Hello,

I found this in Smart Publications´s newsletter
http://hfn-usa.com/articles-text/030206.txt

The human requirement for riboflavin is less than 2 milligrams a
day, but many common vitamin supplements contain 10s or 100s
of milligrams. There is little (if any) scientific justification for
taking supplements of riboflavin greatly in excess of the known
dietary requirement. However, there is a lot of scientific evidence
and speculation that the combination of abnormally high blood,
eye and skin levels of riboflavin, combined with a lifetime of sun
exposure, may have serious negative consequences, and actually
cause the damage we are trying to prevent. The combination of
sunlight and abnormally high tissue levels of riboflavin from
excess supplementation is a toxic combination that should be
avoided.
/

The article is longer and with citations.

I am concerned because most of the multivitamins come with much more than
2mg, except for the ones based on FDA recommendations (like one-a-day maybe)

I feel the effect of Bs but at a dose of 25+mg (like more alertness).

How serious is this B2 risk?.

Thanks

Riso

[Good question! However, you made a major errror when you lumped the B vitamins
together. Since their biochemical properties, benefits and optimal dosages are
vastly different from one another (just as with other vitamins and nutrients), I
have always thought that it was a major mistake for them to have received any
commonality in their names. That is one reason why I generally refer to them by
their chemical names rather than there vitamin name. Another reason is because
even the same vitamin name/number often has several independent chemicals as
contributors to the family, and again each of these have quite different
benefits.

So to continue for riboflavin, yes, this is one vitamin for which I do not take
more than is within the LE Mix (50 mg riboflavin and 2 mg riboflavin phosphate).
WRT sunlight, I try to keep that minimized because it is highly damaging to the
skin and eyes apart from any interaction with riboflavin. However, let's examine
one-by-one the citations which are given in the newsletter mentioned for their
reasonableness for being concerned about supplemental riboflavin, and after that
look for others which might be either a cause for concern or suggest benefits
from certain dosages.

Note: for those articles which are not available online, I am only examining the
abstracts since I do not have the time or money to procure them. If someone
wishes to purchase them or go to a biomedical library and photocopy them, and
then send them to me I will be happy to give my time to analyze their relevance
to humans.

First, some facts to help our analysis:
1) an adult human has roughly 5 liters of blood
2) a liter of blood weighs roughly 1000 grams
3) the molecular weight of riboflavin is 376.37
4) thus 1 uM of concentration of riboflavin is equivalent to an amount of 5 X
376.37 = 1882 mg distributed throughout a human's blood volume.
5) riboflavin is a water soluble vitamin which is excreted in the urine (the
yellow color) very quickly. (The purpose of taking fairly high supplemental
amounts in a distributed manner, as with most other strongly excreted nutrients,
is to keep levels in the body constantly at a reasonable beneficial level).


1. Jernigan HM Jr., Role of hydrogen peroxide in riboflavin-sensitized
photodynamic damage to cultured rat lenses, Exp Eye Res 1985 Jul;41(1):121-9.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4\
029283&dopt=Abstract

The concentration of riboflavin used in this rat lens in culture study (50 uM)
is equivalent to over 94 grams distributed throughout the blood of an adult
human. This is clearly not a physiological amount that anyone is taking. Even
more, the concentration actually bathing the eye lens will be much less than in
the blood since it is very poorly invervated.


2. Kale H, Harikumar P, Kulkarni SB, Nair PM, Netrawali MS, Assessment
of the genotoxic potential of riboflavin and lumiflavin. B. Effect of light,
Mutat Res 1992 Nov;298(1):17-23.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
279412&dopt=Abstract

Insufficient details are given in the abstract to do any analysis of the
applicabiltiy of this standard testing for mutagenicity to human use of
riboflavin. Note however, that an enormous number of foods are mutagenic in the
standard Ames test used and yet bare little potential for practical human harm
(as Ames himself has pointed out).


3. Silva E, Salim-Hanna M, Edwards AM, Becker MI, De Ioannes AE, A
light-induced tryptophan-riboflavin binding: biological implications, Adv
Exp Med Biol 1991;289:33-48.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
897400&dopt=Abstract

Again the abstract of this review article contains too little information for
any analysis of its relevance wrt human consumption of riboflavin.


4. Chessex P, Lavoie JC, Rouleau T, Brochu P, St-Louis P, Levy E, Alvarez
F, Photooxidation of parenteral multivitamins induces hepatic steatosis in
a neonatal guinea pig model of intravenous nutrition, Pediatr Res 2002
Dec;52(6):958-63.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
2438676&dopt=Abstract

This study compared parenteral (IV, intravenous)) nutrition with and without
riboflavin, with and without photoprotection. It found far more peroxides with
riboflavin and no photoprotection. Since the skin normally well protects the
riboflavin in the blood, and riboflavin in dry form will be much less
succeptible to oxidation, this study really only applies to humans requiring
parenteral nutrition and it indicates that such supplies should be kept in the
dark.


5. Bhatia J, Moslen MT, Haque AK, McCleery R, Rassin DK, Total
parenteral nutrition-associated alterations in hepatobiliary function and
histology in rats: is light exposure a clue? Pediatr Res 1993 May;33(5):487-92.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8\
511021&dopt=Abstract

This is another study concerned with TPN [total pareneral nutrition]- in rats
this time. The purpose of the study is to investigate the potential of
riboflavin induced oxidation occuring within TPN solutions and the study has
little relevance for human usage of vitamin supplements (unless you keep them
premixed in liquid form - which is never a wise thing to do).


6. Edwards AM, Silva E, Effect of visible light on selected enzymes,
vitamins and amino acids, J Photochem Photobiol B 2001 Oct;63(1-3):126-31.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
1684459&dopt=Abstract

Not enough information in the abstract of this review paper for any analysis.


7. Frati E, Khatib AM, Front P, Panasyuk A, Aprile F, Mitrovic DR,
Degradation of hyaluronic acid by photosensitized riboflavin in vitro.
Modulation of the effect by transition metals, radical quenchers, and
metal chelators, Free Radic Biol Med 1997;22(7):1139-44.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9\
098086&dopt=Abstract

This is a pure science paper. Since no concentrations or other details are given
in the abstract, it is not even clear if this is even an experimental in vitro
study or merely a theoretical paper. It does make the conclusion that oxidation
products of riboflavin in the transparent tissues such as the eye lens and the
skin could be potentially harmful (but says nothing about concentration of
riboflavin). However, that is simply another reason why we need good antioxidant
protection.


8. Riemschneider S, Podhaisky HP, Klapperstuck T, Wohlrab W, Relevance
of reactive oxygen species in the induction of 8-oxo-2'-deoxyguanosine
in HaCaT keratinocytes, Acta Derm Venereol 2002;82(5):325-8.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
2430729&dopt=Abstract

This study concludes that DNA damage in skin can result from UV excited
riboflavin. But once again the best solution is to not get too much UV radiation
and not take very high doses of riboflavin. One should reduce riboflavin only if
you must be in the sunlight for long times.


9. Oikawa S, Tada-Oikawa S, Kawanishi S, Site-specific DNA damage at
the GGG sequence by UVA involves acceleration of telomere shortening,
Biochemistry 2001 Apr 17;40(15):4763-8.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
1294644&dopt=Abstract

This theoretical study is an attempt (probably successful) to elucidate the
mechanism by which UVA causes teleromeric shortening and DNA damage in skin
cells leading to skin aging and cancer. Again, no riboflavin concentrations are
given so it is hard to gauge its relevance for reasonable human doses and
reasonable sunlight exposure.


10. Salet C, Moreno G, Photodynamic action increases leakage of the
mitochondrial electron transport chain, Int J Radiat Biol 1995 Apr;67(4):477-80.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7\
738412&dopt=Abstract

This study of rat liver submitochondrial particles showed the potential for
reduced efficiency of mitochondrial respiration in cells exposed to UV light. It
then simply "discusses" the dermatological relevance (which we already know).

11. Cho KS, Lee EH, Choi JS, Joo CK, Reactive oxygen species-induced
apoptosis and necrosis in bovine corneal endothelial cells, Invest
Ophthalmol Vis Sci 1999 Apr;40(5):911-9.
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
0102288&dopt=Abstract

This was one more eye cell culture study which proved again for cornea what was
already known for lens. There is no indication of its relevance for humans.

12. Eckhert CD, Hsu MH, Pang N, Photoreceptor damage following
exposure to excess riboflavin, Experientia 1993 Dec 15;49(12):1084-7
Abstract study link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8\
270030&dopt=Abstract

This was a nutritional study of rats given excess riboflavin. The abstract does
not say how much excess and certainly leads one to conclude that if given no
"excess" then there was no problem.

Now lets look at the benefits of riboflavin, from sources not used by the Smart
Publications´s newsletter article:

1: Head KA.
Natural therapies for ocular disorders, part two: cataracts and glaucoma.
Altern Med Rev. 2001 Apr;6(2):141-66. Review.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
1302779&dopt=Abstract

"riboflavin appears to play an essential role as a precursor to flavin adenine
dinucleotide (FAD), a co-factor for glutathione reductase activity."

2: Mahoney DJ, Parise G, Tarnopolsky MA.
Nutritional and exercise-based therapies in the treatment of mitochondrial
disease.
Curr Opin Clin Nutr Metab Care. 2002 Nov;5(6):619-29.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
2394637&dopt=Abstract

"riboflavin has been used as a precursor to complexes I and II"

3: Heap LC, Peters TJ, Wessely S.
Vitamin B status in patients with chronic fatigue syndrome.
J R Soc Med. 1999 Apr;92(4):183-5.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
0450194&dopt=Abstract

Riboflavin (and other B vitamins) were reduced in patients with CFS [chronic
fatigue syndrome] compared with controls.

4: Apeland T, Mansoor MA, Pentieva K, McNulty H, Seljeflot I, Strandjord RE.
The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic
drugs.
Epilepsy Res. 2002 Oct;51(3):237-47.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
2399074&dopt=Abstract

"Subjects were supplemented with B-vitamins
for 30 days: folic acid 0.4 mg, pyridoxine 120 mg and riboflavin 75 mg per day.
After supplementation, serum folate and pyridoxal phosphate had increased, while
fasting and PML p-tHcy had decreased (P<0.0001) by 36 and 26%, respectively."

5: Jacques PF, Chylack LT Jr, Hankinson SE, Khu PM, Rogers G, Friend J, Tung W,
Wolfe JK, Padhye N, Willett WC, Taylor A.
Long-term nutrient intake and early age-related nuclear lens opacities.
Arch Ophthalmol. 2001 Jul;119(7):1009-19.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
1448323&dopt=Abstract

"The prevalence of nuclear opacification was significantly lower in the highest
nutrient intake quintile category relative to the lowest quintile category for
vitamin C (P<.001), vitamin E (P =.02), riboflavin (P =.005), folate (P =.009),
beta-carotene (P =.04), and lutein/zeaxanthin (P =.03)."

6: Kuzniarz M, Mitchell P, Cumming RG, Flood VM.
Use of vitamin supplements and cataract: the Blue Mountains Eye Study.
Am J Ophthalmol. 2001 Jul;132(1):19-26.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
1438049&dopt=Abstract

"We studied 2873 of the 3654 participants (79%) aged 49 to 97 years attending
the cross-sectional Blue Mountains Eye Study who completed a detailed food
frequency questionnaire, which included type, dose, and duration of vitamin
supplement use.
RESULTS: Use of multivitamin supplements was associated with reduced prevalence
of nuclear cataract, odds ratio 0.6, 95% confidence interval 0.4 to 1.0, P =.05.
For both nuclear and cortical cataract, longer duration of multivitamin use was
associated with reduced cataract prevalence (nuclear cataract, trend P =.02;
cortical cataract, trend P =.03). Use of thiamin supplements was associated with
reduced prevalence of nuclear (odds ratio 0.6, confidence interval 0.4 to 1.0, P
=.03, dose trend P =.03) and cortical cataract (odds ratio 0.7, confidence
interval 0.5 to 0.9, P =.01, dose trend P =.02). Riboflavin (odds ratio 0.8,
confidence interval 0.6 to 1.0, P =.05) and niacin (odds ratio 0.7, confidence
interval 0.6 to 1.0, P =.04) supplements exerted a weaker protective influence
on cortical cataract."

7: Schoenen J.
[Anti-migraine treatment: present and future]
Rev Med Liege. 1999 Feb;54(2):79-86. Review. French.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1\
0221059&dopt=Abstract
"In migraine prophylaxis a significant breakthrough came from riboflavin 400 mg,
which has an outstanding efficacy-side effect profile."


Absorption and excretion:

From Modern Nutrition in Health and Disease, 9th ed:

"Toxicity from ingestion of excess riboflavin by experimental animals or humans
is doubtful. The human gastrointestinal tract may be able to absorb less than 30
mg of ribovlavin from a single dose orally administered."

"The limited solubility and absorptivity of this vitamin as encountered in
natural foodstuffs and its ready excretion (which is typical of water-soluble
vitamins) normally preclude any health risk."

"Enhanced excretion of riboflavin occurs in catabolic patients undergoing
nitrogen loss, with protein-calorie malnutrition, with systemic infections and
with use of certain antibiotics."

From Present Knowledge in Nutrition, 7th Ed:

"Diets high in psyllium gum appear to decrease the rate of riboflavin absorption
whereas wheat bran has no detectable effect.

"There is some evidence that the magnitude of riboflavin absorption by the
intestine is increased by the presence of food."

"Periods of major physical activity in young men and moderate exercise in young
women have both been shown to reduce urinary riboflavin excretion. These results
may be interpreted as suggesting an increased requirement for riboflavin during
exercise, particularly because the study in women showed a small increase in the
coefficient of erythrocyte glutathione reductase activity."

"Riboflavin coenzymes are involved in the metabolism of four other vitamins:
folic acid, pyridoxine (B6), vitamin K and niacin."

"Because riboflavin absorption is limited to ~25 mg as a maximum at any one
time, consuming megadoses of this vitamin would not be expected to increase the
amount absorbed."

"several protective mechanisms prevent tissue accumulation of excessive amounts
of the vitamin."


Dosage:

The 2 mg daily "human requirement" which is cited in the Smart Publication
newsletter is the RDA ("Recommended Dietary Allowance", the daily dietary amount
which will prevent a deficiency disease). It is *not* the amount which a human,
who is well protected by antioxidants and limiting sunlight exposure, should
take for optimal health and life extension. Riboflavin is one vitamin which is
often deficient in people and supplementation for them is highly beneficial.

Based on a *full* analysis, I think that 10 - 50 mg daily is a good and safe
amount to supplement.

This question and its analysis has been an excellent example of the care that
must be taken in judging a health newsletter article. It especially shows that
the use of citations to the peer reviewed literature is no guarantee for the
"reasonableness" of the positions taken in the article. In addition, it shows
that there may be, for whatever reason, highly important papers which have been
omitted and important physiological information which has not been presented, is
unknown or whose relevance is not understood. As the saying goes, "a little bit
of knowledge can be a dangerous thing" (in this case it is not dangerous, but
merely "worrying" where there is little scientific evidence for it). --Paul]