of vitamin D consumed and the protective
and synergistic context of a nutrient-rich diet.
With this information, each individual can make
the personal decision of whether and when to test.
Vitamin or Hormone?
Like the active form of vitamin A, the active
form of vitamin D—called calcitriol—is
a hormone.5 Although its structure is
similar to that of the steroid hormones, vitamin
D is classified as a secosteroid because one of
its carbon rings is split open.6
Hormones can act in two ways: first, they can slip
inside of a cell and enter the nucleus, where they
bind to DNA and thereby direct a cell to turn the
expression of a gene on, off, up or down; second,
they can bind to a receptor on the outside of a
cell membrane and thereby transmit a signal to the
cell, telling it to change what it is doing in any
number of ways. Activated vitamin D does both.5,7
Because of the similarities in the molecular nature
of their interaction with genes, the receptors for
activated vitamins A and D together with the receptor
for thyroid hormone constitute a distinct family
of hormone receptors.5
Before vitamin D can act as a hormone, however,
it must go through two steps of activation: first,
it must be converted in the liver into 25-hydroxyvitamin
D, also called calcidiol; second, calcidiol must
be converted into 1, 25-dihydroxyvitamin D, also
called calcitriol, which is formed primarily by
the kidneys but also in small amounts by virtually
all cells (see Vitamin D Pathway
sidebar, below). Calcidiol is the major storage
form of vitamin D. Since it is more water-soluble
than unconverted vitamin D, it is easier to carry
in large amounts in the blood where it is bound
to the water-soluble vitamin D-binding protein (DBP),
readily on hand to be quickly converted into calcitriol
as needed.8
Vitamin
D Pathway
SUNSHINE
AND FOOD
>>
CONVERSION
IN THE LIVER
>>
CONVERSION
IN THE KIDNEY
AND OTHER TISSUES
Vitamin
D
Calcidiol
25(OH)D
25-hydroxyvitamin D
Storage Form of Vitamin
D
Calcitriol
1,25(OH)2D
1,25-dihydroxyvitamin D
Active Hormonal Form
of Vitamin D
Some authors have suggested that we should frame
the discussion of the toxicity of vitamin D by viewing
vitamin D as a hormone rather than a vitamin.9
Although trace amounts of calcitriol and small amounts
of calcidiol are found in butter,10 only
unconverted vitamin D is found in significant amounts
in cod liver oil and most other vitamin D-rich foods.11
It would therefore be a mistake to liken the consumption
of vitamin D to a type of hormone therapy. Since
thyroid hormone is, like calcitriol, produced within
the body by modifying nutrients found in foods,
we can draw an analogy between these two hormones
to illustrate this point.
Whereas calcitriol is produced in the kidneys
and other tissues by chemically modifying vitamin
D, thyroid hormone is produced in the thyroid by
attaching the mineral iodine to several sites on
the amino acid tyrosine. Prescription treatment
with the fully activated calcitriol, therefore,
would be analogous to prescription treatment with
thyroid hormone; treatment with isolated vitamin
D supplements would be analogous to taking isolated
tyrosine and iodine supplements; consumption of
vitamin D-rich foods, finally, would be analogous
to the consumption of foods such as ocean fish,
which contain tyrosine enmeshed in large proteins
and contain iodine from the mineral-rich seawater.
Nevertheless, we cannot ipso facto assume
that because vitamin D-rich foods are natural, they
are 100 percent safe in unlimited quantities and
in any context. While some foods are very rich in
vitamin D, most foods are not. Neither foods nor
the nutrients within them are ever consumed alone;
rather, they are consumed within the broader context
of a diet that provides a full spectrum of nutrients,
not all of which are substantially present in each
individual food. Sunlight is and has been throughout
human existence readily available for vitamin D
synthesis year-round in the tropics, yet even sunlight
cannot be considered standing alone, but must be
seen within the context of a diet that provides
other nutrients, such as vitamins A and K, both
of which have been shown to interact with vitamin
D.
Before beginning any discussion of vitamin D requirements
or safety, therefore, it is important to understand
how we obtain vitamin D, the differences in the
metabolism of vitamin D from various sources and
how vitamin D metabolism interacts with other factors
in our lifestyles and diets.
Sources of
Vitamin D: Sunlight
Sunlight of the ultraviolet-B (UVB) wavelength
converts 7-dehydrocholesterol in the skin into vitamin
D. At most latitudes outside of the tropics, however,
there are substantial portions of the year during
which vitamin D cannot be obtained from sunlight;
additionally, environmental factors including pollution
and the presence of buildings can reduce the availability
of UVB light (see sidebar below).
The Synthesis
of Vitamin D in the Skin and the Vitamin D
Winter
When sunlight of the ultraviolet-B (UVB)
wavelength strikes the skin, it is absorbed
by 7-dehydrocholesterol, a steroid and precursor
to cholesterol, splitting open one of its
carbon rings and thus converting it into the
secosteroid previtamin D3. While
7-dehydrocholesterol is tucked tightly within
the lipids of skin cell membranes, previtamin
D3 is an unstable compound that
over a brief period of time converts into
vitamin D3, causing it to be released
from the cell membrane.12 Vitamin
D3 then travels into the blood
where it binds to vitamin D-binding protein
(DBP).16 Eventually, it is delivered
to the liver where it is converted into its
primary storage form, calcidiol, which is
likewise transported in the blood by DBP.8
Full-body exposure of pale skin to summer
sunshine for 30 minutes without clothing or
sunscreen can result in the synthesis of between
10,000 and 20,000 IU of vitamin D. Two mechanisms,
however, prevent the body from synthesizing
an excessive amount of vitamin D: first, a
given area of skin can only produce a certain
amount of vitamin D before it reaches an equilibrium
in which vitamin D is degraded by sunlight
as fast as it is synthesized; second, after
repeated exposure to sun, the pigment melanin
accumulates, which decreases the formation
of vitamin D.8 Although the various
degradation products of excess vitamin D have
generally been presumed to be inactive, several
of them exert biological activity in skin
cells, where they may prevent hyperproliferative
disorders such as psoriasis.17
The amount of UVB radiation available depends
on the angle at which the sun's rays strike
the earth, the presence of clouds and buildings,
ozone and aerosol pollution, altitude and
reflective surfaces such as snow.18
Because of the effect of the sun's angle,
Webb and colleagues showed in 1988 that, even
in completely clear skies, synthesis of vitamin
D in the skin is impossible for four months
of the year in Boston, Massachusetts and six
months of the year in Edmonton, the capital
of Alberta, Canada. The Webb team found that
such a "vitamin D winter" occurred
during at least part of the year at any latitude
greater than 34 degrees.19 More
recently, one group of researchers used a
computer model to suggest that in the nearly
unattainable condition of truly clear skies,
the vitamin D winters are shorter than Webb's
team suggested, but that under some environmental
conditions, vitamin D winters can occur even
at the equator.18
In addition to environmental factors, racial, religious
and lifestyle factors as well as age can also affect
one's ability to obtain vitamin D from the sun.
Skin pigmentation can reduce the rate of vitamin
D synthesis by a factor of 50.12 Blacks
living in America and Europe are therefore at an
increased risk of vitamin D deficiency both compared
to whites living in the same country and compared
to blacks living in Africa, where UVB availability
is greater.13
Only a given amount of vitamin D can be produced
in a given area of skin before it reaches an equilibrium;
the amount of vitamin D one obtains from the sun,
therefore, is proportionate to the amount of skin
one exposes. Dressing conservatively will for this
reason reduce vitamin D synthesis. A large proportion
of children who have developed rickets, a rare and
extreme disease of vitamin D deficiency, have belonged
to families practicing the use of restrictive clothing
for religious reasons.14,15
Clothing is not the only way to stop vitamin D
synthesis in the skin: even the simple use of a
sunscreen with SPF 8 reduces UVB penetration by
98 percent and essentially abolishes vitamin D production.12
The concentration of 7-dehydrocholesterol in the
skin declines with age, resulting in a 4-fold reduction
in vitamin D synthesis in a 70-year-old compared
to a 20-year-old.12 This suggests that
the dietary need for vitamin D increases substantially
with age, and also forms a basis to question the
safety of administering cholesterol-lowering statin
drugs to the elderly, which could further reduce
levels of 7-dehydrocholesterol.
As shown in the side bar below, the effect of
statins on vitamin D synthesis has not been sufficiently
investigated.
Do Statins
Inhibit Vitamin D Synthesis?
HMG-CoA reductase inhibitors, often referred
to as "statins," block cholesterol
synthesis by competitively inhibiting the
enzyme that converts HMG-CoA into mevalonate.
Mevalonate is a precursor not only to cholesterol,
but also to coenzyme Q10, squalene,
and a wide class of compounds called isoprenes.
Among the isoprenes, dolichol is responsible
for adding physiologically important sugar
groups to thousands of different proteins,
while several others are responsible for anchoring
thousands of proteins to cell membranes.20
Since mevalonate is also a precursor to 7-dehydrocholesterol,
from which vitamin D is synthesized in the
skin, it must be asked whether statins inhibit
the synthesis of vitamin D.
The 7-dehydrocholesterol reductase enzyme
(7-DHCR), which is responsible for converting
7-dehydrocholesterol into cholesterol, possesses
a specific component that is able to sense
the presence of cholesterol and other sterols
and may reduce its activity when the pool
of cholesterol or its precursors is depleted.21
If this is the case, the pool of 7-dehydrocholesterol
could be preserved even in the face of decreasing
mevalonate. Despite this possibility, mevinolin,
the active ingredient in red yeast rice, is
capable of reducing 7-dehydrocholesterol levels,22
and simvistatin (Zocor) not only inhibits
the synthesis of mevalonate but also enhances
the conversion of 7-dehydrocholesterol to
cholesterol by increasing the expression of
7-DHCR.23 Simvistatin thereby hits
the pool of 7-dehydrocholesterol with a double-whammy,
both decreasing its synthesis and increasing
its degradation.
Only four studies have examined the effect
of statins on vitamin D status.24
Three studies using pravastatin (Pravachol)
for durations of eight weeks,25
three months26 and six months27
all showed no effect on vitamin D status.
One Czechoslovakian study of which only the
abstract is available in English claims to
have shown lovastatin (Mevacor) to increase
vitamin D levels over three months,28
although there is no indication in the abstract
that the researchers controlled for the effect
of seasonality, which could easily have confounded
the results.
Dr. Peter Langsjoen of the East Texas Medical
Center in Tyler, Texas and his associates
showed lovastatin to decrease coenzyme Q10
levels over a period of 18 months before they
reached their lowest point.29 The
reduction of coenzyme Q10 levels
in the blood in this case is analogous to
the reduction of 7-dehydrocholesterol levels.
We would expect it to take an even longer
time for this effect to appreciably change
the concentration of 7-dehydrocholesterol
in the skin, and yet longer to measurably
impact the vitamin D levels of the blood.
Since the durations of these studies are therefore
woefully inadequate and since each individual
statin may impact 7-dehydrocholesterol levels
differently, the possibility that statins
reduce vitamin D status remains an unstudied
risk.
Sources of Vitamin D: Foods
As can be seen in Table 1, below,
vitamin D is present in small amounts in fatty animal
products from terrestrial sources, but in large
amounts primarily in seafood. Although fish can
synthesize vitamin D in their skin if they swim
near the surface of the sea, the primary reason
sea animals are such a rich source of vitamin D
is because they consume massive amounts of plankton,
which is rich in precursors—called provitamins—to
vitamin D2, vitamin D3 and
other unidentified forms of vitamin D. Amazingly,
vitamin D3, which fish appear to synthesize
from its precursor without the use of sunlight,
is the only form of vitamin D that has ever been
found in fish, despite their consumption of large
amounts of provitamin D2; whether this
is because they selectively discard provitamin D2
or are able to completely convert it to vitamin
D3 remains a mystery.12
Table
1: Vitamin D3 Content of Selected
Foods33
Food (100 g unless otherwise specified)
Vitamin D (IU)
Anglerfish Liver
4,400
Summer Pork or Bovine Blood (1
cup)32
4,000
High-Vitamin Cod Liver Oil (1 tablespoon)34
3,450
Indo-Pacific Marlin
1,400
Chum Salmon
1,300
Standard Cod Liver Oil (1 tablespoon)
1,200
Herring
1,100
Cultured Bastard Halibut and Fatty
Bluefin Tuna
720
Duck Egg
720
Grunt and Rainbow Trout
600
Eel
200 - 560
Cultured Red Sea Bream
520
Mackerel
345 - 440
Salmon
360
Canned Sardines
270
Chicken Egg
120
Pork Liver
50
Unfortified Summer Milk (1 liter)35
40
Beef Liver
30
Pork
28
Vitamin D concentrates in the ocean's food chain.
A single fish consumes 1.2 percent of its body weight
in plankton every 24 hours. By feeding on fish,
seals consume the equivalent of half a ton of plankton
to produce each pound of their body weight. In turn,
killer whales that feed on seals consume the equivalent
of five tons of plankton for each pound of their
body weight.12 This phenomenon would
explain why Weston Price found seal oil, which he
estimated to constitute 200 calories per day of
the Inuit diet, to be several times higher in the
fat-soluble vitamins than ordinary cod liver oil.30
One rich source of vitamin D from land animals
that is generally overlooked is blood. Since mammals
store their vitamin D primarily in the blood as
calcidiol, which is roughly five times as potent
as unconverted vitamin D,31 the concentration
of vitamin D activity in the blood will be much
higher than that of other tissues. An animal exposed
to optimal levels of UVB radiation could contain
as much as 16 IU/mL. The Masai, who at times drink
the blood of their animals, may obtain a significant
amount of vitamin D from this source. A recipe for
blood sausage using two cups of blood would yield
almost 8,000 IU of vitamin D.32
Absorption of dietary vitamin D occurs in the
jejunum and ileum of the small intestine and is
dependent upon the adequate supply of bile salts.8
Whereas vitamin D synthesized in the skin is carried
by the vitamin D-binding protein as soon as it reaches
the blood, dietary vitamin D is transported by chylomicrons
through the lymphatic system, where some of it is
delivered to vitamin D-binding protein, some to
other lipoproteins including LDL, and some to the
liver. Because chylomicrons and LDL deliver substances
to the liver very efficiently, dietary vitamin D
is converted to calcidiol much more quickly than
is vitamin D that has been synthesized in the skin.16
Sunlight vs. Food
Compared to vitamin D from sunlight, dietary vitamin
D has several advantages and disadvantages. Unlike
vitamin D from sunlight, dietary vitamin D can be
obtained on a year-round basis at any region of
the earth, and can be obtained by people who because
of business or lifestyle do not have the opportunity
or desire for afternoon sunbathing. On the other
hand, there is no known inherent mechanism for protecting
against the absorption of excessive vitamin D when
it is obtained from the diet as there is when it
is obtained from sunlight. Conditions interfering
with the absorption of dietary fat such as celiac
disease interfere with the absorption of dietary
vitamin D, making vitamin D from sunlight, if available,
preferable in such situations.8
The capacity to synthesize vitamin D in the skin
decreases dramatically with age.12 For
the elderly, then, increasing dietary vitamin D
may be much more practical to achieve than extensive
exposure to sunlight, and in many cases may be a
necessity.
Vitamin D3:
Foods, Supplements and Sunshine
While vitamin D3 is the "natural"
form of vitamin D, what's found in foods is
a broader complex of vitamin D compounds.
Some foods, such as blood, butter and milk,
contain the majority of their vitamin D activity
as calcidiol and a minority as unconverted
vitamin D.10 The degradation of
vitamin D by sunlight and its metabolism within
the body lead to the production of possibly
more than 30 vitamin D metabolites. Many of
these are doubtlessly found in foods in at
least small amounts. Forms of vitamin D have
generally been presumed to be "inactive"
when they have failed to contribute to the
correction of rickets in animals,36
yet recent research has shown a number of
"inactive" vitamin D metabolites
to have substantial biological activity when
they are examined for non-classical effects
(those other than correcting rickets).17 While
there is no clear evidence that any of these
differences in and of themselves make food-based
vitamin D more effective or safer than vitamin
D3 supplements, foods and sunshine
are clearly not the same things.
The Vitamin D-Binding Protein
The vitamin D-binding protein (DBP) is a highly
specific carrier for vitamin D and its metabolites
in the blood. DBP is related and very similar to
serum albumin, which is a non-specific carrier of
a wide variety of molecules, but its binding site
is modified to be specific for vitamin D. It is
present in all true vertebrates and in some but
not all species of cartilaginous fish, suggesting
that it first appeared in the latter group, paving
the way for the calcification of the true skeletons
found in all subsequent vertebrates.37
DBP can be likened to a savings account for vitamin
D. If we kept all of our money as cash on hand,
we would on the one hand risk the loss or theft
of large sums of money, and on the other hand be
tempted to spend too much of it at once. Likewise,
if we did not have a way to store extra vitamin
D in the blood, we would on the one hand be forced
to excrete any excess over our immediate needs,
and on the other hand have no way to prevent an
excess of active metabolites from being delivered
randomly to tissues that do not need them. DBP thus
acts both to make our use of vitamin D more efficient
and to reduce the risk of vitamin D toxicity.
DBP also enhances the effectiveness of vitamin
D in a second way: the kidneys possess a protein
called megalin that is capable of binding DBP, thereby
bringing vitamin D into the kidney where it can
be activated into calcitriol as needed.37
Various factors affect our ability to maintain
a healthy supply of DBP. Rats fed protein-deficient
diets have decreased DBP concentrations and a decreased
ability to regulate calcium metabolism.38
Humans with acute liver failure also have depressed
levels of DBP.39 This may be because
the synthesis of DBP in the liver declines during
such a condition, but DBP also plays a secondary
role in scavenging harmful cellular debris from
the blood; therefore, any kind of acute tissue damage
can overwhelm our supply of DBP. Since saturated
fats protect the liver from damage while polyunsaturated
fats from vegetable oils enhance the ability of
toxins to cause liver damage,40,41 consumption
of a diet rich in saturated fats and avoidance of
vegetable oils, excessive alcohol, and drugs that
are toxic to the liver could all help maintain healthy
levels of DBP.
Do
Statins Interfere with the Function of Vitamin
D-Binding Protein?
Cholesterol-lowering statin drugs could
theoretically interfere with the synthesis
or functioning of the vitamin D-binding protein
(DBP). DBP is N-glycosylated,37
which means that it has a specific type of
sugar added to it at certain positions. N-glycosylation
affects a molecule's stability, solubility,
biological activity and localization; inhibiting
N-glycosylation could therefore interfere
with a molecule's ability to perform its physiological
functions. Lovastatin (Mevacor), mevinolin
(red yeast rice) and mevastatin (not in use)
have all been shown to interfere with the
functioning of important N-glycosylated proteins.42
There are no studies to date examining the
effect of statin drugs on vitamin D-binding
protein.43
Vitamin D2 vs. Vitamin
D3
There are two primarily available forms of vitamin
D: vitamin D3 is synthesized by animals
in their skin and the oils of their fur and is provided
by animal foods in the diets of carnivorous and
omnivorous mammals; vitamin D2 is synthesized
industrially by irradiating yeast and is present
in small amounts in common mushrooms and in large
amounts in several obscure mushrooms.33
The notion that these two compounds are biologically
equivalent to each other in humans is so ingrained
that it is sometimes stated as fact in textbooks
even without any supporting references.8
However, research shows that vitamin D3
is between five44 and ten45
times more effective than vitamin D2
at raising serum calcidiol levels. Although not
proven, the most likely explanation is that vitamin
D2 has a lower binding affinity for the
vitamin D-binding protein (DBP).45
If vitamin D2 does not bind as well
to the DBP, this raises the question of whether
it may have more potential for toxicity. After all,
this is as if our bank were to place a cap on the
proportion of our incomes that we were allowed to
deposit into our savings accounts. With more cash
on hand, we are more likely to spend it when and
where we should not. Likewise, if vitamin D2
is more likely to float around freely without being
"deposited" into the DBP savings account,
it may be more likely to be delivered randomly to
tissues when and where they have no need for it,
thereby resulting in toxic effects.
Supporting this view is Dr. Reinhold Vieth, a
medical researcher at the University of Toronto's
Mt. Sinai Hospital, who points out that in all known
cases of vitamin D toxicity where the dose used
was intentional, the form used was vitamin D2.
By contrast, reported cases of vitamin D3
toxicity have all been accidents involving the consumption
of extreme doses that were not intended to be consumed.33
This fact must be interpreted with caution, however,
because vitamin D3 has neither been used
nor studied as extensively as vitamin D2;
therefore the absence of proof of toxicity is not
necessarily proof of the absence of toxicity. Additionally,
some authors contend that there is indeed evidence
that moderately large doses of vitamin D3
can be toxic for some people in some situations.46
These issues will be examined further below.
Will the
Real Vitamin D Please Stand Up?
Vitamins D2 and D3
have long been regarded as equivalent because
they are both capable of curing infantile
rickets. Superficially supporting this premise,
the one laboratory experiment comparing the
ability of the activated forms of vitamins
D2 and D3 to bind to
the vitamin D receptors of isolated cells
and alter gene expression showed vitamin D3
to be only marginally more effective than
vitamin D2.47
The modern criteria for judging nutritional
vitamin D status, however, is the level of
calcidiol in the blood. Two groups of researchers
have shown vitamin D3 to be between
five44 and ten45 times
more effective than vitamin D2
at raising serum levels of calcidiol. Since
vitamin D2 cannot effectively raise
the serum level of calcidiol, the pool from
which activated calcitriol is derived, the
binding affinity of D2-derived
calcitriol to the vitamin D receptor is irrelevant.
Vitamin D2 is therefore incapable
of supporting optimal health.
The most likely explanation for the poor
effectiveness of vitamin D2 is
that it binds with a lower affinity to the
vitamin D-binding protein (DBP). Although
the newest edition of the authoritative textbook,
Vitamin D, claims that in humans calcidiol
binds with equal affinity to the DBP whether
it is derived from vitamin D2 or
vitamin D3,37 the citation
for this statement is the author's own PhD
thesis, in which he reported results obtained
from testing the DBP of a mere two people.48
Since the gene for the DBP is one of the most
polymorphic known (meaning it exists in many
forms), existing in three common alleles and
124 known rarer alleles (alleles are specific
forms of the same gene), each allele itself
having many polymorphisms,37 a
sample size of two is rather unconvincing.
In the early 1970s, Swedish researchers
showed vitamin D3 to have a substantially
higher affinity for human DBP than vitamin
D2.49 Their sample size
was not reported and probably very small,
and they unfortunately could not test the
calcidiol forms of these vitamins because
25-hydroxyvitamin D3 was at that
time not yet commercially available. There
is as yet no conclusive evidence demonstrating
the relative binding affinities of the metabolites
of vitamins D2 and D3
for the typical human DBP. Nevertheless, whatever
the mechanism, the two forms of the vitamin
clearly have disparate biological activities
and cannot be equated.
Interactions Between Vitamins
A and D
If there is one, single most important shortcoming
in the research investigating the toxicity of vitamin
D in humans, it is that despite decades of controlled
animal experiments showing that each of the fat-soluble
vitamins protect against the toxicity of the others,
research in humans continues to address the toxicity
of vitamin D as if its actions were independent
of vitamins A, E, and K.
In 1937, Wayne Brehm presented before the Ohio
State Medical Association the results of an experiment
comparing the effects of the administration of cod
liver oil with that of vitamin D2 to
over 500 pregnant women. Vitamin D2,
especially in conjunction with calcium, produced
extensive abnormal calcification of the placenta,
in one case extending into the uterine wall, and
in three cases producing kidney stones within the
developing fetus; cod liver oil, by contrast, produced
no more tissue calcification than seen in controls.50
Brehm could not demonstrate, however, whether the
results of his experiment were attributable to the
difference between vitamins D2 and D3,
to a protective effect of vitamin A, to a protective
effect of other constituents of cod liver oil, or
to some combination thereof.
The same year, Agnes Fay Morgan, Louise Kimmel
and Nora Hawkins became the first American researchers
to demonstrate that vitamin A protects against the
toxicity of vitamin D.51 Citing German
research that had been completed over the previous
three years showing that the lethal doses of several
fish liver oils fed to mice were identical to that
of synthetic vitamin D2 when the liver
oils were stripped of their vitamin A,52
and that large doses of vitamin A protected against
vitamin D toxicity,53 the Morgan team
fed rats various concentrations of vitamin A with
toxic doses of vitamin D in various forms. The doses
of vitamin D used were 4,000 IU per day or greater,
which is the bodyweight-adjusted equivalent of a
typical human consuming over 5,000,000 IU per day.
The researchers used synthetic vitamin D2
and concentrates of the liver oils of tuna, cod,
sea bass and halibut. Although vitamin D2
was most toxic, massive doses of all forms of vitamin
D when combined with low doses of vitamin A decreased
growth and bone mineralization and increased the
calcification of the lungs, heart and kidneys, while
vitamin A consistently protected against these effects
in proportion to its dose.
In 1951, French researchers showed that intramuscular
injections of a natural fish oil concentrate containing
massive amounts of vitamin A (and potentially other
protective factors) prevented growth retardation,
kidney calcification and death induced in rats by
intramuscular injections of massive doses of vitamin
D2. This showed that the interactive
effect is independent of intestinal absorption.54
Vitamin A has since been shown to substantially
protect against skeletal defects, bone demineralization
and soft tissue calcification induced in rats by
large amounts of vitamin D2,55 nearly
eliminate similar effects induced in rats by vitamin
D3,56 and completely eliminate
similar effects induced in turkeys by vitamin D3,57
even though each of these studies used doses of
vitamin A that were only half the doses used of
vitamin D.
More recently, a group of researchers from the
University of Georgia's Department of Poultry Science
showed that vitamin D3 increased the
need for vitamin A in chickens even when the dose
of vitamin D was insufficient to guarantee protection
from rickets,58 and that even small to
moderate doses of vitamin D decreased liver stores
of vitamin A regardless of whether they were supplied
in the diet or by exposing the chickens to ultraviolet
light.59
Why would vitamin D have depleted the chickens
of vitamin A? In 1935, the German researcher F.
Thoenes put forward the hypothesis that vitamin
D requires vitamin A in order to function, and that
high doses of vitamin D cause toxicity by producing
a state of relative vitamin A deficiency.60
Over 70 years later, molecular biologists have now
proven at least the first part of his hypothesis
correct. On August 25, 2006, a team of researchers
from Spain and Germany published a report showing
that 9-cis-retinoic acid, one of the hormonally
active forms of vitamin A, is an essential factor
for the full functioning of vitamin D.61
In the absence of 9-cis-retinoic acid,
activated vitamin D and its receptor could only
bind weakly to DNA and could therefore only exert
a small effect on gene expression. When 9-cis-retinoic
acid was available, however, it formed a large complex
that included its own receptor, vitamin D, and the
vitamin D receptor; this complex was able to bind
to DNA very strongly and vitamin D was able to fulfill
its full function. Most striking, the "defective"
vitamin D receptor that is present in a genetic
form of rickets that cannot ordinarily be cured
by vitamin D became fully functional in the presence
of 9-cis-retinoic acid.
Although the body can convert the all-trans-retinol
form of vitamin A found in foods and supplements
into 9-cis-retinol,62 it is
tempting to speculate that this research may show
an advantage to cod liver oil over other sources
of vitamin A, which naturally contains a substantial
amount of 9-cis-retinol.63
If high doses of vitamin D use up vitamin A, they
might leave less vitamin A for other important processes—one
of those processes is preventing the calcification
of kidneys, whether that calcification is induced
by vitamin D or by some other means. French researchers
recently found that when they fed rats the equivalent
of a daily human dose of 15,000 IU of vitamin A,
the administration of oxalate was less effective
at inducing the deposition of calcium oxalate crystals
in the kidneys; on the other hand, if they administered
oxalate first, the subsequent administration of
vitamin A was not able to correct the condition.64
This might explain why researchers in the 1930s
and 1940s were finding that over 90 percent of patients
with kidney stones suffered from clinically verifiable
vitamin A deficiency,65 yet in most cases
administration of vitamin A was unable to correct
the problem.66
Nevertheless, researchers at that time also observed
that kidney stones in some cases continued to get
worse in spite of vitamin A therapy,67
and when cod liver oil concentrate was administered
to rats in amounts providing the equivalent to a
daily human dose of over 136,000,000 IU of vitamin
D, the vitamin A appeared to ameliorate the growth
retardation, bone demineralization and kidney calcification
to a much greater extent than it ameliorated the
calcification of the lungs and heart.51
Thus, it appears that vitamin A is only one piece
of the puzzle.
Should We
Stay Away From Cod Liver Oil?
In the Vitamin D Council's May, 2006 newsletter,
Dr. John Cannell wrote that vitamin D deficiency
is the rule in most of the world except in
the Scandinavian countries, yet, he wrote,
"hip fractures in these same countries
are the highest in Europe, probably from the
excessive vitamin A in cod liver oil. Stay
away from cod liver oil."68
To support his contention that cod liver
oil contributes to hip fractures, Dr. Cannell
supplied a single reference.69
This reference was a compilation of estimated
fracture rates in different European countries.
Norway, which is the Scandinavian country
where cod liver oil is widely used,70
was not included. The incidence of hip fracture
was strongly associated with life expectancy;
the authors suggested that this was in part
because the countries with the best medical
care were the most likely to readmit patients
for a fracture after they had already been
discharged once, and therefore count the same
fracture twice. Sweden, where 47 percent of
fractures were counted more than once, had
the highest fracture rate of any country.
No information about the intakes of vitamin
A, vitamin D, or cod liver oil was reported
in the study.
Oslo, Norway has nevertheless reported the
highest fracture rate in the world.71
Although 25 percent of the Oslo population
uses cod liver oil daily,70 those
who use cod liver oil daily during part or
all of the year have a lower risk of fracture
than those who do not.72 Of the
several studies examining the relationship
between blood levels of vitamin A and fracture
risk, the only study to list cod liver oil
as a source of vitamin A found that the people
with the highest levels of vitamin A had the
lowest risk of fracture.73
There is one, single clinical trial testing
the effect of cod liver oil on fracture risk.74
In this study, the researchers compared the
consumption of a daily teaspoon of standard
cod liver oil containing 400 IU of vitamin
D to that of a daily teaspoon of cod liver
oil that had been stripped of its vitamin
D. The cod liver oils were administered to
residents in 51 nursing homes over a period
of two years. Although there was no difference
between the two groups, probably because 400
IU is only half the dose of vitamin D generally
required to reduce fracture risk,33 the fracture
rate of those taking both forms of cod liver
oil was lower than the overall fracture rate
for those living in the nursing homes in which
the trial was conducted. Rather than support
the admonition to "stay away from cod
liver oil," these findings suggest that
cod liver oil can protect us against bone
fractures, especially in old age.
Interactions Between Vitamins
K and D
Whereas vitamins A and D act as hormones, communicating
to cells which proteins they should make, vitamin
K activates a select group of vitamin K-dependent
proteins after they have already been made. Since
some of the proteins that vitamin K activates are
the very same proteins that cells make in response
to signals from vitamins A and D, it would be a
serious error of omission to begin a discussion
of either our requirements for or the toxicity of
vitamin D without first examining its interactions
with vitamin K.
Although vitamin K is most commonly known for
its ability to activate blood clotting factors,
it is also responsible for the activation of two
other important proteins: osteocalcin, which is
involved in the mineralization of bone matrix, and
matrix Gla protein (MGP), which protects soft tissues
from calcification.75 Since vitamin D
is necessary for proper bone mineralization and
its most common toxic effect is the calcification
of soft tissues, the importance of the relationship
between vitamins K and D should already be clear.
Molecular biology clarifies this relationship
even further. Osteocalcin is produced exclusively
by osteoblasts, which are the cells that form new
bone matrix. While collagen forms the main framework
of bone matrix, osteocalcin is responsible for its
mineralization.76 Osteoblasts make osteocalcin
when they are signaled to do so by the hormonal
forms of vitamins A and D. When osteoblast cells
are incubated with activated vitamin A or activated
vitamin D alone, their expression of osteocalcin
increases only minimally; by contrast, when the
same cells are incubated with activated vitamins
A and D together, osteocalcin expression increases
dramatically.77
This osteocalcin, however, cannot function until
it is activated by vitamin K.75 Therefore,
no one of these three nutrients can contribute to
bone health without the presence of the other two.
Epidemiological evidence and clinical trials confirm
the importance of vitamin K to osteoporosis. Blood
levels of inactivated osteocalcin are strongly associated
with an increased risk of fracture, while vitamin
K intake is strongly associated with a reduced risk
of fracture. One study showed people with the highest
levels of inactivated osteocalcin to have six times
the risk of fracture than those with normal levels.
As expected, clinical trials show that vitamin K
supplementation increases the activation of osteocalcin,
decreases bone loss, and increases bone mineral
density.75
Epidemiological studies show an inverse correlation
between bone mineral density and calcification of
the arteries—a major contributor to heart
disease—suggesting that osteoporosis and heart
disease are linked by the common thread of vitamin
K deficiency.75 Since vitamin K is necessary
for the activation of MGP, which has been proven
to be responsible for protecting soft tissues from
calcification,78 researchers from the
Netherlands set out to investigate whether vitamin
K intake was associated with a reduced risk of heart
disease and whether or not this might be mediated
by its protection against arterial calcification.
Between 1990 and 1993, they collected data on
the vitamin K intakes of more than 4,500 people
over the age of 55 and used a procedure called radiography
to measure the extent to which disease, who had
died from it, and how this related to vitamin K
intake and arterial calcification. Calcification
of the arteries turned out to be the best predictor
of heart disease. Those in the highest third of
vitamin K intakes were 52 percent less likely to
develop severe calcification of the arteries, 41
percent less likely to develop heart disease, and
57 percent less likely to die of it.79
Sources
of Vitamin K
There are two forms of vitamin K: vitamin
K1 is found in green vegetables
and plant oils, especially olive oil; vitamin
K2, which is produced by intestinal
bacteria in small and probably inconsequential
amounts, is found in animal foods and fermented
plant foods.87
Although vitamin K1 is most abundant
in the diet, it is very poorly absorbed. Even
the addition of two tablespoons of butter88
or corn oil87 to spinach could
only increase absorption of vitamin K1
to between 10 and 15 percent. By contrast,
the absorption of vitamin K2 is
close to 100 percent.87
The two forms of vitamin K are not physiologically
equivalent: vitamin K1 is preferentially
used by the liver to activate clotting factors,
while vitamin K2 is preferentially
used by bone to activate osteocalcin and by
soft tissues to activate MGP.85
vitamin K1 offers no protection
against Warfarin-induced soft tissue calcification,
while vitamin K2 offers complete
protection.85 Likewise, in over
4,500 men and women enrolled in the Rotterdam
Study, intake of vitamin K2 was
strongly associated with a reduced risk of
arterial calcification and heart disease,
while vitamin K1 had no relationship
to either variable at all, even though it
constituted a full 90 percent of the dietary
vitamin K.79 It is therefore vitamin
K2, and not vitamin K1,
that we would expect to simultaneously enhance
the effectiveness of and increase the safety
of vitamin D.
Since vitamin K2 is produced by
lactic acid bacteria,89 lacto-fermented foods
are an excellent source of vitamin K2.
Sauerkraut contains more than four times as
much vitamin K2 as beef and more
than twice as much as pork, although natto,
a Japanese fermented soy food, contains the
most vitamin K2 of any food measured.
The K2 in lacto-fermented foods, however,
is not the exact same form as the K2 in animal
products. Whether or not the difference is
important is unclear. Egg yolks, butterfat,
and goose meat, especially goose liver, are
excellent sources.87 Among organ
meats, brain, pancreas, and salivary glands
contain the highest amounts, while bone contains
less but is substantially richer than muscle
meat.90 Chicken and duck are decent
sources, followed by beef and pork.87
By contrast, fat-free animal foods do not
contain any vitamin K2 at all,
and low-fat animal foods contain less vitamin
K2 than their full-fat counterparts.91
Although sourdough bread is fermented
partly by lactic acid bacteria, it does not
contain vitamin K2.87
Surprisingly, vitamin K2 is nearly
or completely absent from most seafood that
has been measured, including wild Alaskan
fish such as salmon and halibut87,91
although the eggs of fish have not been analyzed.
By contrast, seafood is an excellent source
of vitamin D. That these two vitamins are
distributed in the food supply so differently
underscores the need for a balanced and varied
diet.
Although there are no studies investigating whether
supplementation with high doses of vitamin K can
reverse the toxic effects of massive doses of vitamin
D, there are several lines of evidence, described
in more detail in the sidebar
below, that strongly suggest vitamin D produces
toxicity by depleting the body of vitamin K: first,
mice that by genetic defect are born completely
lacking the vitamin K-dependent MGP protein bear
a striking resemblance to animals that have been
fed toxic doses of vitamin D; second, the anti-clotting
drug Warfarin exerts toxic effects almost identical
to those of vitamin D by depleting the body of vitamin
K; third, vitamin K completely protects against
the toxic effects of Warfarin, suggesting it would
likewise protect against the toxic effects of vitamin
D.
The
Warfarin Connection
Although there are no studies investigating
whether supplementation with high doses of
vitamin K can reverse the toxic effects of
massive doses of vitamin D, there are several
lines of evidence that strongly suggest that
vitamin D produces toxicity by depleting the
body of vitamin K.
First, mice that by genetic defect are born
completely lacking the vitamin K-dependent
MGP protein bear a striking resemblance to
animals that have been fed toxic doses of
vitamin D. These mice suffer from extensive
calcification of the aorta and its branches,
the arteries, the trachea and the lungs. Just
as those fed toxic doses of vitamin D, the
MGP-null mice also suffer from bone demineralization
and growth retardation. Although the mechanism
by which vitamin D toxicity causes growth
retardation has never been clarified, experiments
with MGP-null mice show that the zones of
cartilage responsible for elongation of the
bones become extensively calcified, disrupting
the process of bone growth. Finally, like
animals fed massive doses of vitamin D, these
animals lived for a short period of time before
their defect caused them to die.78
The second line of evidence comes from the
synergistic toxicity produced by vitamin D
and the anti-clotting drug, Warfarin. Like
other coumadin derivatives, Warfarin—originally
introduced as a rat poison in 194880—inhibits
blood clotting by interfering with the recycling
of vitamin K. Like those fed toxic doses of
vitamin D, animals fed Warfarin develop extensive
calcification of the soft tissues,81
the same that has been reported to occur in
people on long-term and moderate-term treatment
with various coumadin derivatives.80,82
When researchers injected rats with 300,000
IU per kg bodyweight of vitamin D3
each day for three days and every 12 hours
thereafter, the rats suffered the expected
soft tissue calcification. As expected for
this dose of vitamin D, the rats were all
still alive on the tenth day. When vitamin
D3 was combined with Warfarin,
however, the soft tissue calcification was
dramatically amplified and all rats died by
the ninth day. The combination of vitamin
D and Warfarin produced the same result that
would have been achieved with a higher dose
of vitamin D.81
The final line of evidence is drawn from
two findings: first, the same drugs that counteract
calcification induced by Warfarin also counteract
calcification induced by vitamin D; second,
vitamin K is capable of completely abolishing
calcification induced by Warfarin, suggesting
that it would also be capable of completely
abolishing calcification induced by vitamin
D.
University of California researcher Paul
A. Price (no relation to Weston Price) showed
that ibandronate, a drug currently used to
treat osteoporosis, completely abolished the
calcification induced in rats by subcutaneous
injections of both Warfarin83 and
massive doses of vitamin D3.84
Ibandronate protected not only against calcification
of the aorta, arteries, trachea, lungs, and
kidneys, but also against vitamin D-induced
anorexia, weight loss, lethargy, and death.
Although the mechanism by which ibandronate
exerts its protective effect is not understood,
these studies strengthen the concept that
a common mechanism underlies the toxicities
induced by both Warfarin and vitamin D.
Subsequently, researchers in the Netherlands
showed that vitamin K itself is sufficient
to completely abolish Warfarin-induced soft
tissue calcification.85 This convincingly
shows that Warfarin, which is an established
inhibitor of vitamin K recycling, causes soft
tissue calcification by inducing a vitamin
K deficiency, and strongly suggests that vitamin
D does something very similar.
Since vitamin D toxicity is remarkably mirrored
by mice that lack a vitamin K-dependent protein,
since Warfarin induces a remarkably similar
type of toxicity by inducing vitamin K deficiency,
since Warfarin and vitamin D toxicity respond
to similar treatments, and since Warfarin's
toxicity can be completely abolished by providing
sufficient vitamin K, it follows that vitamin
D toxicity is likely to be at least in part
a form of vitamin K deficiency.
Recent research on how vitamins A and D
affect the synthesis of MGP may connect the
interaction between all three vitamins. When
MGP is activated by vitamin K, it protects
the soft tissues from calcification. Although
it isn't known whether MGP is actively harmful
in its inactive form, it is known that calcified
arteries accumulate abnormally high amounts
of the inactive protein,75 and
that toxic amounts of vitamin D dramatically
increase its synthesis.81 If vitamin
D produces its toxic effects by stimulating
the synthesis of more of this protein than
vitamin K can keep up with, it would explain
why vitamin A is so protective: in the cells
that line the walls of blood vessels, vitamin
D increases the synthesis of MGP, while vitamin
A decreases its synthesis.86 It
may be, then, that an extreme imbalance between
vitamins A and D leads to the synthesis of
abnormally high amounts of MGP. If there is
enough vitamin K to activate all of the MGP,
it will help protect the soft tissues from
calcification. If, instead, the vitamin K
cannot keep up with the level of MGP being
produced and the pool of vitamin K becomes
depleted, soft tissue calcification ensues.
Although this mechanism is not proven, it
would provide, if it is correct, a revolutionary
insight into why vitamins become toxic when
administered by themselves but health-promoting
when provided in the context of a balanced,
nutrient-dense diet.
Viewing Vitamin D Through
the Proper Paradigm
Vitamin D's interactions with other nutrients
in the diet make it clear that we cannot consider
the subject of either vitamin D requirements or
vitamin D toxicity by looking at vitamin D alone.
Vitamins D2 and D3 are in
some respects very different from one another. The
types of fat we eat, drugs we use and toxins to
which we are exposed affect our ability to efficiently
use vitamin D. Vitamin A is an essential factor
in vitamin D's hormonal function, and vitamin K
is necessary to activate the proteins made in response
to vitamins A and D. Vitamin D toxicity appears
to result from a depletion of vitamin K, and animal
evidence suggests that even small amounts of vitamin
D increase the need for vitamin A. Therefore, we
must ask a most important question when we consider
the various studies on vitamin D requirements and
vitamin D toxicity: what was the dietary context
in which the vitamin D was consumed? Otherwise,
we are in danger of drawing the wrong conclusion.
Vitamin D in Adults: Requirements
and Safety
Recommendations for what constitutes an adequate
intake of vitamin D vary 20-fold. While the U. S.
Institute of Medicine31 recommends a
mere 200 IU per day for adults under the age of
50, some leading vitamin D researchers such as Dr.
Reinhold Vieth and Dr. Robert Heaney recommend 3,000
to 4,000 IU per day as both necessary and safe.33,98
These differences result largely from the different
paradigms through which these researchers interpret
the uncertainties within the available data. The
Institute of Medicine follows in the tradition of
the National Research Council, which set the adult
RDA for vitamin D at 0 IU in 1941 because it had
not yet been proven that adults require vitamin
D.99 Likewise, in 1997, the Institute
of Medicine set the adequate intake at what it supposed
would protect against severe vitamin D deficiencies
like rickets and osteomalacia, which have been proven
beyond a doubt to be a result of vitamin D deficiency.
Other researchers take into account the fact that
humans living in the tropics have always obtained
between 4,000 and 10,000 IU per day from sunshine;
extensive circumstantial evidence suggests that
these higher amounts protect against cancer and
autoimmune diseases, and support a general state
of vibrant health.33
Recommendations for what constitutes a safe intake
of vitamin D also vary widely. Dr. Vieth argues
that 4,000 IU of vitamin D per day is safe even
if one obtains an additional 4,000 IU per day from
sunlight,33 while the Institute of Medicine
has set the tolerable upper limit at 2,000 IU per
day. Krispin Sullivan, on the other hand, takes
a much stricter position. Sullivan, a well-researched
author and clinical nutritionist, argues that any
intake of vitamin D beyond 800 IU per day from food,
supplements and sunshine combined is unsafe without
testing and supervision.100
Two approaches are necessary in order to distinguish
between the relative merits of each of these positions:
first, to establish a general perspective through
which we can view uncertainties in the scientific
evidence, we must consider what quantity of vitamin
D our ancestors typically obtained throughout our
pre-modern history; second, we must apply our understanding
of the interactive nature of the fat-soluble vitamins
to the available evidence.
Does Vitamin
D Interact with Vitamin E?
There are two international studies, of
which only the abstracts are available in
English, investigating the effect of large
doses of vitamin E on the toxicity of vitamin
D. A Russian study conducted in 1977 found
that a combination of massive doses of vitamin
E and selenium combined were able to reduce
the soft tissue calcification induced by equally
massive doses of vitamin D2 by
between 54 and 96 percent, depending on the
tissue.95 A more recent Ukrainian
study showed vitamin E to substantially reduce
the free radical damage induced in the arteries
of rabbits by large doses of an unspecified
form of vitamin D.96
Whereas there is evidence that vitamin D
toxicity is the result of a relative deficiency
of vitamins A and K, the Russian and Ukrainian
studies could simply be explained by a model
wherein vitamin E fills a generic antioxidant
function that has nothing specifically to
do with vitamin D.
Nevertheless, our understanding of vitamin
E is rapidly changing. Researchers are now
questioning whether vitamin E truly functions
primarily as a free radical scavenger as has
long been assumed, and research is accumulating
showing that vitamin E's primary function
may be to act as a hormone and regulate gene
expression. Some of vitamin E's hormonal functions
appear to involve the retinoid X receptor,
which also interacts with vitamins A and D
and their respective receptors, suggesting
that the functions of vitamins E, A, and D
may be more interrelated than we currently
realize.97
Defining
Toxicity
Before we approach these questions, however, we
need to have an accurate understanding of what vitamin
D toxicity is; otherwise we would not know what
to look for. Because vitamin D toxicity is usually
accompanied by an elevated level of calcium in the
blood, called hypercalcemia, researchers have generally
equated the two and assumed that the toxic effects
of vitamin D are the result of elevated calcium
levels.31 However, the available evidence
does not support this concept of vitamin D toxicity.
First, both vitamin A56,103 and ibandronate84
(a drug that also inhibits Warfarin toxicity) reduce
or eliminate the soft tissue calcification and other
toxic effects of vitamin D without substantially
reducing the vitamin D-induced hypercalcemia. Second,
Warfarin, a vitamin K inhibitor, produces a toxicity
profile almost identical to that of vitamin D, but
does not increase serum calcium levels.81
Third, one group used vitamin D to produce calcium
deposition in the kidneys of chickens at doses that
did not lead to hypercalcemia.104 This
finding is consistent with a case report of four
post-menopausal women who were taking undetermined
doses of vitamin D without their knowledge in the
form of supplements that appeared to be contaminated
with large amounts of vitamin D2: these
patients had abnormally high vitamin D levels, three
times the calcium in their urine as is normal, and
appeared, albeit inconclusively, to have associated
bone loss. Yet none of these subjects had hypercalcemia.105
Taken together, these data suggest on the one hand
that blood levels of calcium can become elevated
without leading to toxicity, and on the other, that
toxicity can occur even in the absence of elevated
calcium.
Dr. Vieth points out that elevated levels of calcium
in the urine, called hypercalciuria, would be a
more sensitive measure of vitamin D toxicity, though
most studies unfortunately have not looked for this
endpoint.33 Even this hypercalciuria,
however, is difficult to interpret. Urinary calcium
would naturally be expected to increase to some
degree from the enhanced intestinal absorption provided
by sufficient levels of vitamin D.
More importantly, vitamins A and D cooperate to
maintain calcium and phosphorus levels in the blood,
apparently by stimulating the absorption of these
minerals in the intestine. In rats, when the two
vitamins are combined, vitamin D increases calcium
levels and decreases phosphorus levels, while vitamin
A decreases calcium levels and increases phosphorus
levels.106 The only researchers to study
this interaction in humans have confirmed that vitamin
A does indeed attenuate the rise in serum calcium
induced by vitamin D, but they did not study the
effect of either vitamin on serum phosphorus.107
Excretion of either mineral into the urine reflects
the ratio between them in the blood: hypercalciuria
will occur not only when calcium levels are too
high, but also when phosphorus levels are too low.108
It therefore is not clear whether hypercalciuria
resulting from vitamin D supplementation reflects
a "toxic" dose of vitamin D, or simply
reflects a relative deficiency of vitamin A.
The best measures of vitamin D toxicity would
be long-term studies lasting several years that
measure the formation of kidney stones, use radiography
to determine the degree of arterial calcification
and measure markers of bone resorption. These studies
would only be of substantial value if they took
into account, at a minimum, the intakes of vitamins
A and K, as well as the use of Warfarin and other
coumadin derivatives, which not only synergize with
vitamin D to produce toxicity,81 but
have themselves been shown to produce arterial calcification
in humans over the course of several years.82
Such studies simply do not exist.
Is
the "Adequate Intake" Really Adequate?
In 1997, the U. S. Institute of Medicine's
Food and Nutrition Board set the "adequate
intake" (AI) of vitamin D for adults
under the age of 50 at 200 IU per day.31
The Institute estimated that 100 IU per day
is adequate in the complete absence of sunlight,
and doubled this figure to 200 IU so as to
provide a margin of uncertainty. This figure
is based on two studies: first, one study
that did not account for sunlight showed a
daily supplement of 100 IU per day given to
women consuming less than this was able to
correct osteomalacia; second, a study of Nebraskans
consuming between 130 and 200 IU per day during
the winter showed that they maintained vitamin
D levels of 12 ng/mL, which is high enough
to protect against osteomalacia but is associated
with an increased risk of fracture.114
These Nebraskans suffered from hyperparathyroidism
and malabsorption of calcium, which led the
authors of the study to conclude that although
"200 IU vitamin D [per day] may prevent
vitamin D deficiency per se, it is not sufficient
to normalize calcium absorption" and
warned that this "would be expected to
cause negative calcium balance and osteoporosis."101
However, the Institute concluded that an AI
of 200 IU per day "may actually represent
an overestimate of true biological need."31
For adults between the ages of 50 and 70,
the Institute cited a study showing 800 IU
per day of vitamin D protected against bone
loss compared to 200 IU per day. Although
the authors concluded that 200 IU per day
"is inadequate to minimize bone loss,"102
the Institute strangely decided that,
since there was no evidence in the study that
a dose lower than 800 IU per day wouldn't
have been just as effective, there was therefore
no evidence that people at this age require
more than 200 IU per day. This fuzzy math
was achieved by ignoring the 100 IU per day
that the low-dose group received from diet.
By pretending that the low-dose group was
only consuming the 100 IU per day that they
were given as a supplement, the Institute
was able to claim that it was "uncertain"
that 200 IU wouldn't have been just as effective
as 800 IU—despite the fact that 200
IU is exactly what the group with the greater
bone loss was consuming. The Institute then
doubled this dubiously derived figure to provide
a margin for uncertainty and set the AI to
400 IU per day for this age level.31
For adults over 70, the Institute cited literature
showing that 800 IU per day is necessary to
reduce the risk of hip fracture. Despite citing
numerous studies showing that 400 IU per day
cannot reduce the risk of hip fracture, the
Institute concluded that 300 IU is adequate
because it protects 85 percent of the elderly
from having a vitamin D level below 10 ng/mL.
It doubled this figure to provide a margin
of uncertainty, establishing the AI at 600
IU—25 percent lower than the minimum
dose shown to lower fracture risk.31
This is a strange definition of "adequacy"
indeed.
The Way It's Always Been
In order to establish a starting point from which
to interpret the available data, it is instructive
to consider what amounts of vitamin D our ancestors
have obtained throughout our history, prior to the
rapid modernization that we have experienced over
the past several centuries, which has far displaced
our foodways and lifestyles from those that constituted
the context of our evolution and provided us with
our birthright to radiant health.
The clearest way to estimate this amount is to
study how much vitamin D is obtained from sunlight
by people leading active outdoor lifestyles in environments
that are saturated with UVB sunshine on a year-round
basis. Vitamin D synthesis in the skin reaches an
equilibrium with its degradation in a rather short
period of time so that only a fixed amount of vitamin
D synthesis is possible on a given area of skin
during each exposure. Over time, the skin adjusts
its melanin content in order to further fine-tune
the amount of vitamin D synthesized. Since the body
has such a well-designed process for regulating
the amount of vitamin D obtained from sunlight,
it seems unlikely that it would allow the synthesis
of inherently toxic amounts of vitamin D or even
amounts in great excess of those needed for optimal
health.
In order to determine how much vitamin D a person
receives from foods and sunshine combined, researchers
measure the levels of 25-hydroxyvitamin D, or calcidiol,
in the subjects' blood. This is the semi-activated
form of the vitamin; because it is the primary storage
form, it reflects the amount of vitamin D obtained
from food, supplements and sunshine, and is therefore
the best measure of a person's vitamin D nutritional
status.31 (These values are usually reported
in nanograms per milliliter, which is abbreviated
ng/mL. For the purpose of simplicity, I will refer
to serum calcidiol levels as "vitamin D levels.")
Farmers and lifeguards who live and work in sun-rich
environments have vitamin D levels between 55 and
65 ng/mL.109 A recent, rigorously controlled
study showed that in Omaha, Nebraska, healthy middle-aged
males required a daily intake of 5,000 IU in order
to maintain 60 ng/mL from October through February.110
In the more northern climate of Toronto, Canada,
men and women of a similar age took 4,000 IU per
day from January through June, a period of time
during which their sunshine exposure would be increasing.
The average vitamin D level at the end of the study
was only 40 ng/mL, although one person's level reached
as high as 48 ng/mL.111 One would expect
that 4,000 IU would have been even less effective
in environments farther to the north. These studies
suggest that someone living in the tropics obtains
an amount of vitamin D from food and sunshine that
is substantially in excess of 5,000 IU per day.
Krispin Sullivan reports that in her practice
she has found that a person's vitamin D level continues
to increase while the person takes a constant dose
of vitamin D over the course of two to three years.112
If this is true, then dose-response studies lasting
five months would be insufficient to estimate the
amount of vitamin D that people living in the tropics
obtain from sunshine. In the aforementioned studies,
however, doses between 4,000 and 10,000 IU all appeared
to reach a plateau in four to five months, which
is precisely what would be predicted by conventional
models of pharmacology based on vitamin D's half-life.109
Nevertheless, researchers have not conducted studies
with these doses that have lasted longer than five
months. Studies examining the effect of these doses
over two to three years, which would be able to
test Sullivan's contention, are necessary if for
no other reason than to convince physicians and
authorities of the safety of obtaining doses of
vitamin D argued by many leading researchers to
be necessary for optimal health. Although the uncertainty
should be acknowledged, our best estimation is that
sun-rich environments provide 5,000 IU or more per
day of vitamin D.
Hypersensitivity
to Vitamin D
Certain conditions involving alterations
in vitamin D metabolism make it unsafe for
a small number of individuals to supplement
with vitamin D or consume vitamin D-rich foods
without the supervision of a knowledgeable
and caring physician. These include:
Primary hyperparathyroidism
Sarcoidosis
Tuberculosis
Lymphoma
Kidney failure
Liver failure
If you have one of these conditions, consult
with a physician before making a decision
to increase the vitamin D content of your
diet.
To Test or Not to Test?
Dr. Vieth has adequately criticized the study
that formed the basis of the Institute of Medicine's
upper limit of 2,000 IU per day: this small study,
short of duration, did not chemically verify the
dose of vitamin D used, nor did it quantify the
study subjects' actual vitamin D levels and was
thus unable to account for the input of vitamin
D from all sources; although it found 3,800 IU (the
Institute divided this amount by an "uncertainty
factor" to derive the upper limit) to produce
a substantial rise in serum calcium, more rigorously
controlled studies have not been able to replicate
the finding.111 Since hypercalcemia is
not a productive model of vitamin D toxicity, however,
we must instead look at real endpoints such as bone
loss, calcification of the arteries, kidney stones,
lethargy, anorexia, and other symptoms associated
with vitamin D toxicity.
In her self-published book, Naked at Noon:
Understanding Vitamin D and Sunlight, Krispin
Sullivan has emphasized one study and several anecdotes
that examine critical endpoints like heart disease
and bone loss to support her argument that any amount
of vitamin D exceeding 800 IU per day from all sources—including
sunlight—is unsafe without testing and supervision.46
Testing
Vitamin D Levels
All people must make a personal decision
whether or not to test their vitamin D levels
based on the amount of vitamin D they are
consuming, their own perception of its risk,
and any concern they may have that they are
not consuming enough. If you choose to test
your vitamin D level, there are several things
to keep in mind:
Order the calcidiol test, not the calcitriol
test. The correct test is also called 25-hydroxyvitamin
D or 25 (OH) D
The laboratory's reference range is likely
to use a very wide definition of "normal."
Sufficient levels of vitamin D are at least
32 ng/mL, and ideal levels are probably
between 40 and 50 ng/mL.
Your vitamin D levels will rise over
the spring and summer and decline over the
fall and winter. Your vitamin D level during
one season will therefore not necessarily
reflect your vitamin D level for other seasons.
The scientific data does not clearly
and consistently define an ideal level of
vitamin D, and we do not know to what degree
intakes of other nutrients affect what constitutes
the ideal level.
It is difficult to conceive of an argument against
testing. After all, physicians routinely test cholesterol
levels on the tenuous assumption that modifying
them will impact their patients' risk of heart disease.
There is no agreement within the scientific literature
identifying an ideal level of cholesterol, no agreement
on what should be done if a level is too high or
too low, and no end in sight to the raging debate
over whether statins should be added to the water
supply or whether they are contributing to side
effects ranging from congestive heart failure to
amnesia in millions of people. By contrast, there
is clear agreement on what level of vitamin D is
deficient and moderate agreement on what level is
ideal—and cod liver oil is cheaper than Lipitor,
even boosting your memory rather than destroying
it to boot.
To contend that amounts exceeding 800 IU per day
are dangerous without testing, however, demands
such an extreme degree of personal restriction that
it requires a rigorous level of substantiation to
be justified. In order to guarantee an intake within
800 IU per day, many fish, modest amounts of cod
liver oil and exposure of more than the face and
hands to summer sunshine would all be considered
unsafe.
Recognizing that some people do not have medical
insurance, that not all insurance companies will
pay for a vitamin D test, that some people have
very little money, and that most people have many
competing priorities, the risk that such small amounts
of vitamin D pose needs to be quantified. According
to Dr. Robert Heaney, one of the experts who sat
on the Institute of Medicine's upper limit panel,
over whose objections (along with Dr. Michael Holick's)
the policy-makers established the current limit,
if everyone in the American population took 2,000
IU per day of vitamin D, the vitamin D levels of
0.6 percent of the population would rise above 60
ng/mL.98 This amount is 2.5 times that
which Sullivan recommends as safe to consume without
testing. Although there is clearly the possibility
that the metabolism of some people will defy the
statistical calculations, this is also true for
the metabolism of virtually every other chemical
in the body.
Sullivan argues that researchers who assume the
safety of any amount of vitamin D that can be naturally
provided by sunlight are making an assumption that
could put some people in danger. To support this,
she cites, in addition to several anecdotes, one
human study. Researchers studying the vitamin D
levels of males residing in South India found that
those with levels exceeding 89 ng/mL had over three
times the risk of heart disease as those with levels
under 89 ng/mL.113 This study is difficult
to interpret because it is retrospective: since
the patients' vitamin D levels were measured after
they were have other explanations. For example,
subjects who were diagnosed with heart disease may
have increased their vitamin D levels afterward
by following advice to increase their outdoor physical
activity or increase their consumption of fish.
Nevertheless, since heart disease is associated
with vitamin K deficiency and can result from soft
tissue calcification,79 which is one
of the primary results of vitamin D toxicity, the
study is worth a closer look.
According to Sullivan, the study showed that toxic
doses of vitamin D can be obtained from sunlight
alone because the researchers used a test that was
specific for vitamin D3, which is not
available as a supplement in India. On the contrary,
the researchers noted that the South Indian diet
is rich in fish, which provides vitamin D3,
and various tubers such as cassava. Cassava is an
unusually high source of vitamin D2,
which may be more toxic than vitamin D3.
Because of the subjects' dietary intake of vitamin
D2, which the researchers did not attempt
to quantify, the use of a test specific for vitamin
D3 made the researchers unable to quantify
the total amount of vitamin D circulating in the
subjects' blood.
The only rigorous dose-response study available110
shows that it would take someone living in an environment
similar to Omaha, Nebraska substantially more than
10,000 IU per day over an extended period of time
to reach the level of vitamin D associated with
heart disease in this study. More importantly, we
don't know what the subjects' intakes of vitamins
A and K were, nor whether any of them were taking
pharmaceutical coumadin derivatives, all of which
are mediating factors in the toxicity of vitamin
D. If the diet of these subjects was rich in vitamin
D2-containing tubers and the meat of
fatty fish but was not rich in the organs of fish
and other animals, butter, egg yolks, or lacto-fermented
foods, the combination of extensive sunshine and
diet may have provided a high amount of vitamin
D without the synergistic and protective context
of the other fat-soluble vitamins.
Dangers
of Vitamin D?
In Naked at Noon,46
clinical nutritionist Krispin Sullivan offers
several anecdotes in support of the potential
toxicity of moderate doses of vitamin D.
The first is a report of four cases of apparent
vitamin D toxicity published in a 1997 issue
of The Annals of Internal Medicine.105 Four
post-menopausal women were found to have elevated
vitamin D levels, up to 88 ng/mL, and urinary
calcium three times the normal level. Although
the authors were criticized for not providing
rigorous measurements demonstrating bone loss,
the patients were originally referred to them
for osteoporosis, and when their vitamin D
supplements were discontinued, their bone
mineral density improved, suggesting that
the toxic level of vitamin D was contributing
to bone loss. An analysis of the supplements
these women were taking showed that they contained
at least ten times the vitamin D advertised
on the label. Two products advertised as "animal
extracts" were found to be contaminated
with massive amounts of vitamin D2,
the vegetarian form of vitamin D.
The second anecdote offered is an unpublished
report of a psoriasis patient who was receiving
narrow band UVB treatment. Sullivan suggests
that since artificial, narrow band UVB treatment
contains only that portion of the spectrum
that is responsible for the synthesis of vitamin
D and not other portions of the spectrum that
degrade it, toxic amounts of vitamin D can
be synthesized. The patient's vitamin D level
rose to 127 ng/mL, which is theoretically
toxic. Physicians are clearly obliged to measure
their patients' vitamin D levels when administering
a treatment that affects those levels.
The third anecdote is an unpublished report
of a woman taking a 2,000 IU per day from
a vitamin D3 supplement. After
14 months, she began suffering from bone ache,
fatigue, and depression. Six months later,
her vitamin D level was 95 ng/mL. Tests revealed
she had elevated urinary calcium and 6 percent
bone loss. Within weeks after dropping the
supplement, her symptoms disappeared. Despite
the resolution of her symptoms, her vitamin
D level continued to rise in response to the
summer sun, reaching 110 ng/mL three months
later. Given the inconsistencies in the timeline
of her recovery, the supplement should have
been analyzed to confirm that its labeled
dose was accurate, that it did indeed contain
vitamin D3 as labeled and not vitamin
D2, and an attempt should have
been made to determine whether she was sensitive
to some unlabeled component of the supplement.
No such attempts, however, were made.
There continues to be no published report
of toxicity resulting from an intentional
dose of vitamin D3.
Revising Our Understanding
of Vitamin D
The need to revise our understanding of vitamin
D and its toxicity is clear: the conventional understanding
that vitamin D's toxicity results from its excessive
elevation of calcium levels cannot account for the
observations that toxicity can result without elevated
calcium and that elevated calcium can result without
toxicity. The ability of the fat-soluble vitamins
to protect against the toxicity of each other clearly
demonstrates a model of toxicity that makes the
study of any one vitamin on its own inherently inconclusive.
Many questions about how long-term intakes of
vitamin D affect blood levels, whether an ideal
level of vitamin D can be truly defined, and whether
there is any such thing as an inherently safe or
inherently toxic dose remain to be scientifically
resolved. What is clear is that the protective and
synergistic context of a nutrient-rich diet is not
only underappreciated, but is essential to consuming
vitamin D in a way that provides optimal benefit
and maximum safety. Dr. Vieth has written that the
purpose of supplementing with vitamin D is to "compensate
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About the Author
Chris Masterjohn
is the author of several articles in Wise Traditions - a
quarterly journal published by the Weston
A. Price Foundation and he is the creator and maintainer of Cholesterol-And-Health.Com,
a website dedicated to dispelling myths about cholesterol. He has
authored two items in peer-reviewed journals: a letter inf the Journal
of the American College of Cardiology criticizing the conclusions
of a study on saturated fat and a full-length feature in an issue
of Medical Hypotheses proposing a molecular mechanism of
vitamin D toxicity. Chris has a a Bachelor's degree in history and
is currently pursuing a PhD in Nutritional Science with a specialty
in Biochemical and Molecular Nutrition at the University of Connecticut.
