The dose makes the poison, who defines poison?

Written by: Michaela Oldfield

Primary Source:  Institute of Food Laws and Regulations Blog

One of the many highlights of IFT16 was an all-star panel (organized by yours truly) on toxicology research, risk communication, and the Generally Recognized as Safe standard.

Our first speaker was Dr. Michael Holsapple, the founding director of the MSU Center for Research in Ingredient Safety (CRIS). Dr. Holsapple is a toxicologist who is establishing CRIS to fill in the gaps in addressing food safety. There are three major components of food safety: allergens, microbial risk and toxicology. While there are university research centers that address allergens and microbial risk, CRIS is the first center focused on determining the toxicological effects of ingredients. Because its work is not limited to food, the center is planning to conduct research on all consumer product ingredients.

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Dr. Michael Holsapple, founder of the Center for Research in Ingredient Safety at Michigan State University.

The quote from Dr. Holsapple that sticks with me is “the dose makes the poison,” originally coined by the Swiss German physician and alchemist Paracelsus – also known as the founder of toxicology. It struck me because while perhaps true, the issue I see the food industry grappling with is who defines when a dose becomes a poison? Industry, regulators or consumers? Legally it’s the FDA, but how it works in practice is complicated.

Our second speaker was Charlie Arnot, of www.foodintegrity.org, speaking about how to communicate risk science to consumers and regulators. His talk was important because even if industry and regulators have determined an ingredient is safe, consumers may not buy products if they don’t trust or believe “the science.

So how can industry communicate science to consumers so that they understand why a particular dose is not considered poisonous.

First is to understand why consumers no longer trust the food industry or regulators. Mr. Arnot noted there have been significant social shifts in the last 45 years that have eroded trust in institutions. Most notably for me were the emergence of television (and now social media) that are changing how consumers obtain and process information, and major violations of trust by institutions and leading public figures such as Clinton, Nixon, Lehman Brothers and quite a few others.

At the same time, the food industry has gone through massive consolidation, integration and industrialization, so that it is now also viewed as an institution that is suspect.

Second is to understand how trust is built and communicated in today’s society. The top variable influencing whether a consumer trusts a message is whether they perceive shared values with the messenger. But the believability also depends on other elements of the message, such as the openness, transparency, and honesty of the message being communicated, as well as “outrage factors” such as familiarity, consumer’s control of the risk, and their sense of fairness at being exposed to it.

There are quite a few other factors I’m not going to identify because I want to discuss GRAS and how the legal complexity of food ingredients and food additives regulations confounds efforts by industry and scientists to build trust with consumers.

According to the Food and Drug Administration’s brochure on food additives:

“In its broadest sense, a food additive is any substance added to food. Legally, the term refers to “any substance the intended use of which results or may reasonably be expected to result – directly or indirectly – in its becoming a component or otherwise affecting the characteristics of any food.” This definition includes any substance used in the production, processing, treatment, packaging, transportation or storage of food. The purpose of the legal definition, however, is to impose a premarket approval requirement.”

If a substance is a food additive, it must go through pre-market approval before it can be used in food. 21 USC 348(a)(2). However, the definition of food additives, at 21 USC 321(s), is complex because it’s also designed to remove commonly used substances, such as salt, from having to go through pre-market approval. So in full, the definition reads:

(s)The term “food additive” means any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for any such use), if such substance is not generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use; except that such term does not include:

(1) a pesticide chemical residue in or on a raw agricultural commodity or processed food; or

(2) a pesticide chemical; or

(3) a color additive; or

(4) any substance used in accordance with a sanction or approval granted prior to September 6, 1958, pursuant to this chapter, the Poultry Products Inspection Act [21 U.S.C. 451 et seq.] or the Meat Inspection Act of March 4, 1907, as amended and extended [21 U.S.C. 601 et seq.];

(5) a new animal drug; or

(6) an ingredient described in paragraph (ff) in, or intended for use in, a dietary supplement.

So the substances in (1)-(6) are all excluded from the definition.

What is important for this discussion is the Generally Recognized as Safe, or GRAS, provision of the sentence. A substance is a food additive if it is not GRAS. That has to go through a clear pre-market approval process, 21 C.F.R. Part 170, which in itself is complicated enough.

But what is GRAS, and what does that really mean for food ingredients? For a substance to be GRAS, and therefore not a food additive, it must be “generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures …to be safe under the conditions of its intended use.”

The FDA’s regulations on GRAS determination standards are in 21 C.F.R. §§ 170.30 and 170.35. I’m not going to go into them, because they’re too complicated to cover in a blog. Instead, I will cover the comments that Prof. Neal Fortin offered on GRAS, because these are important to my discussion of who defines the poison threshold in practice.

  1. Loss of GRAS status is self-implementing

The provision in the Food Drug and Cosmetic Act is self-executing, so it doesn’t require the FDA to approve a substance as GRAS.  If the substance is generally recognized by experts as safe for its intended use, the substance is exempt from the additive approval process.

There are two ways a substance can be considered ‘generally recognized as safe’ – through a long history of use in food prior to 1958, or based on scientific data. Either way, the assessment must be based on the expertise of scientists, but scientists can base their assessments on general use prior to 1958; after 1958 they must base their assessment on scientific evidence. The regulations establish what evidence is needed to establish this. While companies do not have to go through a pre-approval, in choosing to use a substance, they must do their own self-assessment of whether a substance is GRAS according to those regulations. They may choose to notify the FDA, or they may keep their assessment on record in the company.

So while this allows for an easier process for companies to use a substance, it also means that loss of GRAS status is also self-implementing. As in, when new scientific evidence emerges that contradicts or calls into question whether experts generally recognize a substance is safe for its intended use, then it no longer has GRAS status.

  1. There is no such thing as a GRAS substance 

There is no substance that is universally GRAS. GRAS is only for the product’s intended use. The case exemplifying this is United States v. An Article of Food, Coco Rico, Inc., 752 F.2d 11 (1985). In this case, the company took potassium nitrate, which is approved for use in curing meat, and put it in a soda concentrate. The company could offer no affirmative evidence that  potassium nitrate is generally recognized among experts as safe for use in soda; only assertions that they didn’t know of any evidence that it was unsafe. Consequently, it was not exempt from the food additive definition, so it was considered a food additive, which was unsafe because it had not gone through the pre-approval process, and therefore the concentrate was adulterated.

So basically, the GRAS status of a substance needs to be determined for every intended use.

  1. Long history of use never creates GRAS status 

On a related note, a long history of use never creates GRAS status because it’s the intended use that matters. So, for instance, even though caffeine has had long use in coffee and sodas, and had a GRAS status for those uses, when it’s put to a different use – say, caffeinating alcoholic beverages – it is not GRAS until there is general recognition among experts that it is safe for its intended use. Since this is a new use, that is different from what was done prior to 1958, that GRAS determination must be based on scientific studies, not just the fact that caffeine was commonly used in other products prior to 1958.

  1. GRAS proof of safety standard is more stringent than the food additive standard

Finally, the standard of “generally recognized” is actually more stringent than the food additive standard which requires consensus. This means that studies questioning the safety of a produce – even if they don’t prove it is unsafe – can destroy a substance’s GRAS status for a particular use.

So practically what does this all mean for toxicology research, science communication, the food industry, and the dose makes the poison?

There are legally complex standards for a substance to be GRAS that rely on complex scientific evidence. The knowledge of the law and science often resides with experts who are parts of institutions – government and the food industry – that consumers no longer feel they can trust, and understanding these complexities requires expertise that is largely beyond the common consumer.

It is no wonder the food industry has a public relations problem. Even though there are defined standards for determining when a dose becomes poisonous, it is difficult for consumers to understand them or how they operate.

Hence, it looks like an intrigue among a number of distrusted institutions to make a buck at the consumer’s expense.

The dose may make the poison, but the consumer with their purchasing dollar can decide whether he or she is willing to accept a certain dose as poisonous or not. And the law and science do not make it easy to communicate to consumers why one dose should be acceptable and another should not.

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Michaela Oldfield
My name is Michaela Oldfield, and I am the Global Food Law research fellow with the Michigan State University Institute for Food Laws and Regulations and the Global Food Law Program. I have a J.D. from the University of Michigan and a Ph.D. from Michigan State in the Department of Community, Agriculture, Recreation and Resource Studies. My dissertation research was on the Food Safety Modernization Act, but my interests cover a range of regulatory issues from field to fork to waste. I like spending my time thinking about how to design, adopt and implement regulations that balance the diversity of interests affected by food and agriculture policy (without being captured too much by special interests) and are flexible and dynamic to the constantly changing world around us (but without being dysfunctionally unpredictable). Luckily, that is much of what I will be doing here! Being the Global Food Law Research Fellow means I get to interact with food professionals, lawyers, academics and government officials to identify, understand and help educate people on the numerous ways food law and policy is evolving and impacting globalized agri-food systems.