“Let food be thy medicine and medicine be thy food” — Hippocrates of Cos (ca.460 BC – ca. 370 BC)
The Drug-Like Properties of Foods
Many foods have drug-like properties. For example, foods with vitamin C (such as citrus fruit) can cure scurvy, the dreaded disease of 17th Century sailors; likewise, seafood can cure (thyroid) goiters because seafood represents a unique source of iodine; most obviously, food can cure malnutrition and starvation and protein-containing foods are a remedy for kwashiorkor (a protein deficiency disease). Many foods or their constituents have very drug-like properties, such as the anthocyanins in cranberries, which help maintain a healthy urinary tract, essentially by creating an unfavorable environment for urinary tract pathogens, much like fermentable fiber found in peas, beans and bran create an unfavorable colonic environment for pathogens such as Clostridium difficile, a notable killer in hospices. The primary flavoring agent in licorice is glycyrrhizinic acid, which also has corticosteroid activity and can be toxic at high use levels. Omega-3 fatty acids from marine plants and fish are important in preventing cardiovascular disease, gossypol from raw cotton seed oil can act as a male contraceptive (in addition to its anti-malarial properties), but refined cotton seed oil was used to make Crisco® shortening. Theophylline, found in chocolate, is used as a bronchodilator for asthmatics.
How does FDA sort out which of these substances are foods, drugs or supplements and does the status of “natural” have anything to do with FDA’s classification of these substances? In this article, the author will describe FDA’s regulatory framework by classifying the substance according to its intended use (the label statement), how the use then defines the regulatory category and ultimately, the safety standard (Figure 1).
Definitions According to Food Additive Amendment
When the Food Additive Amendment (FAA) became law in 1958, the first task was to define the categories to be regulated in §201 (i.e., drugs, foods, food ingredients) and in 1994 with the passage of the Dietary Supplement Health and Education Act, defining dietary supplements in §201(ff). The definition for drugs is a functionality definition and for our purposes, in §201(g)(1) “The term ‘drug’ means…(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals”. Therefore, any mention of the five words above i.e., “diagnosis, cure, mitigation, treatment or prevention” and identification of a disease, makes the substance a drug. The carve-out of “other than food” was necessary because foods can cure, prevent or mitigate diseases as described in the first paragraph. There is also a provision in this definition for “a food or dietary supplement for which a claim … is made … is not a drug solely because the label or the labeling contains such a claim,” although the claim could not cite the five words + disease name.
Food is defined largely in terms of its functionality as well: “(1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article”.1 The first part of the explanation refers to processed food, such as angel food cake or processed cheese and, unprocessed food such as meat, eggs and produce. Chewing gum was the basis of an argument as to whether it was swallowed or expectorated; the swallower contingent won out, so chewing gum was included in the food definition. Although having much the same function as chewing gum, breath mints were not included in the food definition, because they are considered a cosmetic.
The third part of the food definition – “articles used as components of any such article” – refers to any ingredients going into the articles in the first part of the definition i.e., “articles used for food or drink…” In the statute (§201(s)), these substances referred to as becoming a component or otherwise affecting the characteristics of food. Also, in addition to a label that indicates the substance is a food, a “Nutrition Facts” panel was required by the Nutrition Labeling and Education Act (NLEA) of 1990.
So what about the definition of a supplement? The definition of a supplement (§201(ff)) is both object specific and functionality-based. It is specific as it names vitamins, minerals, herbs or other botanicals, or a concentrate, metabolite, extract thereof, etc. as supplements, with a specific exclusion for tobacco. It is also a function-based definition because the phrase “a dietary substance for use by man to supplement the diet by increasing the total dietary intake” is included, meaning that the candidate substance must have been present in the diet historically and, that it cannot be represented as a conventional food or as the sole item of a meal, to discourage a diet consisting solely of supplements. Also, a dietary supplement label must include a “Supplement Facts” panel.
So where, if at all, does a requirement for “natural” fit into the above definitions? In only one – dietary supplements. That is, with a couple of exceptions, to be a dietary supplement a supplement must be (or have been) present in the human diet because a dietary supplement is used to “increase the total dietary intake” and therefore, if not having been present in (unprocessed) food, it cannot be a dietary supplement. Also, the substance must “remain” a natural; that is, a natural substance cannot be chemically altered (although a few exceptions are permitted).
Safety as a Relative Concept
The standard for safety is relative to the regulated product. For example, the safety of a drug is given in §201(p)(1) “…as safe and effective for use under the conditions prescribed, recommended or suggested in the labeling thereof…” Therefore, a drug is safe if it is being used safely…a benefit vs. risk standard; that is, the benefit derived from the use of the drug should exceed the risk of its use. Further, although the drug is approved by FDA for one or more specific uses, the physician is given considerable latitude and may prescribe an “off-label use” i.e., a use that has not been approved by FDA.
For foods, in FAA §201(u): “the term ‘safe’ [for food] … has reference to the health of man or animal.” This definition is expanded upon in the regulation (21 CFR §170.3(i)): Safe or safety means that there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use. There are three key parts in this CFR elaboration: (1) The rule talks about “competent scientists” which is further elaborated upon at the FDA website Draft Guidance for Industry: Best Practices for Convening a GRAS Panel;2 that is, a person must be competent, but not biased. (2) “Reasonable certainty” is the safety standard, because as the regulation (21 CFR §170.3(i)) notes: “It is impossible in the present state of scientific knowledge to establish with complete certainty the absolute harmlessness of the use of any substance.” (3) “Intended conditions of use” embodies the concept that it is the use of the substance (i.e., for a particular use, for use in one or more particular food categories and at a particular level of use), that is approved via a GRAS or food additive petition, not the substance itself for any food category, purpose or at any concentration. However, like drugs with a provision for “off label use”, food ingredients may be used for non-approved purposes, if the use is “safe and suitable”
Unlike drugs, there is no benefit versus risk for foods, all foods must be safe for the average person, although there are certain exceptions such as for allergens (e.g., soy, shellfish, eggs) which require warning labels under the Food Allergen Labeling And Consumer Protection Act of 2004 and the occasional substance for which a tolerance has been established, such as the sugar alcohols, polydextrose or gluten.
While food is defined in §201(f), for more or less anything that is treated as food, the safety standard for unprocessed food (e.g., meat, eggs, produce), is not identified until §402 (a)(1) wherein it is stated:
§402. A food shall be deemed to be adulterated: (a)(1) If it bears or contains any poisonous or deleterious substance which may render it injurious to health; but in case the substance is not an added substance such food shall not be considered adulterated under this clause if the quantity of such substance in such food does not ordinarily render it injurious to health.
And, or (a)(3) if it consists in whole or in part of any filthy, putrid, or decomposed substance, or if it is otherwise unfit for food…
Therefore, a food (processed or not) is adulterated if it bears or contains a substance that makes it injurious to health, unless the substance is not an added substance; that is, a food may contain a non-added (i.e., naturally present), deleterious (i.e., poisonous, toxic or carcinogenic) substance, so long as the conventional use of the food does not result in injury (otherwise, it would be unlikely to be called a “food”). In some instances, FDA has placed upper limits (called tolerances or action levels), wherein a food containing a toxic substance that is not an added substance and, might have been formed or incorporated into the food during growth and normal metabolic processes essential to the normal development of the organism, but not as the result of human actions. Therefore, in the absence of an added toxin, the food is considered safe, so long as it is not rotten, decomposed or unfit [to be consumed as] food.
In the broad view, foods themselves are presumed to be safe (subject to §402, above). An example would be a pea or carrot to be added to canned beef stew as an already GRAS ingredient for addition to the stew and not requiring a separate GRAS determination of a food additive petition. In regulatory parlance, there is a presumption of safety of food.
The safety standard for a dietary supplement in FAA §413(a) is that …the dietary supplement will reasonably be expected to be safe… based on the opinion of the submitter i.e., no requirement for demonstration of scientific expertise as for a GRAS determination, when submitting a New Dietary Ingredient Notification. The safety standard of reasonable expectation, although worded differently than the food ingredient standard of reasonable certainty is seen by FDA as a distinction without a difference; that is, a substance is either safe or it is not. The author agrees with the FDA binary standard of safe versus not safe, but believes the FDA fails to recognize the distinction between reasonable expectation and reasonable certainty as being analogous to the evidentiary standards of a “preponderance of evidence” versus “clear and convincing evidence”. That is, if the latter (clear and convincing) is equivalent to the food standard of reasonable certainty, then the dietary supplement standard should be equivalent to “preponderance of evidence”; therefore, the evidence of safety for reasonable expectation might not be as clear-cut and compelling as the reasonable certainty standard, but the reasonable expectation standard points persuasively to a positive outcome from exposure to the supplement and there is no evidence contraindicating a safe exposure. This level of evidence is greater than a simple lack of demonstrated adverse effect, but an affirmative declaration of safety whose supporting body of evidence is less than comprehensive (i.e., clear and convincing).
It has been said that FDA, as an agency, is primarily concerned with labeling and safety. As mentioned above, the intended use of the substance is stated on the label (e.g., therapeutic effect, nutritional effect). This intended use determines the regulatory category (e.g., drug, food or supplement), which in turn, determines the safety standard (see Figure 1).
Therefore, when considering a read-across-like illustration of the relationship of intended use, consequent regulatory category and the appropriate safety standard, the comparison appears as follows (Figure 2). The regulatory framework makes sense after all.
- Can a drug withdrawn from the market for commercial reasons (not attributable to adverse reactions) be used as a dietary supplement? In general no, even if the drug is of natural origin.
- Can a dietary supplement or a food ingredient be used as a drug? Yes, but not the reverse.
- Because the threshold for filing by FDA of a New Dietary Ingredient Notification is so high, is there another route? Possibly, as FDA has said that, in most cases, a GRAS ingredient can be sold as a dietary supplement. However, the safety of a substance as a result of the cumulative exposure as a food ingredient and a supplement must be demonstrated.
- §201(f) of the FFA
- Best Practices for Convening a Generally Recognized as Safe Panel: Draft Guidance for Industry; Availability