Tolerable Upper Intake Level for Vitamin D Called Too Low

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day based on a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000-IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published (Am. J. Clin. Nutr. 2004;80:1689S-96S). This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

“It's one thing to say high doses of vitamin D are bad, but it's also very important to recognize how high we are talking about. What dose are we talking about?” he asked. “At least in animals, these doses are way off the curve in terms of anything we've been talking about.”

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]2D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment.

Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

In support of a UL of 10,000 IU/day, Dr. Vieth noted that a colleague has used 1,250 mcg/day vitamin D₃ “for some time,” and induced 25(OH)D levels of up to 643 nmol/L without hypercalcemia. Others also have used vitamin D several times higher than the current upper limit of 2,000 IU/day. Sunshine also can safely provide a dose of 10,000 IU/day to an adult, he said.

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day based on a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000-IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published (Am. J. Clin. Nutr. 2004;80:1689S-96S). This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

“It's one thing to say high doses of vitamin D are bad, but it's also very important to recognize how high we are talking about. What dose are we talking about?” he asked. “At least in animals, these doses are way off the curve in terms of anything we've been talking about.”

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]2D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment.

Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

In support of a UL of 10,000 IU/day, Dr. Vieth noted that a colleague has used 1,250 mcg/day vitamin D₃ “for some time,” and induced 25(OH)D levels of up to 643 nmol/L without hypercalcemia. Others also have used vitamin D several times higher than the current upper limit of 2,000 IU/day. Sunshine also can safely provide a dose of 10,000 IU/day to an adult, he said.

ARLINGTON, VA. — The currently recommended tolerable upper intake level of vitamin D is too low and is hindering clinical research efforts to determine a more accurate optimal intake of the vitamin, said Reinhold Vieth, Ph.D., at a conference sponsored by the American Society for Bone and Mineral Research.

Preliminary research and case reports on the use of high doses of vitamin D suggest that the tolerable upper intake level (UL) could be much higher than it now is, yet some researchers think that higher doses will cause hypercalcemic toxicity, according to Dr. Vieth, director of the bone and mineral laboratory at Mount Sinai Hospital, Toronto.

The lowest adverse-event level for vitamin D intake was established at 3,800 IU/day based on a 1984 study in which six patients developed hypercalcemia at that level. In the same study, a dosage of 2,400 IU/day of vitamin D resulted in a statistically significant increase in serum calcium levels but was not regarded as hypercalcemic and was considered safe. But because of an uncertainty factor of about 400 IU/day, the UL—defined as the highest level of daily vitamin D intake likely to pose no risk of adverse effects in almost all individuals in the general population—became 2,000 IU/day (50 mcg/day), Dr. Vieth said (J. Am. Diet. Assoc. 1998;98:699–706).

Research on the effects of vitamin D has been driven by the 2,000-IU/day UL rather than by a more careful dose-finding study of when toxicities begin to appear, he said.

There is no recommended dietary allowance (RDA) for vitamin D because when RDAs were established in 1995, there was perceived to be not enough evidence to recommend one, so an adequate intake level was “guesstimated,” Dr. Vieth said.

Vitamin D and its metabolites are stored at their highest concentration in adipose tissue, but a roughly equal amount overall is stored in muscles, contrary to what has been published (Am. J. Clin. Nutr. 2004;80:1689S-96S). This leaves a large reservoir to store vitamin D. If one extrapolates a study of vitamin D toxicity in rats to humans, the highest dosage that did not cause hypercalcemia was equivalent to 5,000 IU/kg per day; hypercalcemia began to occur when the serum 25-hydroxyvitamin D (25[OH]D) level reached an equivalent of 2,000 nmol/L (Arch. Biochem. Biophys. 1980;202:43–53).

“It's one thing to say high doses of vitamin D are bad, but it's also very important to recognize how high we are talking about. What dose are we talking about?” he asked. “At least in animals, these doses are way off the curve in terms of anything we've been talking about.”

Perhaps the best study of vitamin D toxicity in humans is a report of a family that stole a container from a shipping dock of what they thought was vegetable oil but was actually a concentrate of vitamin D that was for veterinary use, according to Dr. Vieth (Ann. Intern. Med. 1995;122:511–3). In the family, hypercalcemia began to occur at serum 25(OH)D levels that were well above the reference range upper limit of 500 nmol/L; their serum 25(OH)D concentrations ranged from 847 nmol/L to 1,652 nmol/L.

Normally the vitamin D-binding protein binds more than 99% of all 1,25-dihydroxyvitamin D (1,25[OH]2D) and only a “very small proportion” of vitamin D metabolites. But more than 1% of 1,25(OH)₂D was unbound from the binding protein in the family members and more of it was effectively displaced from the protein than normal because of the relatively high level of vitamin D metabolites in the patients. The levels of total 1,25(OH)₂D were just high-normal in the family members, but most had a high level of unbound 1,25(OH)₂D. This suggests that the likely mechanism through which vitamin D causes toxicity is the displacement of 1,25(OH)₂D from vitamin D-binding protein, Dr. Vieth said.

The capacity of vitamin D-binding protein for all metabolites of vitamin D is 4,000–5,000 nmol/L, but when concentrations of 25(OH)D approach 1,000 nmol/L, vitamin D-binding protein cannot bind as much 1,25(OH)₂D, he said.

“One problem with the vitamin D nutrition story is that we start to think of it as a drug, something to be used in treatment.

Unlike any other drug I'm aware of, there's never been a dose-finding study done,” said Dr. Vieth, who is also a professor in the departments of nutritional sciences, pathology, and laboratory medicine at the University of Toronto.

In a preliminary study of 12 patients with active-phase multiple sclerosis, Dr. Vieth and his colleagues studied the safety of using up to 40,000 IU/day of vitamin D₃ in treatment. The dosage of vitamin D₃ in the study increased from 4,000 IU/day up to 40,000 IU/day during the course of the study.

Many of the patients had already been taking vitamin D supplements; they had baseline concentrations of 100 nmol/L of 25(OH)D. The patients also received about 1,000 mg/day of calcium phosphate.

“So if you've got a cohort that's going to be susceptible to vitamin D toxicity in a phase I study, this is it,” he said.

No events of hypercalcemia and no change in urinary calcium levels have occurred. The investigators have received funding to extend the study.

With the results of his study and after a review of the literature, Dr. Vieth concluded that about 1 mg/day or 40,000 IU/day of vitamin D₃ might be the threshold at which toxicity begins.

But the actual UL for vitamin D should be about 10,000 IU/day, or 250 mcg/day, Dr. Vieth suggested. This is not an RDA, but it is a level not likely to cause harm in most individuals.

In support of a UL of 10,000 IU/day, Dr. Vieth noted that a colleague has used 1,250 mcg/day vitamin D₃ “for some time,” and induced 25(OH)D levels of up to 643 nmol/L without hypercalcemia. Others also have used vitamin D several times higher than the current upper limit of 2,000 IU/day. Sunshine also can safely provide a dose of 10,000 IU/day to an adult, he said.