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B12 and B6 Vitamin Supplementation Linked to Cancer in New Study

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1. J Clin Oncol. 2017 Oct 20;35(30):3440-3448. doi: 10.1200/JCO.2017.72.7735. Epub

2017 Aug 22.


Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation

to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort.


Brasky TM(1), White E(1), Chen CL(1).


Author information:

(1)Theodore M. Brasky, The Ohio State University College of Medicine, Columbus,

OH; Theodore M. Brasky and Emily White, Fred Hutchinson Cancer Research Center,

Seattle, WA; Chi-Ling Chen, College of Public Health and College of Medicine,

National Taiwan University, Taipei, Taiwan.


Purpose Inconsistent findings have been reported of a link between the use of

one-carbon metabolism-related B vitamins and lung cancer risk. Because of the

high prevalence of supplemental vitamin B use, any possible increased association

warrants further investigation. We examined the association between long-term use

of supplemental B vitamins on the one-carbon metabolism pathway and lung cancer

risk in the Vitamins and Lifestyle (VITAL) cohort, which was designed

specifically to look at supplement use relative to cancer risk.


Methods A total

of 77,118 participants of the VITAL cohort, 50 to 76 years of age, were recruited

between October 2000 and December 2002 and included in this analysis. Incident,

primary, invasive lung cancers (n = 808) were ascertained by prospectively

linking the participants to a population-based cancer registry. The 10-year

average daily dose from individual and multivitamin supplements were the

exposures of primary interest.


Results Use of supplemental vitamins B6, folate,

and B12 was not associated with lung cancer risk among women. In contrast, use of

vitamin B6 and B12 from individual supplement sources, but not from

multivitamins, was associated with a 30% to 40% increase in lung cancer risk

among men. When the 10-year average supplement dose was evaluated, there was an

almost two-fold increase in lung cancer risk among men in the highest categories

of vitamin B6 (> 20 mg/d; hazard ratio, 1.82; 95% CI, 1.25 to 2.65) and B12 (>

55µg/d; hazard ratio, 1.98; 95% CI, 1.32 to 2.97) compared with nonusers. For

vitamin B6 and B12, the risk was even higher among men who were smoking at

baseline. In addition, the B6 and B12 associations were apparent in all

histologic types except adenocarcinoma, which is the type less related to



Conclusion This sex- and source-specific association provides further

evidence that vitamin B supplements are not chemopreventive for lung cancer and

may be harmful.


DOI: 10.1200/JCO.2017.72.7735

PMID: 28829668








Some media articles interviewing an author of the new study and also referencing previous studies showing links between B12 and B6 supplementation and cancer:



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Very high doses of a vitamin are deleterious to health - and water is wet :)... but seriously, yes, this is important. Some here might take at least B12 since a vegan might have problems getting it from diet. Presumably not super high doses, but it's a cautionary note.

In my experience it's uncommon to find B12 tablets less than 100µg, which is over 40 times the RDI and almost twice the dose shown in this study to be linked to a doubling of lung cancer risk. My impression is that 1000µg B12 tablets may actually be the most commonly available dose - over 400 times the RDI. So it wouldn't surprise me to find people taking such doses.

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Well, as a precautionary measure now I reckon we vegans should forget about the once-a-week B12 2000 mcgs megadose strategy and fall back to daily small dosages.


Or we should rather eat animal food once or twice a week... But that wouldn't meet the RDAs and wouldn't make happy the ethical vegans.

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Use of supplemental vitamins B6, folate, and B12 was not associated with lung cancer risk among women. In contrast, use of

vitamin B6 and B12 from individual supplement sources, but not from  multivitamins, was associated with a 30% to 40% increase in lung cancer risk

among men.




I'd like to see some fine-grained analysis of this associational study before drawing any practical conclusions.

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Some interesting points in the study (emphasis added):



Table 3 lists associations between 10-year use of B vitamins in male smokers, stratified by smoking status (as defined in Methods). There were too few patients among never smokers to evaluate associations.


Several studies have examined the associations of B6 intake and lung cancer (Supplemental Data). No significant associations have been reported on dietary intake11,13 or supplemental use3; however, inverse associations were reported from studies of serum B6 concentrations. These latter studies reported about half the lung cancer risk in those with higher serum B6 levels.17,18 A randomized controlled trial by Ebbing et al3 with four groups (B12 plus folic acid, B12 plus folic acid plus B6, B6 only, and placebo) found no effect of 40 mg/d of vitamin B6 on lung cancer (HR, 1.06; 95% CI, 0.62 to 1.82). In contrast, we found that supplemental intakes of B6 were associated with a 40% to 82% increased lung cancer risk in men. Associations were further elevated among smokers. These conflicting results could be explained by either serum measures being a more accurate reflection of vitamin B6 intake than the FFQ or serum levels differing between participants with lung cancer and participants without lung cancer because of different absorption, distribution, or catabolism of the circulating nutrient, rather than the total amount they consume.18 Evidence supporting the second hypothesis comes from a study reporting that among B6 metabolism markers, it was the inflammation-related changes in a vitamin B6 catabolism marker, the 4-pyridoxic acid/pyridoxal plus pyridoxal 5′-phosphate ratio, that was linked to increased lung cancer risk.19


;...] two prospective biomarker studies reported elevated lung cancer risks when comparing the highest versus the lowest categories of serum B12. Johansson et al18 reported an odds ratio of 1.35 (95% CI, 1.00 to 1.82; P trend = .04) in both sexes; whereas Hartman et al17 reported no association in men (odds ratio, 1.41; 95% CI, 0.80 to 2.50). Similar to our findings, elevated risks were observed among smokers in the first study.18The randomized trial by Ebbing et al3 reported an HR of 1.59 (95% CI, 0.92 to 2.75) among those randomly assigned to the vitamin B12 plus folic acid groups versus those who did not receive such treatment. Notably, the B12 dose used in this trial, 0.4 mg/d (ie, 40 μ/d), was greater than the cutoff dose of > 55 μ/d for which we found a two-fold increased risk, albeit over a shorter period.


No association was found in women or for B vitamins from multivitamin sources.

We found that B6 and B12 had sex- and source-specific associations with lung cancer risk. In addition, the association in men was more pronounced in cigarette smokers. Shi et al20 reported that the genetic polymorphisms of an important enzyme involved in folate metabolism, 5,10-methylenetetrahydrofolate reductase, interacted differently between men and women with dietary vitamin B6 and B12 intakes, cigarette smoking, and lung cancer. Men and women have different susceptibility to tobacco-induced lung cancer and supplementation with high-dose vitamins B6 and B12 for longer duration may support more rapid cell growth and promote carcinogenesis in already mutated cells in smoking men. Because androgen signaling regulates key enzymes involved in the one-carbon metabolism pathways, the increase of androgen levels or activity in men may lead to a more profound effect.21 A study by Suzuki et al22 reported significant interaction between a polymorphism in methionine synthase reductase and smoking, resulting in synergistically increased lung cancer risk. This evidence may help explain our observations.


Compared with nonuse, former use of vitamin B6 from individual supplements was associated with an 84% increased risk (multivariable-adjusted HR, 1.84; 95% CI, 1.01 to 3.36), whereas former use of vitamin B12 from individual supplements was associated with more than a two-fold lung cancer risk (HR, 2.42; 95% CI, 1.49 to 3.95). Current use of each supplement at baseline conferred weaker associations with lung cancer risk (HR, 1.37, 95% CI, 1.03 to 1.84; HR, 1.22, 95% CI, 0.91 to 1.64 for vitamins B6 and B12, respectively)
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