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BLOG: November 2009

 Folic acid cancer risk

Folic acid studies - Folic acid cancer risk

Are you confused? After over a decade of having our foods fortified with folic acid, studies are coming in with worrisome, consistent indications that the elevated intake of this form of vitamin B9 - produced synthetically for food supplements and fortification - can increase the risk of developing cancer.

For a while, we've been told exactly the opposite.

The National Health Institute still maintains that folic acid safeguards from cancer on its Web page, although admits that there is no direct evidence for it (and, typically, assumes folic acid having for all practical purposes identical biological effect as the natural B9 forms). Safe upper limit of 1mg (1,000mg) of supplemental folic acid intake - cut somewhat loosely by the Institute of Medicine as a safeguard from masking vitamin B12 deficiency - still counts as the official recommendation.

On the other hand, as far back as 1940s it's been discovered that high level of folates worsens acute lymphoblastic leukemia in children, while lower folate levels generally produce improvement. Based on that, chemotherapy drugs inhibiting body conversion of folates into their usable form have been developed and used to fight leukemia, other cancer forms, and autoimmune diseases (for instance, Lederle's antimetabolite/antifolate drug methotrexate).

What is going on?

The only thing actually surprising is that folic acid's showing it can have double face seems to be surprise to so many. We ought to know that there is

no such thing as unconditionally good nutrient,

i.e. good regardless of its body level and individual biochemistry. By virtue of its body function - synthesis of nucleotides needed for DNA building and repair, as well as production of S-adenosyl methionine (SAM), needed for proper DNA function (methylation) - vitamin B9 is directly included in development of both, normal and cancerous cells.

We know that it is rather common for nutrients in general that the excess produces similar adverse effects as deficiency. We shouldn't expect it to be different with vitamin B9. In its optimum range, it is cancer-protective by providing the cells with what they need for optimum DNA function. Too little of it will compromise DNA synthesis/replication, making it easier to go awry, and too much of it will benefit quickly dividing, DNA-hungry cancerous cells.

Too much of vitamin B9 could also help cancerous growth by stimulating SAM production, which tends to increase the level of DNA alkylation. Unlike the main, generally beneficial effect of SAM, DNA methylation - technically also form of alkylation, in fact the most common one - which transfers a single carbon (methyl) group, (bad) DNA alkylation causes transfer of multiple carbon groups, often in chains, resulting in DNA damage (this is how alkylizing chemotherapy agents destroy cancerous - and quite a few normal - cells).

  It is also not surprising that it is the elevated levels of folic acid, and not what is generally termed as dietary B9 (folate) that is implicated in increased cancer risk. Unlike all other (natural) forms of vitamin B9, which are chemically unstable and quickly degrade into inactive compounds, folic acid - naturally present in foods in miniscule amounts compared to other folates, but nearly exclusively the form synthetically produced for supplements and food fortification -

is extremely stable.

It was considered to be an advantage, increasing its bioavailability to the body vs. other B9 forms but, apparently, it can have a flip side too.

The flip side is that higher levels of vitamin B9 intake with significant folic acid proportion can overrun body's capacity of converting it into its (unstable) primary and secondary active metabolites, resulting in elevated blood levels of unmetabolized (stable) folic acid.

Its blood levels can remain relatively high much longer, continuously feeding cancerous cells with what they need for accelerated replication. In general, cancerous cells develop more efficient receptor/metabolism modes for compounds they need for proliferation, such as folic acid. Plainly put,

they benefit from elevated blood folic acid
more than normal cells do.

Ironically, it is bioavailability of folic acid that makes it dangerous. On the rational side, considering very low levels of folic acid in natural foods, the combination of its high bioavailability and high blood levels

is not natural to the body.

As such, it runs the risk of been suboptimal, even dangerous for health. It is for the reason - some may call it nature's wisdom, but evolutionary selection seems to be more appropriate term - that our DNA has taken its present shape, and that our body has limited B9-conversion ability. Both balance well with vitamin B9 as it comes naturally, but not with the presence of highly bioavailable, unnaturally elevated folic acid.

While it is very likely that body level of other (unstable) B9 forms have its upper safe limit when it comes to cancer-related risk as well, it is reasonable to expect it to be significantly higher than for folic acid.

Considering the sensitivity of body's vitamin B9 function, these fairly obvious facts should have gotten more attention. Especially knowing what we have known about folate-cancer link for decades.

That hasn't been the case.

Study results offer de facto database for establishing, at least to a rough approximation, the relationship between folate status and cancer risk.

In her article (Folate and cancer prevention: a closer look at a complex picture, 2007), Ulrich presents graphically such extraction for folate status and breast cancer risk. It could be expanded to the relationship between folate status and cancer risk in general, emphasizing that we still don't know specifically which cancer forms, to what extent and under what circumstance are instigated by high folate blood level, specifically those resulting from high supplemental folic acid intake.

Specific optimal range, hence range of deficiency and excess, vary individually. While moderate supplementation may be desirable, the Institute of Medicine's upper save limit for supplemental intake of 1mg (1,000μg) a day doesn't seem recommendable. Estimated postfortification era daily dietary folate intake in the U.S. is ~400μg, about half of it coming from fortified foods. It seems prudent to stay below 1mg/day total intake, which sets daily supplemental limit to ~500μg (except for those with compromised folate metabolism, serious deficiency, or other health issues).

As frightening as it may be - it is unsettling coming to fear most basic nutrients - this new development is even more sobering and empowering. It is opening a

new chapter in our understanding of the complex link
between nutrients and health.

Instead of (happily?) rushing to conclusions, such as that "supplements are of no benefit for preventing cancer", or even plain dangerous, it is, as always, much more productive to take a good look of the facts, and act accordingly.

And what the facts are telling us is that we still need to learn to use the nutrients - particularly in their supplemental forms - wisely.