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U.S. Department of Health and Human Services

Animal & Veterinary

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Assessment of Risk: Food Additives

Alan Rulis, Ph.D.

DR. RULIS: All right. Thank you. Can I be heard in the back there Am I clear here. Okay. I am going to spend my time to give a broad overview of the safety standard that is used in the food additives area. My responsibility ---

(Audio missing due to technical malfunction.)

--- we are in the Center for Food Safety and Applied Nutrition.

(Slide.)

And the statute that governs --- all the way back to 1938 had an adulteration standard, which you can see up here, 402(A)(1). Food is adulterated if it contains any -- if it bears or contains any poisonous or deleterious substance which may render injurious to health.

But in the case of substances not an added substance, such food shall not be considered adulterated under this clause if the quantity of the substance in such food is not ordinarily rendered injurious to health. So that is the adulteration standard that had been in effect since 1938.

In 1958, Congress enacted the Food Additives Amendment to that statute. And on the bottom, you will see -- and we will raise it up just a little bit -- you will see a Section 402(A)(2)(c) says it is adulterated if it is or bears or contains any food additive which is unsafe within the meaning of 409. So that clause was added in 1958. Okay. Go ahead and change the slide.

(Slide.)

Now, the Act as we use it in the food additive area, in '58 and '58 amendments, defines food additive. It requires pre-market approval for new uses of food additives. It establishes the standard of review which we will talk about briefly. It establishes the standard of safety which is one of the topics that you are interested in this workshop. And it establishes formal rule-making procedures for effectuating our decisions. Okay, next.

(Slide.)

Just for your edification, there are some characteristics of food additive approvals that are unique, a little bit different from some of the other approval activities that FDA engages in. And I want to just focus on a few of this at this time. The first one is that approvals are safety-based only. There is no explicit balancing of risks and benefits. Okay Safety per se is the standard.

The kinds of substances that we review for safety in the food additive area are generally not very toxic in comparison to what you might think of industrial chemicals or possibly drugs that have distinct pharmacological effects on living systems. These effects that we study are generally subtle and chronic.

Food additives are consumed for a lifetime by all segments of the population. So the target population is everybody from infants to aged people. The statute requires that a food additive cannot be approved until a regulation is published in the Federal Register. So there is rule-making required by Section 409. It is formal rule-making and there is an opportunity for objections, hearings and court challenges.

And a Federal Register preamble is usually prepared laying out the rationale for FDA's approval or denial of a petition. Further, the regulations that are issued are generic. They are not licenses in the drug or devise sense. Anyone who is in compliance with the conditions of use laid out in a regulation may add that additive to food, although some additive approvals are protected by patent legislation or patent -- existence of a patent.

Careful consideration of these conditions of safe use is therefore required prior to any decision. And usually in our area, there has not been a lot of extensive pre-filing interaction, although I think we are moving more in that direction. This is in contrast to the drug approvals that the Agency gets. Okay.

(Slide.)

Now, the term, "food additive", is very broadly defined. It is 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.

And then there are exclusions. And of course, pesticide chemicals are excluded, animal drugs are excluded. But it is a broad definition when you are in the food area itself.

We exclude a huge category of substances, those that are generally recognized as safe. And that is a common-sense exclusion that Congress realized they had to put in there because otherwise if you make the food by mixing foods, by this definition, of butter and eggs and vegetable oil, it would be food additives. And, of course, they are not. Okay, next.

(Slide.)

Now, the statute talks about safety, but rather circuitously and in a not very helpful way. It says in effect that the food additives shall with respect to any particular use be deemed to be unsafe unless there is in effect a regulation prescribing the conditions under which the additive may be safely used. But it doesn't here define safely.

(Slide.)

And in the next overhead, you will see, again, it says that the Agency shall by order establish a regulation prescribing the conditions under which such additive may be safely used and the reasons for such action. But again, no definition of safely. Okay.

(Slide.)

Just for your edification, in the process that goes on in the food additive area, petitioners responsible for establishing the safety of the requested use, the burden is on the petitioner. This is a pre-market approval system. FDA is responsible for conducting a full and fair evaluation of the data and issuing a regulation if we believe that the use is, in fact, safe. We do not consider the benefits of the use of the additive.

(Slide.)

The standard of review is a fair evaluation of the data. That is a legal standard, fair evaluation of the data. There is some legislative history behind that. Next overhead.

(Slide.)

References a House report back in 1958. "The Committee feels that the Secretary's findings of fact and order should not be based on isolated evidence in the record which evidence in and of itself may be considered substantial without taking account of the contradictory evidence of equal or even greater substance." In other words, the whole record has to be looked at.

(Slide.)

Again, the statute, "No such regulation shall issue if a fair evaluation before the Secretary fails to establish that the proposed use of the additive under the conditions to be specified will be safe." Again, no definition of safety here.

And the last part of that long version that I have up there is, in fact, a food additive part, the food additive version of the Delaney Clause which says that a food additive cannot be a carcinogen. Okay.

(Slide.)

The help on the safety definition came from Congress in the legislative history of the Act. And so here we see that safety finally is defined by Congress for us in the legislative history. "Safety requires proof of a reasonable certainty that no harm will result from the proposed use of an additive."

Reasonable certainty of no harm thankfully was what Congress gave us as a handle to help us deal with this definition of safety. And it has been -- I think some folks have felt it to be not that helpful. Actually, it turns out I think with the tradition of 40 years of experience in this area and with a lot of thought, the reasonable certainty of no hard standard has become I think a useful tool.

Congress went on in their legislative history to the '58 Act and said that in addition to saying that safety is reasonable certainty of no harm, that the standard does not and cannot require proof beyond any possible doubt that no harm will result under any conceivable circumstance.

So this is an admission, in fact, that science cannot prove things with absolute certainty. Certainly, you cannot prove, you know, a lack of any risk with absolute certainty. So reasonable certainty is what you have to work with. And it is, in fact, a no harm standard.

So what you are after is no harm, but you know that you can't get there except by reasonable certainty. And that means there will be some uncertainty. There will be some residual uncertainty in the decisions. Next.

(Slide.)

So the standard of safety is that the petitioner has the burden to demonstrate a reasonable certainty of no harm from the intended use. And one of the ways we describe this is to say that the -- this requires that the FDA assess whether it has received adequately documented answers to appropriate questions of probative value. Okay, adequately documented answers to appropriate questions of probative value. Okay.

Now, to help tease out this reasonable certainty of no harm definition, we have tried to put a few points up here about what we think it is not. What it is not is it is not an academic inquiry. We are not after the answer to every conceivable question.

It is not a search for complete knowledge. It is not intended to assure, nor is it possible to ensure safety with absolute certainty. In other words, reasonable certainty of no harm is the goal. And what we are not after is certainty of no theoretical possibility of harm. That is sometimes what people think it is, but that is not the goal. It does not weigh risks and benefits. And it is not intended to enforce or limit consumer choices among safe foods. It is not an ethical standard. It is not a value standard about what foods people should select to eat. Okay.

(Slide.)

What it is -- what it does do, in fact, is ensure safety. It is a consensus decision among our reviewers made under uncertainty. And that provides a fair evaluation of all the data of record. Remember the standard of review.

In the end, it has to protect public health. It is made in the absence of complete knowledge. We admit up front that there will be residual uncertainty. It will withstand scientific, procedural and legal challenge from all sides. And there will be residual uncertainty, but we try to keep that residual uncertainty not out of line with what has been previously tolerated in the context of all previous similar safety decisions.

So the idea here is that once you have developed an institutional framework and a base of institutional knowledge, you can gage your decisions on whether or not the residual uncertainty is out of line with the decisions you have made in the past. And this is very helpful, although in new areas this can be perplexing because we don't always know all the questions that have to be asked and we are not always sure that the answers purport with the standard of safety. And so in some cases in the new areas, we have to feel our way.

(Slide.)

My last slide is along those lines just to point out that as we move from the trivial situations of tiny exposures to, let's say, even packaging materials. In the upper left, we have low exposure. And at the lower right, we have high exposure. Think of this little road way, sometimes people refer to it as the yellow brick road -- this little road way as a spectrum upon which food additives are laid out from low exposure to high exposure.

The low exposure, we have maybe packaging materials that migrate into foods in minuscule quantities, parts per billion or less. And in the lower right in the large part of the road way, you will see whole foods, additives that are added in large quantities, macro-additives.

Of course, we don't regulate whole foods as food additives. But there are macro-additives that are added to food and can be regulated that way.

And in the traditional low exposure part of that spectrum, we apply what we call a toxicology-based review. It is a classical toxicological approach that basically uses animal feeding studies, assesses the lowest -- assesses the most sensitive, longest duration study to determine what is the dose, what is the highest no-effect level. In other words, what is the dose that is known not to cause an adverse effect and what is the highest value of that dose in the animal species of the longest duration, most sensitive study.

And that highest no-effect level then is reduced by an uncertainty factor. Typically, it is a factor of 100 that is really two factors of ten that have to do with the variation among humans and the translation of the data from animals to humans. And what you arrive at is an acceptable daily intake, ADI which many of you are familiar with.

That ADI is compared with the likely exposure. We are charged by the statute to determine the probable exposure to humans in the course of our safety evaluation. The probable exposure is sometimes called the estimated daily intake, or the EDI.

The ADI and the EDI are compared. And when the estimated daily intake is determined not to exceed the ADI, the acceptable daily intake, then we have determined as a matter of science and as a matter of law in this case that we are in compliance with -- the petitioner has met the standard of reasonable certainty of no harm. So that is the classical picture.

Now, when we move into the macro-ingredients where there are lots of other kinds of questions than just simply classical toxicological end points, the picture gets a little more complicated. And in the newer types of additives that we have had to deal with that push more in the direction of macro-ingredients or functional foods, we are also considering nutrition-related questions such as vitamin depletion or gastrointestinal effects.

And Olestra is a good example of an additive that we reviewed that is also -- was subjected to toxicological review in a classical sense, but had, as well, a nutritional component to its review. Nevertheless, the safety standard was the same reasonable certainty of no harm.

And the decision was made in that light and was described. And all decisions on that end of the spectrum are described in the same way in the Federal Register. Here is the standard; how did we get there, just the logical series of steps that leads you to the conclusion that you have met reasonable certainty of no harm.

So this was just a quick overview of the statutory framework, the standard of use in the food additive area; some glimpse at how it is evolving to take into account new kinds of additives that we have to deal with. And I hope it is helpful to your workshop. And I would be happy to take any questions that you have.

(Applause.)

MS. : I wanted to know what the responsibility of CFSAN is after a food additive has been approved to monitor whether its use is coming up as anticipated And also, what are the regulations that they are required to go through if they want to withdraw a food additive

DR. RULIS: Right. Okay. Well, safety is really a function of time. It is not static. So once something is approved, it is not -- it is on the books. And if nothing else happens, it is on the books forever. But we know that safety is a function of time.

So new toxicological information could come up. The exposure could change. And so as a result of that, we monitor the use of food additives over time. We keep track of their exposures in the population. We monitor literature to determine if anyone has done any studies to raise questions that were not even anticipated when it was approved.

If -- and in particular for the macro-ingredients where we are into new areas of safety evaluation, we will often work with the companies to determine whether they can and will be able to do post-market surveillance and will monitor the use of the additive in the public in a very conscious and explicit way. So there is monitoring. There is kind of assessment of the safety over time of all additives.

If an additive is determined to be unsafe at some point in time, then there is a procedure for getting it off the market. Anybody can file a petition that says here is the safety data. This additive is clearly unsafe. The Agency should pull it off the market. We get petitions like that.

It has to meet all the standards, of course. And you have -- the scientific basis for that decision has to be solid. But we would entertain a petition for that. And there is a regulatory and legal process then for removing an additive. We have done it. It doesn't happen very often, but it has happened.

DR. STERNER: Yes, our next speaker to address the assessment of risk with regard to drug residues is Dr. Kevin Greenlees. He received his doctorate in cardiopulmonary physiology from Colorado State University in 1983. He joined the FDA Center for Veterinary Medicine in 1989 and has been involved in the review of new animal drugs ever since. He is a diplomat at the American Board of Toxicology and a member of the toxicology team in the Division of Human Food Safety. Kevin.