High dose nutritional supplements and cancer risk

Regular readers know I don't have strong feelings about nutritional supplements and herbal medicine, unlike some of my medical blogger colleagues. I don't recommend or use them but for the most part it's not a subject that really gets me going, probably because I don't know enough about abuses. A lot of regular medical practice is not that soundly based, either, and some of it is pretty harmful. That's also not a subject that gets me going.

The one prejudice I do have I got from my physician and surgeon father. His diet advice was "everything in moderation." That goes for nutritional supplements as well and I consider it as wise now as it was 60 years ago when he gave it to his patients. Since we all look for items that reinforce our prejudices, here's one I found that works for me:

High doses of antioxidant nutritional supplements, such as vitamins C and E, can increase genetic abnormalities in cells, which may predispose supplement-takers to developing cancer, according to a new study from the Cedars-Sinai Heart Institute.

The study, led by Eduardo Marbán, M.D., Ph.D., director of the Cedars-Sinai Heart Institute, was published online today in the medical journal Stem Cells. The study also will appear in the journal's July printed edition.

Marbán and his team accidentally discovered the danger of excessive antioxidant doses while seeking a way to reduce the genetic abnormalities that occurred naturally when the scientists sought to multiply human cardiac stem cells.

Marbán stressed that the study's finding applies only to excessive nutritional supplements and not to foods that are rich in antioxidants, such as milk, oranges, blueberries and peanuts. In recent years, multiple studies have touted the benefits of foods rich in antioxidants.

"Taking one multivitamin daily is fine, but a lot of people take way too much because they think if a little is good, a lot must be better," said Marbán, who is also the Mark Siegel Family Professor at Cedars-Sinai. "That is just not the case. If you are taking 10 or 100 times the amount in a daily multivitamin, you may be predisposing your cells to developing cancer, therefore doing yourself more harm than good." (Cedar Sinai press release via Science Blog [not related to scienceblogs.com])

Marbán is not an anti-supplement crusader (nor am I), so how he discovered this is interesting. He is working on ways to regenerate heart muscle damaged by a heart attack. He removes a bit of heart tissue from the patient and he uses it to grow cardiac stem cells in tissue culture. He then reinjects the stem cells into regions of the damaged heart so that healthy heart tissue can be regenerated. He has actually tried this in a patient and is awaiting results early next year.

Cells grown in a petri dish need much higher oxygen levels (about 20%) than present in normal tissue (3 - 5%). But the technique of growing the cardiac stem cells is technically difficult and many cells are rejected because they have genetic abnormalities, presumably from the higher oxygen tension. So he tried adding anti-oxidants like vitamins E and C. That's when he accidentally discovered these compounds were causing genetic abnormalities that might later lead to cancer.

This doesn't mean that super doses of nutritional supplements cause cancer. There is a long way between this finding and that conclusion. But it doesn't rule it out either and it is a red flag, even if a small one.

And for me it reinforces one of my prejudices: everything in moderation. Including nutritional supplements.

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Revere, This is interesting. I sent you a paper of mine on what I think is going on.

My opinion is that a state of âoxidative stressâ is too important for organisms to rely on dietary levels of antioxidants for its regulation. Cells evolved the ability to regulate their state of oxidative stress a couple of billion years ago. A state of oxidative stress is a powerful modulator of physiology. Essentially every type of âstressâ ends up producing a state of oxidative stress because oxidative stress is the generic stress response.

I think the association of a âgoodâ diet with good health may be because people in good health self-select a diet rich in antioxidants. People in bad health self-select a diet poor in antioxidants so that their bodies don't need to spend metabolic resources generating more superoxide to destroy those excess antioxidants.

Because all diet studies use self-selected diets, there is no data on health independent of diet choice.

Every long term placebo controlled study of supplemental antioxidants has shown no benefit. Many have shown slight negative effects. I think this is because dietary antioxidants don't control a state of oxidative stress at all.

When you consume antioxidants in excess of your oxidative stress "setpoint", your body will generate more superoxide to destroy them (which physiology has unlimited capacity to do). It is the excess superoxide generated to destroy excess antioxidants that (I think) caueses the adverse effects of too much antioxidants.

If this hypothesis is correct, then excess antioxidants from any source, including food will have the same adverse effects. I appreciate that those finding adverse effects from supplemental antioxidants always say their findings don't apply to antioxidants from food, but they don't have any data to make that statement.

Apoptosis, my friends.

Perhaps its really as simple as antioxidant overkill, over-riding the apoptosis signal in aneuploid cells leading to the persistence of said cells.

Cell culture application of high dose free radical scavengers is not the same as exposures in situ. I need to read the paper :-)

Nika: or perhaps not. Remains to be seen. Meanwhile, I think "everything in moderation" is a good guideline.

Humans are among the only mammals that don't produce their own vitamin C. Many mammals produce an amount equivalent to 10 grams daily for humans. Marban's finding is an unusual one.

Much more common are cell studies like this one, which show vitamin C can repair damaged DNA in skin.

Also more common are animal studies like this one, which show antioxidants can prevent damage to eyes.

Completely agree with moderation!

Moderation means you keep an open mind, eat broadly, and dont become a purist (something many people fall into as they strive for perfecting their health - many in the health industry and consumers of those supplements).

Of course, to me moderation isnt eating only a small McD fries but rather, eating no fries and eating homegrown organic potatoes in moderation.

Moderation, to me means, getting your vitamins and minerals from whole foods. Thats likely what your dad meant too!

Thing is, and many supplement consumers know this, our food today is grown on depleted soils and nutrient content in our fruits, veg, meats have faded to mere suggestions of what they should be.

There is no easy answer, especially since the concept of depleted soils is 1) invisible to most of us and 2) non-intuitive.

But can we extrapolate from this how much "too much" is?

I think 3 grams of vitamin C a day might be too much, but is 500mg too much? One might consider it excessive, given that the RDA is much lower than that, and tissue saturation (at least of leukocytes) occurs at around 200mg. But the randomized Physician's Health Study did not find any adverse effects on all-cause mortality, nor did it increase cancer risk to a substantial degree in men. On the other hand, it may have benefits for conditions like age-related macular degeneration.

I agree that as a rule, too much of anything can be detrimental. I just think that we lack knowledge about the optimal nutrient intakes for several vitamins and minerals.

I guess the simple answer here is research, research, research. Funding? Well....you know how that goes. From a clinical perspective treating high dose supplements as pharmaceuticals makes sense to me, using Niacin as an example. It is effective for raising HDL but has serious liver effects and needs monitoring. Now that Niaspan has been on the market it is treated as a pharmaceutical and is given proper respect. However,unless someone can patent a formulation and make a profit I do not see how research will be funded for large scale studies of supplements and, cynically speaking of course, negative results may not see light of day.

The role of the patient's health, physiology and nutritional deficiencies is also important in any drug study in determining dosage, after all what is being treated? Personally, on the vitamin C issue, I will not take more than 1000mg a day after seeing a dear friend get kidney stones on higher dosages. Of course in vitro studies make enormous sense to study carcinogenicity and should be taken seriously IMHO.

By Dr Denise (not verified) on 05 May 2010 #permalink

Moderation can and does kill. One of many the tragic coverups of modern medicine is the compelling research of Dr F.R Klenner's use of megadoses of Vitamin C to CURE polio in the late 1940's, a cure replicated by other doctors. He and other doctors also used megadoses of C to cure pneumonia and other bacterial and viral illnesses. The results were known to the medical establishment as Klenner published his results. But how could a country doctor cure illnesses with a simple vitamin protocol? Impossible of course, so the data was suppressed -as has been the case with so many other natural cures.



for the story.

The best part of herb's article (I do NOT recommend reading) is the following:

Around 1942 Klennerâs wife suffered bleeding gums and her dentist recommended pulling out all her teeth. Dr. Klenner thought that solution too Draconian and remembered reading about research using vitamin C to cure chimpanzees with a similar problem. He gave her several injections of the vitamin and the bleeding stopped. Soon, after, this dramatic result encouraged him to try vitamin C on an obstinate man who was near death from viral pneumonia.

She suffered bleeding gums, eh? From Wikipedia's entry on scurvy: "Scurvy leads to the formation of spots on the skin, spongy gums, and bleeding from the mucous membranes." So Doc Wonder here gives his scurvy-inflicted wife some vitamin C, and HOLY FUCKING SHIT it helps. Shocking, I tell you. So from there, you just jump to trying it on pneumonia? Okaaaay . . . and then we get into conspiracy theories! Revere, why are you trying to help the EVIL medical establishment keep vitamin C from us? Don't you know it's one of the cures "they" don't want you to know about? (h/t to Kevin Trudeau, a giant douche/turd sandwich if there ever was one)

Seriously dude, vitamin C is one of the cheapest, easily-produced chemicals out there. If it really cured people, don't you think somebody more reputable than GNC would be pushing megadoses?

By Rob Monkey (not verified) on 06 May 2010 #permalink

We teach our tox students that high doses of Vitamin A are toxic to the liver, and that we shouldn't eat polar bear liver for that reason.

The carotene chemoprevention study carotene arm was stopped because the carotene treated suffered higher rates of lung cancer.

If we are into metaphors, the cancer cells are sicker than the normal tissue, so they benefit more from vitamins.

This metaphor addresses progression, not really initiation. (recognize these are archaic terms, but we have to teach them in tox because they are still on exams)

By Frank Mirer (not verified) on 07 May 2010 #permalink


You are so naive as to believe that anyone can successfully fight big pharma and actually use Vitamin C in megadoses to alleviate disease.

Let me give you one example. There actually was an RCT study published in a mainstream medical journal (Annals of Surgery) a few years ago using moderate doses of C and E for people in surgical intensive care units - leading to significant benefits in morbidity and length of stay and a non significant reduction in mortality. If those results were achieved with a patent medicine it would be a billion dollar drug.

I wrote to a number of local hospitals with a copy of the study and not one would even consider using this protocol. None gave me a coherent reason.

Can you explain why people are suffering and dying unnecessarily because the medical paradigm can't or won't accept that simple vitamins like c and e can dramatically benefit people with no risk and a cost of pennies a day? Bet you can't.

Here's the summary in case you think I'm just making this up.

"Vitamins C, E Aid Recovery from Surgery in Critically Ill

Supplementation with vitamins C and E can reduce the incidence of life-threatening complications in critically ill surgical patients, according to a report in the Annals of Surgery (2002;236:814â22). The results of this study suggest that this simple, safe, and inexpensive treatment might help save the lives of people who have sustained serious injuries, while at the same time reducing the cost of medical treatment.

Five hundred ninety-five people admitted to a surgical intensive care unit (ICU), 91% of whom were victims of trauma, were randomly assigned to receive standard care (control group) or standard care plus vitamins C and E. Vitamin E was given orally in the amount of 1,000 IU three times per day, and vitamin C was given intravenously in the amount of 1,000 mg three times per day.

Treatment was continued until the person was discharged from the ICU, or after 28 days, whichever was shorter. The incidence of multiple organ failure was significantly lower (by 57%) in the group receiving antioxidants than in the control group (2.7% vs. 6.1%). In addition, the average length of stay in the ICU was significantly lower (by 17%) in the antioxidant group. After 28 days, the mortality rate was 44% lower in the antioxidant group than in the control group (1.3% vs. 2.4%), but this difference was not statistically significant."

Herb, the study you cite is interesting but I don't agree that if it were a patented molecule rather than vitamins that it would be a blockbuster drug. Leaving aside questions about whether it is a billion-dollar dollar market to begin with, you seem to be assuming that this study alone would be sufficient for FDA approval (if it were for a drug).

There are a few concerns about the design of the study, the biggest being that it was not blinded or placebo-controlled. This can introduce bias into the study. I don't have access to the full paper, so I cannot determine what the primary endpoint of the study was.

Nonetheless, the results are promising and the logical next step would be to confirm these findings in a large, blinded multi-centre clinical trial. Such a trial is already underway: