Archaic RDA Methodology for Vitamin C

Abstract

Frei et al's 2012 review entitled "Authors' Perspective: What is the Optimum Intake of Vitamin C in Humans" is both flawed and misleading. RCTs are ill suited to determining the RDA, it is debatable that there is sufficient scientific evidence to determine the optimum intake of vitamin C in humans, observations regarding high-doses of ascorbate have been ignored, and there are inaccuracies of fact with respect to the saturation of blood plasma following low dose intake. Until the limitations of current knowledge are recognised it is unwise to set limits on the dose.

Full text

Archaic RDA Methodology for
Vitamin C
STEVE HICKEY, GERT SCHUITEMAKER, ATSUO YANAGISAWA, LEONARDO
NORIEGA, MICHAEL J. GONZ

ALEZ, JORGE R. MIRANDA-MASSARI, CAROLINE
CHIBELUSHI, AND DAMIEN DOWNING
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Archaic RDA Methodology for Vitamin C
Steve Hickey, Gert Schuitemaker, Atsuo Yanagisawa, Leonardo Noriega, Michael J. Gonz
alez, Jorge R. Miranda-massari,
Caroline Chibelushi, and Damien Downing
BFSN #747486, VOL 0, ISS 0

Archaic RDA Methodology for
Vitamin C
STEVE HICKEY,
1
GERT SCHUITEMAKER,
2
ATSUO YANAGISAWA,
3
LEONARDO NORIEGA,
4
MICHAEL J. GONZ

ALEZ,
5
JORGE R. MIRANDA-MASSARI,
6
5CAROLINE CHIBELUSHI
7
and DAMIEN DOWNING
8
1
Newlyn Research Group, Newlyn, Cornwall, England
2
Ortho Institute, Gendringen, Netherlands
3
Japanese College of IV Therapy, Tokyo, Japan
4
Staffordshire University, Stafford, England
10
5
Medical Sciences Campus, University of Puerto Rico, San Juan, PR, USA
6
University of Puerto Rico, San Juan, PR, USA
7
Staffordshire University, Stafford, England
8
British Society for Ecological Medicine, London, EnglandQ2
The 2012 review by Frei et al. (2012), entitled Authors’
15 Perspective: What is the Optimum Intake of Vitamin C in
Humans is both flawed and misleading. Their assertion that
there is a tradition for basing the RDA for vitamin C on pre-
vention of acute scurvy, true as it may be, is irrelevant unless
it is also based on scientific data. The reviewers provide
20 numerous illustrations to suggest that vitamin C “may exert
additional health benefits” with respect to chronic disease.
However, their claim that studies “have not found consistent
benefit with respect to chronic disease prevention” stems from
a lack of understanding of the dosing and pharmacokinetics of
25 vitamin C, as has been explained previously, in detail
(Duconge et al., 2008; Hickey et al., 2008).
The reported belief of Frei et al. that there is a “lack of
apparent proof of benefit” from RCTs might be considered in
terms of the irrationality of a requirement for scientific proof.
30 Refutation, not proof, is core to the scientific method (Popper,
2002). Nevertheless, Frei et al. are aware that RCTs are ill
suited to determining an RDA. A more appropriate scientific
methodology would employ a Bayesian interpretation of all
the available data (Gelman et al., 2003).
35 We do not agree that the currently available scientific
evidence is sufficient to determine the optimum intake of
vitamin C in humans while omitting relevant information,
including the epigenetic, genetic, and evolutionary data. We
do agree with Frei et al. that vitamin C supplementation
40 lowers hypertension, endothelial dysfunction, chronic
inflammation, Helicobacter pylori infection, and acts as a
biological antioxidant lowering oxidative stress, which con-
tributes to chronic disease prevention. In addition, biologi-
cally plausible data and mechanisms of action suggest that
45shortage of vitamin C is a key feature in coronary heart dis-
ease, stroke, and cancer.
The idea that the data from human metabolic, pharmacoki-
netic, and observational studies supports an optimal intake of
200 mg per day of vitamin C is demonstrably incorrect. Frei
50et al. have ignored decades of observations and results
reported for high dose supplementation. In particular, the
ascorbate requirement variation reported by Cathcart (1985)
and others (Pauling, 1987; Hickey et al., 2005, 2008) are disre-
garded. Cathcart (1981) reported that, during periods of stress
55or illness, the body’s tolerance to oral doses increases in pro-
portion to the disease severity. The magnitude of this increase
is large and obvious—two to three orders of magnitude (from,
say, 2 g to 300 g). This is consistent with the body requiring
increased intakes. Such reports also suggest a definitive clini-
60cal response, with a clear pharmacokinetic explanation. These
data imply that people require a reserve daily intake (Hickey
et al., 2008). Importantly, they also invalidate the Frei et al.
claims concerning limited “bioavailability.”
Frei et al. claim, wrongly, that blood plasma is “saturated”
65at 60–80 mM/L following a low dose of vitamin C. The graph
presented to support this contention (Frei et al.,) has been
shown conclusively to be incorrect, since the measurements
were taken 12 hours after the dose, and vitamin C has a dual
phase elimination process (Hickey et al., 2005). The half-life
70of plasma ascorbate above this level is approximately
30 minutes. Disconcertingly, this graph shows plasma levels
of vitamin C measured after the vast majority of the dose had
Address correspondence to Caroline Chibelishi, Faculty of Computing Engi-
neering and Technology, Staffordshire University, K318, Octagon Building, Bea-
conside, Stafford, ST18 0AD, United Kingdom. E-mail: c.chibelushi@staffs.ac.uk
Critical Reviews in Food Science and Nutrition, 0:1–2, (2015)
Copyright c
OTaylor and Francis Group, LLC
ISSN: 1040-8398 / 1549-7852 online
DOI: 10.1080/10408398.2012.747486
1

been excreted. The reviewers’ physiological conclusions are
therefore invalid.
75 In healthy humans, graphs of concentration against time,
after a single large oral dose of ascorbic acid, peak some hours
later at about 250 mM/L. The NIH’s misleading “saturation”
concept has been discredited, though it was used to determine
the current RDA. Even the NIH’s own research suggests that
80 plasma “saturation” does not occur below at least 18 g a day,
leading to a sustained plasma level of at least 220 mM/L
(Padayatty et al., 2004). We should not need to point out that
this level is well above the reviewers’ claimed 60–80 mM/L
saturation point.
85 Independent studies suggest that some oral forms of vita-
min C, other than standard ascorbic acid tablets, can achieve
far higher plasma levels than this (Hickey et al., 2008). Such
reports suggest that plasma levels of 400–800 mM/L can be
achieved, and thus sustained levels approaching a millimole
90 (1,000 mM/L) may be attained using oral intakes. It has been
noted elsewhere that long-term supplementers may have base-
line plasma levels of about 150 mM/L after 12 hours deple-
tion, suggesting a modified distribution within the body
(Hickey et al., 2008).
95 Frei et al. quote figures for the absorption of vitamin C by
lymphocytes, platelets, monocytes, and neutrophils. These are
specialized cells, known to absorb millimolar concentrations
of vitamin C (U.S. Institute of Medicine, 2000). Indeed, at low
intakes, most of the body stores of vitamin C are contained in
100 such sensitive tissues, including brain, adrenal, and white
blood cells. Even a proverbial back-of-the-envelope calcula-
tion shows that the majority of other body cells must contain
far less than this else the adult body pool would be 8–26 g (1–
3 mM/L in a 70 kg human allowing for extracellular fluid and
105 a molecular weight of ascorbate of 176 g/mol); the total body
pool is only about 1,500 mg for people taking RDA levels
(Kallner et al., 1979) or an order of magnitude lower. Thus,
the claim of Frei et al. that results from these cells are typical
and suggest “saturation of all tissues at this dose” is demon-
110 strably inaccurate.
Frei et al. assert that the current RDA approach has left 40–
50% of people in developed countries severely (<11 mM/L)
or marginally deficient (<28 mM/L), illustrating the failure of
the RDA methodology. Specifying a micronutrient-based
115 RDA has not provided the population with an adequate intake.
The reviewers provide an account of how such low plasma lev-
els are associated with the major chronic diseases, including
cardiovascular disease, stroke, and cancer. However, observa-
tions on the benefits of megadose intakes are excluded. Con-
120 trary to popular belief, a gram of vitamin C is considered a
low dose for both disease prevention and therapy by many
experts in the field, such as Linus Pauling who consumed 18 g
per day (Pauling, 1987). The hypotheses that these chronic
diseases are primarily a result of chronic shortage of vitamin C
125is entirely consistent with the data presented, but is not even
mentioned. This is particularly disturbing, as the first author is
head of research at the Linus Pauling Institute, an organization
formed to investigate these ideas.
In presenting an author’s perspective, it is important to not
130exclude internationally accepted interpretations, particularly
when they present a direct challenge to the authors’ hypothe-
sis. This is especially the case when proposing a case for an
RDA that is substantially that of the NIH (Levine et al., 1996,
2001), uses controversial NIH data, and the lead author’s main
135source of funding is an NIH organization. Critically, the essen-
tial research to establish an optimal intake has not been per-
formed particularly in respect of claims for chronic vitamin C
deficiency being a primary driver of chronic disease. Until we
can recognize the limitations of current knowledge it is unwise
140to set limits on intake.
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