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Between Safe and Unsafe Is There an Optimal Middle Ground?

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Safe and Unsafe Safe and Unsafe

Safe is safe, right? And unsafe is unsafe? It seems ludicrous at first blush to think of these terms as moving targets, or that “safety is in the eye of the beholder,” or in the eye of the risk assessor. But the continuum from helpful to harmful is not a sudden deathly chasm. When asking what is toxic, you’d think chemicals like arsenic and rat poison would be no-brainers. On the flip side, table salt and vitamin A would be safe. But as we have learned from the famed ‘father of toxicology’ Paracelsus, “[a]ll things are poison and nothing is without poison; only the dose permits something not to be poisonous.”

And so it is with all four of the previous examples.

Arsenic may soon be qualified as a required micronutrient in animals as it seemingly (albeit in very tiny amounts) has a role in the metabolism of the amino acid methionine in gene silencing and through positive interactions with selenium.

Warfarin, the widely prescribed blood thinner, was developed as a rodenticide in the 1940s and was effective in killing rats by preventing coagulation and causing those animals to bleed to death internally. By the 1950s, it was authorized for use as a human clinical anticoagulant, in fact, treating President Eisenhower after he had a myocardial infarction.

Consider, also, that we all, consciously or unconsciously, ingest salt on lots of foods, now frequently used on chocolate and caramel! But the lethal dose (if consumed acutely) is estimated to be less than five teaspoons of salt in children and less than four tablespoons in adults. Hypervitaminosis A is the severe and sometimes lethal condition from too much vitamin A. At the same time, vitamin A is a critical required nutrient. Clinically deficient levels of vitamin A can cause blindness, limit the body’s ability to fight infections, and/or death. The U.S. Institute of Medicine has both a Recommended Daily Amount (RDA) of vitamin A of 900 micrograms (mcg) for adult men and 700 mcg for adult women and, at the same time, a Daily Tolerable Upper Level (UL) of intake for vitamin A of roughly 2,000 to 3,000 mcg/adult/day. The toxic dose is only three to four times the required dose! There’s little room for error.

Avoid Toxicity

So how can we intentionally be exposed to safe levels of Agatha Christie’s favorite murder weapon and a rodenticide, and avoid the toxicity from physiologically required sodium chloride and vitamin A? Back to Paracelsus and the mantra of all toxicologists—”the dose makes the poison!”

In the world of nutrition, scientists and regulators rely on scientific data and expertise to derive not only levels of nutrients that are required to avoid deficiency diseases and their manifestations (and also through accepted and rigorously proven risk assessments) but also to determine the levels of nutrients that would be considered unsafe. For dietary supplements, manufacturers are required to offer the consumer supplements that are ‘reasonably expected to cause no harm’ while ameliorating unsafe exposures by addressing the other piece to the safety paradigm—the dosing instructions on every product to reduce the likelihood that safety would be jeopardized.

The question is how do scientists (and wistfully, regulators) navigate the exposure continuum between ‘safe’ and ‘unsafe,’ i.e., between the RDA and UL? Does an arbitrary number or generalized multiplier make sense? More and more nutrition research makes the case that sufficient vitamin and mineral intake (the amount needed to avoid outward signs of deficiency) is not the physiological optimum, and this is a body of research which is rapidly expanding. Nevertheless, some regulatory authorities make the convenient, impulsive, and down-right indolent determination that the RDA, or some low multiple of the RDA, should be the allowable limit for dietary supplements. However, these determinations are devoid of scientific validity!

Relying on the RDA-based levels to determine upper safe levels limit question is, well, opaque, subjective and contrary to established science. The scientifically accepted and globally accepted principles of scientific risk assessment are the only methods that consider both the inherent hazard identification of the compound (in this case, a vitamin, mineral or other dietary ingredient), and the exposure (which is the most important aspect).

Unfortunately, regulators are increasingly turning to a convenient shortcut—blind acceptance of a non-scientific precautionary paradigm that turns this calculus on its head and dictates that any amount of risk is too much. That decision becomes even more skewed when detractors deny or dismiss the proven health benefits of dietary supplements and their ingredients. When regulators (or consumers) don’t perceive any value and benefit from the product(s), it’s easy to amplify the supposed risks. And the precautionary principle dictates that if there is any uncertainty, whether real or fantasized, then the authorities must prohibit any use of the ingredient and product.

The catalogue of decisions using “ignorance of exposure,” where there is a failure to appreciate the difference between the dose and the poison, is extensive and growing, and inappropriately scares consumers away from the judicious use of dietary supplements. Examples proliferate from a myriad of countries and regions focused on (1) the ‘precautionary principle’ wherein an unknown risk at some level leads to zero allowable exposure, and/or (2) a maximum-allowable dietary supplement ingredient is capped at one or two times the RDA, regardless of its scientifically agreed upon true upper limits.

FDA Limits

FDA (U.S. Food and Drug Administration) is not immune to this error either. The agency’s education materials for food labeling describe “Daily Values” (DV) for food macro-ingredients and supplement RDAs as the recommended amounts of nutrients to consume or not to exceed each day. And the phrase “not to exceed” to my thinking would be the same as the upper limit (UL). So, for foods and food-based macro-constituents like salt, sugar and trans-fat, the DV on a food’s Nutrition Facts box is, in reality, the UL. However, for nutrients listed on a dietary supplement’s Supplement Facts box, the DV is inconsistently magnitudes below the true scientifically agreed upon upper limit. There is no information on a “not to exceed” level for dietary supplements and their ingredients, implying that the DV is the “not to exceed” level in the eyes of the FDA. A supplement ingredient labeled at 300 percent of DV can appear excessive and dangerous when it is most certainly not.

This confusion is evidenced in a recently issued “checklist” by the U.S. Department of Defense (DOD) to help service members and their dependents navigate the dietary supplement aisles in their PXs and on-line. As part of the DOD “Operation Supplement Safety,” the department offers a seven-question scorecard requiring either “Yes” or “No” answers to pinpoint problematic supplements, but its lack of objectivity has the potential to discourage the use of safe and beneficial supplements. For example, one of the seven questions asks, “Are all the percent Daily Values ( percent DV) on the Supplement Facts label less than 200 percent?” If any of the percent DVs are greater than twice the RDA—including for remarkably safe vitamins like C, or B12—the answer must be “No,” so this response contributes to a negative outcome which then identifies the product as a stigmatized DOD-unacceptable supplement.

So how do we change the paradigm toward proper demarcation between safe and unsafe levels and re-establish a baseline and sensible tolerance of risk?

We could start with more government attention to modernizing Dietary Reference Intakes (DRIs) from which RDAs are developed. The majority of the US DRIs developed under the auspices of the Institute of Medicine (now the National Academy of Medicine, NAM) occurred decades ago. We need NAM to promptly consider the ensuing new scientific data and give the public DRIs and RDAs that optimize health, not just prevent full-blown nutrition diseases. NAM should update the science behind existing DRIs, which will generate higher levels than previously issued, and consider other nutrients for inclusion that we didn’t know were essential even a few years ago (e.g., omega-3 fatty acids, lutein/zeaxanthin, vitamin K2, choline).

In September, CRN recommended to the White House Conference on Hunger, Nutrition, and Health to fast-track this research review as a public health mandate. CRN’s recommendations included that the Administration should: (1) ensure adequate resources are allocated to regularly update Dietary Reference Intakes (DRI) and establish new DRIs for nutrients and bioactives as needed; and (2) develop initiatives to educate about the relationship between nutrition and better health as well as the role dietary supplements can play in filling nutrient gaps. One could dream that proposals such as these will fall on receptive nutrition policymakers.

One could also hope FDA will become more proactive in developing educated consumers by addressing knowledge gaps around RDIs versus Upper Safe Levels and acknowledge that, for most nutrients, there is a range of dosages between the two numbers that contribute to optimal nutrition. Notions that Upper Levels can be identified as a multiple of RDAs must be replaced with rigorous risk assessment. Health care practitioners, doctors, pharmacists, dieticians and anyone else in contact with consumers making dietary supplement decisions, need current and complete training on basic concepts such as DVs, RDAs, ULs, etc. And so do regulators charged with managing dietary supplement intakes; they need to focus on science and not lazy RDA-based limits.

In conclusion, there must be access to nutrition, from appropriate foods as well as nutritionally dense supplementation. Even more critically, there must be access to the information needed to grasp and put into practice proven nutritional opportunities. Nutrition science is moving away from RDAs that only prevent overt deficiency manifestations, like scurvy and pellagra, toward understanding truly optimized nutrition in the broader context of dietary patterns, and the complexity of dietary interactions. Optimal is greater than the sum of the merely sufficient. NIE

James C. Griffiths, PhD, is senior vice president of international and scientific affairs at the Council for Responsible Nutrition.

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