361

Food Additives

THE LANCET

LONDON 16 AUGUST 1969

DURING the course of a year, everyone in this

country consumes, on average, some three pounds ofchemical substances which are not normal constituentsof food; and the quantity is increasing. Some, such aspreservatives, colouring agents, and sweeteners, aredeliberately added, while others, such as insecticides,antibiotics, or products of fungal metabolism (myco-toxins), get there unintentionally. The total numberof known additives exceeds 20,000. Some appear onlyin minute amounts, but some are poisonous to animalsin equally small quantities. Do they harm man ? TheNuffield Foundation has for the past ten years takenclose interest in this question and has supportedresearch to find its answer. These efforts culminatedin the Foundation sponsoring a conference on foodsafety, held in Cambridge last month. Its organisationwas the idea of the late ALASTAIR FRAZER, a pioneer infood-science research, and the book arising from theproceedings 1 will be dedicated to his memory. At theconference, his paper, completed shortly before hisdeath, and read by Sir ERNST CHAIN, gave a masterlysummary of the present situation. Its plea was formore biochemical information about the additives andtheir metabolism and for more workers to enter thearea of food science.The question of the ultimate effects of food

additives on man is unanswered. Human experimentsare possible only on a very small scale and, in any case,they do not mimic the life-long very low doses towhich man is usually exposed. The problem differsfrom that of drug toxicity, where a recipient can beexpected to benefit from the treatment and where alarger quantity of the chemical is given over a shortertime. Animals may react differently from man: thereis, for instance, considerable species difference in themetabolism of the flavouring agent, propyl gallate 2 ;and animals differ from man in their metabolism ofthe additive.3 The action of intestinal flora may beconcerned: they are responsible, for instance, for theconversion of the sweeteners, the cyclamates, to thepossibly toxic cyclohexylamine.4 The flora differfrom species to species 5; and germ-free animals andprimates available for long study are hard to obtain.1. Metabolic Aspects of Food Safety (edited by F. J. C. Roe). Oxford

(in the press).2. Dacre, J. C. N.Z. Inst. Chem. 1960, 24, 161.3. Daniel, J. W., Gage, J. C., Jones, D. I. Biochem. J. 1968, 106, 783.4. Frazer, A. C. J. R. Soc. Hlth (in the press).5. Drasar, B. S., Shiner, M., McLeod, G. M. Gastroenterology, 1969,

56, 71.

Moreover, even in man, individuals may vary in theirresponse to the additive. These differences are basedon such factors as genetic background, underlyingdisease, and state of nutrition. Government agenciesdemand a vast amount of toxicological data before anadditive is released for general use. Recommendationsmade by the F.A.O./W.H.O. in 1967 and U.S. Minis-try of Agriculture, Fisheries and Food include acute,short-term, and long-term studies of overall toxicityon several species of animals, data on the metabolismof the compound, and its effect on reproduction inyoung animals and on basic enzyme systems. TheWorld Health Organisation holds meetings from timeto time on the effect of food additives. 6 7

Enzyme induction is defined as an increase inenzymes relative to cell protein, and many of the foodadditives, or their metabolites, are highly efficientinducers of the microsomal enzymes in the liver. 8

This action may be recognised experimentally by anincrease in liver weight, by measuring an increase inthe microsomal cytochrome enzyme p450, or bynoting an increase in the smooth endoplasmicreticulum under the electron microscope. Dicophane(D.D.T.) is a known inducer of microsomal enzymes inanimals, and it has been used to treat jaundice in apatient with a rare form of unconjugated hyper-bilirubinaemia marked by a reduction of conjugatingenzymes in the liver.9 Conversely, it has been shownthat the metabolism of dicophane may be increased ifthe subject is receiving a drug which has induced thehepatic microsomal enzymes. Anticonvulsant drugswould act in this way, and, in fact, the blood levels ofthe principal metabolites of dicophane were muchlower in epileptic patients taking these drugs than in acontrol group.l0 Practically, it seems very unlikelythat the small amount of additives taken with foodwould be sufficient to induce hepatic enzymes in man.Nevertheless, hepatic-enzyme induction remains ofgreat theoretical interest, and an increase in liver weightis an important test of the toxicity of a food additive.Some additives, such as butylated hydroxytoluene

(B.H.T.), an anti-oxidant used to preserve fats and oils,or dicophane, are stored in the body’s adipose tissue,sometimes for many years. The amount of exposurein a lifetime can be estimated by postmortem analysisof the adipose tissue. In Great Britain, human fataverages 0-49 parts per million of B.H.T., and in theUnited States it is up to 3-19 p.p.m.ll Dicophanemetabolites increased in the adipose tissue ofUnited States citizens from 5-3 p.p.m. in 1950 to 10-3

6. Reports of the Expert Committee on Food Additives. Wld Hlth Org.techn. Rep. Ser. 1958, no. 144, 1962, no. 228, 1967, no. 348, 1968,no. 373, 1969, no. 382.

7. Ministry of Agriculture, Fisheries and Food: Memorandum onProcedure for Submissions on Food Additives and Methods ofToxicity Testing. H.M. Stationery Office, 1965.

8. Conney, A. H. Pharmac. Rev. 1967, 19, 317.9. Thompson, R. P. H., Stathers, G. M., Pilcher, C. W. T., McLean,

A. E. M., Robinson, J., Williams, R. Lancet, July 5, 1969, p. 4.10. Davies, J. E., Edmundson, W. F., Carter, C. H., Barquet, A.

ibid. p. 7.11. Collings, A. J., Sharratt, M. Fd Cosmet. Toxicol. 1968, 6, 79.

362

in 1962.12 The significance of these deposits isuncertain. Conceivably, any sudden reduction ofbody fat (for instance, by slimming or as a result ofdisease) might release them from the depots in toxicamounts. Mounting concern about their storagelevels has led Sweden and several States in the UnitedStates to ban the use of dicophane within theirborders for a trial period.

Perhaps the greatest fear about food additives istheir possible role as carcinogens, and indeed there issuggestive evidence that they could sometimes act inthis way. The danger, however, is usually predictablefrom toxicity studies and, for the intentional foodadditives, it can almost certainly be avoided. Some-times there is an accident: in 1957, in the UnitedStates, a carcinogenic pesticide, 3-aminotriazole, wasapplied to cranberry plants at the wrong time and intoo large quantities; the fruit was contaminated, butthe mistake was realised and the cans of cranberry jellywere rapidly withdrawn from the stores. Nitrites, usedto smoke fish such as salmon and herring, can reactwith secondary and tertiary amines produced in thefish to form highly carcinogenic nitrosamines. Nitro-samines have been responsible for liver disease insheep fed fish meal to which sodium nitrite had beenadded as a preservative.l3 Nitrosamines have alsobeen found in foodstuffs such as smoked fish and mealintended for human consumption 14 ; and they areprobably present in some African alcoholic bever-ages.l5 Nitrites, however, have been for many yearsthe traditional method of curing fish; so it seems likelythat, had they been carcinogenic in man, this wouldhave been detected long ago. The polycyclic hydro-carbons which are such potent carcinogens in

laboratory animals seem to be without carcinogenicactivity in subhuman primates.I6 More importantcarcinogens are the unintentional additives, the result,for instance, of fungal contamination of food. Such

mycotoxins could account for the very high incidenceof primary liver-cell cancer in Africa and in othertropical areas where grain is the staple diet and isstored under conditions in which it could become

mouldy. Aflatoxin, the mycotoxin that has been mostclosely studied, is derived from Aspergillus flavus,17and it was first detected as a contaminant of ground-nut meal when it produced an outbreak of fatal diseasein turkeys and other domestic animals. Aflatoxin is

highly carcinogenic to rats, mice, and trout; andhepatic tumours have been induced in rats by a singledose.18 So far, aflatoxin does not seem to be carcino-genic to primates, even when fed for three years.I912. Dacre, J. C. in Metabolic Aspects of Food Safety (edited by F. J. C.

Roe). Oxford (in the press).13. Ender, F., Havre, G., Helgebostad, A., Koppang, N., Madsen, R.,

Ceh, L. Naturwissenschäften, 1964,51,637. See Lancet, 1968,i,1071.14. Ender, F., Ceh, L. Fd Cosmet. Toxicol. 1968, 6, 569.15. McGlashan, N. D., Walters, C. L., McLean, A. E. M. Lancet, 1968,

ii, 1017.16. O’Gara, R. W. Cancer Res. 1968, 28, 2272.17. Newberne, P. M., Butler, W. H. ibid. 1969, 29, 236.18. Carnaghan, R. B. A. Br. J. Cancer, 1967, 21, 811.19. Cuthbertson, W. F. J., Laursen, A. C., Pratt, D. A. H. Br. J. Nutr.

1967, 21, 893.

Cirrhosis and cytological changes may appear in theliver but no tumours-which is comforting, althoughsuch experiments are limited in time and do notcover the lifetime during which the native Africanwould be expected to be exposed to the mycotoxin.Full epidemiological surveys must be undertaken ofthe content of mycotoxins in food from various partsof the world, and the findings must be related to theactual diet of the native and to the incidence of primaryliver cancer in the regions.

Intentional food additives have now become bigbusiness. They add not only to the preservation butto the visual attractiveness of foods. The line that" the additive is O.K. if it helps sales and does notmake the consumer noticeably ill " is clearly not goodenough, and food producers are making strenuousefforts to ensure that their products are as far as pos-sible harmless and pure. It is also true that theintentional additives, such as B.H.T. or cyclamates, are,by and large, much less toxic than the unintentionalones, such as dicophane. Moreover, the good achievedby the additives often far exceeds any possible risk:the supply of adequate quantities of safe food to largeurban communities would be very difficult withoutthem. Again, agricultural productivity relies on pestcontrol, antibiotics, and hormones; and the nutritionof the overexpanding world population depends onthese sophisticated methods of food production andpreservation. Nevertheless, vigilance must be strictlymaintained. The additives should be permitted onlyin the smallest amounts possible, the most poorlyabsorbed from the intestine should be preferred, andthe substance must be fully examined before it is intro-duced. It is fortunate perhaps that fashions in foodadditives change, so that any one person is unlikely tobe exposed to the same chemical over his entire life.If cooperation continues and increases between allthose interested in the food sciences, whether manu-facturers, industrial chemists, toxicologists, pharma-cologists, pathologists, or clinicians, a disaster fromfood additives intentionally introduced seems veryunlikely.

Electrical Stimulation of the Carotid-sinusNerves for Angina Pectoris

IN 1928, WASSERMANN reported that manualstimulation of the carotid sinus relieved anginapectoris, an observation which was confirmed in 1937by WAYNE and LAPLACE 2 and in 1945 by LEVINE,swho seventeen years later was to use the techniqueas a diagnostic test for angina pectoris.4 Two yearsago, BRAUNWALD and his colleagues 5 described thebeneficial effect of electrical stimulation of the1. Wassermann, S. Wien. klin. Wschr. 1928, 41, 1514, 1560.2. Wayne, E. J., Laplace, L. B. Clin. Sci. 1937, 1, 103.3. Levine, S. A. Clinical Heart Disease. Philadelphia, 1945.4. Levine, S. A. J. Am. med. Ass. 1962, 182, 1332.5. Braunwald, E., Epstein, S. E., Glick, G., Wechsler, A. S., Braun-

wald, N. S. New Engl. J. Med. 1967, 277, 1278.