By Rob Verkerk PhD; founder, scientific and executive director, ANH-Intl

As I started digesting the latest scientific paper to land on my desk, passed to me by our able outreach and communications officer, Melissa, I breathed a sigh of relief. In the next breath, I felt myself tense up. That was my autonomic nervous system’s response to the realisation that many more lives would still be lost or damaged unnecessarily because science, nutrition and policy continue to be uncomfortable bedfellows.

The review paper in question was published by Professor Nicholas Wald and colleagues, including Professor Joan Morris, at Barts in London. Profs Wald and Morris are serious players, about that there is no doubt. Wald pioneered antenatal screening, is a world renowned epidemiologist and specialist in preventative medicine, having also been a key scientist to point to the link between passive smoking and cancer. Morris, another world class epidemiologist, is one of the leading authorities on Down’s syndrome and other chromosomal aberrations. The third author is no junior scientist either. He’s one of the most eminent scientists in Britain, Sir Colin Blakemore, made particularly famous for his work on the plasticity of the human brain.

At the heart of review paper from these esteemed scientists, published in Public Health Reviews earlier this month, is a justification and push for folic acid fortification of flour in the UK to help reduce cases of spina bifida and related neural tube defects (NTDs). Wald and colleagues reveal the 84 countries that have implemented mandatory fortification of flour with folic acid and they point to an increasing body of work that shows that NTDs in these countries have been declining because of it. The countries include the USA, Canada, Australia – and oddly very few other OECD countries. This anomaly is the result of a significant difference in opinion over the benefits or risks of food fortification in different parts of the world, and there is a glaring absence of European countries in the mix.

Neural tube defects. [Source: Centers for Disease Control].

Breakthrough

My excitement about the paper came from discovering that the three eminent scientists had cemented the very point that has been so central to our work over the last decade – recognition that arbitrary and excessively low ‘tolerable upper levels’ of intake of vitamins can cause more harm than good.

Wald and colleagues write: “A matter of public health concern is that some authorities, such as the European Commission Scientific Committee on Food, put greater weight on the hypothetical possibility of harm than on the proven evidence of benefit, apparently ignoring the fact that withholding a benefit is itself a harm.”

This is one of the central points we have been making since publishing our two papers in Toxicology back in 2010 (here and here). If you impose an unnecessarily low legal maximum limit for a nutrient in your efforts to protect a very small, super-sensitive group of a given population, you run a considerable and simultaneous risk of causing harm to a much larger sector of the population. These low levels may be determined either intentionally or unintentionally using flawed science.

This paradox occurs because, in reality, risks and benefits overlap. This was the subject of what I refer to as my ‘vitamin paradox’ paper from 2010. From a policy point of view, this means that any government regulation that is centred only on risks from over-consumption by the most sensitive population group is entirely flawed and can represent a public health disaster for the majority. That’s one of our central complaints with the EU approach to setting Tolerable Upper Levels (TULs).

Fair and square, Wald and colleagues have said that the 1,000 mcg/d TUL set by EFSA’s predecessor, European Commission’s the Scientific Committee on Food in 2000, is unnecessarily killing babies because European national authorities are too scared to fortify flour with folic acid for risk of some people consuming more than this arbitrary level. With sound reasoning, Wald et al have exposed the flawed thinking not only of the European Commission, all of which was adopted by EFSA in 2006, but they’ve also gone after the US Institute of Medicine for its incorrect interpretation of the science around high dose folic acid intake. It’s good to see such eminent scientists doing this – that’s what good science is about.

Folic follies

I mentioned at the outset some concerns I had over the paper, concerns that were sufficient to trigger an uncomfortable upregulation of my sympathetic nervous system. The five major concerns with the views expressed by the eminent epidemiologists:

• The authors have ignored recently exposed potential risks associated with high dose folic acid that are part of folic acid’s double-edged sword that I wrote about for Nutraingredients back in 2014 as well as elsewhere. If blood serum levels of folic acid are very high, bearing in mind folic acid is the synthetic, oxidised version of naturally-occurring folate, there is a theoretical risk, supported by a limited number of studies, that the folic acid might promote existing tumours given its fundamental role in cell division and one-carbon metabolism. When convenient, the authors have simply leaned on a statement by the IOM as follows: “The IOM found no evidence of harm from folic acid or food folate in respect of toxicology, reproductive, and developmental health or cancer.” While the authors are clear about the potential, but overrated, risk of high dose folic acid masking B12 deficiency, they don’t comment on any other possible health concerns. Lambasting the IOM for the things you object to and supporting the IOM when you like its position, in the absence of scientific analysis, is called scientific cherry picking. It’s also known as bad science.
• Very high intakes of folic acid can result in unmetabolised folic acid in the bloodstream in its oxidised form, something Wald and colleagues didn’t mention. If people consume more than 400 mcg/day of folic acid from fortified foods, it is highly likely that unmetabolised folic acid will accumulate in the bloodstream – and this may be harmful. In nature, consumption of the unstable, reduced forms of food folate results in trafficking of folate between different pools (e.g. as dihydrofolate, tetrahydrofolate) and ensures that appropriate amounts of the bioactive form, 5’-methyltetrahydrofolate (5-MTHF), are delivered to key cells, tissues and organs at the right times.
• The authors don’t take into account that the key target group for which they have concern over intake, preconceptual and pregnant women, only require very high intakes of folate for a short period of their lives to minimise NTDs. Therefore there could be risks to other groups if they overdose with the synthetic, oxidised form – something Wald et al seem to be unconcerned about. This is made all the more easier because it's hard to control how much white flour related products people are consuming. What should health authorities be telling preconceptual women? "Go gorge on white bread and pizza!" Surely not!
• The authors don’t consider other public health policies free from known risks, such as the promotion of folate supplements not associated with the risks of unmetabolised folic acid (i.e., the calcium and glucosamine bound forms of 5-MTHF)
• The authors don’t take into account differences between individuals (including of different ethnicities) in their metabolism of folic acid to the bioactive form, 5-MTHF, owing to genetic variations in key metabolising enzymes.

Should everyone who eats products made with white flour ingest synthetic folic acid, along with thiamin and riboflavin that have never been associated with any health concerns?

Solutions

We are concerned that the eminent professors, by ignoring important elements of the science of risk, while being so focused on the science of benefit for one particular population group, have, in effect, done little better than our over-cautious EU regulators who imposed the 1 mg/day ‘tolerable upper intake’ level. Like these regulators, the professors have also ignored the influence of nutrient form – so further weakening their position scientifically.

Their ploy to reduce NTDs by increasing folate intake – a clearly laudable objective – may so encounter a major stumbling block once the risk-averse EU regulators and supporting scientists get to engage with their proposal.

I can’t help but feel we at ANH-Intl have been right about this, possibly ahead of our time, for over 7 years now. To protect lives with vitamins, there are four things, all of which we have long advocated, that should be done with a degree of urgency to protect lives. These are:

• Risk/benefit analysis of all micronutrients, taking into account differences in the risk and benefit profile of different forms of the same nutrient is now essential. We have helped to develop a model for how this might be done and it’s high time this work was done in earnest.
• ‘Tolerable upper intakes’ as set both by EFSA and the IOM must be urgently reviewed using a more appropriate scientific approach. We have exposed many of the limitations of the existing approaches that are derived, inappropriately, entirely from a toxicological perspective.
• We need to consider a range of options that benefit public health and also allow the public to exercise its fundamental freedoms. That doesn’t only involve fortifying flour, given the amounts consumed vary vastly between different people at different stages of their lives. Supplementation of specific forms at varying doses can be highly targeted. Governments, as well as many scientists and policy makers, should stop being so prejudicial towards supplementation given it is an incredibly cheap, safe and targeted way of ensuring different groups in society can consume optimal levels of specific micronutrients in the forms they wish.

Let’s get serious about protecting the next generation. And let’s accept that policy, politics, business and science need to sort out their differences and work towards this common goal. But the good professors have an important message - and their voices should be welcomed in this complicated scientific, cultural and political debate.

Good Science Campaign