Long-term use of high doses of vitamin B6 and B12 supplements has been associated with an increased risk for lung cancer. Overall, men who took these high doses over 10 years had a 2- to 4-fold increased risk for lung cancer compared with men who did not take such supplements, and the risk was particularly elevated among smokers. However, no such increase was seen in women.

These findings come from the Vitamins and Lifestyle (VITAL) cohort study and were published online August 22 in the Journal of Clinical Oncology.

"Our data shows that taking high doses of B6 and B12 over a very long period of time could contribute to lung cancer incidence rates in male smokers. This is certainly a concern worthy of further evaluation," commented lead author, Theodore Brasky, PhD, from The Ohio State University Comprehensive Cancer Center, Columbus, in a statement.

He emphasized, however, that the doses involved were well above those found in a daily multivitamin tablet.

"These are doses that can only be obtained from taking high-dose B vitamin supplements, and these supplements are many times the U.S. Recommended Dietary Allowance," he said

This point was also emphasized by several experts not involved in the study.

The National Institutes of Health Office of Dietary Supplements suggests that men who are age 51 years and older need B6 at a dose of 1.7 mg daily (women, 1.5 mg daily), while for B12 the recommended dose for adults is 2.4 µg daily.

In this study, men who were taking the highest dose of vitamin B supplements (and who were found to have a two-fold increased risk in lung cancer compared with men not taking supplements) had been taking B6 at 20 mg daily and B12 at 55 µg daily for 10 years.

Study Details

The VITAL study had 77,118 participants, aged 50 to 76 years, who were recruited between October 2000 and December 2002.

For this study, Dr Brasky and colleagues focused on the 808 participants who developed incident, primary invasive lung cancers, as ascertained by prospectively linking the participants to a population-based cancer registry.

Just over half (55%) of these patients with lung cancer were men (n = 449).

The team then studied the vitamin supplement use among these patients with lung cancer. This was based on recall — participants answered questionnaires about the supplement use, as well as food intake and smoking habits.

The team found an association between vitamin B supplements and lung cancer among men, but not among women.

Men who had taken the highest doses were nearly twice as likely to develop lung cancer as men who had not taken supplements.

Men who were smokers and who were taking B6 at this high dose were three times as likely — and male smokers taking B12 at this high dose were four times as likely — to develop lung cancer as men not taking these supplements.

The analysis controlled for numerous factors, including personal smoking history, age, race, education, body size, alcohol consumption, personal history of cancer or chronic lung disease, family history of lung cancer, and use of anti-inflammatory drugs.

"This sets all of these other influencing factors as equal, so we are left with a less confounded effect of long-term B6 and B12 super-supplementation," Dr Brasky commented.

The researchers address the intriguing finding of why the association was seen only in men and not women, who actually formed a sizeable proportion of the study population (44% of total).

"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," they write in the discussion. "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," they add.

A further study is underway to confirm the findings in men and to investigate whether an association is seen in postmenopausal women.

Warning to Consumers

"Half of the US adult population uses one or more dietary supplements," the researchers comment.

"Our study found that consuming high-dose individual B6 and B12 vitamin supplements over a 10-year period is associated with increased lung cancer risk, especially in male smokers," they conclude.

"Consistent with prior evidence of harm for other vitamin supplements on lung cancer risk in smokers, the associations we observed provide evidence that high-dose B6 and B12 supplements should not be taken for lung cancer prevention and, in fact, may increase risk of this disease in men," they warn.

The Council for Responsible Nutrition (CRN), the trade association for the dietary supplement and functional food industry in the United States, was quick to react to the headlines highlighting harm from vitamin supplements — the study has been widely reported in the lay press and was featured on CNN.

"We urge consumers to resist the temptation to allow sensational headlines from this new study to alter their use of B vitamins," the trade association commented, while at the same time emphasizing the "well established" benefits of B vitamins, including supporting cognition, heart health, and energy levels.

The association emphasized that relying on recall was a major limitation of the study and also that its findings "conflict with the results of previous studies, including a randomized control trial as well as two studies that measured vitamin B6 serum levels and demonstrated reduction in lung cancer risk."

"Probably Don't Need to Worry"

Reacting to the study findings, Jennie Jackson, PhD, lecturer in human nutrition and dietetics, Glasgow Caledonian University in the United Kingdom, suggests that patients "probably don't need to worry." She wrote a blog post on The Conversation, a site that promotes "academic rigour, journalistic flair" and is funded by several charities and 65 British universities.

Dr Jackson pointed out that this was an observational study, and, as such, it cannot "provide proof of causation. There may be an entirely different factor that is affecting the risk of cancer, which just happens to be related to supplement usage. Although the researchers did their best to account for known factors that influence cancer risk (such as age and history of lung disease) there may be other yet-to-be-discovered factors."

"To prove that these vitamins directly cause cancer, an experimental design such as a randomized clinical trial would be needed," she emphasized.

"If massive doses of individual supplements of B6 and B12 do indeed promote cancer, this is not the first time that mega doses of vitamins have been seen to cause harm," she commented. "Nutrients that are likely to prevent cancer when eaten in the form of foods may cause harm when taken as purified supplements."

"For example, beta-carotene is the precursor form of vitamin A, which is found in fruits and vegetables," she continued. "Eating plenty of fruit and vegetables containing beta-carotene can help to prevent cancers, but taking high dose supplements of it is linked with an increase in incidence of lung cancer in smokers."

This study was supported by the National Institutes of Health, the National Cancer Institute and the Office of Dietary Supplements. Dr Brasky and coauthors have disclosed no relevant financial relationships.

J Clin Oncol. Published online August 22, 2017. Abstract

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