The Seventh P. F. Frankland Memorial Lecture CHEMISTRY AND NUTRITION The Late Alastair Frazer, C.B.E., M.D., Ph.D., D.Sc., F.I.Biol., F.R.C.P. British Nutrition Foundation. London SE I . . . . .. . . . . . . . . . . 144 . . . . . . . . . . .. . . 144 What is food? What does food do? Some factors responsible for the development of modern methods of food production and distribution . . . . . . . . . . 145 . . . . . . . . . . . . . . . . 146 Population growth, 145 Increased urbanization, 145 Changed ways of living, 146 Raw materials Main nutrient constituents, 147 Natural toxicants, 149 Residues of chemical aids used in agriculture, 150 The role of the chemist in relation to raw materials, 152 The development of foods from raw materials .. . . . . . . 153 Modification of nutritional value of a food, 153 Formation of potentially deleterious toxic substances in food, 154 Safety evaluation of food additives, 156 Contaminants introduced into foods, 157 Packaging materials, 157 The role of the chemist in relation to food production, 158 Effects on the consumer . . . . . . . . . . . . . . 158 Availability of nutrients, 158 Metabolism in foods, 159 Genetic factors, 159 Pathology and drug therapy, 160 The role of the chemist in the study of the consumer, 161 Conclusion . . . . . . . . . . . . . . . . . . 161 References . . . . . . . . . . . . . . . . . . 162 The seventh P. F. Frankland Memorial Lecture was delivered at the University of Birmingham on 8 November 1968 by Dr Alastair Campbell Frazer.Dr Frazer was born in London in 1909 and was educated at Lancing and S t Mary’s Hospital Medical School. He lectured in physiology and pharmacology at the latter institu- tion from 1929 until 1941. From 1943 until 1967 he was Professor of Medical Biochemistry and Pharmacology in the University of Birmingham. On leaving Birmingham, he became Director-General of the British Nutrition Foundation, a post he held until his death in June 1969. In addition, he was a consultant t o the UKAEA, president of both BFMIRA and BIBRA, scientific adviser t o the Ministry of Agriculture, Fisheries and Food, and Chairman of the Food Section of IUPAC. Frazer 143 I greatly appreciate the honour of being invited to give the seventh Frankland Memorial Lecture, since it enables me to follow in the footsteps of a number of friends and colleagues whom I greatly respect and admire.It also gives me particular pleasure because for nearly 25 years, from 1943 until 1967, I occupied an established Chair in this University in which Frankland worked. Percy Faraday Frankland was Professor of Chemistry first at Mason College and then in the University of Birmingham from 1894 until 1918, and during that time he built up a world reputation for his Department, which has been further enhanced by those who followed him. He was a remarkable man, whose characteristics and personality were fully and affectionately described by the late Dr Leslie Lampitt in the first lecture in this series in 1949.1 Birmingham owes much to Frankland.I owe a great deal to Birmingham, which gave me the opportunity of developing some new ideas in biochemical education and research. In the development of the Department of Medical Biochemistry and Pharmacology, I had the active help and co- operation of the successors of Professor Frankland-first the late Professor Sir Norman Haworth and subsequently Professor Maurice Stacey. They provided me with a series of first-class chemists without whose help the Honour School of Medical Biochemistry and the graduate training facilities in my department would never have been created. I have no doubt that Frankland himself would have appreciated the need for more adequate development of chemistry and biochemistry in relation to medicine, especially in such fields as pharmacology, toxicology, nutrition and metabolic diseases, with which I have been associated.They have much in common, especially as regards the background sciences needed for their development. Here I will deal only with chemistry and nutrition, although, as will become apparent as we proceed, this subject cannot be entirely divorced from some aspects of pharmacology, toxicology and metabolic diseases. WHAT IS FOOD? This seemingly simple question calls for careful consideration and analysis. Contrary to the impression given by naturists, the great majority of foods are not consumed in a form that nature provides. Animal or vegetable raw materials require slaughter or harvesting, respectively, followed by various procedures which lead to the development of food.Furthermore, a variable time interval is needed to ensure that the food is in an acceptable state. Freshness may be an important feature in a vegetable, such as a lettuce, but it often does not enhance the palatability of meat, game, cheese or wine, which improves with the passage of time. Thus, food consists of substances derived from raw materials by the application of various procedures over an appro- priate time interval. Most food is unstable and it will only remain acceptable for a limited time period; if it is eaten too soon, it may be unpleasantly immature, but, if too late, it may be found to have deteriorated. WHAT DOES FOOD DO? Food has many effects on the body.Most of them are beneficial and necessary, but some may be unwanted or even harmful. The detailed study of these various effects and their definition in chemical, physical or biochemical R.I.C. Reviews 144 terms forms an important part of the subject matter of nutrition. It is not sensible to separate food chemistry from nutrition; both fields are inter- dependent and should be integrated as closely as possible. A substance is only a food when it is eaten and assimilated; the definition of the properties of a food is inadequate if it does not include the effects the food might have on the consumer. I propose to consider the role of chemistry in the field of food and nutrition in three steps : first, in relation to the raw materials from which food may be produced; second, in connection with the ways in which foods are developed and, third, with reference to the possible influence of the characteristics of the consumer on the effects that food may have on the body.Before doing this we must briefly consider the factors that have changed food production and distribution from a simple cottage handicraft into a major undertaking that calls for the full collaboration of science, industry and government. Three main factors have been responsible for this change: population growth, increased urbanization, and alteration in ways of living. SOME FACTORS RESPONSIBLE FOR THE DEVELOPMENT OF MODERN METHODS OF FOOD PRODUCTION AND DISTRIBUTION Population growth The world’s population has doubled in the last 40 years and it is likely to double again by the end of the century unless some check is applied.Not more than half of the present world population is adequately fed; by the year 2000, the proportion is likely to be much less than this, unless steps are taken to improve matters. Food production today is not sufficient to overcome the wastage and faulty distribution of food supplies. It is important that every- thing possible should be done to increase yields and food production generally, to reduce wastage, to improve distribution and storage, and to make better use of land. Much can be done by improved methods of husbandry, but it is also necessary to make full use of scientific advances, such as the use of fertilizers, pesticides and other agricultural aids, and to develop new methods of large-scale food manufacture and better methods of packaging, storage and distribution.While many of these advances will help to improve the world food situation, they may also raise problems on their own account which have to be taken into consideration. Increased urbanization A time there was, ere England’s griefs began, When every rood of ground maintained its man; For him light labour spread her wholesome store, Just gave what life requir’d, but gave no more. So wrote Goldsmith2 in the middle of the 18th century. The flight from the country into the towns has vastly increased since that time. The changes in population in Britain and the percentage that was urbanized between 1801 and 1951 are indicated in Table 1.It has been said that every year between now and the end of the century another urban area the size of Bristol will be created. This trend towards living in towns greatly affects the provision of adequate food supplies. Clearly, the amount of land for food production is progres- Frazer 145 Population (m.) Urban (%) 29 50 75 RAW MATERIALS Table 1. Urbanization in Great Britain I 80 I -I 95 I 10.5 21 37 49 80 Year 1801 1851 1901 1951 sively diminishing. At the same time, there has been a demand that more of our daily food should be produced in this country. If these two lines of action are to be followed, further intensification of farming and food production in Britain is inevitable.This will require the full use of all scientific aids. It is only possible to achieve these various objectives without lowering standards in food and nutrition if there is a continuing and coordinated effort in research and development covering the whole field, a matter discussed in some detail by Sir Gordon Cox in the fifth Frankland Memorial L e ~ t u r e . ~ Changed ways of living Urbanization itself results in a change in the pattern of living. More people tend to eat away from home; more housewives go out to work and have less time for preparing and cooking food; problems of storage and distribution increase. In spite of all these difficulties, there is no doubt that the range and quality of food that is generally available today to the great majority of town- dwellers is enormously superior to anything that was possible in the ‘good old days’ of 100 years However, changes are still occurring.Thus, there is an increased tendency for foods to be separately packaged and held on display either in the supermarket or in deep-freeze cabinets. Because of the lack of time for food preparation and the greater number of old people trying to fend for themselves, there has been a steady increase in so-called ‘convenience foods’. These foods are prepared and possibly cooked, or partly cooked, so that they can be brought to the table much more easily and speedily. A further extension of this approach is the introduction of precooked frozen foods. These foods are cooked centrally by experts and then held in store or distributed frozen.The reheating process can be relatively unskilled, so that such a system opens up possibilities of improving various forms of institutional catering, such as food supplies in large hospitals or schools or social services, such as ‘meals-on-wheels’ for old people. This system may also help to resolve difficulties that arise from a shortage of cooks and the need to cook food throughout the whole day seven days a week. It is important that the pattern of food production and supply should be properly adapted to community needs; these trends must, therefore, be taken into account when considering problems of food and nutrition. The raw materials used for food production may be either of animal or vegetable origin.Materials are chosen that contain useful components, such as carbohydrates, proteins, fats, electrolytes, trace elements and vitamins. R.I.C. Reviews 146 They also contain other constituents that are of more limited value, such as fibrous tissue, bone, lignin, or cellulose. Some of these, however, may have a significant nutritional role in giving acceptable texture to the food. Raw materials may also contain other groups of substances, such as natural toxicants, residues of chemical aids used in agriculture, or natural contami- nants derived from micro-organisms or moulds. All these components have to be given due consideration if the raw material is used for food production. Main nutrient constituents The amount of useful nutrients present in the raw material will vary, due to genetic and environmental factors. Thus, different varieties or strains of cereals will contain different amounts of protein or other nutrients.The same is true of all other plant and animal raw materials. A considerable amount of work is being done on the breeding of new varieties or strains of plant raw materials and of developing better animal stocks. The composition of any particular variety or strain may also vary according to the conditions under which it is grown. Thus, climatic conditions materially affect the protein content of wheat. Since man consumes a mixed diet, variation in the composi- tion of any particular food is not in itself of paramount importance. It is essential to know what the composition is, so that this can be taken into account in the construction of the whole diet.In general, the utilization of the main nutrients by the consumer is well understood; the chemistry of some of them was discussed in the second and third Frankland Memorial lecture^.^^^ I only propose to emphasize that the chemical nature of these nutrients is a matter of major importance. This can be illustrated by reference to two main food components, proteins and fats. In the case of proteins, the nature and the amounts of various con- stituent amino acids have great nutritional significance. Certain amino acids cannot be formed in the body by transamination. These are essential compo- nents of the diet; if one essential amino acid is deficient in a protein its use- fulness is seriously limited.Therefore, in discussing the nutritional significance of any protein it is necessary to consider the amounts of these essential amino acids present. The biological value of a protein can be assessed chemically on the basis of its essential amino-acid content. There are also certain fatty acids that cannot be synthesized in the body. These are polyunsaturated fatty acids with certain characteristics. The most important features of these essential fatty acids are: the presence of two or more double bonds, the separation of the double bonds by a methylene bridge, the spatial arrangement of the double bonds, which should start from the ~6 position, and the presence of cis configuration about the double bonds.7 The presence of polyunsaturated fatty acids of this type in a dietary fat has a significant effect on the blood cholesterol and P-lipoprotein levels of the consumer.* In some animals a definite essential fatty-acid deficiency syndrome can be demonstrated ; it is possible that deficiency may also occur in the young baby,gJO but it has not been adequately defined in adult man.Nevertheless, no-one doubts that these fatty acids play an important part in cell biochemistry in man and that they are and should be present in adequate quantities in the human diet. Frazer 147 All too frequently one still hears reference made to animal and vegetable proteins or fats as an indication of their chemical composition. This differen- tiation is totally inadequate.Some vegetable proteins are the equal of animal proteins in nutritional value; many vegetable fats contain plenty of poly- unsaturated fatty acids, but there are some that consist mainly of saturated fats; similarly, animal fats from ruminant animals contain a high proportion of saturated and little polyunsaturated fatty acid, but other animal fats, for example, pig fat, may contain substantial amounts of polyunsaturated fatty acids. Nutrients should be adequately defined in chemical terms. Table 2. Some possible pharmacological or toxic effects of foods Occurrence Tea, coffee Bananas and some other fruits Some cheeses Soya beans Almonds, cassava and other plants Quail Mussels Cycad nuts Some fish, meat o r cheese Sassifras Legumes Some beans Ackee fruit Brassica seeds and some other vegetables Rhubarb Green potatoes Many fish Many fungi Active agent Caffeine 5-hyd roxytryptam i ne; ad renal i n e ; no rad renal in e Tyramine Oestrogens Cyanide Due t o consumption of hemlock Due t o consumption of dinoflagellate, Gon yaulax Met hylazoxymet hanol N it rosami nes Safrole (p-ally1 methylene dioxybenzene) Haemogl u ti ni ns Vicine P-aminopropionitrile a, y-diaminobutyric acid cyano- I -alanine a-ami no-8-methylene cyclopropane propionic acid Th iooxyazol id ine, t h iocyan ate Oxalate Solanine; possibly other sapotoxins Various, often confined to certain organs o r seasonal Various non-edible fungi Possible erects Cerebral stimulant; diuretic Effects on central and peripheral nervous system Raises blood pressure; enhanced by monoamine oxidase inhibitors Similar to female sex hormones Interferes with tissue respiration Hemlock poisoning Tingling, numbness, muscle weakness, respiratory paralysis Liver damage; cancer Liver damage; cancer Cancer Red cell and intestinal cell damage Haemolytic anaemia Interferes with collagen formation Toxic effects on nervous system H ypogl ycaem ia Enlargement of thyroid gland (goitre) Oxalu ria Gastro-intestinal upset Mainly toxic effects on nervous system Mainly toxic effects on nervous system 148 R.I . C. Reviews Natural toxicants Plants are a well-known source of pharmacologically active substances.It would be surprising, therefore, if some of the plants chosen for food produc- tion did not also contain some pharmacologically active or even toxic principles. Some of the possible effects of a number of such agents are indi- cated in Table 2. It should be emphasized that most of the possible ill effects are avoided by proper choice and preparation of the raw materials. Some of these effects may be wanted; for example, the effect of caffeine in tea and coffee, which helps to allay fatigue.-Some of the more serious effects, such as poisoning by unsuitable fungi, fish, or shellfish, may be avoided by correct choice of edible varieties or restriction of consumption to a safe season.Many of these natural toxicants are of considerable interest chemically. I have chosen three for further comment. First, ackee fruit poisoning: The ackee fruit (Blighia sapida) grows in Jamaica and it is made up into a dish rather like scrambled egg, which is traditionally served with salted cod. It is an excellent dish, but, unfortu- nately, now and again it causes untoward effects in the consumer, such as vomiting, convulsions, and coma, which may prove fatal. These effects are due to a sudden fall in the blood sugar and the signs and symptoms can be dramatically relieved by intravenous injection of glucose. The action of the ackee fruit is due to the presence of a-amino-/l-methylenecyclopropane propionic acid (hypoglycin) ~ H,C=C’I NH3 ‘CH-CH~-CH-COO- I which is a metabolic blocking agent interfering with the storage of liver glycogen and the maintenance of the normal blood sugar level.11-13 Hypo- glycin is found particularly in unripe ackee fruit.A high protein diet and riboflavin afford some protection and the effect most commonly occurs in undernourished children. Coming nearer home, there is green potato poisoning. The normal potato tuber (Solanum tuberosis) contains less than 0.01 per cent of solanine, an alkaloid which has a sapotoxin-like effect, and causes severe gastro-intestinal disturbance. Under certain circumstances the solanine content can increase up to 0.05 per cent or more; this increase is commonly associated with the development of chlorophyll. The chlorophyll is, of course, harmless, but the accompanying solanine is toxic to man at a dosage level of about 200mg.There have been reports of epidemic outbreaks of green potato poisoning from time to time.14J5 A third example of a natural toxicant is a form of musselpoisoning, which occurred in NE England last May.16 Some 80 people were seriously affected, but fortunately none died, although fatalities have occurred in other out- breaks. The poisoning was considered to be due to the consumption of mussels that had been feeding on a dinoflagellate marine organism of the genus Gonyaulax, which gives rise to a neurotoxic agent, saxitoxin. Dino- flagellate organisms may suddenly increase in great numbers in late spring Frazer 149 11 or early summer and when this occurs the sea may appear red or brown- termed by fishermen ‘the red tide’.Such brown masses were reported by fishermen in early May off the east coast. Consumption of poisonous mussels results in paraesthesis and numbness, resembling the effect of a local anaesthetic, and this is followed by inter- ference with muscle movements. In severe cases the respiratory muscles may be paralysed. Cooking the mussels removes about 50 per cent of the toxic agent into the cooking water. This outbreak was limited partly by the fact that most of the mussels were well cooked before eating and partly by very prompt action on the part of the physician who saw the first case and the Medical Officer of Health. This episode illustrates the importance of seasonal restriction of some foods.The old adage ‘Do not eat shellfish if there is no R in the month’ may have a sounder and broader basis than might be expected. Residues of chemical aids used in agriculture In order to increase yields and prevent wastage, various chemical aids are used, some of which were discussed in detail by Professor R. L. Wain in the sixth Frankland Memorial Lecture.17 Their significance in relation to food production can be illustrated by reference to some of the problems concerned with nitrate fertilizers, pesticides, oestrogens and antibiotics. Nitrate fertilizers. It is often helpful to treat the soil with nitrates. These nitrates are converted into protein by plants. Under certain circumstances, however, some of the nitrate added to the soil is washed away in surface water into reservoirs and shallow wells, where it may stimulate the growth of blooming algae, some of which are toxic.The nitrate-containing water itself may also be used for human consumption. The nitrate taken up by the plant may not be completely converted into protein, so that an increased nitrate content may result. The increased use of nitrates as fertilizer may, therefore, lead to an increased intake of nitrate by the consumer either in water or in food. Nitrate is, however, a substance which is formed in the body in the course of metabolism in small amounts and it has a low toxic potential; there seems little likelihood that this increase in nitrate intake would in itself cause any harm. A different situation arises if the nitrate is reduced to nitrite, which is about 10 times more toxic than nitrate and causes quite different effects on the body.Conversion of nitrate to nitrite may occur if food containing an excess of nitrate is allowed to undergo bacterial spoilage, or if the nitrate is exposed to the reducing flora of the intestine. This is avoided by careful choice of raw materials for baby foods, by proper food hygiene, and by restricting nitrate intake in food or water in babies or in others with an active flora in the upper part of the intestinal tract, including ruminant animals. The maximum permitted level of nitrate nitrogen in drinking water for human use varies from one country to another-it is commonly 10-20 ppm.However, this does not allow a great margin of safety.18t19 Pesticide residues. Many pesticides leave no detectable residue, but others, notably the organochlorine pesticides, are more persistent. When these are R. I.C. Reviews 150 DDTIDDE Range 0.00-0.0 I 0.00 I5 Range ( p m ) headlday) (PPm) 0.00 I8 0.00- I .2 0.04-0.20 0.00-0.005 0.00 I 3 0.00-1 0.0 0.0 I 5 0.10- 0.8 0.00067 Corned beef 0.00425 0.00026 Potatoes 0.00-0.09 0.0033 - - - Table 3. Some pesticide residues in food (derived from Cook Report, 1964. More recent studies show no increase. Consumption calculated from National Food Survey.) BHC Dieldrin Consump- tion (mg/ Range (Wm) Consump- tion (mg/ headlday) 0.0065 Butter Milk Mutton fat Beef fat Consump- tion (mg/ headlday) 0.00 -0.24 0.0023 000 -001 0.0013 0.00 4 .7 0.0033 0.00 -0.15 0.00054 0.00 -0.25 0.00039 0.00 1-0.0 I9 0.00 I7 - - - 0.00-0.062 0.00054 used, residues may remain in the soil for years and they are also likely to find their way into the food chain. Consequently, the residues of these persistent pesticides can be found in many animal and plant tissues, including human adipose tissue. Minute amounts have also been detected in rain and in animals or birds in places remote from pesticide use.2o Fortunately, sensitive methods are available for the detection and measurement of these pesticide residues and it has, therefore, been possible to monitor them in raw materials and in foods.The amounts present in foods in this country at the present time are extremely small (Table 3).21 There is no evidence to suggest that the traces found in food have any significant effects on the consumer and it is also doubtful whether the small residues found in adipose tissue of man and ani- mals have any toxicological significance. Much higher amounts have been found in the adipose tissue of people occupationally exposed to these sub- stances, but these higher residues apparently have no ill effect.20 Oestrogens. Oestrogenic substances occur in many plantsZ2 and they are normal body constituents. Many oestrogens have an anabolic effect; that is to say, they may stimulate protein synthesis and assist in the more economic use of food.They have been administered to cattle and to sheep as implanted pellets or in animal feed. In these animals no significant amount of the administered oestrogen can be demonstrated in the carcass meat. Oestrogens are also used in poultry. In addition to an anabolic effect, they alter the composition of the carcass and the distribution of fat. Thus, their use pro- duces a more acceptable table-bird, which closely resembles the caponized bird. These birds do, however, have a small residue of oestrogen demon- strable in the carcass meat. For this reason, the use of oestrogens in poultry is not permitted in a number of countries. The amount present is extremely small and causes no biological effects in the consumer. Large doses of certain oestrogens may affect the incidence of mammary cancer in certain strains of mouse.In United States law, the Delaney Amend- ment forbids the use of any substance, as a food additive, if it causes an increase in cancer incidence in any animal when administered at any dosage level by any route. This precludes the use of oestrogens in poultry. There is, however, evidence from human as well as animal studies that the minute Frazer 151 amounts of oestrogens present in poultry meat after chemical caponization do not give rise to any cancer risk in the consumer.23 Care must, of course, be taken to ensure that unexpended oestrogen pellets are not included in food products. Natural contaminants: mycotoxins. In 1960, 100 000 young turkeys suddenly died in Britain due to the mysterious ‘turkey X disease’.In due course it was shown that death was due to the eating of groundnuts infested with Aspergillus flaws. This mould, which grows readily in damaged groundnuts, especially if they are kept under hot humid conditions, results in the formation of a lactone, aflatoxin : Oral LD,, for 50 g duckling: 18.2 p g (5 per cent fiducial limits 14.0 -23.8 pg ) Aflatoxin is highly toxic to ducklings and young turkeys. A dose of 20 pg can kill a one-day old duckling. Other animals, such as rats, guinea-pigs, cattle and monkeys, develop liver damage when fed aflatoxin. In the rat this liver damage is followed by the development of malignant tumours.14-28 Thus, contamination with this mould results in the presence in the raw material, and possibly in the food made from it, of a highly toxic and perhaps cancer -inducing substance.Aspergillusflaws can produce aflatoxin when it grows in other cereals, or even in cheese. There are potent mycotoxins produced by other moulds. The significance of aflatoxin in the human diet is still uncertain. Extensive epi- demiological studies are in progress. Fortunately, mould growth is not acceptable on prime materials destined for human consumption and the processes used for refining oil for margarine manufacture remove any aflatoxin that might be present. Methods are available for detection of aflatoxin29 so that quality control of raw materials can be carried out. Efforts are being made to establish acceptable methods at an international level by the Food Section of IUPAC.The role ofthe chemist in relation to raw materials The chemist plays a vital part in the choice of raw materials for food produc- tion, since he can establish the presence and the amount of useful substances they contain. Chemical analytical methods for nutrients are usually quicker and more accurate than biological methods of assay. It is obviously necessary to make certain that the chemical assay method gives a true picture of bio- potency and this may require cross-checking from time to time. The chemist also plays an important part in controlling the presence of undesirable com- ponents, whether they are natural toxicants, residues of chemical aids to R .I . C. Reviews 152 agriculture, or natural contaminants. Thus, suitable specifications and tolerable levels of each of these groups of substances can be established. The chemist also plays a part in the development of new chemical aids and, from the study of biodegradation and other properties, he may be able to devise effective pesticides or other agents that are equally effective, but do not give rise to problems in food. THE DEVELOPMENT OF FOODS FROM RAW MATERIALS As already mentioned, many processes may be applied to raw materials to facilitate food production. Some of these aim to reduce the time interval required to develop acceptable food, others help to produce the measure of uniformity needed for large-scale manufacture, others improve shelf-life, while others again modify the appearance, texture, or other properties of the food to make it more acceptable to the consumer.The use of food additives and processes should be based on certain principles.30 1. A food additive or process should be technologically effective. 2. The amount of the additive used, or the extent to which the process is applied, should not be more than is required to secure the technological objective. 3. A food additive or process should never be used in a manner that might mislead the consumer as to the nature or quality of the food treated. 4. A food additive or process should be safe and give rise to no deleterious effect in the consumer, when properly used. 5. Non-nutrient substances should be kept to the practicable minimum in foods for general use.It is clearly necessary to study the possible effects of any new food additive or food process and this is required in Britain under the terms of the Food and Drugs Act, 1955.3l What are the sort of problems that require study in this connection ? They may be considered under four heads : modification of nutritional value, formation of toxic substances, safety evaluation, and control of contaminants. ModiJication of nutritional value of a food There is nothing sacrosanct about the nutritional properties of a particular food. It is important that the true nutritional value at the time of assimilation should be known. The amount of nutritional modification that the use of an additive or process might bring about can be assessed by chemical analysis, by biological assay, or by both methods.If modification has occurred, the action that is appropriate depends upon the importance of the nutrient in question and the significance of the particular food as a source of that nutrient. Thus, milling to about 70 per cent extraction causes a marked reduction in the thiamine content of flour. Thiamine is an important nutrient for man and flour is a significant source of this vitamin in the human diet. In Britain, flour milled to 70-72 per cent extraction must be supplemented with thiamine and certain other n~trients.3~ This is also required in several other countries. Milling, storage, aeration, treatment with maturing agents and baking all reduce the tocopherol content of flour. However, the nutritional value of Frazer 153 tocopherols in man remains obscure. It has not been thought necessary, therefore, to supplement flour with tocopherols.Variation in tocopherol levels in flour and bread does not appear to have any significant effect on the nutritional status of the consumer.33 In any case, if there was a shortage of tocopherols in the diet of the community, it would be more sensible to supple- ment margarine, since the tocopherols in flour are so labile. Formation of potentially deleterious toxic substunces in food In 1947, Mellanby34 showed that heavy loading of the diet of dogs with flour that had been over-treated with nitrogen trichloride (agene) caused the animals to have ‘running fits’.It was subsequently shown that this effect was due to the formation of an antimetabolite, methionine sulphoximine35 (Fig. 1). This substance causes neurological effects in a number of other animals. Such large doses are required to bring about minimal electro- encephalographic changes in man that it seems unlikely that bread made from agene-treated flour would ever have caused deleterious effects in the consumer. Nevertheless, on the basis of the animal studies, agene was withdrawn from use as a flour maturing agent and its place was taken by chlorine dioxide, which has been shown to give rise to no deleterious effe~ts.3~ The formation of antimetabolites by food additives or food processing is always a possible hazard.Small changes, such as the introduction of a hydroxyl or an amino group, may alter an essential nutrient, such as a vitamin, into a Treatment with I (CH2 )2 Not reversible C H j I HN=S=O I (CH2 12 I CH.NH2 I I COOH Methionine sulphoximine (Toxic anti metabol i te; ’running fits’ in dogs) Fig. I . Comparison of effects of two flour-maturing agents, nitrogen trichloride (agene) and chlorine dioxide, on methionine. 154 I Treatment with s=o I I COOH I CH.NH2 ((32 )z Methionine sulphoxide (Non-toxic m eta bo I i t e) R.Z.C. Reviews Structure R CH3 Pyridoxin HobcH2oH NH2 p -Amino- benzoic acid - - - - - - - - Fig. 2. Some antimetabolites that illustrate the effect of small modifications in chemical structure on biological effects.lethal blocking agent. Some well-known examples of these antimetabolites are shown in Fig. 2. Ever since the demonstration of the action of agene, it has been the practice to test treated or over-treated food as well as the food additive itself when assessing safety-in-use. This gives some assurance that a serious toxic agent has not been formed, especially if the study is combined with an intelligent appraisal of the possible modifications that might occur. The effects of antivitamins or other similar blocking agents may be prevented by the presence of an excess of the normal nutrient; thus, modification of only a small proportion of a nutrient may not be serious. Recently,37 attention has been drawn to another possible problem of this nature.Nitrates and nitrites have been used for many years as preservative agents for meat; they have considerable advantages and the nitrate or nitrite residues involved are known to be harmless. However, when fish is treated in this way, it may have toxic effects on the liver and this has been shown to be due to the formation of nitrosamines; these troublesome effects have been demonstrated in animals fed nitrite-treated fish-meal. The nitrate and nitrite treatment of fish for human consumption is not permitted in Britain. Certain nitrosamines, especially small molecules such as dimethylnitrosamine, Frazer Name of effective vitamin y 3 Thiamin OH NH2 CHZOH I CH3 CH3 \ N=NO / CH3 155 can give rise to cancerous changes in cells.Because of this, a considerable amount of work is now being done to find out whether nitrites can produce nitrosamines in other foods that contain secondary and tertiary amines in much smaller amounts than occur in fish. If nitrosamines are formed, it is important to discover their nature and the amounts present. Evidence from extensive feeding studies that have already been carried out on various meats seems to support the view that the nitrite treatment of meat is safe. Neverthe- less, further analytical and biological studies are now being undertaken to provide definitive evidence on the nature and effects of any substance formed in food as a result of treatment with nitrites. 6. CHECK SPECIFIC EFFECTS IN MAN (if necessary) 7.CONTROL BY ‘PERMITTED LISTS’ and ZONED DISTRIBUTION (if possible) Safety evaluation of food additives There are many food additives used and all new ones are thoroughly studied before they are introduced. Final control is commonly based nowadays on a permitted list system. This is a great improvement on the older approach, which required evidence to show that a substance was harmful before control could be exercised. The main steps in safety evaluation are given in Table 4. Since much has been written on this subject,38,39 I shall only comment on certain aspects. First, the establishment of adequate specifications for a new additive is of major importance. If this is not done, it is impossible to identify the substance or to validate tests alleged to have been made on it.Second, metabolic and biochemical studies are important and often neglected. They should form the basis for the choice of animals for study; in practice, many other factors determine the selection of animals for investigation. Third, the most important studies are long-term studies in animals. Human studies may be useful to indicate the pattern of metabolism in man, or as a means of checking whether some particular effect occurs in the human subject. Otherwise, studies in man have only limited value, especially in the food addi- tive field.40 Experience with drugs suggests that important toxic effects may only be seen when several hundreds of thousands of people are treated and they may well not occur in a clinical trial that only involves a few hundred Table 4.Scheme for control of the safety-in-use of a food additive I. SPECIFICATIONS: Identification: control impurities 2. BIOCHEMICAL STUDY (a) Effects on treated food (b) Digestion, absorption, metabolism, distribution, excretion, half-life 3 . BIOLOGICAL EFFECTS: Short, medium, long-term studies Multi-generation test (Test treated food as well as additive; choose animals on basis of metabolic pattern) 4. ASSESS ‘NO EFFECT’ LEVEL OF IN TAKE: From animal studies Usual safety margin x 100 5. CALCULATE ACCEPTABLE DAILY INTAKE (ADI) FOR MAN: 156 R.I.C. Reviews patients. There is no machinery at the present time for the effective screening of the effects of a new food additive on a large population of consumers.Fourth, this approach to the food additive problem is based on evaluation of scientific evidence. When policy is so based, allowance must be made for new scientific evidence to be taken into account when it becomes available. The system of control needs to be flexible so that appropriate action can be taken quickly. Some of the present administrative machinery used for the control of food additives in Britain is not satisfactory in these respects. Contaminants introduced into foods Certain polycyclic hydrocarbons, such as benzralpyrene, can induce cancerous changes in cells and many aspects of this problem were discussed in detail by Professor Haddow in the fourth Frankland Memorial Lecture.41 Benzpyrene seems to be ubiquitous and it often contaminates our daily food.This contamination may arise in several ways. Benzpyrene could get into food as a result of atmospheric pollution, or because of its presence in smoke used for smoking food. If smoke is generated from old ships’ timbers or road blocks, the tars in them may give rise to considerable amounts of benzpyrene and other related substances in the smoke; other unsuitable fuels may do the same. If such smoke is used for smoking fish or meat, the products may be significantly contaminated with this polycyclic hydrocarbon. A high incidence of cancer was shown to occur in a small community that consumed large amounts of smoked foods, which had been prepared by unsatisfactory methods.42 Contamination can also occur due to faulty cooking stoves.Another possible source of benz[a]pyrene is from paraffin wax containing this hydrocarbon. Changes in the cracking of petroleum may yield wax contaminated in this way; it is important to ensure that such contami- nated waxes are not used for making waxed cartons for f00ds.~3 Milk readily extracts benzopyrene from a contaminated waxed carton. Fortunately, there are sensitive methods available that make it possible to screen foods or waxes for benz[a]pyrene, and a generally acceptable method of analysis is now being elaborated by the Food Section of IUPAC. This problem illustrates the need for careful scrutiny of food preparation method, taking into account all the factors that may be involved.Packaging materials Canning was introduced rather more than 150 years ago and since that time many other forms of food packaging have been developed. No-one would deny that food packaging has made major contributions to the more effective preservation and distribution of food, to the development of cleaner food and to many other aspects of food supply. However, it is necessary to set off against all these advantages some possible disadvantages. The most important Frazer 157 one in this context is contamination of the food with chemical substances leached from the package. Many packaging materials contain substances in addition to the main ingredients, which help to give the package the proper- ties required. These include such substances as curing agents, antioxidants and plasticizers. Some of these substances might have significant toxic effects.Proposed packaging materials are subjected to extraction tests. Clearly, the most satisfactory packaging materials for food are those that give relatively little residue on extraction into a range of solvents simulating food materials. Furthermore, the substances that are extracted in anything more than trace amounts require careful scrutiny and should, if possible, be tested for biological effects. This has been done for many packaging materials, but some substances are not used in sufficient quantities to cover the cost of full toxicological investigation. Clearly, particular attention should be given to packaging materials that are used for staple foods, or for those foods or beverages likely to be consumed in quantity, especially by children.If packag- ing formulations are changed often enough, it is possible that the consumer will not be exposed to any of the ingredients for long periods. It is possible that some use might be made of clearance for relatively short periods of exposure, so that a rotation in the use of some packaging ingredients could be established. Such an approach is worthy of further study. The role of the chemist in relation to food production The chemist is involved at every step that the food technologist may take. He must provide the specifications for food additives used. He must also define in precise chemical terms the nature of the modifications brought about by the use of the food additive or process.He can assist in the identification and control of antimetabolites or other toxic agents that might be formed. He can provide suitable analytical methods which will ensure the control of contami- nation. In these analytical activities, his attention should also be directed to fuel used for food preparation and packaging materials that may be used for wrapping food. The chemist also has an important part to play in the study of the chemical basis of taste and flavour, so that the important organoleptic properties of food can be preserved, enhanced or replaced. EFFECTS ON THE CONSUMER There are a vast number of possible effects of food on the consumer. Some of the more important issues at the present time seem to be concerned with the availability of nutrients, the metabolism of foods, genetic factors and the relationship of food to the pathology and drug therapy of the consumer.Availability of nutrients The food manufacturer is required by law to ensure that food has its correct properties at the moment of sale. For the nutritionist, however, it is more important to know the state of the food at the moment of assimilation. Many things can happen to food between sale and assimilation; it is often stored, prepared, cooked or subjected to other procedures under very variable conditions. The food material may be consumed with other food materials and these might interfere with the absorption of nutrients in the food.For R.I.C. Reviews 158 example, it is well known that phytic acid, present in flour, may interfere with the absorption of calcium. Other factors that may modify the availability of a nutrient include faulty digestion or preparation for absorption, or changes due to the overgrowth of micro-organisms in the intestinal lumen. It should never be assumed that an individual is assimilating the nutrients that are eaten; even less should it be thought that the nutrients indicated from tables of food composition as being present in the foods purchased are necessarily available to the consumer. In the case of some nutrients, such as folic acid, the methods of assay may only indicate what is available to micro-organisms and not what is available to man.A great deal more research is needed on methods of assessing the availability of nutrients to the individual consumer. Metabolism in foods Substances may be modified during the course of digestion and absorption, and they may undergo further changes as a result of enzyme action in the liver or elsewhere. The pattern of enzymes concerned in all these processes differs from one individual to another, since it is genetically determined. It follows that each person deals with nutrients in a different manner. No doubt there are close similarities between a great many people, but each person is, in fact, unique. The pattern is not entirely dependent on genetic factors ; metabolizing enzymes may also be affected by the previous experience of the individual. Such changes have been extensively studied in the case of drugs and it is now well recognized that drug metabolizing enzymes can be increased in activity by induction.There is no reason to suppose that food materials differ funda- mentally from drugs so far as metabolism is concerned. Thus, the previous dietary experience of the individual might be expected to have some bearing on the way in which food is dealt with metabolically. The products of meta- bolism may differ in activity from the parent substance. The development of particular metabolizing enzymes may vary with species, sex, age, or other constitutional characteristics, and this may largely explain differences ob- served in the effects of drugs or of foods on different species of animals or different individuals.An aspect of metabolism that should never be forgotten is the possible effect of the intestinal flora. These micro-organisms may modify food materials and profoundly influence their effects on the body. This may become especially important if there is an overgrowth of intestinal organisms which invade the small intestinal lumen, since the products of floral meta- bolism are more likely to be absorbed from this part of the alimentary tract than from the colon. Genetic factors The influence of genetic factors can be dramatically illustrated by considering some of the so-called inborn errors of metabolism.44 For example, in a child suffering from phenylketonuria, there is an inability to convert phenylalanine into tyrosine due to a defect of the enzyme, phenylalanine hydroxylase (see Fig.3). As a result, phenylalanine accumulates in the tissues and cells, and this causes damage to important tissues, including the brain. Some 1 per cent of mental deficiency in Britain was found to be attributable to phenylketon- uria. Thus, this genetic fault converts a substance which is a dietary essential Frazer 159 Normal individual Phenylalani ne hydroxy lase CH2 CH2 I CH.NH2 CH.NH2 I COOH COOH Phenylketonuric individual Phenylalan i ne h droxylase agsentor deficient I Phen ylalan i ne - - - - - - - - - - - - - - - - - - - - - - - - - - - Phenylalanine accumulation I\‘...-------, Converted to: Damage to cells of central nervous I Ty rosi ne Tyrosine deficient Reduced melanin formation (pigment) Reduced adrenaline formation t phenylpyruvic, phenyllactic, p hen y lacetic acids Excreted in Mental retardation urine 1 ‘ X u 1s ions Fig.3. Enzyme defect i n phenylketonuria and its main consequential effects. for the great majority of people into a disastrous cell-damaging agent in a few. Fortunately, if this genetic fault is detected early enough in life it is possible to exclude phenylalanine from the diet sufficiently to permit normal develop- ment. This is but one example of this type of problem. It is also interesting that the heterozygote parents of these children, who show no apparent ill effect from eating a normal phenylalanine-containing diet, can be shown to deal with phenylalanine less effectively than normal individuals.Metabolic deviations of this sort due to heterozygote traits require much more detailed study. While such abnormalities may only produce the overt metabolic disease in the homozygote, they might contribute to other types of pathology over a much broader field. Detailed study of genetic factors in the nutritional field is much overdue. Pathology and drug therapy Food is consumed by sick people as well as by those that are healthy. For this reason, possible relationships between pathological changes in the consumer and the effects of food require careful consideration. It is well known, for example, that much larger amounts of sodium chloride can be ingested safely by a normal person than by one with hypertension.Again, patients with disease of the small intestine may not be able to tolerate disaccharides in the 160 R. I . C. Reviews diet due to lack of disaccharidases. There is undoubtedly a great deal more to be learnt about the aggravating and damaging effects of food in certain individuals, One of the more dramatic observations of recent years has been the complete recovery of many patients crippled by intestinal malabsorption due to their inability to deal effectively with wheat gluten. If such patients are placed on a gluten-free diet, they return to normal, but will relapse if wheat gluten is reintrod~ced.~5 Drug therapy also calls for consideration. This was well shown a few years ago in patients who were being treated with monoamine oxidase inhibitors.If such patients consumed foods, such as cheese, that are rich in amines serious toxic effects were manife~t.~6 The more that drugs which effect meta- bolizing enzymes are developed, the more careful one will need to be to adjust the diet appropriately to avoid unwanted effects. The role of the chemist in the study of the consumer Although the effects on the consumer may be primarilyamatter of clinical observation, the chemist also plays an important part. The chemist can help to unravel problems of availability of nutrients and he is an essential member of any team concerned with the study of metabolites. The sort of metabolitis formed, the enzymes that are concerned and the factors that affect the nature and amount of metabolites require the attention of chemists and biochemists.Chemical analysis is necessary to establish the biological half-life of any substance. Identification of abnormal levels of nutrients or metabolites in the blood or tissues also calls for skilled analysis. Thus, the whole problem of demonstrating the effects of food on the consumer and of controlling effects to those that are wanted, requires assistance at every turn from chemists and biochemists, working in close collaboration with nutritionists, microbiologists, pathologists and clinicians. CONCLUSION I hope that I have said enough to illustrate my theme-chemistry and nutrition. Nutrition is a broad subject; it is concerned with the chemistry and physics of food and the effect of food on life and health.It has to span the whole field from the production of raw materials through the complex processes of food development into the intricacies of the effects of all the components of food on the cells and tissues of the consumer. It is essential that these problems should be studied at the molecular, cellular and subcellular levels, and it is in this area that advances are likely to be made in the next 25 years. Chemists and biochemists of the highest quality are needed to unravel these problems. Skilled biologists and medical scientists are also needed to elucidate the effects on the consumer, for I hope that I have convinced you that genetic factors and previous experience of the individual must also be taken into account.It is no easy matter to bring about co-operation and collaboration over so wide a field. However, the newly-formed British Nutrition Foundation aims to do just this. It will do everything possible to promote and encourage research and education over the whole field of food and nutrition. I hope that we may count on the help and support of research workers in all relevant fields in this great undertaking. Frazer 161 REFERENCES 1 L. H. Lampitt, Lect. Monogr. Rep. R. Inst. 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