epidemiology in food safety evaluation-past and present
TRANSCRIPT
CLINICAL TOXICOLOGY 9( 5), pp. 665-690 (1976)
Epidemiology in Food Safety Evaluation-
Past and Present
W. HARDING LE RICHE
Faculty of Medicine University of Toronto Toronto, Canada
Las t yea r I had the privilege of visiting the Sittingbourne Research Centre, Shell Research Limited, Kent, England to see what they were doing. While I had known of the vast number of chemicals used in food protection and production, this enormous institute brought the whole business home to m e very forcibly: We are very dependent on a whole range of chemicals for food production. And it is not mere ly a question of fert i l izers. They cover a huge range, from pesticides, to plant growth regulators, to selective weedkillers, to soil nemato- cides, to special insecticides, fungicides, bacteriocides, and viru- cides. Then there are a whole range of chemicals that kill paras i tes harmful to the animals that human beings eat. Human schistosomiasis is one of the most debilitating worm diseases in the tropics, while the liver fluke (fasciola) ha rms the health of domestic animals. Fo r all these we need special chemicals for the i r control. In the future, with- out doubt, plant growth regulators will be of increasing importance.
And all these chemicals may have harmful effects in humans and the other animals. The investigation of toxicologic proper t ies of chemicals is of great importance and becoming increasingly more so. In Canadian medical schools, toxicology, so far, has been grievously neglected. Money, in la rge amounts, is available fo r fashionable projects like health ca re research , but it is not available in adequate amounts for a study, not only of chemicals, which are applied to
66 5 Copyright 0 1976 hy Marcel Dekker. Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retr~eval system. without permission in writing from the publisher.
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foodstuffs for various purposes, but for substances in the industrial environment, such as mercury, lead, and asbestos. Governments are curiously reluctant to protect their people against this type of hazard, surely a strange reflection on our political mas te r s who should, by this time, know that we are living in an industrial and a highly chem- ical environment. In our modern world, ranging from food production on the farm, to the manufacture of food products, we are completely dependent on the chemical industry for making new and more effective chemicals. On the other hand, we must increasingly be on our guard to s e e that our new chemicals are not harmful, because we have now reached a point a t which we cannot do without many of them. We are inextricably in the chemical age, and we must learn to make the best possible use of these remarkable substances which we have made. However, they are being manufactured at such a rapid rate that it is very difficult to keep up with all the needed testing. The government officials who are supposed to monitor all these chemicals have my deepest sympathy.
Before proceeding with this presentation i t is clearly necessary to give some definitions of epidemiology, taken from le Riche and Milner [13], There a re , of course, many more definitions.
S O M E D E F I N I T I O N S O F E P I D E M I O L O G Y
Quoting from le Riche and Milner, T e r r i s has pointed out that during most of the past century epidemiology was generally defined, to use the words of Wade Hampton Frost , as "the science of the mass-phenomena of infectious diseases. It But even then the defini- tion was inaccurate, as a number of epidemiologic achievements had been made by James Lind (1716- 1794) on scurvy, S i r George Baker (1722- 1809) on lead colic in Devonshire, and Percival Pott ( 1714- 1788) on scrota1 cancer in chimney sweeps.
fiable infectious d iseases were brought under control, particularly in the rich countries of the world. At the same time grea t s t r ides were being made in the study and control of nutritional and occupa- tional diseases.
ically illustrated by the resignation of Dr. John A. Ryle, Regius Pro- fessor of Physic at the University of Cambridge in 1943 to become professor of social medicine a t the University of Oxford. In Britain the term "social medicine" does not r e fe r to any political organiza- tion of medical ca re , but to what in Canada o r the United States would be called medical ecology, o r the study of all d iseases in groups of people in relation to environment and other factors.
During the f i r s t half of the twentieth century, virtually all the noti-
The change in orientation in the study of mass disease was dramat-
The following statement is from Ryle: "Public health, in the f i r s t
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FOOD SAFETY EVALUATION 667
instance, and again for obvious reasons, has been largely preoccupied with the communicable d iseases , their causes, distribution, and pre- vention. Social medicine is concerned with all d i seases of prevalence, including rheumatic heart disease, peptic ulcer, the chronic rheumatic diseases, cardiovascular disease, cancer, the phychoneuroses, and accidental injuries-which a l so have the i r epidemiologies and their correlations with social and occupational conditions and must eventu- ally be considered to be in grea te r o r less degree preventable."
In o rde r to give an idea of different concepts concerning epidemi- ology we give a number of additional definitions:
Epidemiology is the science of the infective diseases- their p r ime causes, propagation and prevention. More especially i t deals with their epidemic manifestations.
"The origin of epidemiology is historical, the e a r l i e r authors mainly describing the epidemics of the past; while this aspect has not been overlooked, it is the history of ideas, ra ther than of epidemics, which is here recorded. But the bas i s of the science is the knowledge of the process of infection of the individual, and of the responses to infection of the individual and of the herd. So clinical medicine, pathol- ogy, bacteriology and immunology are all gr i s t to the epidemiologist 's mill. Latterly, mathematical methods, both analytic and synthetic, have been applied to epidemiological problems, whilst the experimental method has a l so been used with the hope of simplifying the issues ' ' (Stallybras).
"Thus usage has extended the meaning of epidemiology beyond i t s original l imi t s to designate not merely the doctrine of epidemics but a science of broader scope in relation to the mass-phenomena of dis- ea ses in their usual as well as their epidemic occurrences. The sub- ject is pursued here with a homocentric bias, since ou r concern is primarily with human welfare. For present purposes, therefore, epidemiology is defined as that field of medical science which is con- cerned with the relationships of the various factors and distributions of an infectious process, a disease, o r a physiological s ta te in a human community. It seeks to advance rational conceptual schemes of causation of the various ills that afflict mankind medically speaking. To the extent that this body of knowledge is advanced and valid, it be- comes possible for appropriate community agencies to take effective measures directed toward prevention, control o r eradication" (Maxcy).
"If communicable d isease so evidently conformed to biologic laws, i f these processes could be interpreted in t e r m s of medical ecology, then other d i seases of population groups presumably could be ap- proached in s imi l a r fashion, Gradually it becomes apparent that the
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epidemiological method is applicable to most m a s s d iseases of man, and to injuries, to the extent that they represent problems of popula- tion groups" (Gordon and l e Riche).
"But f i r s t let me explain that what I a m writing of is the study of health and d iseases of populations and groups, the epidemiology of which Farr, Snow and Goldberger are the modern mas ters . By con- t r a s t with clinical medicine, the unit of study in epidemiology is the population o r group, not the individual" (Morris) .
"Epidemiology i s the study of the distribution and determinants of disease prevalence in man" (Macmahon, Pugh, and Ipsen).
In its broadest s ense the epidemiologist looks at m a s s manifesta- tions of disease, and of d i sease processes. These d isease processes may be due to agents that are alive, such as in the communicable diseases; they may be due to agents which are present, such as toxic drugs o r industrial agents; o r they may be due to the absence of agents, such as in dietary deficiency diseases. Then they may be due to various combinations of agents and environmental factors, such as cigarette smoking and air pollution combined, o r they may be due to self-induced diseases, such as those caused by overeating, lack of exercise, and the use of mood-modifying drugs, ranging from alcohol o r marijuana to heroin o r barbiturates. And last but not least, we a r e now beginning to realize more fully than eve r that there is a strong genetic component to certain diseases, such as, fo r instance, atherosclerosis and ischemic hear t disease. And there is a strong genetic component in the reactions of different patients to certain pharmacologic agents. For instance, people with glucose- 6-phosphate dehydrogenase deficiency are susceptible to the fava bean, primaquine, and phenacetin. This phenomenon makes the job of the regulatory pharmacologist all the more difficult. And in this a r e a the whole mat te r of synergism and antagonism in drugs is an added complicating factor.
In the usual public health epidemiology there are at least three essential s teps in the process of evaluation. The f i r s t is accurate diagnosis of the condition under study, the second is the adequate use of laboratory aids, and the last is the most effective use of statist ical analytical methods. This could be regarded as one branch of epi- demiology. Another, and most important branch of epidemiology, is the planning of prospective and retrospective studies on populations and the design of clinical trials, of considerable interest to the present audience.
But since the title of my talk includes the past as well as the present, I will at this juncture introduce the work of two famous clinical epidemiologists, James Lind, M.D. (1716- 1794) and S i r George Baker, M.D. ( 1722- 1809).
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FOOD SAFETY EVALUATION 6 69
T W O E A R L Y E P I D E M I O L O G I S T S W H O D E A L T W I T H F O O D S
James Lind was an Edinburgh man, who served as a surgeon in the Royal Navy. In 1753 he published h i s T rea t i s e of Scurvy in which he showed how scurvy, at that t ime a t e r r ib l e scourge, particularly in navies and a rmies , could not only be cured , but prevented, Lind was the first of the modern clinical investigators. He had faith in the validity of h i s own observations and in the logic of h i s inductions from them. He had no elaborate apparatus, and the only computer he had was that situated between h i s own two ears-in h is case , a most efficient instrument. His clinical study on the c u r e of scurvy is a model of excellence. Because he lacked numbers, h i s t r i a l was not statist ically significant, but i t certainly was of grea t biologic im- portance.
We quote from Lind' s Trea t i s e of Scurvy, reprinted in 1953 [ 181.
"The following a r e the experiments. "On the 20th of May 1747, I took twelve patients in the scurvy,
on board the Salisbury at sea. Thei r c a s e s were as s i m i l a r as I could have them. They a l l in general had putrid gums, the spots and lassitude, with weakness of the i r knees. They lay together in one place, being a proper apar tment for the sick in the fore-hold; and had one diet common to all, viz, water-gruel sweetened with s u g a r in the morning; f resh mutton-broth often t imes f o r dinner; a t o ther t imes puddings, boiled biscuit with sugar , &c.; and f o r supper , barley and ra i s ins , r i ce and cu r ran t s , sago and wine, or the like. Two o thers took twenty-five gutts of e l ix i r vitr iol th ree t imes a-day, upon an empty stomach; using a gargle strongly acidulated with i t for the i r mouths. Two o thers took two spoonfuls of vinegar th ree t imes a-day, upon an empty stomach; having their g rue ls and the i r o ther food well acidulated with it, as a l so the gargle fo r the i r mouth. Two of the worst patients, with the tendons in the ham rigid, ( a symptom none of the r e s t had), were put under a cour se of sea- water. Of th i s they drank half a pint every day, and somet imes m o r e o r less as it operated, by way of gentle physic. Two o the r s had each two oranges and one lemon given them every day. These they eat with greediness, at different t imes , upon an empty stomach. They continued but s ix days under th i s course , having consumed the quantity that could be spared. The two remaining patients, took the bigness of a nutmeg th ree t imes a-day, of an e lec tuary recom- mended by an hospital-surgeon, made of garlic, mustard-seed, g. raphan., balsam of Peru , and gum myr rh ; using fo r common drink, barley- water well acidulated with tamar inds ; by a decoction of which, with the addition of c r e m o r t a r t a r , they were gently purged th ree o r four t imes during the cour se (Table 1).
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TABLE 1. The Treatment of 12 Patients with Scurvy, by James Lind 1747
They all had one common diet, gruel with sugar in the morning, mutton broth for dinner, puddings, boiled biscuits at other times: fo r supper, barley and raisins, r ice, cur ran ts , sago, and wine. The additional treatment regimens were as follows.
Type of treatment Results
1. A quart of c ider a day Some effect
2. 2 5 drops of elixir of vitriol three t imes daily No effect
3. Two teaspoons of vinegar three t imes daily No effect
4. One half pint of sea-water daily No effect
5. Two oranges and one lemon daily "Sudden visible good effects"
6. An electuary of garlic, mustard seed, and other constituents, three t imes daily, barley water, tamarinds, and cream of t a r t a r
No effect
"The consequence was, that the most sudden and visible good effects were perceived from the use of oranges and lemons; one of those who had taken them, being a t the end of s i x days fit for duty. The spots were not indeed at that t ime quite off h i s body, not h i s gums sound; but without any other medicine, than a gargarism of elixir vitriol, he became quite healthy before we came into Plymouth, which was on the 16th of June. The other was the best recovered of any in h is condition; and being now deemed pretty well, was appointed nurse to the rest of the sick.
"Next to the oranges, I thought the cyder had the best effects. It was indeed not very sound, being inclinable to be a ig re or pricked. However, those who had taken it, were in a fairer way of recovery than the o thers a t the end of the fortnight, which was the length of t ime all these different courses were continued, except the oranges. The putrefaction of their gums, but especially their lassitude and weakness, were somewhat abated, and their appetite increased by it.
"As to the elixir of vitriol, I observed that the mouths of those who had used it by way of gargarism, were in a much cleaner and better condition than many of the res t , especially those who used the vinegar; but perceived otherwise no good effects from its internal use upon the other symptoms. I indeed never had a grea t opinion of the efficacy of this medicine in the scurvy, since our longest c ru i se
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FOOD SAFETY EVALUATION 671
in the Salisbury, from the 10th of August to the 28th October 1746; when we had but one scurvy in the ship. The patient was a marine, (one Walsh); who, after recovering from a quotidian ague in the latter end of September, had taken the elixir vitriol by way of res tora t ive for three weeks; and yet at length contracted the disease, while under a course of medicine recommended fo r its prevention.
"There was no remarkable alteration upon those who took the electuary and tamarind decoction, the sea-water, o r vinegar, upon comparing the i r condition, a t the end of the fortnight, with o thers whti had taken nothing but a little lenitive electuary and c r e m o r t a r t a r , at times, in o rde r to keep their belly open; o r a gentle pectoral in the evening, for relief of the i r breast. Only one of them, while taking the vinegar, fell into a gentle flux at the end of ten days. This I attributed to the genius and course of the disease, ra ther than to the use of the medicine. As I shall have occasion elsewhere to take notice of the effects of other medicines in this disease, I shall he re only observe, that the result of all my experiments was, that oranges and lemons were the most effectual remedies for this distemper at sea. I am apt to think oranges preferable to lemons, though perhaps both given to- gether will be found most serviceable."
Strictly speaking this trial did not have a placebo control group, as under the circumstances some so r t of treatment had to be given to all patients. Perhaps the electuary could be regarded as the placebo.
La ter I duscuss the work of S i r George Baker, a contemporary of J ames Lind, when naturally occurring experiments, which are used by the epidemiologist to elucidate a d isease process, are discussed.
A R A P I D R E V I E W O F T H E T Y P E S O F C H E M I C A L S IN F O O D S
The epidemiologist always t r i e s to see the whole picture before looking at the details. So I hope you forgive m e for giving you the following summary of those chemicals which may o r may not be in ou r foods (Table 2).
A F E W W O R D S ON F O O D A D U L T E R A T I O N IN T H E P A S T A N D E A R L Y L E G I S L A T I O N
In taking an historic view of chemicals added to foods, we can safely say that the past, i.e., the eighteenth and nineteenth centuries, was much worse than the present.
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TABLE 2. A Summary of Common Food Chemicals of Health Interest
1.
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
15.
16. 17.
18.
Trace elements. For example, lack of iodine produces cretinism. Zinc deficiency helps to produce certain dwarfs in Egypt and Iran.
Naturally occurring toxicants in foods. This fascinating subject has been very well discussed by Munro in this issue of Clinical Toxicology.
mercury compounds are used as fungicides to preserve wheat seed grain that recently has been eaten with disastrous conse- quences, in northern Iraq, Pakistan, and Mexico. Parathion is a poisonous spray used on fruit trees.
Coloring materials. In North America, eight art if icial colors are authorized and they are assumed to be harmless.
Alkalis, acids, and buffering agents. For example, acids in soft drinks destroy our children' s teeth.
Preservatives. A large number of substances, with sodium chloride being one of the oldest.
Antioxidants. Retard rancidity in fat foods. Why for instance do we remove vitamin E from our edible oils and supplement i t with butylated hydroxyanisole (BHA) and other substances ?
Sequestrants. Is i t a good thing to inactivate t r ace metals with ethylene-diamine tetraacetic acid (EDTA) ?
Emulsifying agents.
Flavoring agents. More than 1000 of these synthetic chemicals
Stabilizers. For body, smoothness, and consistency. Maturing and bleaching agents in the baking industry. How have
Anticaking agents.
Texturizing agents.
Indirect additives from packaging.
Added vitamins and minerals, such as iron. The whole range of biologic agents causing food poisoning. They
Pesticides, fungicides, and substances. For example, certain
are in use.
these substances affected ou r daily b read?
tend to be forgotten by chemists. Physicians, on the other hand, tend to think that they are the only causes of food poisoning.
Radioactive substances in foods.
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FOOD SAFETY EVALUATION 673
From Drummond and Wilbraham [6], The Englishman's Food, we find that in the eighteenth century vinegar often was dilute sulfuric acid, while copper sal ts were used to improve the color of green vegetables. In 1751 some types of I'gin" included the following:
Oil of vitriol (sulfuric acid) Oil of almonds Oil of turpentine Spirits of wine Lump sugar Lime water Rose water Alum Salt of t a r t a r (presumably potassium hydrogen t a r t r a t e )
This "gin" must have had quite a kick. According to Goodall [8] the first general food law was the Nether-
lands Law of 1829 (Wetten van het Koninkrijk de r Nederlanden 1829), followed by the British pure food law of 1860 (Public General Acts 1860). At this time adulteration of food had been going on for a t least 150 years, before action was taken. And there is still, in many countries today, a great deal of tardiness in dealing with food adulter- ation. At this level the epidemiologist o r rather the Medical Officer of Health had to deal with gross adulteration of foodstuffs and the additives of obvious poisons to many foods. At that t ime he had to have a substantial knowledge of chemistry as he had to supervise many of the analyses. Similar legislation was in due course passed in North America, but we will not go into the details, except to say that in recent years international agencies such as the World Health Organization and the Food and Agricultural Organization of the United Nations are taking increasing interest in food adulteration and con- tamination.
A N E P I D E M I O L O G I S T ' S P L A N O F A C T I O N I N S T U D Y I N G F O O D S A F E T Y
The approach, in a reasonably orderly form, to the epidemiologic study of food safety evaluation may be stated under the following headings:
1. Know al l the existing legislation on food safety. This is not merely a matter for lawyers, but also for senior administrators, whatever their background.
Remember biologic food poisoning as well.
ments, and possibly drugs taken for fun.
2. Study clinical cases of suspected chemicals in food poisoning.
3. Remember the possibility of synergism between foods, medica-
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4. Acquire a good knowledge of natural experiments and situations involving toxic food additives, accidental o r deliberate.
5. Have a good knowledge of the logic of determining causal rela- tionships. This is where a great deal of intuition and original thought are needed.
6. Learn about animal experimentation. It is a highly skilled and sophisticated procedure.
7. Plan good clinical t r ia ls in humans and t ry to find out how to transpose animal data to the human situation. It is not an easy task.
8. Develop various general monitoring studies on accidental poisonings. (The Drug Adverse Reaction and Poison Control Program of The Health Protection Branch.) Plan additional studies on autopsy material (in spite of legal difficulties), and possibly sample studies on hospital patients to find out what drugs are in their bodies on admis- sion. Here again we have overlapping between chemicals in foods and other ingested chemicals.
9. Study possible effects of pesticides and other agricultural chem- icals by methods mentioned above. 10. Consider possible effects of carcinogens, mutagens, and tera-
togens, but maintain a sense of proportion and balance in these matters. 11. Special clinical trials are now again needed in overdosing with
allegedly "good" substances, like vitamins. We have certainly not seen the end of megavitamin and megamineral therapy. Humankind will forever search for the Holy Grail, The Elixir of Life, and The Fountain of Eternal Youth, and there are many prophets and seers to help them in their quest.
K n o w l e d g e o f L e g i s l a t i o n
It is of considerable importance that senior administrators in the field of food safety have a good knowledge of the legislation of their own and other appropriate countries, as well as that of international organizations. The hysteria in the United States about mutagens, carcinogens, and teratogens, may well influence legislation in other countries, based on mindless emotion rather than fact. The Delaney Amendment, concerning "zero tolerance" for chemical carcinogens is a dogma which has made scientific cri t icism redundant and the ex- ercise of informed judgment impossible.
S t u d y o f C l i n i c a l C a s e s
The good clinician with an enquiring mind will always pick up strange manifestations of disease, because he deals with sick people. Where there are no physicians, o r nurses , the wise men o r women in the village will notice manifestations of strange diseases. This is
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FOOD SAFETY EVALUATION 675
usually the basis for start ing an epidemiologic investigation, and it is also a strong argument for the existence of a t least a certain number of medically qualified epidemiologists who maintain their clinical skills. No one can take their place.
A S I M P L E C A S E : F A T A L T O X A P H E N E P O I S O N I N G I N A 9 - M O N T H I N F A N T , A T L A N T A , G E O R G I A
"A 9-month-old Negro girl was brought to the emergency room a t 8:15 P.M.; she was convulsing in the a r m s of h e r deaf mother. The chief complaint was that of "cold, vomiting, and diarrhoea." It was difficult to get a history, because the mother was deaf. There are many causes of convulsions in infants, so the physi- cians concerned must have been competent and imaginative in their history taking. It was found that she had been playing with a tan powder used for dusting cotton. The insecticide was as- sumed to be an organic phosphate poison in the parathion cate- gory. Immediate atropine therapy was commenced, combined with pyridine aldoxime methiodide, said to reactivate cholin- es terase inhibited by organic phosphate insecticides. The child died. Chemical analysis showed the dust to contain dichloro- diphenyl trichlorethane (DDT) and toxaphene. It was assumed that the toxaphene was more important than the DDT plus atro- pine, 2-PAM in causing death because the toxaphene was found in high concentrations in the brain [91.
A M U C H M O R E C O M P L I C A T E D C A S E : T H E E P P I N G J A U N D I C E
"Early in February 1965 one of the medical students attached to St. Margaret ' s Hospital, Epping, reported sick with a history of severe upper abdominal pain of two days duration followed by mild jaundice. At about the same time a woman anaesthetist, marr ied to a local general practitioner presented with s imi l a r symptoms." In all there were 84 persons attacked by the disease.
I will not go into the intricacies of the diagnosis of jaundice, except to say that there a r e at least 150 causes of this one symp- tom. If we exclude hemolytic anemia and some rare cases of hepatic unconjugated hyperbilirubinemia we are left with a broad list of possible causes (Table 3).
In the investigation, infectious causes of the i l lness were excluded on clinical and laboratory evidence. This was a more difficult pro- cedure than may appear on the surface, because there were "infectious"
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TABLE 3. Jaundice Due to Acute Hepatocellular Damage
Infections Virus hepatitis
Infectious mononucleosis Yellow fever Other virus infections Portal pyaemia Septicaemia Leptospirosis Relapsing fever Syphilis Tuberculosis Other bacterial infections Protozoal infections
(infective hepatitis and serum hepatitis)
Poisons Carbon tetrachloride Dicophane (Chlorophenothane, DDT) Benzene derivatives Aflatoxins Tannic acid Muscarine 4, 4' - Diaminodiphenylme thane Phosphorus (yellow form) Physical agents (burns, irradiation)
Drugs Hydrazines and related drugs Halo thane Cytotoxic drugs The tetracyclines Paracetam ol Obsolete drugs
symptoms such as generalized aches and pains and a fever. The final diagnosis was made from a needle liver biopsy, which showed patho- logic changes that differed from those produced by known infective, toxic, o r therapeutic agents in humans.
The epidemiology of the condition was unusual. Cases were found in a restricted geographic area, in a high proportion of people of the professional class, husband and wife living together, o r mother and daughter living together. The medical student' s wife a lso became ill.
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FOOD SAFETY EVALUATION 677
The only common factor here was a loaf of wholemeal bread, bought by him in Epping. A s bread is so uncommon a vehicle of food poison- ing, her case was considered to be a Coxsackie virus infection. How- ever , the bread lead was followed, and i t proved to be a common link. Small pieces of leftover bread were fed to mice who developed hep- atic lesions. Control animals were not affected. No sign of a poison was found in the mill o r the bakery. The situation was most puzzling until someone thought of how the sacks of flour were transported to the bakery. The vans were also used to transport chemicals for a chemical company.
After persistant enquiry (epidemiologists must be firm and per- sistant ! ), it was discovered that on the day the flour was transported, a plastic jar containing a liquid had fallen and the cap had come off. Some of the contents were spread in the van. The flour bag was thought not to be contaminated. But i t was, and as it had stood for a week before the contents were used, the flour was well contaminated. The poison turned out to be 4, 4’ -diaminodiphenylmethane, a hardener for epoxy resin. The chemical identification of the toxic material was not easy. However, i t was carr ied out and the problem was solved by the combined effects of a clinician, an epidemiologist, a chemist, and a pathologist: So one case of jaundice with a severe bellyache, re- vealed a most unusual situation.
T h e I m p o r t a n t M a t t e r o f S y n e r g i s m B e t w e e n F o o d s a n d D r u g s o r D r u g s w i t h O t h e r D r u g s
The relationship of drugs such as Parnate (tranylcypromine), used to t reat psychotic states, to the development of hypertensive c r i s e s , when the patient eats foods high in the tyramine content, is most inter- esting and a t t imes dangerous. High tyramine foods include particular- ly, well-aged cheese, but a lso Marmite, chicken l ivers, pickled herring, chocolate, o r yeast extracts, in susceptible people. A recent paper on the subject, describing a large series of cases is by Cooper, Magnus, and Rose [4]. These situations, again, will be discovered mainly by clinicians.
S o m e N a t u r a l A c c i d e n t a l E x p e r i m e n t s o n F o o d C o n t a m i n a n t s
Well known in this area are water with high fluoride content, o r with high nitrate content, harmful particularly to young infants where the water is used to mix their formula. Such infants may show cyano- sis from methemoglobinemia produced by the nitri tes formed in the gut of the infants from the nitrates.
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T H E " E N D E M I A L C O L I C " O F D E V O N S H I R E
Si r George Baker M.D., in 1767, wrote a very well-reasoned account of the endemic colic of Devonshire. He surveyed the l i terature, and found amongst other mat te rs , that a d isease called "novus et popularis apud Pictones dolor colicus biliosus" was described by Francois Citois in 1617. This colic of Poitou only happened to those people who drank acr id Rhenish o r Moselle wines, which had been treated with litharge (lead mon- oxide) to improve the flavor.
In answer to the theory that the consumption of acid as such may produce this disease he noted that the Turks drink la rge quantities of acid sherbet with no ill effects, and likewise that jockeys who drink vinegar in o rde r to lose weight, do not get the dolor colicus biliosus. Likewise the inhabitants of the Bahamas drink much small punch made of l imes and they like- wise seem well.
He describes giving 3-1/2 ounces of very strong vinegar to a dog, who died, but there was no inflammation of h i s organs, except his lungs, presumably from inhalation of the vinegar. On the other hand, he quotes Brannerus who killed a dog with an ounce of powder of litharge, dissolved and boiled in vinegar (i.e., lead acetate). The effects were principally in the stom- ach, intestines, urinary bladder, and the rest of the abdominal viscera.
The endemial colic did not occur among the c ider drinking inhabitants of Worcester, Gloucester, and Hereford. What was the reason? Why did only t h e people of Devonshire develop the costiveness and paralytic weakness of lead poisoning and the madness ?
The answer to the riddle was the widespread use of lead in the Devonshire apple p re s ses to close the in te rs t ices between the grinding stores.
Baker and a colleague also ca r r i ed out chemical experi- ments, using "volatile tincture of sulphur" ( HzS) to precipitate lead sulfide ( PbS) from the cider. He car r ied out other chem- ical experiments, of great interest , but they are not mentioned here.
So we have the keen epidemiologist, who used his powers of observation far beyond the hospital, to the c ider p re s s , and who used laboratory methods to determine the nature of the noxious material in the drink. He a l so quotes animal experi- ments. In 1975 our chemical analytical methods are much better than those of Baker, but a r e our reasoning powers as good?
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FOOD SAFETY EVALUATION 679
P A R A L Y S I S I N M O R O C C O
The following is f r o m a n in te res t ing p a p e r by Smi th and Spalding [ 171.
We went t o Morocco on Sept. 25, 1959, as temporary ' ' ad- v i s o r s to the World Health Organisa t ion in o r d e r to a d v i s e the Moroccan heal th au thor i t ies in invest igat ing a n outbreak of a para lys ing d i s e a s e of unknown origin.
E p e d i m i o l o g y
T o s u m m a r i s e the information we w e r e given: 1. The f i r s t cases o c c u r r e d between Aug. 3 1 and Sept. 2.
The incidence then rose unt i l between Sept. 18 and 24, 200 to 300 new c a s e s w e r e being r e p o r t e d daily. By Oct. 2, when we left Morocco, m o r e than 2000 cases w e r e a l r e a d y known and i t was c l e a r that m o r e w e r e to be expected.
2. The outbreak was c e n t e r e d on Meknes and the towns in the vicinity, notably Sidi S l imane , Sidi Kacem, and Khemisse t . Of the few pa t ien ts s e e n e l s e w h e r e , a l m o s t a l l had recent ly been in Meknes. One m a n developed the d i s e a s e in M a r r a k e s h fourteen d a y s a f t e r leaving Meknes.
s h a r p l y f r o m d i s t r i c t to d i s t r i c t . With one exception (a man who had adopted the Moslem way of life), no c a s e s w e r e s e e n among the Eurpoeans , a m o n g the Jews , or a m o n g the be t te r - to- do Moslems. The c a s e s w e r e grouped in d is t inc t areas on the per iphery of the town where the p o o r e s t of the Moslem popula- tion live. Even in these areas, however , the dis t r ibut ion w a s uneven in that the poores t of the poor w e r e l a r g e l y s p a r e d .
4. Both sexes and all a g e s w e r e l iab le to the d i s e a s e , but the chief incidence was in adul t women, adul t men, and o l d e r children-in that o r d e r . When t h e r e w a s m o r e than one case in the s a m e fami ly they tended to follow one a n o t h e r a t i n t e r v a l s of four to five days.
5. From Sept. 14 to 18 o v e r a q u a r t e r of a mil l ion people vis i ted Meknes and i t s neighbourhood to c e l e b r a t e t h e feas t of the b i r th of the Prophet . So far as was known, not one of the v i s i t o r s had developed the d i s e a s e e i t h e r in Meknes o r a f t e r leaving it. It i s usual f o r s u c h v i s i t o r s t o br ing t h e i r own food with them.
6. A company of 100 s o l d i e r s was s ta t ioned at Meknes d u r - ing the outbreak. Only 2 of t h e s e developed the d i s e a s e , and
3. Within Meknes i tself the dis t r ibut ion of cases v a r i e d
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6 80 L E RICHE
both w e r e unusual in being a c c u s t o m e d t o e a t in the town, not in b a r r a c k s . S imi la r ly n o cases w e r e s e e n in the p r i s o n in Meknes, but a few p r i s o n e r s developed the d i s e a s e within a few d a y s of the i r re lease .
C l i n i c a l P i c t u r e
In the typical c a s e , the i l l n e s s began with aching pain and ten- d e r n e s s in t h e calf, followed by p a r a e s t h e s i a e and loss of s u p e r - ficial sensa t ion of stocking-and-glove dis t r ibut ion. Af te r a day o r two the d is turbance of sensa t ion d e c r e a s e d and might disap- p e a r , and a t about the s a m e t i m e m o t o r weakness appeared , in- volving f i r s t the m u s c l e s of dorsif lexion and e v e r s i o n of the foot and a l i t t le later the calf musc les . L a t e r s t i l l the m u s c l e s of the hand w e r e commonly affected also. Only the m o r e s e v e r e c a s e s w e r e admi t ted to hospi ta l , and v i c t i m s of the d i s e a s e who w e r e not in hospi ta l could e a s i l y b e identified at a d is tance by t h e i r ungainly high-stepping gait.
found to be los t , and although in except ional ly s e v e r e cases the m u s c l e s of the thigh and even of the pelvic g i r d l e might be af- fected, i t was often s u r p r i s i n g how abrupt ly t h e weakness stopped a t t h e leve l of the knee-joint. The hands might be s p a r e d , but m o r e commonly t h e r e w a s obvious weakness of the in t r ins ic m u s c l e s of t h e hand, which developed a few d a y s a f t e r the weakness in the l o w e r l imbs . Muscular wast ing was not conspicuous, but no pat ient had been p a r a l y s e d f o r m o r e than t h r e e weeks by the t i m e we s a w them. The tendon re f lexes in the upper l i m b s w e r e commonly p r e s e r v e d ; and although, as might be expected, ankle- j e r k s w e r e usual ly diminished o r ab- sen t , i t was s o m e t i m e s s u r p r i s i n g that even in c a s e s with s e v e r e weakness the ankle- j e r k s w e r e n e v e r t h e l e s s obtainable. The knee- je rks w e r e usual ly exaggera ted , i n c o n t r a s t t o t h e predominant ly lower-motor -neurone type of weakness dis ta l ly . The super f ic ia l reflexes w e r e n o r m a l , with the exception of the p lan tar reflexes which w e r e n e c e s s a r i l y a b s e n t when movement of the toes w a s paralysed.
Signs of genera l ill health w e r e uncommon. About one- th i rd of the pat ients , however , had a h is tory of r e c e n t d ia r rhoea . Some pa t ien ts had had a l i t t l e t r a n s i e n t f e v e r and s o m e a s h o r t - lived bradycard ia , not iced within a few d a y s of t h e i r a d m i s s i o n to hospital. All rout ine invest igat ions w e r e negat ive, including ana lys i s of t h e c e r e b r o s p i n a l fluid and of t h e blood.
The p ic ture , t h e r e f o r e , w a s essent ia l ly one of a c u t e p e r i p h e r a l n e u r i t i s in which the dis t r ibut ion of the weakness w a s overwhelm-
On examinat ion all voluntary movements below the knee w e r e
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FOOD SAFETY EVALUATION 68 1
ingly dis ta l . In addition t h e r e w e r e l e s s s t r i k i n g s i g n s of a n upper-motor-neurone les ion. T h e t h e o r i e s of causa t ion w e r e infective and toxic.
F i n d i n g s
A v is i t to Meknes convinced u s that the infect ive theory was untenable.
In B o r j Moulay O m a r , a s u b u r b of Meknes w h e r e the s tand- a r d of l iving is low, both the poor and v e r y p o o r e s t s e c t i o n s of the population w e r e so c lose ly in te rmingled that i t w a s impos- s i b l e to conceive of a n infection a t tack ing one sec t ion and s p a r - ing the o ther . It was equally imposs ib le to imagine that one sec t ion could r e a c t to a n infection as "a virgin population" while the o t h e r sec t ion r e a c t e d as an i m m u n e community. Final ly , those condi t ions favouring the s p r e a d of infection e n u m e r a t e d above b o r e m o r e heavi ly on the p o o r e s t of the poor , a m o n g whom the incidence was lower. T h i s opinion was conf i rmed by the lack of infection among the v i s i t o r s t o Meknes for the fest ival . T h e s e v i s i t o r s had r e t u r n e d to t h e i r h o m e s in all p a r t s of the country, and had they been exposed to a highly infect ious i l l n e s s they m u s t have cont rac ted the d i s e a s e o r a c t e d as carriers. Whether t h e incubation per iod was f o u r to five d a y s ( t h e s h o r t - e s t p o s s i b l e ) o r fourteen d a y s ( t h e longest) , new cases m u s t have a p p e a r e d by then in different p a r t s of the country. No such cases had been seen .
By c o n t r a s t the toxic theory r e c e i v e d overwhelming support . The doc tor in c h a r g e of the d i s p e n s a r i e s a t Meknes told u s
that he had recent ly s e e n s a m p l e s of cooking oil which w e r e as d a r k as old m o t o r oi l and that s o m e pa t ien ts bel ieved that t h i s oil w a s respons ib le for t h e i l lness . One fami ly had been so suspic ious that they gave s o m e food cooked in th i s oil to t h e i r dog. A s the dog showed no immedia te s ign of i l l n e s s they ate the food themselves . Within a few d a y s both the fami ly and t h e dog w e r e affected.
of the medina-the old A r a b town, occupied l a r g e l y by A r a b s of the a r t i s a n c lass -where t h e r e had been a s e v e r e but s h a r p l y c i r c u m s t a n c e d outbreak. In a g r o c e r ' s shop in t h i s area we found and bought a co loured bot t le t h r e e - q u a r t e r s full of v e r y d a r k oi l , bear ing a t r a d e n a m e of a c h e a p brand of o l ive oil. Other bot t les , of c o l o u r l e s s g l a s s , b e a r i n g the s a m e t r a d e n a m e s w e r e s e e n in the s a m e and neighbouring s h o p s contain- ing oil of the n o r m a l yellow colour . In the meant ime, the heal th au thor i t ies had invest igated the manufac ture and dis t r ibut ion of
Af te r leaving B o r j Moulay O m a r we v is i ted a c e r t a i n q u a r t e r
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cooking oils in Meknes and discovered that the same wholesaler supplied oil to all affected areas. Finally those questioned de- clared that the dark oil had been offered for s a l e only during the past month.
There was thus strong evidence that at least one consign- ment of cooking oil had been contaminated and was the cause of the outbreak. The contaminant was, we then supposed a miner- a l oil. In the f i rs t place the clinical picture corresponded closely to that described in outbreaks of O.C.P. poisoning seen in Germany and Switzerland since 1939 and in the U.S.A. before the war, and O.C.P. is added to certain oils for special purposes. Secondly, this hypothesis accounted for the pattern of the out- break: the well-to-do people could afford to buy better brands of oil, while the very poor could hardly afford to buy any oil at all. It explained the absolute immunity of the Jews, who have their own market. It also accounted fo r the extraordinary im- munity of visi tors to Meknes for the festival, since such visitors ordinarily bring their own food. Finally, the period during which the dark oil had been on sale corresponded precisely to the period of the outbreak.
and other samples of "olive" oil bought both in affected and un- affected areas, were analysed. Before we left, the Institute of Hygiene at Rabat had demonstrated the presence of phosphates and cresols. In this country a well-known industrial company with a highly specialised knowledge of oils very kindly under- took further examination of the samples. This firm demon- strated that the "olive" oil obtained in the medina at Meknes contained about 33% of vegetable oil and, much to our surpr ise , no mineral oil. The firm then showed that the toxic oil was a man-made lubricating oil containing nearly 3% of mixed cresyl phosphates, mainly the e- and - para-compounds. These oils are synthesised in o rde r to withstand the very high tempera- tures to which oils used to lubricate turbo-jet engines are ex- posed. They are very expensive, but as engine design a l t e r s and the science of lubrication progresses the oils periodically become out of date, and are then of little value. The firm was able to identify the specification to which the oil was made, and i t was one that is no longer current. Cresyl phosphates occur as a mixture of ortho-, meta-, andpara-compounds; but, as the dangers of the ortho-compounds are well known in the industry, manufacturers remove as much of them as possible.
The oil bought a t the g roce r ' s shop in the medina of Meknes,
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FOOD SAFETY EVALUATION 683
D i s c u s s i o n
Ortho-cresyl phosphates are highly toxic to the nervous system. Tri-ortho-cresyl - phosphates, though by no means the most toxic member of the group, is nevertheless the best- known, and was held responsible for the great outbreak of paralysis in the U.S.A. in the early 1930s. The disease then earned the name of Jake paralysis because the O.C.P. was present in a soft drink called "Ginger Jake'' o r I'Jamaica Ginger".
C a u s a l R e l a t i o n s h i p s
There is a whole philosophy about causal relationships, par t of the philosophy of science, often forgotten by scientists. Mausner and Bahn [15] give an excellent description of these matters and I briefly note some of the points they mention. Apart from observational and experimental studies, we have the natural experiment, which i f prop- er ly interpreted, can lead to sound conclusions. We have already men- tioned the "Epping jaundice" and the "endemial colic," which were natural experiments. There a r e many c a s e s of spurious association, particularly accepted by naive dependence on correlation coefficients. There must be much more than correlation, either negative o r posi- tive, to mean that A "causes" B, o r that B is the inevitable result of the existence of a situation called A.
Another point is that of indirect causation. It was once known and found that cholera occurred most often in low-lying areas, lending support to the idea that altitude had something to do with the disease, and that this was related to the "bad airt ' o r miasmatic theory of disease. The British, particularly, have always been very interested in "foul air" and I'fresh air." We know now that cholera is related very closely to contaminated water supplies, usually more common in densely populated, low-lying areas.
is that of sugar and ischemic heart disease. Yudkin has for years claimed that sucrose helps to cause ischemic heart disease in certain people. He may be correct, but it has a lso been found that heavy sugar ea t e r s also often are heavy smokers. And we know that the cigarette smoking is not health promoting, for the heart , the lungs, and the larynx. So this story is by no means solved. When there is multiple causation, i t is very difficult to unscramble the exact "strength" of each constituent causative element.
Another instance of probable indirect association, st i l l not clarified,
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I do not d i scuss Koch' s postulates in microbiology, except t o say that they should be considered in food additive studies. However, as in microbial d i seases , animal experiments do not always solve prob- l e m s in this a rea .
strength of association, consistency of such association (by ca r ry ing out many supporting studies), temporally c o r r e c t association (which is not always simple), and a l so the specificity of association (in that the occurrence of one variable can be used to predict the occurrence of the other). Findings usually should a l so show some coherence with existing information. This, however, is not always true. The re is a place for brilliant new ideas that have no obvious relationship to previous work.
An excellent discussion of these ma t t e r s has been presented by Susse r [19].
Without going into detail, we must a l so cons ider m a t t e r s such as
A n i m a l E x e e r i m e n t s a n d T r a n s D o s i t i o n t o M a n
I do not go into any detail about an imal experiments and the i r extrapolation to humans, except to say that animal experiments a r e by no means the whole answer in determining drug toxicity, carcin- ogenicity, teratogenicity, o r mutogenicity.
The f i r s t and s imples t point to be made is that animal experi- ments must be well designed, properly monitored, and in te rpre ted by people who know what they are doing. This means that the invest- igator must himself o r herself look a t the an imals daily and not leave everything to the technician. Another important point is that the toxi- cologic examination must be done on all the organs of all the an imals by a competent t i s sue pathologist. Biochemical and o ther laboratory observations of the an imals must be done by competent people.
We know that up to about 1950 there had not been se r ious testing on animals of most new drugs. A s a resu l t of the thalidomide tragedy of 1961 everyone woke up, and perhaps s ince that t ime regulatory agencies have m o r e and m o r e been asking what is c lear ly impossible from people who develop new therapeutic drugs. It s e e m s that the government agencies expect a miraculous drug that is at the s a m e t ime therapeutically efficacious but with no s ide effects whatsoever. This looks l ike an impossible dream.
in the s a m e way to the s a m e drug. So, how many spec ies of an imals must we t e s t ? I somet imes have the i r r eve ran t impress ion that the man in the regulatory agency will say: "Oh yes, you have tested this drug in mice, rats, guinea pigs, ca t s , dogs, hams te r s , Chinese ham- s t e r s in communes and out of communes, but have you tested i t in the aardvark , the wombat, and Tyrannosaurus r ex?" The danger here ,
Clearly we need animal experiments. But all an imals do not reac t
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FOOD SAFETY EVALUATION 68 5
will be more tests, giving the regulatory agency more t ime to stall. I would say, stalling is quite acceptable if there is a reason for it, but artificial "make- work" activities are immoral.
In animal experiments, and their transposition to humans, the very difficult question is: "What is the same dose?" Is i t to be determined by weight, by surface area, by metabolic r a t e ? How long should the experiment be run for chronic toxicity? And when regulatory agencies lay down such trials, what is the evidence for their requirements?
On the basis of animal toxicology we need immensely better pharma cologic thinking and design, and much closer cooperation between human clinical experience and the animal laboratory [ 3 ] .
For instance, chemically such widely divergent drugs as phenyl butazone, corticosteroids, and others, which al l have an anti-inflam- matory action, have also produced duodenal ulceration in man, and this is seen even more commonly in dogs. Could a more selective drug be developed which avoids this particular side effect?
What must not be forgotten is that there is no assurance that the metabolism of a particular drug, o r food additive, is necessarily the same in all animal species. However, what we need here are sophis- ticated chemical analytical techniques that can discover such differ- ences, which may possibly be of use in the f i rs t human clinical t r ia ls , to s ee whether human metabolic reactions are s imilar to those of a particular animal.
T h e C l i n i c a l T r i a l
Clinical t r ia ls in humans are a complex, highly skilled, and very responsible activity, calling not only for clinical, but for pharma- cologic skil ls of a high o rde r as well. Clinical effects on Caucasians, f o r instance, may be different from results on certain other groups. Primaquine, for instance, is well tolerated by Northern Europeans, but i t may cause hemolysis in Negroid peoples and Mediterranean r aces who may have an inherited deficiency of glucose- 6-phosphate dehydrogenase. There a r e genetic differences in reactions to cer- tain drugs. There a r e placebo reactors who feel better on inert sub- stances. Should they be included in clinical t r i a l s? In human experi- mental subjects, i f we a r e not very careful, there may be drug inter- actions if they a r e taking other drugs as well during a trial , and las t but not least, we must be quite s u r e that they are actually taking the drug which we are testing. There are various ways of determining this, ranging from radioactive tagging to studies of metabolites in the urine o r serum.
Finally, a few words on numbers. Of course, i f a t all possible, numbers of ca ses should be large enough to make statist ical analysis possible. But we should not become obsessed with this. Lind carr ied
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686 LE RICHE
out his scurvy trial in 1747 on 1 2 people. His results were, biologic- ally, clearly significant, although his numbers would not have satis- fied the statistician. In 1940, one hundred and ninety-three years later, John H. Crandon M.D. of Harvard, published the other par t of this type of tr ial , on one case, himself [5]. H i s question was: How long does i t take to produce scurvy on a diet containing no ascorbic acid, but with all the other dietary constituents 7 His classic study provided the answer, although the experimental purist no doubt would like to see i t repeated. After 134 days small perifollicular hyper- keratotic papules began to develop over the buttocks. These lesions a r e s imilar to those found in vitamin A deficiency. Other tes ts showed no vitamin A deficiency. After 161 days there appeared, for the first time, small perifollicular hemorrhages o r petechia over the lower legs. Fatigue started at the beginning of the third month. At the end of 3 months also, there was lack of wound healing. f i r - ther details a r e provided in the paper for the interested reader.
It is unnecessary to mention that planned clinical t r ia ls need ap- propriate selection of subjects, control groups, double-blind design, and sound common sense. It a lso r eas su res the experimental volun- t ee r s if they are told that all the people who are running the t r ia l have themselves taken the new drug under test, on the principle that what’s sauce for the goose is also sauce for the gander.
However, animal experimentation cannot fully take the place of human trials. No rat o r rabbit can tell whether he has a headache, o r whether he feels apprehensive o r depressed, for instance.
The ad hoc Subcommittee on The Use of Human Subjects in Safety Evaluation of The Food Protection Committee of the National Academy of Sciences [16] points out:
mal data the toxicity that would occur in humans with respect to the liver, kidneys, bone marrow, and gastrointestinal tract.
2. While the dog gave a better indication than the r a t of toxicity in humans neither of these species predicted hypersensitivity o r allergic reaction in humans.
3. The effect of a particular drug on humans can be determined only by testing i t on humans themselves.
4. The greater the variation of activity between species, the greater the possibility of e r r o r in extrapolating these effects to humans.
5. While a great deal can be learned from animal experimenta- tion, human evaluation is essential, particularly in regard to hyper- sensitivity, headache, some anemias, minor central nervous system and psychological distrubances, and the effects of groups of drugs given simultaneously.
the following studies in humans may be useful:
1. In the view of Litchfield [14] i t is possible to predict from ani-
According to the National Research Council report No 1270 [16]
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FOOD SAFETY EVALUATION 687
A. Planned exposure studies 1. Metabolism, mode of action, enzymatic effects, a f t e r laboratory
and animal study have indicated likely lines of approach. 2. Simple feeding tes t s involving observation of response to safe
levels. 3. Absorption and storage. 4. Skin sensitization.
1. Chronic occupational exposure (with some estimate of amount of intake): ( a ) comparison of reactions with those in experi- mental animals:excretion, storage, and metabolism; (b) long- te rm observation, epidemiology.
2. Acute poisoning (occupational, accidental, suicide): Compari- son with reactions of experimental animals.
3. Population surveys: ( a ) t issue storage-surgical and necropsy samples; (b) placental transmission; ( c ) mammary transmission.
B. Environmental and epidemiologic studies
G e n e r a l M o n i t o r i n g S t u d i e s
To s t a r t with, there should be studies on pesticide and t r ace metal content of various foods, as purchased, and as eaten, particularly in communities where danger is known to exist, such as mercury o r a rsen ic contamination in some North American lakes and s t reams. There seems to be great keenness on the par t of certain governmental agencies and departments to get excited, fo r instance, about minor mat te rs such as cyclamates, but to be r a the r silent about radon in uranium mines, fluoride in fe r t i l i zer plants, lead in Toronto, and as- bestos in various places.
Other types of routine monitoring should be done on people in in- dustrial employment where noxious substances of all types are present.
Since we cannot easily do toxicity studies on humans we should col- lect data on accidental exposure. This is being done by the Drug Adverse Reaction Program which collects data on accidental, suicidal, and homicidal deaths that have a chemical origin. In hospitals there should be far more, o r possibly routine, studies of the drugs in the bodies of patients before they en ter hospitals. This, obviously, cannot be done in all hospitals but periodic surveys should be undertaken in hospitals where the technical knowledge exists to do this work. How- ever, these studies should be well planned so as not to become gener- alized woolly fishing expeditions.
T h e S t u d y o f P e s t i c i d e s a n d A g r i c u l t u r a l C h e m i c a l s
These substances are very closely related to food safety for ob- vious reasons. The problem here is not those obviously poisonous chemicals like parathion, fo r instance, but marginal chemicals like
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DDT. We know what DDT does to insects and predator birds, but what does it do to humans? Where is the evidence of its harmfulness as an agricultural chemical to humans at the present t ime?
dieldrin. This may be justified. However, these chemicals and o thers are essential for the protection of foods. We seem to have reached the c ross roads already, and the choice is: more food through the use of various pesticides, and other chemicals, o r more starvation in a clean and pure external environment. If one were to choose the la t te r situation, the world population would have to be reduced from the cur- rent four billion to about one billion, which could be supported on a sustained-yield, no-chemical type of agricultural environment.
The technical study of pesticides is complicated and difficult. Cer- tain aspects of the subject are well covered by Jage r [ l l] and Golberg
There is currently a campaign being waged against aldrin and
[71.
C a r c i n o g e n s , M u t a g e n s a n d T e r a t o g e n s
I note with a sense of relief that a number of authors, whose a r t ic les follow this one, speak to this particular can of worms. This area is of great importance, and it engenders a great deal of emotion, often not based on reason.
As Golberg [7] points out, many factors influence an an ima l ' s re- sponse to a carcinogen and any extrapolation to humans of a "no-effect" level is filled with uncertainty with o r without mathematical embelish- ment and the use of computer models.
We should not forget that subcutaneous malignant tumors have been produced by water, salt , glucose, and a host of common nutrients. We have the impression that by appropriate dose concentration of solution, and frequency of administration by the subcutaneous route, virtually any substance could produce a carcinoma in the r a t and possibly in other animals as well. The rat is a most obliging little creature.
Teratogenic effects have been produced by air transport of mice on days 12 and 13 of pregnancy, fasting for 24 h r o r less a t a c r i t i ca l s ta te of gestation, a diet of ra i s ins for one day, many other mecha- n isms acting as stress factors, and hyper- and hypothermia. Even sodium chloride subcutaneously is teratogenic in mice. And we have not even mentioned the deficiency o r excess of many vitamins o r minerals on teratogenesis in certain laboratory animals.
When we get to mutagens, their numbers are so l a rge that we are surpr i sed that all of us in this room do not have webbed feet, wings, and pinheads. A s a student of human biology, I would suggest that the human animal is much more res i s tan t to noxious chemicals than are our little laboratory c rea tures . We should not lose o u r sense of balance, proportion and humor when studying carcinogens, teratogens, and mutagens. Life is not really as earnes t in this a r e a as we have been led to believe.
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FOOD SAFETY EVALUATION 689
S p e c i a l C l i n i c a l T r i a l s o n " G o o d " V i t a m i n s a n d M i n e r a l s
The time has a r r ived for far more studies on various vitamins such as vitamin C [l] , vitamin E, and many others. The last word has not been sa id on vitamins ( o r minera ls ) as pharmacologic agents.
For classical scholars of ancient pharmacology I should add a few words on definitions, kindly provided for m e by P ro fes so r George Walker, Faculty of Pharmacy, and Emer i tus Professor Char les Hanes, University of Toronto. Electuaries are confections of various consistencies. Elixir of Vitriol is aromat ic sulfuric acid. The tamarind is the fruit of Tamarindus indica, preserved in sugar, and Rad. raphan. is Raphanus sativus the lowly garden radish. In the report by S i r George Baker, we find that Saccharum Saturni is lead acetate, while volatile t incture of sulfur is hydrogen sulfide.
R E F E R E N C E S
[31
[41
T. W. Anderson. D. B. W. Reid. and G. H. Beaton. Vitamin C ~~
and the common'cold: a double-blind trial , Can. Med. Assoc. J., 107, 503 (1972). G. Baker. An essay Concerning The Causes of the Endemial - -
Colic of Devonshire, London J-Hughs near Lincoln' s-Inn- Fields. MDCCLXVII ( 1767) (Reprinted Delta Omega Society, 1958) S. B. de C Baker and D. G. Davey, The predictive value for man of toxicological t e s t s of drugs in laboratory animals, Brit. Med. Bull., 26, 208 (1970). A. J. Cooper, R E M a g n u s , and M. J. Rose, A hypertensive syndrome with tranylcypromine medication, Lancet, 1964- 1, 527. J. H. Crandon, C. C. Lund, and D. B. Dill, Experimental human scurvy, New Engl. J. Med., 223, 353 (1940). J. C. Drummond and A. Wilbxham, The Englishman's Food, Jonathan Cape, London, 1940. L. Golberg, T race chemical contaminants in food: Potential for harm, Food. Cosmet. Toxicol., 9, 65 (1971). H. M. Goodall, Control of food additives and contaminants, Proc. Nutr. SOC., 31, 9 (1972). E. C. Ham and C. Cueto, Fatal toxaphene poisoning in a 9- month old infant, Am. J. Dis. Child., 113, 616 (1967). A. F. Hess, Scurvy P a s t and P resen t ,xpp inco t t , Philadelphia and London, 1920. K. W. Jager , Aldrin, Dieldrin, Endrin and Telodrin. An Epidemiological and Toxicological Study of Long-term Occupa- tional Exposure, Elsevier, Amsterdam, 1970.
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H. Kopelman, M. H. Robertson, P. G. Sanders, and I. Ash, The Epping jaundice, Brit. Med. J., 1966-1, 514. W. H. le Riche and J. Milner, Epidemiology as Medical Ecology, Churchill Livingstone, Edinburgh and London, 1971. J. T. Litchfield, Symposium on clinical drug evaluation and human pharmacology. P a r t XVI. Evaluation of the safety of new drugs by means of tes ts in animals, Clin. Pharmacol. -' Therap 9 3, 665 (1962). J. S. Maugner and A. K. Bahn, Epidemiology, An Introductory - Text, Saunders, Philadelphia, Pa., 1974. National Research Council, Committee on Food Protection: Some conclusions in the use of human subjects in safety evalua- tion of pesticides and food, chemicals. National Research Council Publication No. 1270, National Academy of Sciences, National Research Council, Washington, 1965. H. V. Smith and J. M. K. Spalding, Outbreak of paralysis in Morocco due to ortho-cresyl phosphate poisoning, Lancet,
C. P. Steward and D. Guthrie (eds.), Lind's Treat ise on Scurvy, A Bicentenary Volume Containing a Reprint of The Firs t Edition by James Lind M.D. Edinburgh At The University Press, 1953. M. Susser, Causal Thinking in The Health Sciences Concepts and Strategies of Epidemiology, Oxford Univ. Press, New York, London, 1973.
1959-2, 1019.
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