The behaviour of foreign substances in the human body Adrien Albert

Oxygen and ethanol admirably illustrate the Parucelsian doctrine that foods, drugs and poisons are much the same and fhaf the type of effect obtained depends mainly on the dose. The present review compares and contrasts these three cufegories of xenob~o~cs. The uncomfo~able fucf that good, pure, wholesome food has ~~idio#s~y toxic properfies has been brushed under the carpet for too many centuries, but can now be seen emerging. Adrien Albert discusses the main aspects of malnutrition (too much, too little, and the wrong mix) and indicates opporfunities for wider reading. A clear separation of medicines from poisons, Paracelsus notwithstanding, is faking place at last, in our own times, fhrough implemenfafion of the principles of selectivity, a colzcept fhaf flows from Paul Ehrfich’s discover of the C~mofherape~tic index in 2911.

The principal foreign substances to which the human body is tqularly subjected are: food, medicines and poisons. That these three categories are related was realized as early as the sixteenth century when Paracelsus (1493- 1541), the noted Swiss sage and physician, wrote: What is not a poison? All things are poisons and nothing is without toxicity. Only the dose allows something not to be poisonous. For example, every food and every drink is a poison if consumed in excess”.

Whenever I lecture on ‘Xeno- biosis’ toseniorstudents, I find that some have difficulty in accepting that food is foreign to the human body. I have to point out that all of us, as infants, consumed mother’s milk; yet even the fat in this food, so like our own fat, must be broken down to fragments before it can be absorbed and then it must be reassembled before we can make any use of it. Another learner’s difficulty is with the concept of ‘in’. ‘If you swallow something, isn’t it in your body? Well, no! The gastrointestinal tract, from mouth to anus, is outside the body; and just as well because it is thickly populated with bacteria. Thus

Adrien Albert is resident Professor Emeritus in the Australian Naticngf University, Canberra and Research Professor in the Department of Phu~~cofogicui Sciences, School of Medi- cine, State ~~iv~~ Brook, USA.

of New York, Stony

digestion occurs outside the body and the ensuing fragments are passaged through the intestinal wall, to enter the inside.

~~n,a~ood,a~g,ora poison?

We may feel confident that we can separate, in our minds, the three classes of xenobiotics: foods, drugs, and poisons. However, there are many areas of overlap. Let us consider oxygen. It is as much a food as any of the items which we swallow at meal-time. Without it, food wo-uld be consumed in vain. At the dilution of 1 in 5 at which we feast on oxygen, all day and all night, it is evidently doing more good than harm; but at higher concentrations, such as are used in medicine, it becomes potentially dangerous. With proper caution, oxygen is advantageously used in heart and lung disease, e.g. to relieve the cyanosis of cardiac decompensation and to remedy pulmonary fibrosis and oedema. As a drug, oxygen is mostly used at a concentration of NJ-100% under normal atmospheric pressure; yet even at SO%, toxic effects set in at about 12 hours’.

Having viewed oxygen as a food and a medicine, we can now discuss it as a poison, an aspect first (though unwittingly) demon- strated by Antoine Lavoisier in 1785. The first systematic study of oxygen toxicity was made in 1874 by another Frenchman, Paul Bert,

TIPS - July 2987 Wok 81

who concluded: Z’oxygene, a trop haut dose, est done un agent mortel pour toutes les especes animalesf3.

Because no p~phylaxis or treat- ment for oxygen damage in humans is known, it must always be administered with care. Most of the rules have been learnt from experiments on healthy human volunteers, usually in naval estab- lishments. Such subjects, exposed to pure oxygen at 1 bar of pres- sure, developed coughing and chest pains after about six hours. Central nervous system symptoms appeared at 3 bars, in the form of vertigo and vomiting followed by convulsions in less than an hour. No subject sustained permanent injury if decompressed before convulsions set in. When fatalities occurred, the cardiovascular and respiratory systems were seen to be ~rofoun~y damaged, and ultrastructural inspection revealed destruction of plasma membranes, mitochondria, and nuclei*.

The biochemical basis of oxy- gen toxicity lies in the conversion of Lipids to lipo-peroxides, which inflict injury by (1) oxidation of -SH groups in enzymes, (2) des- truction of glutathione, and (3) disruption of membranes5. An hypothesis that oxygen toxicity derived from the superoxide radi- cal is disproved.

EthanolandtheParacelsiantriad Ethanol, also, provides a clear

illustration of the Paracelsian doc- trine, for it can be a food, a medicine or a powerful poison, depending on the dose. Ethanol is metabolized mainly in the liver’s cytosol where it is slowly oxidized to acetaldehyde; the latter is rapidly converted to acetyl-CoA which, in turn, provides energy for the citric acid cycle. Provided that the amo~t consumed is small, ethanol can replace its caloric equivalent of food as an energy source for steady, unde- manding work. However, because ethanol is oxidized only at a slow, invariable rate (and not on demand as is the case with glu- cose), its clearance from the blood cannot be increased by muscular exertion. Such energy as it pro- vides, if not immediately utilized as work, can be stored as fat, but not as carbohydra&. The contour of the regular imbiber often owes much to this storage peculiarity.

@ 1987. Elsevier Psablications, Cambridge 0165 - 6147/87/WZ.M)

TIPS - jzdy 1987 &‘ol. 8f

Somewhere between a food and a medicine is the low-dose use ef ethanol to add to the jollity of a repast. The consumption of etha- nolic drinks with meals is appreci- ated by many civilized people who view it as a social agent that promotes good fellowship. Early tribal groups in many parts of the world (though not in Australia, North America, or Oceania) disco- vered how to produce ethanolic drinks and formulated rules to limit their use.

Taken in moderation, ethanol promotes appetite for food. However, even moderate use impairs judgment, and the atten- dant eilphoria (usually experi- enced at a blood l.evel of 30 mg dl-‘, or 0.03%) can prevent the subject from appreciating his loss. At 50 mg dl-‘, some incoordina- tion is evident, and at 100 mg dl-‘, the diner (who often upsets his chair on rising} demonstrates ata- xia. At 200 mg dl-‘, he becomes drowsy and confused’. Because the over-consumption of ethanol can be specially dangerous for motorists, drivers’ blood levels are subject to legal control in many countries.

Ethanol used to be given as a stupefacient in those quick, crude operations practised before ihe introduction of ether in l&46. However, no dose was ever found, orally or by inhalation, that could produce anaesthesia without risk- ing respiratory arrest and death. Today, ethanol is used less in medical practice than as a house- hold remedy for insomnia, or to make the common cold more bear- able. However, it can usefully be injected near a nerve trunk or ganglion in inoperable cancer to relieve the pain.

We now come to the third, or toxic, aspect of ethanol. Social drinking, although completely forbidden by several religions, has little adverse effect on health when practised in moderation, say, within the range of one to six drinks (each containing about 10 g of ethanol) a day. Comfortably adapted to their habit, social drinkers are exposed to two hazards. First, they may, from time to time, go on a spree (social or solitary) and second, they may become dependent on ethanol.

A spree (bout, bender, or bin& lasts for several hcurs during which little food, but up to 500 g

of ethanol, is consumed. Because the liver cannot oxidize more than 100 mg of ethanol per kg body weight each hour, gross ethanolic intoxication sets in. The blood is unlikely to be clear of ethanol until two days later. Then, pro- vided the subject has not become involved with the police, he may be little the worse for the incident. Many people never repeat it. However, if a spree occurs each weekend, gastric erosion often begins and pancreatitis may set in as a painful and often terminal conditior?.

To become dependent on etha- nol is a much more serious matter. People in this situation cannot stop drinking even when there is every reason why they should. A man who consumes from 6 to 12 drinks a day, incurs grave physi- cal, mental and social problems; more than 12 drinks a day produce severe physical and mental dam- age. Because continual exposure to ethanol induces an oxidase in the liver’s endoplasmic reticulum and the established alcoholic often develops some CNS tolerance, he seldom shows signs of his severe intoxication. Yet he is far from sober, and his reactions are capri- cious and his judgments unreli- able. Moreover, in spite of the acquired tolerances, there is no elevation of the lethal dose.

In spite of a ruddy, healthy appearance, the alcoholic suffers chronically from digestive and neurological illnesses. His chronic gastritis leads to malnutrition, and

the incidence of peptic ulcer is high. Reversible enlargement of the liver (akoholic fatty he-+&is) is high and about 8% of alcoholics develop permanent liver damage (cirrhosis) from the attempt by fibrous tissue to repair eroded lobular tissues*9.

Illustration of the Paracelsian triad could easily be continued with caffeinaceous beverages and many other familiar xenobiotics. However, we might do better to look at the insidiously toxic aspects of food.

Is food good forus? Whether food is good for us

depends on two factors that may be verbalized as ‘how much? and ‘what kind?‘. The first question is studied as ‘quantitative malnuti- tion’ which comprises the two extremes of overeating and under- eating. The second -question is dealt with as ‘qualitative malnu- trition’, a matter of unbalanced diets.

The World Health Organiza- tionfo and many of the industrial- ized nations individually, have issued guidelines. These are, in part, aimed at caring for the nutrition of disadvantaged groups, but are also concerned to stave off those diseases (stroke, coronary heart disease and cancer) that terminate the lives of most of the well-nourished. For the latter, the principal recommendations are to eat less animal fat, to take less sodium chloride and ethanol, to monitor low-density lipopro-

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t&n-cholesterol and to increase consumption of fruits, vegetables and cereals.

A special problem is presented by the many people who are overweight. Apart from the bur- den (physical and psychologi&l) of carrying so much surplus trigly- ceride, the obese suffer from the principal diseases of old age sev- eral decades too soon! People who are 30% overweight incur about a 30% increase in mortality which rises to 50% for those who are 40% in exces#*”

The essentially toxic nature of food, in excess, was put on a quantitative footing by the classi- cal experiments of E. M. Boyd who showed that each major consti- tuent of a human meal was lethal to laboratory animals. Thus, glucose (25.8 g kg-*), given orally, killed half of a colony of rats in five hours; early onset of convulsions led to stupor and death. The corresponding figure for water was 70 ml kg-‘, given every 20 minutes. Quite simply, the excess of water had removed encugh sodium ions to inactivate nervous conduction”.

At the other pole of quantitative malnutrition is unde~u~~on, defined as a body-weight less than 75% oi normal. In 1945, the United Nations set up its Food and Agricultural Organization with the comment that at least twc- thirds of the World’s people were ill-nourished. Much is being done to remedy this imbalance, but the problem appears to be more administrative than medical”.

Proceeding, now, to qualitative malnutrition, we note that the proportions of carbohydrate, lipid and protein in a diet may be varied greatly without impairing health. The principal guidelines are (1) not to let protein intake fall below 37 g day-l, (2) to make sure that this protein intake contains enough of all the essential amino acids , (3) to maintain the total fat intake beIow 35% of the total dietary energy, and (4) to make sure that much of this is unsaturated fat13.

Whereas underprivileged peo- ple continue to suffer from vitamin deficiencies, it is now realized that, because vitamins are powerfully-acting chemica!s, large excesses must be avoided by the mere fortunate. A recent review identifies five mechanisms by which water-soluble vitamins are

injuring human beingsI (the toxic effects of vitamins A and D, even in small excess, have long been known).

Excess or deficiency of minerals can also unbalance a diet. Particu- lar attention is now being paid to selenium, a deficiency of which seems to favour cancer”.

Toxicants occurring naturally in wholesome foods

Man’s foods are complex mix- tures that contain many minor constituents, any one of which could be harmful or even lethal, if consumed in sufficient amounts. Two kinds of eater have been found to be at special risk: those who are disadvantaged either geographic- ally or economically and have very few kinds of food to eat and those who are so enthusiastic about some or other item of food that they eat quite unreasonable quantities of it. When the US National Academy of Science published the book: Toxi- cants Occurring Naturally in Foods, in 1966, it became better known that many wholesome foods have constituents that can affect normal people adversely*6*17.

Just how boun~~y Nature bestows a whole host of chemicals on each of her species is illustrated by the common potato in which about 150 different substances had been identified by 1967. When baked (without fat), 228 new, volatile chemicals were produced, each one identified by mass spectra after gas-liquid chromatographic separationr8. When, instead, the potatoes were boiled or fried, many other substances were synthe- sized. For the most part, the toxicities of these constituents re- main unknown. In fact, there are hardly enough toxicologists in the World to investigate them, not to mention all the other chemicals in the whole of the human diet. Fortunately, the potato has been eaten in Peru for about 4000 years9 and so it has undergone a long period of biological testing in humans.

Here, as usual, we have to distinguish between toxicity and hazard. The toxicity of a natural food constituent is the injury that it produces when tested alone and in unlimited quantity. The hazard is the injury likely to arise by eating a customary serving of food contain- ing it. The potential toxicity (but low hazard) that we have been

discussing for a typical vegetable is found again in the fruits. For example, the pineapple contains methanol and at least 19 methyl esters. This is disquieting because as little as 4 ml of methanol has produced permanent blindness in humans. However, the pineapple has been eaten in South America as a stapIe item of diet for about 6000 yearslg. When coffee beans are roasted, many hundreds of new compounds are generated, most of which have now been identified.

Many foods, particularly grains and beans, contain highly toxic proteins, such as lectins and the protease inhibitors. These are inactivated by cooking, a culinary refinement thought to date back about ~000 years. Until they learnt how to ~~u~~vei~t the natu- ral, self-protecting toxicity of most plants, countless numbers of our ancestors sacrificed themselves while finding out what is safe to eat and what is not. This knife- edged situation still exists. For instance, the cassava root which, when processed by its traditional growers into such nourishing foods as tapioca, maniac, and yuca, furnishes more than 10 per cent of the World’s carbchydrate :equire- ments. Unprocessed cassava is acutely toxic because of its high content of linamarin, a cyanogene- tic glucoside which liberates hyd- rogen cyanide in the stomach. The same hazard is presented by the lima bean, although this has safely been eaten in Peru for more than 8000 years”*.

How safe are additives? The word additive often gets a

bad press, as though these food- improvers, most of them natural products, were inimical to health. Today, the consumer is protected fmm possible ill effects in two ways: at the national level by Pure Foods Acts and their implementa- tion through the Courts and at the in~mational level by the Joint Expert Committee on Food Addi- tives operated by the Food and Agricultural Organization and the World Health Organization. This Committee’s annual reports of acceptance, rejection, and pen&- ted limits of additives have earned wide respect. It is interesting to compare this controlled situation with (1) the prolific and random inclusion, by Nature, of a huge

TIPS - ]uly 1987 [Vol. S]

profusion of chemical substances in natural foods and (2) the pro- lific and random multiplication of foreign substances effected in pre- paring family meals. Whereas a skilled organic chemist would be proud to be able to synthesize one new compound each week, the housewife, busying herself in the kitchen for just an hour, is bound to generate hundreds, most of them of unknown toxicity.

Medicines and poisons, differentiated from foods

Of the xenobiotic triad (foods, drugs and poisons), this review, so far, has paid attentish mostly to foods because most readers of TiPS are well informed about medicines and poisons. However, an even-handed treatment of all three topics is available as a book*O.

Although a substance may be a food, a medicine, or a poison depending on the dose, some fundamental differences exist between these three categories. For example, foods have to be taken thoughout life, to furnish energy and to facilitate growth and repair, whereas medicines are used to treat illness and are needed only so long as that illness persists. Again, the catabolism of foods and drugs proceeds by very different biochemical pathways. For foods, catabolism is obligatory and uses much NADP, whereas it is not obligatory for medicines but, when it occurs, uses NADHP.

Medicines and poisons, differentiated from one another

The common characteristic of drugs and poisons is that they both exhibit powerful biological activity in humans whereas food, in moderation, does not. An important aspect of toxicology is to study how a small molecular change can convert an inert mole- cule into a biologically active one. However, even when the activity has been achieved, one has made nothing better than a poison until a further property, known as selectivity, is built into the mol- ecule. The introduction of selec- tivity converts. a poison into a drug. Toxicity in a drug is no drawback; in fact it can be the very core of its usefulness. What is important, however, is that the toxicity should be selective*‘. Althoueh most drugs iniure the

uneconomic cells, even though only temporarily (as ether injures the CNS to provide anaesthesia), they must spare the economic cells which are in the majority.

Realization of the part that selectivity could play in improv- ing the safety of a drug dates from the first decade of the pre- sent century when Paul Ehrlich devised his therapeutic index as a means of measuring it?. Since that time, the ever-increasing knowledge of how to build selec- tivity into a molecule has begun to break the Paracelsian link between drugs and poisons.

The Paracelsian doctrine that what is a poison depends on the dose has to be kept in mind should (as an expert witness) we be asked, ‘Is this substance a poison? To answer this question, we need to know: (1) are people likely to come in contact with it; (2) if so, at what comed-ration; and (3) does it cause a harmful effect at that concentration? It may help to point out that the two substances that most often kill people acci- dentally are constantly, and harm- lessly, being generated in the human body, namely: hydrogen cyanide in leucocyteP, and car- bon monoxide by the routine degradation of haemoglobin24.

References 1 Paracelsus (Theouhrastus von

Hoheni&n. :5&; :rk; in ?-l-p W-k of Paracelsus in five Volumes (Peukert, W., ed.). Vol. 2. u. 510, Schwabe

2 Smith, T. C., Gr&s, J. B. and WoUman, H. (1985) in Goodman and Gilman’s Pharmacological Basis of Therapeutics (Gilman. A. G.. Goodman, L. S.. RaB, T. W. and Murad, F., eds), 7th edn, pp. 322-338, Macmillan

3 Bert, P. (1878) La Pression Baromt+ique. Recherches de Physiologic Expdrimentale, Paris: Masson et tie (reprinted, in English translation, in 1978 by the Undersea Medical Society -

4 Balenttne, J. D. (1982) Pathology of

261

Oxygen Toxicity, Academic Press 5 Chance, 8. and Boveris, A. (1978) Lung

Biology in Health and Disease; 8,18%237 6 Davidson, S.. Passmore, R., Brock, J. F.

and Truswell, A. S. (1979) Human Nubi- tion and Dietetics, 7th edn, Churchill Livingstone

7 Miles, W. R. (1922) J. Pkarvtncoi. Exp. Ther. 20,265-319

8 Victor, M. and Adams, R. D. (1983) in Harrison’s Principles of lnternnl Medicine, 10th edn (Petersdorf, R. G., Adams, R. D., Braunwald, E., Isselbacher, R. J., Martin, J. B. and Wilson, J. D., eds), pp. 1285-1295, McGraw-Hilt

9 Jaffe, J. H. (1985) in Goodman and Gilman’s Pkarmacological Basis of Tker- apevtics, pp. 548-550, Macmillan

10 Passmore, R., Nicol, B. M., Rao, M. N., Beaton, G. H. and de Maeyer, E. M. (1974) Handbook 0.1 Human Nutritiannl kequiremmts, FAO Nutritional Series No. 28, Food and Agricultural Dmani-

11 Garrow, J. S. (1978) Energy Bnhznce and Obesity in Mnn, 2nd edn, Elsevier

12 Boyd, E. M. (1973) Toxicity of Pure Foods, CRC Press

13 US National Research Council (Food and Nutrition Board) (1980) Recom- mended Dietary Albwancss, 9th edn., National Academy Press

14 Alhadeff, L., Gualtieri, T. and Lipton, M. (1984) Nub. Rev. 42,3w

15 Yu, S.-Y., Chu, Y.-J., Gong, X.-L., Chong, H., Li, W.-G., Gong, H.-M. and Xie, J. P. (1985) Biol. Trace Elem. Res. 7, 21-31

16 National Academy of Sciences (1973) Toxicants Occurring Naturally in Foods, 2nd edn, Washington

17 Liener, I. E. (ed.) (1980) Toxic Covsti- tuents of PZant Foodstufis, 2nd edn, Academic Press

18 Coleman, E. C., Ho, C. T. and Chang, S. S. (1981) J. Agti. Food Ckem. 29,424

19 Heiser, C. B. (1981) Seed to Civilization: the Story of‘ Ma& Food. 2nd eda, Freeman

20 Albert, A. (19&r) Xenobiosis: &o&, Drugs, and Poisons in the Human Body, Chapman and Halt

21 Albert, A. (1985) Selective Toxicity, 7th edn, Chapman and Hall

22 Ehrlich, P. (1911) Tkeorie und Praxis van Chemothempie, Rlinkhardt

23 Stelmaszy&ka, T. and ZgBcaynski, J. M. (1981) in Cyanide in Biology (Ven- nesland, B., Conn, E. E., Rnowles, C. J., Westley, J. and Wissing, F., eds), pp. 371- 383, Academic Press

24 White, P. (1970) Ann. N.Y. Acnd. Sci. 174, 2531

Drug nomenclature

The house style of Trends in Phannacolagical Sciences is to use recommended international Non-proprietary Names (or pro- posed INNS) wherever these exist. This may result in spellings of drug names that differ slightly from nationally approved or pharmacopoeial names - e.g. indometacin (recINN)Iindo- metha& (BP, USP); ceklotin (recINN)kephalotin (BP, USP); ciclosporin (pINN)/cyclosporin 0; pronetalol (recINNY pronethelol ,(BAN). See the latest WHO Cumulatiuz List of INNi3 for Phatntaceutical Substances or E.EJ. MarleA Phannacolwi- Cal and Chemical Symnytns for guidance.