To be blunt -- the NIH gave a dose of vitamin C, waited until it had been excreted, and then measured blood levels.

Dr. Steve Hickey

Jump to Mark Levine Letter

June 12, 2004

Dear Jennifer,

Thank you for your help.

I have emailed my ascorbate RDA concerns to the following members of the

"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK
"mailto:''"''; HYPERLINK

I did not find an email address for Susan Ference.

While I have not waited for an extended period, I have not yet had a 
single reply, despite sending the emails twice. 

Normally I would attribute such  a failure to bad manners. Since this 
is an issue concerning the fundamental validity of the RDA 
recommendations, and communication between scientists is
standard practice, I am astonished not to have heard back from anyone.

In producing the book, Ascorbate, we initially gained much appreciated 
help from Mark Levine at the NIH. However, when we raised our objections 
to the published NIH pharmacokinetics, he provided no response and stopped
responding to my emails. This is now a matter of public record.

If I fail to get a response from IOM, my next option must be to report 
my findings to the medical journals. I have delayed this action, as it 
could have a negative impact on the scientific reputation of the IOM.

Could you please bring this email to the urgent attention of the board

 Linda D. Meyers, Ph.D., Director, Food and Nutrition Board
 Geraldine Kennedo, Administrative Assistant
 Gail Spears, Administrative Assistant, Editor

Thank you in anticipation of your help,

Dr Steve Hickey
(A copy of this email has been sent to the Vitamin C Foundation.)
Copy of email sent to board members:

To: Members of the Food and Nutrition Board of the Institute of Medicine 
of the National Academies

Dear Member,

I question the veracity of the evidence upon which the board has 
recommended an RDA for vitamin C.

We have examined the explanation for the RDA in "Dietary Reference 
Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids" and found 
it severely wanting in scientific content.

We also studied the research papers upon which your generalisations were
based. It seems that the board has misunderstood the data and, on 
occasion, used inappropriate references to support statements.

In short, your RDA recommendations are severely compromised, for the 
reasons given below. Indeed, the recommendations seem largely based on 
the idea of blood and tissue saturation, for which there is no evidence. 
In particular, the NIH pharmacokinetics studies that purport to show 
such saturation are little more than pseudo-science.

The problems underlying the controversy with vitamin C are explained in 
our book Ascorbate: The Science of Vitamin C (details attached and below). 
I have emailed several international scientists working in the field and,
so far, not one has been willing to support your claims. Those contacted
include the NIH scientists, who have not been able to provide answers to 
my questions about the basis of their conclusions on plasma and tissue

I assert that the ideas of plasma and body saturation used to generate 
the RDA are false and unsupported by the evidence. These ideas are 
misguided: there is insufficient information to recommend an RDA with any 
scientific basis whatsoever.

The choice is:

a) Retract or modify the RDA recommendations

b) Provide a valid scientific justification for your current 

c) Admit that there is no scientific justification and the RDA is based 
on politics

I expect an urgent answer to my questions, as the health of millions of
people may be being compromised by your recommendations.

Thank you for taking the time to consider this important issue.

Yours sincerely,

Dr Steve Hickey


To illustrate the scientific problems with claims supporting the current
RDA, please consider these issues:

Point 1:

The NIH (Levine et al Proc. Natl. Acad. Sci. USA, 93, pp. 3704=963709, 
1996) measured the blood concentration of ascorbate about 12 hours after 
the dose.  That is approximately 24 half-lives for vitamin C 
concentrations above background level. This means that they did not 
measure a steady state, since the definition of steady state in 
pharmacology depends on the dose interval being short relative to the 
half-life. This is a basic pharmacological error, which should have been 
picked up by your committee.

To be blunt -- the NIH gave a dose of vitamin C, waited until it had 
been excreted, and then measured blood levels. The fact that they 
repeated the process is irrelevant, as basic pharmacology indicates 
that the doses were independent. The small increases reported clearly 
relate to background levels and probably reflect tissue compartmentation. 
Specifically, when the blood levels are high, the tissues take up 
ascorbate, then release it when the blood levels drop.

Levine did not achieve a steady-state, merely a "pulsed steady-state" 
or a waveform with a period of 12 hours. In the recent NIH paper on
pharmacokinetics and cancer, (Ann Intern Med. 2004 Apr 6;140(7):533-7) 
they discuss the case of a near-true steady state, that is 3 grams every 
4 hours, which produces a predicted stable level > 200 microM.

Point 2

The NIH (Levine et al., several papers of which you are doubtless aware)
describe the plasma as being "saturated" at 65 -70 microM. This is 
clearly wrong as, from the graphs in these same papers, the plasma levels
immediately following the dose are much higher. The NIH 
pharmacokineticist may have made the mistake of confusing (enzymic) saturation of the kidney ascorbate pumps with plasma (chemical) saturation. These are two =
entirely different things.

Point 3:

White blood cells are biologically inappropriate for estimation of body
tissue requirements. These cells live for only a few days and 
manufacture oxidants. They have specific pumps for uptake of dehydroascorbate 
during activation. Mark Levine of the NIH tried to justify use of these 
cells on the grounds that these were the only cells he could reasonably 
sample,  but that does not make them suitable for estimation of body 
tissue  requirements.  

These are specialised cells with a distinctive ascorbate metabolism. I 
find it difficult to believe that you are unaware of this, as it is basic

These white blood cells actively concentrate vitamin C, to many times 
plasma levels. So, by your arguments, the dose of vitamin C required would 
be the amount that produced similar levels in normal body cells. I am sure 
you did not wish to imply such a dose.

Point 4:

Bioavailability is a relative measure of absorption from the gut. It is
misinterpreted, but this is a minor point and difficult to cover in one 
or two sentences. Relative measures require care in their interpretation, 
which was not undertaken in the NIH experiments.
Ascorbate: The Science of Vitamin C Unscientific medical research may condemn millions to death. The relationship between vitamin C and health has been controversial for decades. Many influential scientists, including double Nobel Prize winner Linus Pauling, argued that ascorbate could prevent or cure serious diseases, such as heart disease, stroke, cancer and infections. Conventional experts disagreed, disparaging supplements in favour of fruits and vegetables. In their recent book Ascorbate: The Science of Vitamin C, Steve Hickey and Hilary Roberts describe the background science needed to understand the controversy. They explain the history of vitamin research, starting with James Lind=92s classic 1747 experiment on scurvy: a turning point in the application of science to medicine. This simple experiment is used to illustrate how science works. By separating real science from pseudo-science, the authors show that the medical establishment has come to value pathological science more highly than solid, replicable experiments. Advances in medical research are restricted by unsound demands for scientific "proof". It would be more appropriate if medical decision-making were based on cost-benefit analyses, derived from the theory of games. Using basic scientific principles, the book shows how the research underlying the establishment disdain of vitamin supplementation is both misleading and flawed. The recommendation that supplements are redundant if the person consumes five daily portions of fruit and vegetables is based on a misinterpretation of this research. Indeed, over the last half a century, medical research into vitamin C has frequently been hindered by failure to understand how the vitamin is used by the body. This re-evaluation of the evidence leads to a new, dynamic flow model for the action of this vitamin, extending the ideas of Dr Robert Cathcart. In the light of the new model, the vitamin C controversy is resolved. At first sight, the claims for vitamin C in heart disease, infection and cancer appear astonishing. However, the claimed benefits have a scientific basis and demand to be considered seriously. The difference between nutritional supplementation and therapeutic use of ascorbate is made clear. The dynamic flow model indicates that, for good health, an optimal nutritional strategy is to take repeated doses of vitamin C throughout the day: say a gram with every meal. The book describes an updated regimen for prevention and treatment of heart disease, called antioxidant network therapy; this needs to be tested experimentally as a matter of urgency. The authors also explain the scientific basis of ascorbate treatments for cancer, which are potentially curative. The failure of the medical establishment to perform critical follow-up experiments may have resulted in much suffering and countless deaths. As Dr Hickey says, "If this book doesn't shock you, you haven't understood it". For this reason, the book lists the essential experiments necessary to restore respectability to the scientific evaluation of vitamin C. If even a few of the hypotheses are confirmed, readers will understand why double Nobel Prize winner Dr Linus Pauling was prepared to stake his scientific reputation on ascorbate. Based on the evidence presented in this book, Dr Hickey has demanded that the US National Institutes of Health (NIH) and the Linus Pauling Institute urgently revise their suggested recommended dietary allowance (RDA). Book details: Ascorbate: The Science of Vitamin C, by Steve Hickey and Hilary Roberts=20 (1-4116-0724-4, Trade paperback, 264 pp, 6 x 9, $28.72). Barnes and Noble: HYPERLINK

Online download: HYPERLINK

Open Letter to NIH Vitamin C Researcher Mark Levine

Hi Mark,
        You appear to have stopped responding to my emails. 

I have explained to you that the background science to your claims on
vitamin C pharmacokinetics is at best suspect. You have provided no valid
response to my objections. Indicating that your pharmacokineticist "does not
understand" is not an explanation.  

Your published results have been taken to be strong evidence for low doses
of vitamin C being appropriate for humans. We both now know that this is not
the case. Since your published work is used as the basis of incorrect
dietary advice, including the RDA in the United States, it is imperative
that the situation is clarified.

The core problems are:

Your claim that plasma saturation occurs with vitamin C is wrong. There is
no evidence that blood plasma in the living human can be saturated with
ascorbate. Certainly, from your own data, oral doses do not saturate blood
plasma, as higher levels can be achieved with intravenous administration.

Bioavailability, as described in your papers, is a relative and biased
measure. From basic physics, your estimate of bioavailability will give
misleadingly high values for low doses. It is also inappropriate for use
with vitamin C, according to the basic principles of pharmacology.  

White blood cells are a poor model for normal body tissues. White blood
cells manufacture oxidants and have very specific requirements for vitamin
C. Their use as a model for normal body tissues produces inadequate levels.
You must be aware that this is biologically indefensible.

Your ideas that high blood levels of ascorbate have no value ignore large
numbers of published research results.

Fundamentally, your current position is scientifically untenable.

As I indicated before, your research team has made some basic mistakes and I
might fail an undergraduate student for such errors. I have explained where
you have gone wrong in our new book, Ascorbate.

I suggest you retract your claims for this work with vitamin C as a matter
of urgency. People are restricting their intake of vitamin C on the basis of
your results. The consequences of this in terms of health, illness and death
are explained in our book.   
Best wishes
(Dr Steve Hickey)