More on Cyanocobalamin Safety/Toxicity

 

Cobalamin (vitamin B-12) is synthesized only by certain microbes (bacteria and archaeon), and five forms of vitamin B-12 have been found in foods, according to the British Journal of Nutrition: adenosylcobalamin and hydroxocobalamin are the predominant forms, and other forms found include methylcobalamin, cyanocobalamin, and sulphitocobalamin. Most of these forms are considered synthetic substances, with additional compounds subsequently bonded to the already-synthesized cobalamin.

Methylcobalamin is produced commercially from cyanocobalamin, which is initially produced by fermentation and conversion processes. Adenosylcobalamin is directly produced by bacteria, while methylcobalamin requires an additional process of stripping off the cyanide group (CN, a carbon and a nitrogen atom with a triple bond) and adding a methyl group (CH3). Fermentations producing cyanocobalamin, methylcobalamin, and adenosylcobalamin do not utilize genetically engineered bacteria. The cyanocobalamin form is safe, stable, and bioavailable, and has been used for the vast majority of public health studies over the past century.

The amount of cyanide in cyanocobalamin is trivial, less than in an almond or apple; cyanide tends to be ubiquitous in the food supply in extremely tiny amounts. Cyanide is also produced by our own cellular processes (no great surprise since it's simply a single carbon and nitrogen molecule bonded together), but is quickly absorbed into the bloodstream, converted into thiocyanate (a less toxic form), and excreted in the urine or converted to carbon dioxide and exhaled. 

In fact, the Institute of Medicine has not set an Upper Limit for vitamin B-12 because “no adverse effects have been associated with excess vitamin B-12 intake from food and supplements in healthy individuals” (and both supplementation and food fortification primarily use cyanocobalamin). That same IOM report features this quote: “the amount of cyanide in cyanocobalamin is considered to be physiologically insignificant.” It would take about 2,500 doses of 1,000 microgram cyanocobalamin tabs to approach a dangerous amount of cyanide.

The adenosylcobalamin form is predominant in foods as well as in the human body, whereas methylcobalamin is typically in the body at only half the amount of the adenosyl form. Both are coenzyme forms with separate enzyme systems, and both are needed by the body. Cyanocobalamin feeds both pathways and is an inexpensive, stable, safe, and effective form of vitamin B-12 that does not require genetically engineered bacteria to produce.

Folic Acid: Risks or Myths?

There are theoretical risks for isolated folic acid in high doses. But these supposed risks fly in the face of established science and are controversial, not at all conclusive. There is also confusion over the significance of the supposed risks of high dose isolated folic acid in test tube and animal studies which do not identify a danger for moderate level supplementation - or even higher dose supplementation if combined with multivitamins or vitamin B-12. In other words, if the theoretical risks do not reflect real world human activities and the way that people actually obtain essential vitamins from their diet, including supplementation, aren’t these improbable risks really irrelevant to us? On the other hand, these negative reports may stop people from taking essential vitamins in quite reasonable amounts even though they are known to promote human health. Published human clinical science has determined that folic acid can reduce birth defects and has been proven to do so. Clinical science has also found mechanisms by which folic acid can prevent cancers, as well as the theoretical possibility that very high doses given in isolation can stimulate colorectal cancers including prostate cancer. There is stronger evidence that taking B-12 or a multivitamin along with high folic acid actually reduces rates of prostate and colon cancers. For example, in one human clinical trial where food intake, blood and plasma levels of folic acid were considered, Multivitamin users had about 2/3 the risk of subsequent prostate cancer as Non-Multivitamin users; only the independent use of folic acid was considered a risk factor. The report concluded, “…on the whole, the biological and epidemiological evidence supports the potential for folate supplementation to prevent colorectal neoplasia in humans.” (Cole) This shows that single nutrient studies, especially if unpublished and not peer reviewed or subjected to subsequent comments by experts in the field, should not be given overinflated importance when they are merely preliminary studies that may conflict with more relevant published human clinical studies. In the case of such conflicts, the human clinicals should bear more weight and be seen as more convincing, especially those that mimic the full range of variables (nutrients) in the human diet. Folic acid itself is considered non-toxic. Also, “data from in vitro and in vivo studies indicate that folic acid is not genotoxic [damaging to genetic material]”. (UK Food Standards Agency) There have been reports of levels as high as 50,000 micrograms per day given with no signs of toxicity in humans. There are accepted problems associated with levels exceeding 5,000 micrograms a day, which resulted in a far more conservative Upper Limit of 1,000 micrograms daily being set. This effect has been demonstrated in patients suffering from pernicious anemia taken off of their successful medicine (vitamin B-12), which was replaced by 5,000 mcg/day of folic acid. The substitution of one vitamin for another was unsuccessful in treating pernicious anemia, but did mask some symptoms. This test – and a large safety margin - provided the rationale given for the current Upper Limit. But it does not logically imply danger to those who are not severely anemic and who obtain B-12 in adequate amounts. (Oakley) It is very uncommon for people to take folic acid singly in doses of thousands of micrograms daily, but this is the method which test tube and animal studies often use. Overemphasizing unproven cancer risks requires ignoring valid studies showing reductions of cancers by taking folic acid and multivitamins. Needlessly scaring people from taking their vitamins, which have in human clinical trials shown significant improvements in birth defect and cancer rates, is not helpful to our common goal of protecting public health. Neil E. Levin, CCN, DANLA QUOTES & REFERENCES: Dr. Gideon Koren, director of the Motherisk Program at the Hospital for Sick Children in Toronto , note that rates of birth defects such as spina bifida and cancers such as neuroblastoma have plummeted since folic acid supplementation was begun. He believes that the known benefits outweigh theoretical risks. "I think it is very important to remember that the scares about cancer are mostly from animal studies and laboratory studies, not from human experience," he says. "We are still awaiting to see such human experience." http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20090417/folic_acid_090418/20090419?hub=SciTech Health Canada recommends all women of childbearing age take 0.4 mg of folic acid a day, but says taking more than 1 mg a day of folic acid without the advice of a doctor is not recommended. "We continue to encourage all women who could become pregnant to take a daily supplement," the agency says on its website. "We caution against taking more than one multivitamin tablet a day, as excess amounts of certain vitamins can be toxic." http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20090417/folic_acid_090418/20090419?hub=SciTech “All women who could become pregnant should take a multivitamin containing 0.4 mg of Folic Acid every day. To help reduce the risk of NTDs, you should start taking the vitamin supplement at least three months before you get pregnant and continue through the first three months of your pregnancy. Talk to your health professional to find the supplement best for you…If you have had a previous pregnancy affected by an NTD or have a family history of this problem, see your doctor. You may be advised to take a higher dosage of Folic Acid. If you have diabetes, obesity or epilepsy, you may be at higher risk of having a baby with an NTD, and you should see your doctor before planning pregnancy… Do not take more than one daily dose of vitamin supplement as indicated on the product label. Increasing your dose of Folic Acid beyond 1 mg per day without the advice of a doctor is not recommended.” (Public Health Agency of Canada , 2/27/08; http://www.phac-aspc.gc.ca/fa-af/index-eng.php) The NIH’s Office of Dietary Supplement reports on the prevention of cancer with the use of supplemental folic acid as part of a multivitamin: “Over 88,000 women enrolled in the Nurses' Health Study who were free of cancer in 1980 were followed from 1980 through 1994. Researchers found that women ages 55 to 69 years in this study who took multivitamins containing folic acid for more than 15 years had a markedly lower risk of developing colon cancer.” (Giovannucci E, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129:517-24; http://ods.od.nih.gov/factsheets/folate.asp) Cole BF, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. Polyp Prevention Study Group. JAMA. 2007 Jun 6;297(21):2351-9. PMID: 17551129 Figueiredo JC, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009 Mar 18;101(6):432-5. Epub 2009 Mar 10. PMID: 19276452 Folic Acid, CASRN: 59-30-3. NLM TOXNET Hazardous Substances Database accessed online 28 March, 2009. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@na+folic+acid Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. N Engl J Med. 2006 Apr 13;354(15):1567-77. Epub 2006 Mar 12. Erratum in: N Engl J Med. 2006 Aug 17;355(7):746. PMID: 16531613 Oakley GP Jr. When will we eliminate folic acid-preventable spina bifida? Epidemiology. 2007 May;18(3):367-8. PMID: 17435446 http://www.food.gov.uk/multimedia/pdfs/evm_folicacid.pdf