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Welcome
REGULATORY TOXICOLOGY AND PHARMACOLOGY ARTICLE NO.
23, S1–S2 (1996)
0014
Welcome GIO BATTA GORI The Health Policy Center, Bethesda, Maryland 20816 Received December 11, 1995
Good morning. I am President of the Society for International Regulatory Toxicology and Pharmacology which sponsored this meeting here with ILSI N.A. This is the last of three meetings on the safety evaluation of macronutrient substitutes, which followed a seminal paper by Joseph Borzelleca published some 2 years ago. The main reasons for interest in macronutrient substitutes is that we are contemplating a new category of substances that are not foods in the traditional sense, substances that are intended to provide the organoleptic, physiologic, psychologic, and chemical functions of food without the nutritive and especially without the caloric attributes of food. Even before addressing their safety, one may ask why macronutrient substitutes exist in the first place. Are they simply a clever invention of the market or have they a legitimate place in human nutrition? Indeed, what we do know is a lot about nutrition. There is ample evidence that nutrition offers by far the most important opportunities in prevention in public health. The reasons for this are relatively recent. Technological gains during the second half of the century have created conditions whereby for the first time in history millions can afford lifestyles of affluence with energy requirements much reduced compared with traditional conditions of the past. As part of this technological miracle, wholesome and inexpensive foods are now almost matter of fact available through a leisurely trip to the supermarket. These achievements have freed masses from the oppressive toil of subsistence. Eventually, these achievements will be recognized as major new incentives to civilization. Still, they have been sudden experiences, within one or two generations in a culture where historic worries of famine and starvation are still fresh. The inevitable consequences have been overeating, an increasing prevalence of obesity, and a variety of physical and mental health adversities. Most everyone is familiar with this scenario, but most are not familiar with the added relationship of nutrition and functional longevity. Evolution is likely to have promoted adaptations only in functions of reproductive success, but not beyond. Indeed, the anthropologic record indicates that humans can reach successful reproductive age on almost any
diet, but for millennia, the average life expectancies rarely exceeded 30 years. So what are the optimal nutritional requirements from infancy on if the modern goal is not only reproduction, but a vigorous adult life and functional longevity at age 75 and beyond? Could it still be reduced caloric intake, as animal experiments continue to imply? The overeating, obesity, longevity, and functionality challenge must reckon with much reduced muscular energy demands of modern humans. On the other hand, modern humans have inherited a set of digestive, metabolic, anatomic, and psychologic functions that are often inconsistent with these reduced demands, and, of course, they are constantly tempted by readily available, inexpensive food. The desirable somatic adaptations could not emerge in the foreseeable future. For the time being, it will be necessary to devise low-energy, fully nutrient and safe diets that may satisfy the filling, the transit times, and the clearance requirements of the human GI tract in its present evolutionary configuration, and, of course, food that will provide the necessary behavioral signals of cessation. Thus, enter what we call macronutrient substitutes, specially aimed at providing the necessary functions of traditional diets, while reducing the caloric loads that seem so much the cause of most chronic diseases. In a true sense, therefore, macronutrient substitutes cannot be seen as inventions of the market, but are justified by pressing public health motivations. The argument that reduced caloric intake should be achieved by individual dietary discipline sounds sanctimonious and would lead to frustration. Dietary behavior is also the result of millennia of evolutionary and cultural pressures. Its forcible modification has been shown to trigger psychogenic stress and somatic adversities. Now, what could qualify as macronutrient substitutes? In addition to the necessary attributes of taste and texture, they should be capable of displacing from a few to perhaps 20% or more of ingested calories, by providing no calories, no utilizable calories, or the sequestration of otherwise available calories. Much attention, practical and theoretical, has been focused on sugar substitutes, synthetic lipids, vegetables, and fruits with increased fractions of nondigestible fiber, S1
AID
RTP 0936
/
6e06$$$$$1
03-26-96 01:40:45
0273-2300/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
rtpa
AP: Reg Tox Pharm
S2
SAFETY/REGULATORY ASPECTS OF SUBSTITUTES
natural and synthetic carbohydrates, chitins, synthetic polymers, mineral composites, and other configurations. What new issues of safety and safety evaluation could these substances pose? For substances that could make up a significant fraction of the diet, LD50 doses would have to be very large and virtually impossible to determine. They will be substances of no overt, acute toxicity. Their potential adverse effects, if at all, could only be subtle and long term. Most likely, these potential effects would also be indirect, the result of secondary interferences. The substances may affect the availability and absorption of other nutrients, especially vitamins and minerals. They may interfere with the GI tract dynamics for mastication, digestion, peristalsis, intestinal flora, transit times, and so on. In general, it is reasonable to assume that no macronutrient substitute would be proposed that retains any overt toxicity in the classical sense. These substances can be expected to possibly generate only vanishing clues of potential chronic toxicity. Thus, from a regulatory and public health point of view, the normal challenge that macronutrient substitutes pose is to define what these clues might be and at what levels their possible signals should be of concern. These challenges need to be resolved by novel approaches to animal and clinical toxicology and to their interpretation and new standards of premarketing clinical trials and postmarketing surveillance. These are the questions addressed in more detail in the original paper by Joe Borzelleca, questions that eventually need to be resolved
AID
RTP 0936
/
6e06$$$$$1
03-26-96 01:40:45
in a regulatory consensus. The preceding workshops, the workshops before this one on macronutrient substitutes, have been specifically directed at creating a regulatory framework for these substances with the close participation and the encouragement of regulatory officials. Today’s meeting represents a culmination of these efforts and aims at bringing this dialog closer to fruition. In my view, and in addition to the scientific issues involved, the risk and benefit considerations should have a most significant weight in determining the direction and the urgency of a regulatory agenda. The development of low-energy, safe, and fully nutritional diets should be encouraged as a matter of pressing public health policy. The effort will require working on uncharted ground and difficult manufacturing, marketing, and regulatory decisions. However, for modern affluent societies, the decision to move vigorously in this direction is no longer an option, nor can it be postponed. The adversities of inaction are already a matter of troubling everyday experience and they are likely to expand if not urgently contained. GIO BATTA GORI is the Director of the Health Policy Center, Bethesda, MD, a consulting practice with a program of research in toxicology, epidemiology, risk assessment, and the formulation of public policy alternatives. Previously, he was Deputy Director of the Division of Cancer Causes and Prevention at the National Cancer Institute with simultaneous responsibilities as Acting Associate Director of the Carcinogenesis Program, Director of the Smoking and Health Program, and Director of the Diet, Nutrition, and Cancer Program. Dr. Gori is also a fellow of the Academy of Toxicological Sciences. He holds a Doctorate in Biological Sciences from the University of Camerino, Italy, and a Masters of Public Health from Johns Hopkins University.
rtpa
AP: Reg Tox Pharm
23, S1–S2 (1996)
0014
Welcome GIO BATTA GORI The Health Policy Center, Bethesda, Maryland 20816 Received December 11, 1995
Good morning. I am President of the Society for International Regulatory Toxicology and Pharmacology which sponsored this meeting here with ILSI N.A. This is the last of three meetings on the safety evaluation of macronutrient substitutes, which followed a seminal paper by Joseph Borzelleca published some 2 years ago. The main reasons for interest in macronutrient substitutes is that we are contemplating a new category of substances that are not foods in the traditional sense, substances that are intended to provide the organoleptic, physiologic, psychologic, and chemical functions of food without the nutritive and especially without the caloric attributes of food. Even before addressing their safety, one may ask why macronutrient substitutes exist in the first place. Are they simply a clever invention of the market or have they a legitimate place in human nutrition? Indeed, what we do know is a lot about nutrition. There is ample evidence that nutrition offers by far the most important opportunities in prevention in public health. The reasons for this are relatively recent. Technological gains during the second half of the century have created conditions whereby for the first time in history millions can afford lifestyles of affluence with energy requirements much reduced compared with traditional conditions of the past. As part of this technological miracle, wholesome and inexpensive foods are now almost matter of fact available through a leisurely trip to the supermarket. These achievements have freed masses from the oppressive toil of subsistence. Eventually, these achievements will be recognized as major new incentives to civilization. Still, they have been sudden experiences, within one or two generations in a culture where historic worries of famine and starvation are still fresh. The inevitable consequences have been overeating, an increasing prevalence of obesity, and a variety of physical and mental health adversities. Most everyone is familiar with this scenario, but most are not familiar with the added relationship of nutrition and functional longevity. Evolution is likely to have promoted adaptations only in functions of reproductive success, but not beyond. Indeed, the anthropologic record indicates that humans can reach successful reproductive age on almost any
diet, but for millennia, the average life expectancies rarely exceeded 30 years. So what are the optimal nutritional requirements from infancy on if the modern goal is not only reproduction, but a vigorous adult life and functional longevity at age 75 and beyond? Could it still be reduced caloric intake, as animal experiments continue to imply? The overeating, obesity, longevity, and functionality challenge must reckon with much reduced muscular energy demands of modern humans. On the other hand, modern humans have inherited a set of digestive, metabolic, anatomic, and psychologic functions that are often inconsistent with these reduced demands, and, of course, they are constantly tempted by readily available, inexpensive food. The desirable somatic adaptations could not emerge in the foreseeable future. For the time being, it will be necessary to devise low-energy, fully nutrient and safe diets that may satisfy the filling, the transit times, and the clearance requirements of the human GI tract in its present evolutionary configuration, and, of course, food that will provide the necessary behavioral signals of cessation. Thus, enter what we call macronutrient substitutes, specially aimed at providing the necessary functions of traditional diets, while reducing the caloric loads that seem so much the cause of most chronic diseases. In a true sense, therefore, macronutrient substitutes cannot be seen as inventions of the market, but are justified by pressing public health motivations. The argument that reduced caloric intake should be achieved by individual dietary discipline sounds sanctimonious and would lead to frustration. Dietary behavior is also the result of millennia of evolutionary and cultural pressures. Its forcible modification has been shown to trigger psychogenic stress and somatic adversities. Now, what could qualify as macronutrient substitutes? In addition to the necessary attributes of taste and texture, they should be capable of displacing from a few to perhaps 20% or more of ingested calories, by providing no calories, no utilizable calories, or the sequestration of otherwise available calories. Much attention, practical and theoretical, has been focused on sugar substitutes, synthetic lipids, vegetables, and fruits with increased fractions of nondigestible fiber, S1
AID
RTP 0936
/
6e06$$$$$1
03-26-96 01:40:45
0273-2300/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
rtpa
AP: Reg Tox Pharm
S2
SAFETY/REGULATORY ASPECTS OF SUBSTITUTES
natural and synthetic carbohydrates, chitins, synthetic polymers, mineral composites, and other configurations. What new issues of safety and safety evaluation could these substances pose? For substances that could make up a significant fraction of the diet, LD50 doses would have to be very large and virtually impossible to determine. They will be substances of no overt, acute toxicity. Their potential adverse effects, if at all, could only be subtle and long term. Most likely, these potential effects would also be indirect, the result of secondary interferences. The substances may affect the availability and absorption of other nutrients, especially vitamins and minerals. They may interfere with the GI tract dynamics for mastication, digestion, peristalsis, intestinal flora, transit times, and so on. In general, it is reasonable to assume that no macronutrient substitute would be proposed that retains any overt toxicity in the classical sense. These substances can be expected to possibly generate only vanishing clues of potential chronic toxicity. Thus, from a regulatory and public health point of view, the normal challenge that macronutrient substitutes pose is to define what these clues might be and at what levels their possible signals should be of concern. These challenges need to be resolved by novel approaches to animal and clinical toxicology and to their interpretation and new standards of premarketing clinical trials and postmarketing surveillance. These are the questions addressed in more detail in the original paper by Joe Borzelleca, questions that eventually need to be resolved
AID
RTP 0936
/
6e06$$$$$1
03-26-96 01:40:45
in a regulatory consensus. The preceding workshops, the workshops before this one on macronutrient substitutes, have been specifically directed at creating a regulatory framework for these substances with the close participation and the encouragement of regulatory officials. Today’s meeting represents a culmination of these efforts and aims at bringing this dialog closer to fruition. In my view, and in addition to the scientific issues involved, the risk and benefit considerations should have a most significant weight in determining the direction and the urgency of a regulatory agenda. The development of low-energy, safe, and fully nutritional diets should be encouraged as a matter of pressing public health policy. The effort will require working on uncharted ground and difficult manufacturing, marketing, and regulatory decisions. However, for modern affluent societies, the decision to move vigorously in this direction is no longer an option, nor can it be postponed. The adversities of inaction are already a matter of troubling everyday experience and they are likely to expand if not urgently contained. GIO BATTA GORI is the Director of the Health Policy Center, Bethesda, MD, a consulting practice with a program of research in toxicology, epidemiology, risk assessment, and the formulation of public policy alternatives. Previously, he was Deputy Director of the Division of Cancer Causes and Prevention at the National Cancer Institute with simultaneous responsibilities as Acting Associate Director of the Carcinogenesis Program, Director of the Smoking and Health Program, and Director of the Diet, Nutrition, and Cancer Program. Dr. Gori is also a fellow of the Academy of Toxicological Sciences. He holds a Doctorate in Biological Sciences from the University of Camerino, Italy, and a Masters of Public Health from Johns Hopkins University.
rtpa
AP: Reg Tox Pharm