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,3
* Nutrition Department, Pharmacy School, Paris 5 University and Biochem Lab, Hotel-Dieu Hospital, Paris, France and Laboratory of Human Nutrition, Massachusetts Institute of Technology, Cambridge, MA 02139
2 To whom correspondence should be addressed. E-mail: luc.cynober{at}htd.ap-hop-paris.fr.
Fürst: This discussion session is devoted to the major question: what should we do about variability in response among individuals and groups? This was the question proposed by the organizer. Personally, I am also very interested in how we consider this question in the clinical setting. The major question then is whether the variability is a disease-related problem or not. For instance, it was shown that high arginine containing immune-enhancing diets increased mortality and complications. The immediate consequence was that one of the companies withdrew a preparation with high-arginine content intended to treat critically ill patients. I would like now to open the discussion.
Young: But in attempting ultimately to establish a so-called upper limit, does one set it at a level that the most sensitive individual in that population has responded to by way of an adverse effect? Or are we setting up upper limits as sort of population recommendations rather than recommendations that are related to an individual?
Caldwell: If you take the normal variability in that relation, you can understand that. But when you get down to the business that you were talking about, we are considering the most sensitive person in the population. And let‘s face it, when you are starting to look at incidences like the ones we are talking about here, 1 in 10,000, 1 in 50,000, whatever it may be, it is actually very difficult to show a clear association between a specific intervention and the effect that you have observed. Because quite clearly, once that happens, you want to see it again, to provide evidence. And if you’re going to wait such a long time to see another one, it becomes very difficult. You‘re also finishing up on that basis from a food viewpoint. In terms of trying to regulate these things as if they were drugs, when they are not drugs, in the drug field, there has been a great deal of concern about what is called the "acceptability of foreign clinical data," that is, extrapolating from one population with its own ethnic and genetic makeup, whatever that may be, into another population. I think we had a fine example earlier in terms of the citrine issue that was raised, which may be something that is important in one population but that has no significance somewhere else. You know, that represents another level of complexity.
Martin: I want to comment from the point of view of a nonspecialist. I am surprised at the difference in the management of problems related to two different types of acids, namely amino acids and fatty acids. For example, for fatty acids, the long-term consequences, in terms of cancer, cardiovascular disease, immunology, allergy, and so on, of fatty acid intakes have clearly been taken into account in setting dietary reference intakes. It is always a surprise for me to see that for proteins and amino acids, there is a very limited focus on that type of question. As reported by Joe Millward this morning in his very interesting presentation, to maintain the lean body mass is very important, of course, for mobility and mortality; but for me, it is, in some way, like zootechnology in animal feeding, to obtain higher and higher productivity of meat for butcher shops! And I wonder why there is no consideration of long-term effects on various aspects related to health, as there is for many other nutrients. Consequently, I have something that is still probably an open question: Is it necessary for an official food agency (such as the French Food Safety Agency) to improve food composition tables for amino acids so that the epidemiologists can work with more precise data to possibly manage multivariate tools as indicated by William Rand. Perhaps if we have better tables and better availability of statistical tools, we shall be able, starting from epidemiological data, to build a better link between intakes and long-term health consequences. If somebody has ideas or concerns about these questions, I am very interested.
Bier: I think some of the data sets that we used for some of the long-term primary or secondary intervention trials presumably have protein, but they do have other information that some could look at in that sense. I guess just to comment on amino acids, I am not sure I want to give epidemiologists any more variables to manipulate.
Pencharz: I just wanted to come back to what Dr. Caldwell was saying in terms of low prevalence of adverse effects. I would like to start from the level of the health food store in North America, where if you go into these health food stores, which are basically drug stores selling various amino acids individually or as mixtures, they are recommending to their customers that they take large amounts of amino acids. Apart from John Fernstrom's discussion of the toxic effects of too much phenylalanine or too much in the way of branched-chain amino acids, in the case of maple syrup urine disease, we have very little information about taking excess amounts of amino acids. For example, we do not know what the genetic variability is. I would not be surprised if we found there are some people who could tolerate less, and some people who could tolerate more of amino acids. From the point of view of regulators, whether it is health or functional foods, we really do need to start to understand what are the toxic levels of intake. I expect we will find that there are more people involved and at risk than we think at the moment.
Renwick: Another thing John Caldwell said was that perhaps by now we know most of the major single-gene defects. But probably what we do not know is the potential human variability, as the dose is increased outside the normal intake range. The variability of enzyme activities expressed as Vmax values may mean that there is more variability as the dose is increased. At the moment we know the all or none type of genetic effects of toxicity at very low levels, but there may be more genetic variability as we increase the dose.
Caldwell: That is why I was trying to stress the issue of the heterozygotes, but as well, of course, the complexities of the biochemical pathways. I think we have already found most of the major single-gene defects.
Young: Ambroise Martin was concerned with what Andy Renwick said. You had your two lines of areas of investigation. Was it not necessary to include concerns for genetics also in the case of the information of acute studies? You ruled out the need to carry out chronic studies. Well, there are acute problems, with respect to amino acids; somebody at the Cleveland clinic was unfortunately overdosed with an acute dose of methionine and subsequently died. That is the problem of an acute nature. Naomi was talking about chronic consequences of sulfur amino acids intakes. Why have you ruled out those particular aspects in evaluation?
Renwick: Well, the genetic effects are ruled out in the standard genetic toxicology testing. It is quite possible we may get effects on mediating gene expression but they would be more subtle, and I think the standard package for genetic toxicity testing for amino acids should not be that long. As far as acute effects are concerned, we do need acute toxicity data for workers handling the material. I was thinking more in relation to establishing safe upper levels. Similarly, you do need some acute single-dose data for designing clinical trials. Normally these are based on animal data, if you think of drug analogies, and then you begin studying low doses in humans. There can be a need for acute toxicity data. But what I was trying to point out there was that such data are not going to give us the upper level or the risk assessment for the general population, unless of course, the material is taken in short periods of time. Then the safe intake would be the equivalent of something like the acute reference dose, where you do need to come up with both the long-term safety data and also take into account higher doses for short periods. But I did say you have to match the exposure characteristics of humans to data from safety testing and vice versa.
Garlick: But in terms of amino acid intake, the people who are taking an amino acid supplement could quite easily go into a shop, buy a bottle, and theoretically swallow the whole bottle. They may be taking 10 grams, and they may suddenly take quite a large amount. And the testing has to take into account the huge range of variability of what people might do.
Renwick: For medicines the dosage will be clearly related to the patient. For the person taking a supplement at extremely high intakes, they should think they are taking a medicine. You could have a label on the high-dose preparation: "Do not consume more than three doses a day." If it is a food supplement, they may be taking it in the absence of food, in which case, it would be absorbed very quickly. Or the supplement could be taken with large amounts of water or food. So there are a host of different things that have to be taken into account, unfortunately.
Gibney: I think Peter Garlick has already made a point I was going to make, in a sense. I want to emphasize that I really think it is going to be so difficult to gather data that you will want to seriously think about alternative approaches to traditional toxicology. The difficulty is you have every combination of amino acids on sale at those shops. Not only do they differ in what amino acids are present, but they also differ in doses and brands. Now in a single study or a set of studies you might have phenylalanine, but how much work have you done with phenylalanine? Plus tryptophan? Minus methionine? Plus something else? Your toxicology is out the window, because you do not have the data. You are going to have to find a way around thinking through the toxicology, exactly for that reason. Also as Vernon Young pointed out, you are also going to have big differences between chronic intake and acute intake. And again, looking at the toxicology data you have at the moment on acute intake and chronic intake, I definitely recommend alternative thinking perhaps.
Renwick: Can I just respond to that? First you have to have the hazard identification for the single amino acid. Then you can look at the combinations. But you have got to know the toxicity.
Millward: What are the real issues, which are most important in this area, and where do we put our effort? We could put a lot of effort into trying to develop models for toxicology to enable people to make informed choices about whether or not they should go and consume large amounts of amino acids. But should we not be putting much more effort into trying to identify the validity of claims behind the reasons why people actually go and do that? Once we ask these questions in the clinical nutrition area, we have examples of really trying to find evidence whereby amino acids may save patients' lives. And if you think about glutamine and all the work that is being done on the potential benefits of glutamine in clinical nutrition, the fact is that today, at many major teaching hospitals in the UK, the decision has been made that there still is not enough data to warrant the expense of using total parenteral nutrition with glutamine. Because of the extra cost of doing it, the managers in these hospitals, who are often very informed, argue that there still is not enough firm evidence to demonstrate that it is going to be cost effective. The issue of why we are doing it at all, and what benefit it will have to people, seems to me the area where we still need to put in an enormous amount of investment. Are the branched-chain amino acids in practice going to improve muscle wasting in the elderly? That is the sort of question where we really need our effort, rather than what is the variability in the toxic dose to phenylalanine.
Young: Joe (Millward), you are right in a scientific context, but people are still going to consume branched-chain amino acids irrespective of whether or not there are really good data that actually define efficacy, and the mechanism that underlies it. They are not going to wait around until you provide the nice scientific answer. In that sense, there is a need to know the consequence of higher than normal intakes, such that consumers can be advised as to whether or not there is a problem; and if there is, at what level of intake it occurs.
Millward: That moves us into the area of individual choice in doing things, which may or may not be safe. How much effort should we put into researching what is the safe level of a recreational drug like ecstasy, for example?
Fukagawa: I just wanted to comment with respect to thinking out of the box and not using toxic levels of amino acids as an outcome. Perhaps we should be looking at other surrogate markers of functional consequences of either excess intake or inadequate intake. For example, one can look at endothelial function or vaso-active blood flow measures, with respect to the toxic level. I'm sure a lot of athletes, if they were told that consumption of excess amino acids, beyond a certain amount, would affect blood flow to their muscles, would certainly consider whether or not they would take them. That is my thought with respect to using surrogate markers instead of necessarily looking for upper levels of toxicity.
Bier: I think the studies we have done on growth hormone and testosterone and other things administered to athletes basically showed they will take anything that gives them a half-percent edge or a one-second advantage. We have no scientific method that would allow us to determine the difference between speeds of 4.02 min and 4.03 min, and they are going to believe it makes a difference, irrespective of our negative data.
Fernstrom: Vernon (Young), I agree with you completely. As I understand it, the issue here is safety, not efficacy; efficacy is something for others to worry about. Here, it is specifically a safety issue. So I think that is fair enough. There are a lot of government "terms" that have popped up during this discussion. One is "safe at any level," and that label applies to a natural component of food. However, listening to the DRI for the past few years, it‘s clear that natural components of foods are not safe at any level of intake. So there is a basic concept that seems in need of revision: to be in the food supply, a component has to be safe at any level of intake. This now appears to be untrue for certain "macronutrients", such as "fat", for example, which can contain saturated fats and trans-fatty acids.
In terms of safety assessment, I like Dr. Renwick's comments, because it seems that those worrying about upper levels are thinking in terms of applying a model involving hazard identification, etc. If that is the case, focusing on the scaling factors and trying to make them as accurate as possible is one extremely productive way to go. I hope you will pursue that. Finally, the reason I raised the phenylalanine data as a possibility for examination is that they exist and are fairly good; thus, using them, one can begin tests immediately of the appropriateness of extant toxicity models and scaling/adjustment factors using an existing, published database. It seems that your (Dr. Renwick) model lends itself to certain databases already, with which you could begin to test this coefficient of variation idea. I hope you will, because I suspect it is one productive way to go.
Baker: Maybe our Ajinomoto colleagues can help us here; I cannot help but wonder if there are data in corporate files that could be useful to us in terms of assessing risk. For example, we are talking about phenylalanine, and it is my understanding that if a corporation markets an amino acid product, and plans efficacy claims, they are obligated to do safety studies. So Searle must have safety data and toxicity data on aspartic acid and phenylalanine, although it has probably never been published. Has anybody looked for that? And what about Ajinomoto? They must know something about glycine and glutamate, because of their use in flavor compounds. Surely, toxicity work has been done on these amino acids. And there is the corporation that has a patent (but never pursued it) on the use of lysine to treat herpes-induced cold sores. Has anybody looked for these data to see if safety/toxicity studies have been done?
Baracos: I want to cast a vote for something, rather more meat and potatoes, and I think about this a lot because I sit right next door to it at the university. It is Paul Pencharz and Ron Ball going through baby piglets and infants amino acid by amino acid by amino acid. By the end of the day, their methodologies and their more recently adapted, minimally invasive approaches, will have spit out a rather complete characterization of the amino acid requirements of baby piglets and of a very vulnerable patient population, preterm and low birth–weight infants. I wish there was an awful lot more of that research going on for the kind of patient populations that Peter Fürst feels very strongly about. In fact we have absolutely no frame of reference. We do not know what is first limiting, second limiting, last limiting, or nth limiting. We have no information!
Bier: In closing, I would like to thank you very much.
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FOOTNOTES |
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3 The 3rd Amino Acid Assessment Workshop is dedicated to Vernon R. Young who recently passed away.
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