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Toxic Chemicals in Food
J. Forens. Sci. Soc. (1 977), 16, 189
Toxic Chemicals in Food D. V. PARKE Department of Biochemistry, University of Surrey, Guildford, Surrey, England The various classes of toxic chemicals that may be present in food namely encironmental contaminants, natural toxins, pesticide residues, food additives and contaminants, are reviewed. It is emphasized that the real hazards from toxic chemicals in food are the result of gross contamination, deliberate or accidental, and a number of such incidents are bri&y described. ( A paper presented at the Scientijs Symposium of the Society's 16th Annual General Meeting held at the Mchforran Hall, City of London Police Station, Wood Street on 15th November 1975.)
Introduction Poisoning of food, whether by accident or design, advcntitiou;ly or the result of nature, is still one of the most common routes of administration of noxious substances. This year marks the centennial celebrations of the 1875 Safety of Food Act, and at a recent scientific meeting to celebrate this event Dr. Schmidt, Commissioner of the United States Food and Drug Administration, listed, in order of importance, the major causes of food poisoning in that country. I t is significant that these health hazards, and alsa their order of importance, are common to the United Kingdom and to many other countries as well as the United States (see Table l ) , and broadly represent the risks from food poisoning the world over. Contamination of food by micro-organisms, primarily Salmonella and staphylococci, is still the major cause of food poisoning but I do not propose to consider this aspect in any detail. I shall also omit further reference to the second item in Table 1, faulty nutrition, as this is too vast a subject for consideration in this paper and, like bacterial contamination, lies outside my terms of reference. Environmental Contaminants This category of toxic chemicals in food is usually well controlled by legal regulations in most countries. I t includes the heavy metals such as lead, cadmium and mercury (Kazantis, 1974) (see Table 2), the persistent organohalogens such as the polychlorobiphenyls (PCBs) and tetrachlorodibenzodioxin, and nitrate and nitrite. The toxicity due to heavy metals has been widely publicised in recent years, primarily as the result of methylmercury poisoning in the Minimata episode in Japan (Kazantis, 1974). Mercury which is used as a catalyst in various industrial chemical processes is lost in small concentrations in chemical effluents. The discarded metal is metabolised by various marine organisms and converted into the mercury alkyls, such as methylmercury, which then tend to accumulate in food chains and reach a considerably high concentration in fish (Magos, 1975). Consumption of the fish by local populations resulted in the progressive accumulation of mercury and methylmercury in these individuals with the appearance of symptoms of damage to the central nervous system, characteristic of Minimata disease. Similarly, the presence of cadmium in soils, a contaminant from nearby zinc refineries, or its presence in some red and orange glazes of ovenware; may through progressive leaching contaminate food resulting in hepatic and renal
TABLE 1 HEALTH HAZARDS F R O M FOOD
Salmonella, B. botulini saturated fatty acids, alcohol, refined carbohydrate heavy mrtals, persistent organohalogen compounds mycotoxins, cycasin chlorinatcd hydrocarbons, organophosphates, carbarnates anti-oxidants, dyes, nitrites
Bacterial contamination Faulty nutrition Environmental contariinants Natural toxins Pesticide rr3idurs Food additives
TABLE 2 EVALUATION 01: HEAVY METAL F O O D CONTAMINANTS*
iV1etal
Provirional tolernble weekly i~ttake img/l)etson) ,'..-*/kg> -s 3 0.05 0.4 0.007
Idcad Cadmium Mercury total methyl mercury (Hy)
--
0.3 0.2
0.005 0.003
Acceptable daib intake None None None None
damage. In general, shellfish contain more lead and cadmium than other foods, probably due to the dumping of refinery wastes in coastal estuaries. I t is thought that cadmium may compete with the similar, divalent metal zinc which is an essential component of many enzymes. Possibly as a consequence of this cadmium exerts its toxic effects, resulting particularly in damage to the kidney, leading to high blood pressure. Undoubtedly the most important of the heavy metal contaminants of food is lead and contamination of food with this metal has been recognised for a considerable number of years (Clayton, 1975). Until recently most of the contamination of food by lead resulted from poor manufacturing processes, the use of lead-containing folls, and lead-containing solders used in the canning process. Recently, due to the improvement in technology the contamination of canned food by lead has been considerably reduced, but the use of lead foil, particularly for capping the bottles containing wine and beer is a practice which should be discontinued. I t has been shown that crops grown in areas near lead smelters contain a much higher concentration of this metal than is normal, the plants reflecting the increased amounts of lead which are deposited in the soil. I t has also been shown that a similar hazard, but probably to a much lesser extent, occurs from growing vegetables in areas near motorways with heavy traffic. The lead in this situation presumably results from the lead alkyls added to motor fuel. Nevertheless, the health hazard resulting from environmental contamination bv lead ~ r e s e n tin motor fuel has ~ r o b a b l vbeen considerably exaggerated. Efforts to increase the use of petrol free from lead were singularly unsuccessful until regulations in the United States made automobile catalytic after-burners compulsory to minimise atmospheric pollution from exhaust gases of carbon monoxide and oxides of nitrogen and sulphur. It was soon discovered that the lead alkyls in petrol contaminated and damaged the platinurn and palladium catalysts in the after-burners, and as a consequence lead-free petrols are now being used on an increasing scale in the United States. Consequently we may find that the motorist will refrain from contaminating the environment with lead, but only at the expense of adding the possibly even more toxic metal alkyls of platinum and palladium to the environment. The second category of environmental contaminants are the persistent
organohalogen compounds. This group of chemicals includes the polychlorodibenzodioxins, highly toxic compounds formed in the manufacture, and possibly from the photochemical decomposition of the herbicides 2,4-D and 2,4,5-T. Similarly many other polyhalogenated and polycyclic compounds, such as the polychlorinated biphenyls, are known to exist in our environment, and only a few of these as yet have been identified. Some of these chemicals are possibly formed by photochemical decomposition and polymerisation of various simpler organohalogen compounds involved in the manufacture of pesticides or drugs and may also occur as by-products of other chemical manufactures. The hazards from these compounds result from their resistance to microbial metabolism, their consequence persistence in the environment, with build-up in concentration in food-chains. The anions, nitrate and nitrite are leached from soils that have been heavily dressed with nitrate fertilisers, the nitrite being formed as a microbial byproduct. The nitrate is subsequently taken up in high concentration by the plants and also leached from the soil into river water. Plants with high concentrations of nitrate, e.g., spinach, have presented real hazards because of the oxidative effect of nitrate on haemoglobin, resulting in methaemoglobinaemia. This is of considerable concern with infants (Phillips, 1971) who are more susceptible to this toxic effect than adults, and the consumption of vegetable produce, especially spinach, which contain high concentrations of nitrate resulted in a number of infants being affected by methaemoglobinaemia. The problem is now well recognised and baby food manufacturers monitor for high nitrate concentration in vegetable produce. Apart from the oxidative hazard due to nitrate, microbial reduction to nitrite may lead to another health hazard, namely the formation of carcinogenic nitrosamines by the interaction of nitrite with secondary amines present in foods.
Natural Toxins The most important of the natural toxins are the mycotoxins (Newberne, 1974; Austwick, 1975), but in different parts of the world various other naturally toxic chemicals, such as cycasin, the pyrrolizidine alkaloids of Senecio, the fluorofatty acids present in a number of African plants, the toxic entity of bracken, may also present hazards in various degrees to the human individual (Crampton and Charlesworth, 1975) (see also Table 3). These natural toxins form one of the more hazardous classes of toxic chemicals in food because there is little or no control over their presence, although statutory regulations are being directed towards eliminating contamination by traces of the various mycotoxins. The importance of the mycotoxins was first realised in 1960 when several million turkeys died through a form of food poisoning, the result of feeding TABLE 3 SOME NATURAL TOXINS PRESENT IN FOOD
Agent Hypoglycin A
Food Ackee fruit
Effect
Hypoglycaemia (vomiting sickness) Cholinesterase inhibition Potato Solanine Neurological disorder Lathyrogens Lathyrfcs spfi Favism Vicine, isouramil Fava beans Amyotrophic lateral a-Amino-8-methyl- Cycad nuts sclerosis pro~ionicacid Myoglobinuria Coniine Para!ytic shell-fish Saxitoxin poisoning Fugu or puffer fish Central respiratory failure Tetrodotoxin (From Crampton and Charlesworth, 1975)
Locality Jamaica Widespread India Mediterranean Guam, Mariana Islands N. Afi-ica U.S.A., Europe, Japan Japan
the birds a diet containing mouldy peanut meal. The peanut meal had become contaminated with Asbergillus Jlavus, a mould, which produced the aflatoxin as a natural metabolite. Much work has since been undertaken on these mycotoxins and it has been established that they are potent hepatocarcinogens, which are also acutely toxic to the liver and to the gastrointestinal tract. Since this first occasion many different mycotoxins have been discovered, all the products of a variety of moulds, which may under suitable conditions contaminate our food. Nevertheless this source of toxic chemicals in food has been quickly checked and producer countries, such as Nigeria, now ensure that the food is harvested and stored under conditions which minimise contamination with moulds such as Aspergillus Jlaaus. Furthermore, there are now highly sensitive chemical methods (fluorescence spectrometry) for the determination of minute quantities of these mycotoxins and surveillance of our food for the presence of aflatoxin and other mycotoxins is constantly maintained. Among the other natural contaminants of some consequence is cycasin which is found in cycad nuts, the staple diet in many tropical countries. Cycasin is the glycoside of methylazoxymethanol and when ingested, may undergo hydrolysis to yield the aglycone methylazoxymethanol. This aglycone is a potent hepatocarcinogen and undergoes further metabolism, by the liver microsomal enzymes, to form a potent methylating agent, similar to dimethylnitrosamine, which alkylates the DNA. Animals, especially cattle which have highly active populations of microflora in the rumen, can most readily effect the hydrolysis of cycasin and are, therefore, more susceptible than man to its toxic - - - - - - effects. --~~. -. I t is also mostly cattle that are affected by the poisons in bracken and Senecio. The poison(s) in bracken has been shown to be haemorrhagic, haemolytic, radiomimetic and carcinogenic and recently it has been suggested that the carcinogenic entity is shikimic acid. The carcinogenic chemical of bracken appears to be water-soluble and could be leached from the powdered ferns into the soil and thence into human drinking water. A world map of the bracken-growing areas shows a very close resemblance to a map of the areas of a high incidence of gastrointestinal and liver cancer, and it has been suggested that the incidence of human cancer, particularly in soft water areas, may be contributed to by the potent carcinogen present in bracken. The pyrrolizidine alkaloids are found in plants belonging to Senecio, a genus notorious for its toxic and carcinogenic effects upon the liver of the animals that consume this material. In certain areas of the world these alkaloids have also been associated with the formation of cyclops in cattle and sheep, and it is tempting to speculate that consumption by humans may, in the Grecian past, have been responsible for some of the allegories of cyclopian man. The occurrence of the fluorofatty acids in a variety of African plants has been associated with the toxicity of food containing these materials and also with certain African tribal practices. The fluorofatty acids are metabolised by P-oxidation to give rise to fluoroacetic acid or fluoroformic acid and the former enters the citric acid cycle resulting in lethal synthesis. I n this metabolic process, fluoroacetic acid is metabolised into fluorocitrate which subsequently blocks the citric acid cycle by inhibiting the enzyme aconitase. The result is the accumulation of citrate within the body's tissues and the lack of energy generation via the citric acid pathway. The high levels of citrate result in a reduction of ionic calcium and the poisoned subject dies in tetanic spasm. I n recent years fluoroacetate and fluoroacetamide, used as rat poisons, have found their way into pastures and streams and have resulted in the poisoning of sheep and cattle. These substances are extremely toxic, even in very small amounts, and it is exceedingly difficult to provide a n antidote.
Pesticide Residues The next category of toxic chemicals that find their way into our food, the fifth in importance with respect to hazard, are the pesticides. There is a con-
siderable degree of control over pesticide residues (Egan and Hubbard, 1975), which is exerted both at a national level and by international agreements, and the World Health Organisation has produced a list of acceptable daily intakes (ADI's) for most of the pesticides in current use. The chlorinated hydrocarbons are the most widely distributed pesticides, and these include DDT and its various metabolites, dieldrin, benzene hexachloride (y-BHC), chlordan, etc. (see Table 4). DDT and dieldrin have found disfavour in some countries because of their reported carcinogenicity in mice. Nevertheless, this finding of carcinogenicity in a rodent species may not have significance in man, and it has been suggested that DDT may be carcinogenic in the mouse because this species metabolises DDT to DDE, a pathway not common in other mammals. Similarly, dieldrin may be producing malignant tumours in mice because of its hepatic enzyme induction properties, the pesticide potentiating the level of natural carcinogenesis in this species. Nevertheless DDT is sometimes found in significant concentration in human milk and it is necessary to thoroughly examine this situation to ascertain if the enzyme induction effects of DDT and dieldrin in neonates presents any hazard to the human baby. Another class of pesticide residues is the organophosphate pesticides, such as parathion, malathion, etc. Some of these, such as parathion, are highly toxic not only to insects but also to humans, and the use of parathion as an insecticide has resulted in several deaths of agricultural workers, largely through errors in its application. This resulted in the development of more selective pesticides, such as malathion, which while having a very high toxicity for insects have a relatively low degree of toxicity for man. Malathion and similar safe pesticides are used to combat weevils and are added to grain stored in grain silos, as a result of which small amounts of these pesticides are consumed in our daily food, with no apparent harm. Residues of the herbicides 2,4-D and 2,4,5-T, used as defoliants in the recent Vietnam war have been claimed by various individuals to have resulted in considerable ill-health to the local inhabitants and to the birth of deformed babies. Although the two herbicides, 2,4-D and 2,4,5-T have been shown not to result in teratogenicity in experimental animals, they are associated with traces of a new class of compounds, namely the polychlorodibenzodioxins. These compounds may be impurities occurring during the manufacture of the herbicides, or are formed from these herbicides by the action of ultraviolet light in the environment.
Food Additives and Contaminants This is the last category of toxic chemicals in food and the category responsible for the least hazard to man, probably because there is the most rigorous control over the individual chemicals which comprise this group. As food additives we have antioxidants such as butylated hydroxytoluene (BHT), colourants such as the azo-dyes, sweeteners such as cyclamate and saccharin, and as contaminants we have the carcinogenic nitrosamines, polycyclic hydrocarbons, TABLE 4 ORGANOCHLORINE PESTICIDE RESIDUES IN THE TOTAL DIET IN THE UNITED KINGDOM Years 1966-67
1970-71
p,pf-DDT 0.003-0.038 (0.0125) 0.002-0.01 5 (0.0045)
p, p'-DDE 0.004-0.02 1 (0.009) 0.001-0.022 (0.004)
Dieldrit~ 0.002-0.01 1 (0.004) 0.001-0.003 (0.0015)
Values. given in mg/kg, are ranges with the mean value in parenthesis (From Egan and Hubbard, 1975)
.(-BHC 0.002-0.013 (0.004) 0.001-0.017 (0.0035)
and various drug residues, in addition of course to the three classes of chemicals previously dealt with. Most food additives constitute little or no hazard to man, although it i~ this category of compound which generally receives the widest public attention. Antioxidants such as butylated hydroxytoluene are known to cause liver hypertrophy in experimental animals, but this has been repeatedly shown not to constitute any hazard to experimental animals or to man. Of the various colourants used in foods many are azodyes and it is known that these can undergo reduction by the intestinal microflora to produce various aromatic amines. Several of the aromatic amines are known to be carcinogenic and there has been a very careful classification of these food colours to ensure that only those not constituting any carcinogenic risk are allowed to be added to our food. Similarly cyclamate and saccharin have been indicated as bladder carcinogens, but it is now believed that the real risk to humans is exceedingly small or even non-existent. However, cyclamate undergoes metabolism to cyclohexylamine, a metabolite which is known to be more toxic than the food sweetener. Recent work has shown that in both rats and man feeding of small amounts of cyclamate for long periods may change the intestinal microflora resulting in substantial increases in the metabolism of cyclamate to the more toxic chemical cyclohexylamine. The consequences of this adaptation to increased metabolic conversion, particularly in respect of the carcinogenic hazard of cyclamate, are as yet unknown. Of the food contaminants, probably the most important are the nitrosamines (Magee, 1971), products formed by the action of nitrite on secondary amines, although other amines and amides have also been shown similarly to give rise to these nitroso derivatives. The addition of nitrate and nitrite to meat pies and sausages, and their use in the production of bacon, to prevent the growth of the highly toxic bacterium Clostridium botulinum, have been considered to present a real risk from the formation of nitrosamines. However, it has been shown that the concentration of nitrosamines is highest in the rind of bacon and if this is removed, especially before cooking, a considerable amount of the carcinogenic hazard to the consumer is removed. Similarly, it was shown that the high nitrosamine content of the spices added to sausages and meat pies occurred because of the previous mixing of the herbs and spices with nitrite (Sen, et al., 1973) which was then left for a considerable period of time before adding to the sausage and pie meats. As the result of recent advice, sausage and pie manufacturers now mix their nitrite and spices just prior to adding to the meat, and the nitrosamine contents of these products are consequently very greatly reduced. I n this way simple changes of established manufacturing procedures can result in a considerable reduction of potential risk. Similarly, polycyclic hydrocarbons which are known to be very potent carcinogens, occur in smokes and smoked foods (see Table 5) (Malanoski, et al., 1968). Again it is the exterior of the foods which contain the highest concentrations of these polycyclic hydrocarbons, and removal of the outer layers of the food will considerably reduce the hazard. Most regulating TABLE 5 A R O M A T I C H Y D R O C A R B O N S IN S M O K E D F O O D Compound
Ham
Benz[a]anthracene Benzo[a]pyrene Benzo[g,h,i]perylene Fluoranthene Pyrene Chrysene
9.6 0.7
2.9 0.9 2.6
Values are expressed i n pg per kg (From Malanoski, et al., 1968)
Smoked Cod
Smoked Whitinp
4.0 2.2
6.6 2.4
0.6 1.4
g0.5
Barbecued Beef 13.2 3.3 4.3 2.0 3.2 9.6
Smoked Sousnge 0.5 0.4 1.5 1 .O
authorities allow the sale and consumption of smoked foods, where the food has been smoked with natural wood smoke. However, the practice of using tarred road blocks and old railway sleepers as the source of the wood smoke, with a consequent meteoric rise in the level of polycyclic hydrocarbons is a process to be condemned. New developments in this field have resulted in the use of the new smoke flavours (smoky bacon flavours) which are used to flavour foods yet are reputed to be low in content of polycyclic carcinogenic hydrocarbons. These smoke flavours are prepared by various processes, including the solvent extraction of smoke-flavour chemicals from animal offal treated with woodsmoke. With all the publicity that has recently been given to the hazards from smoking, it should be remembered that a kipper is equivalent, in its content of carcinogenic polycyclic hydrocarbons, to the smoking of many cigarettes. Various packaging materials also may present certain hazards in the way of food contaminants (Villeneuve, et al., 1973). The recent scares concerning the carcinogenicity of vinyl chloride monomer have ensured that the plastic food wrappings are relatively free from this dangerous material, and the hepatotoxic polychlorinated biphenyls and terphenyls which arise from plastic materials lining grain silos (Fries and Marrow, 1973), are also monitored to ensure that they do not reach significant levels in foods. The last category of food contaminants are drugs residues such as stilboestrol and antibiotics. Stilboestrol has recently been shown to be carcinogenic to humans and resurrects once again the possibility of hazard from its use in implantation in steers and cockerels for the more rapid production of meat. Nevertheless, there are statutory requirements to ensure that the level of this and other oestrogens remaining in the meat are acceptably low and constitute no risk to human consumers from cancer or other ill-effect. The presence of antibiotics in milk, resulting from the use of antibiotics to treat mastitis, and their presefice in meat, where they had been added to animal feedstuffs, presents a very real hazard because of the possible development of antibiotic-resistant human pathogens. The Swan Report (1971) has recently criticised the indiscriminate use of antibiotics in animal feedstuffs, and current veterinary and agricultural practice is eliminating this risk.
Gross Contamination of Food with Toxic Chemicals The real risk to man from poisoning by toxic chemicals in food comes from gross contamination, usually the result of accidents, adulteration, or ignorance. Such examples are the milllng of cereal grains for flour, when these have been specially treated with fungicides preparatory for sowing as seed. Grain treated with hexachlorobenzene, to prevent damage by wheat-bunt, was mistakenly consumed by peasants in Turkey in the 1960's leading to severe outbreaks of the liver disease, porphyria. More recently, in Iraq, seed grain treated with a mercury fungicide was sold and consumed as food, with even more disastrous consequences. I n Morocco in 1959 several hundred people were admitted to hospital suffering from the effects of a n acute virus disease. This 'viral epidemic' turned out to be the result of the presence of toxic chemicals in the food consumed by these people. An enterprising Moroccan had purchased engine oil from an American surplus store and had used this to adulterate vegetable cooking oil. Unfortunately, the engine oil contained triorthocresyl phosphate, a known nerve poison, similar to the organophosphate pesticides, which had been added to the mineral oil as a n antioxidant. Another such episode of gross contamination occurred in Epping in 1965 when some 84 people were stricken with jaundice, the result of eating wholemeal bread made from flour that had become contaminated with 4,4'-diaminodiphenylmethane, a n epoxy resin hardener which had contaminated the wholemeal flour during transport. Conclusion The potential contamination of our food with toxic chemicals is considerable,
but the vigilance of food manufacturers, food regulatory authorities and public analysts ensures that known contaminants and additives are kept to an absolute minimum, and the hazard to the public from these sources is consequently very small indeed. Moreover, the trace amounts of toxic chemicals present in our foods are quite adequately dealt with by the body's defence mechanisms against toxic chemicals (Parke and Williams, 1969). The real hazard comes from the occasional gross contamination of our food by toxic chemicals, the result of negligence, deliberate misuse, or accident. These events still occur resulting in epidemics of food poisoning, such as the episodes involving aflatoxin, methylmercury, triorthocresyl phosphate and hexachlorobenzene, which present the toxicologist and the forensic scientist with challenging situations. References AUSTWICK, P. K. C., 1975, Br. Med. Bull., 31, 222-229. CLAYTON, BARBARA E., 1975, Br. Med. Bull., 31, 236-240. CRAMPTON, R. F. and CHARLESWORTH, F. A., 1975, Br. Med. Bull., 31,209-213. A. W., 1975, Br. Med. Bull., 31, 201-208. EGAN,H. and HUBBARD, FRIES,G. F. and MARROW, G. S., 1973,J. Ass. Off. Anal. Chem., 56, 1002-1007. KAZANTZIS, G., 1974, Postgrad. Med. J., 50, 625-628. MAGEE,P. N., 1971, Fd. Cosmet. Toxicol., 9, 207-218. MAGOS, L., 1975, Br. Med. Bull., 31, 241-245. A. J., GREENFIELD, E. L., BARNES, C. J., WORTHINGTON, J. M. and MALANOSKI, JOE, F. L., 1968,J. Ass. Off. Anal. Chem., 51, 114-1 2 1. NEWBERNE, P. M., 1974, Clin. Toxicol., 7, 161-1 77. R. T., 1969, Br. Med. Bull., 25, 256-262. PARKE,D. V. and WILLIAMS, PHILLIPS, W. E. J., 1971, Fd. Cosmet. Toxicol., 9, 219-228. BARBARA, PANALAKS, T. and IYENGAR, SEN,N. P., MILES,W. F., DONALDSON, J. R., 1973, Nature, 245, 104-105. SWANREPORT,1971, Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine, H.M. Stationery Office. W. E. J., VILLENEUVE, D. C., REYNOLDS, L. M., THOMAS, G. H. and PHILLIPS, 1973,J. Ass. Off. Anal. Chem., 56, 999-1001.
Toxic Chemicals in Food D. V. PARKE Department of Biochemistry, University of Surrey, Guildford, Surrey, England The various classes of toxic chemicals that may be present in food namely encironmental contaminants, natural toxins, pesticide residues, food additives and contaminants, are reviewed. It is emphasized that the real hazards from toxic chemicals in food are the result of gross contamination, deliberate or accidental, and a number of such incidents are bri&y described. ( A paper presented at the Scientijs Symposium of the Society's 16th Annual General Meeting held at the Mchforran Hall, City of London Police Station, Wood Street on 15th November 1975.)
Introduction Poisoning of food, whether by accident or design, advcntitiou;ly or the result of nature, is still one of the most common routes of administration of noxious substances. This year marks the centennial celebrations of the 1875 Safety of Food Act, and at a recent scientific meeting to celebrate this event Dr. Schmidt, Commissioner of the United States Food and Drug Administration, listed, in order of importance, the major causes of food poisoning in that country. I t is significant that these health hazards, and alsa their order of importance, are common to the United Kingdom and to many other countries as well as the United States (see Table l ) , and broadly represent the risks from food poisoning the world over. Contamination of food by micro-organisms, primarily Salmonella and staphylococci, is still the major cause of food poisoning but I do not propose to consider this aspect in any detail. I shall also omit further reference to the second item in Table 1, faulty nutrition, as this is too vast a subject for consideration in this paper and, like bacterial contamination, lies outside my terms of reference. Environmental Contaminants This category of toxic chemicals in food is usually well controlled by legal regulations in most countries. I t includes the heavy metals such as lead, cadmium and mercury (Kazantis, 1974) (see Table 2), the persistent organohalogens such as the polychlorobiphenyls (PCBs) and tetrachlorodibenzodioxin, and nitrate and nitrite. The toxicity due to heavy metals has been widely publicised in recent years, primarily as the result of methylmercury poisoning in the Minimata episode in Japan (Kazantis, 1974). Mercury which is used as a catalyst in various industrial chemical processes is lost in small concentrations in chemical effluents. The discarded metal is metabolised by various marine organisms and converted into the mercury alkyls, such as methylmercury, which then tend to accumulate in food chains and reach a considerably high concentration in fish (Magos, 1975). Consumption of the fish by local populations resulted in the progressive accumulation of mercury and methylmercury in these individuals with the appearance of symptoms of damage to the central nervous system, characteristic of Minimata disease. Similarly, the presence of cadmium in soils, a contaminant from nearby zinc refineries, or its presence in some red and orange glazes of ovenware; may through progressive leaching contaminate food resulting in hepatic and renal
TABLE 1 HEALTH HAZARDS F R O M FOOD
Salmonella, B. botulini saturated fatty acids, alcohol, refined carbohydrate heavy mrtals, persistent organohalogen compounds mycotoxins, cycasin chlorinatcd hydrocarbons, organophosphates, carbarnates anti-oxidants, dyes, nitrites
Bacterial contamination Faulty nutrition Environmental contariinants Natural toxins Pesticide rr3idurs Food additives
TABLE 2 EVALUATION 01: HEAVY METAL F O O D CONTAMINANTS*
iV1etal
Provirional tolernble weekly i~ttake img/l)etson) ,'..-*/kg> -s 3 0.05 0.4 0.007
Idcad Cadmium Mercury total methyl mercury (Hy)
--
0.3 0.2
0.005 0.003
Acceptable daib intake None None None None
damage. In general, shellfish contain more lead and cadmium than other foods, probably due to the dumping of refinery wastes in coastal estuaries. I t is thought that cadmium may compete with the similar, divalent metal zinc which is an essential component of many enzymes. Possibly as a consequence of this cadmium exerts its toxic effects, resulting particularly in damage to the kidney, leading to high blood pressure. Undoubtedly the most important of the heavy metal contaminants of food is lead and contamination of food with this metal has been recognised for a considerable number of years (Clayton, 1975). Until recently most of the contamination of food by lead resulted from poor manufacturing processes, the use of lead-containing folls, and lead-containing solders used in the canning process. Recently, due to the improvement in technology the contamination of canned food by lead has been considerably reduced, but the use of lead foil, particularly for capping the bottles containing wine and beer is a practice which should be discontinued. I t has been shown that crops grown in areas near lead smelters contain a much higher concentration of this metal than is normal, the plants reflecting the increased amounts of lead which are deposited in the soil. I t has also been shown that a similar hazard, but probably to a much lesser extent, occurs from growing vegetables in areas near motorways with heavy traffic. The lead in this situation presumably results from the lead alkyls added to motor fuel. Nevertheless, the health hazard resulting from environmental contamination bv lead ~ r e s e n tin motor fuel has ~ r o b a b l vbeen considerably exaggerated. Efforts to increase the use of petrol free from lead were singularly unsuccessful until regulations in the United States made automobile catalytic after-burners compulsory to minimise atmospheric pollution from exhaust gases of carbon monoxide and oxides of nitrogen and sulphur. It was soon discovered that the lead alkyls in petrol contaminated and damaged the platinurn and palladium catalysts in the after-burners, and as a consequence lead-free petrols are now being used on an increasing scale in the United States. Consequently we may find that the motorist will refrain from contaminating the environment with lead, but only at the expense of adding the possibly even more toxic metal alkyls of platinum and palladium to the environment. The second category of environmental contaminants are the persistent
organohalogen compounds. This group of chemicals includes the polychlorodibenzodioxins, highly toxic compounds formed in the manufacture, and possibly from the photochemical decomposition of the herbicides 2,4-D and 2,4,5-T. Similarly many other polyhalogenated and polycyclic compounds, such as the polychlorinated biphenyls, are known to exist in our environment, and only a few of these as yet have been identified. Some of these chemicals are possibly formed by photochemical decomposition and polymerisation of various simpler organohalogen compounds involved in the manufacture of pesticides or drugs and may also occur as by-products of other chemical manufactures. The hazards from these compounds result from their resistance to microbial metabolism, their consequence persistence in the environment, with build-up in concentration in food-chains. The anions, nitrate and nitrite are leached from soils that have been heavily dressed with nitrate fertilisers, the nitrite being formed as a microbial byproduct. The nitrate is subsequently taken up in high concentration by the plants and also leached from the soil into river water. Plants with high concentrations of nitrate, e.g., spinach, have presented real hazards because of the oxidative effect of nitrate on haemoglobin, resulting in methaemoglobinaemia. This is of considerable concern with infants (Phillips, 1971) who are more susceptible to this toxic effect than adults, and the consumption of vegetable produce, especially spinach, which contain high concentrations of nitrate resulted in a number of infants being affected by methaemoglobinaemia. The problem is now well recognised and baby food manufacturers monitor for high nitrate concentration in vegetable produce. Apart from the oxidative hazard due to nitrate, microbial reduction to nitrite may lead to another health hazard, namely the formation of carcinogenic nitrosamines by the interaction of nitrite with secondary amines present in foods.
Natural Toxins The most important of the natural toxins are the mycotoxins (Newberne, 1974; Austwick, 1975), but in different parts of the world various other naturally toxic chemicals, such as cycasin, the pyrrolizidine alkaloids of Senecio, the fluorofatty acids present in a number of African plants, the toxic entity of bracken, may also present hazards in various degrees to the human individual (Crampton and Charlesworth, 1975) (see also Table 3). These natural toxins form one of the more hazardous classes of toxic chemicals in food because there is little or no control over their presence, although statutory regulations are being directed towards eliminating contamination by traces of the various mycotoxins. The importance of the mycotoxins was first realised in 1960 when several million turkeys died through a form of food poisoning, the result of feeding TABLE 3 SOME NATURAL TOXINS PRESENT IN FOOD
Agent Hypoglycin A
Food Ackee fruit
Effect
Hypoglycaemia (vomiting sickness) Cholinesterase inhibition Potato Solanine Neurological disorder Lathyrogens Lathyrfcs spfi Favism Vicine, isouramil Fava beans Amyotrophic lateral a-Amino-8-methyl- Cycad nuts sclerosis pro~ionicacid Myoglobinuria Coniine Para!ytic shell-fish Saxitoxin poisoning Fugu or puffer fish Central respiratory failure Tetrodotoxin (From Crampton and Charlesworth, 1975)
Locality Jamaica Widespread India Mediterranean Guam, Mariana Islands N. Afi-ica U.S.A., Europe, Japan Japan
the birds a diet containing mouldy peanut meal. The peanut meal had become contaminated with Asbergillus Jlavus, a mould, which produced the aflatoxin as a natural metabolite. Much work has since been undertaken on these mycotoxins and it has been established that they are potent hepatocarcinogens, which are also acutely toxic to the liver and to the gastrointestinal tract. Since this first occasion many different mycotoxins have been discovered, all the products of a variety of moulds, which may under suitable conditions contaminate our food. Nevertheless this source of toxic chemicals in food has been quickly checked and producer countries, such as Nigeria, now ensure that the food is harvested and stored under conditions which minimise contamination with moulds such as Aspergillus Jlaaus. Furthermore, there are now highly sensitive chemical methods (fluorescence spectrometry) for the determination of minute quantities of these mycotoxins and surveillance of our food for the presence of aflatoxin and other mycotoxins is constantly maintained. Among the other natural contaminants of some consequence is cycasin which is found in cycad nuts, the staple diet in many tropical countries. Cycasin is the glycoside of methylazoxymethanol and when ingested, may undergo hydrolysis to yield the aglycone methylazoxymethanol. This aglycone is a potent hepatocarcinogen and undergoes further metabolism, by the liver microsomal enzymes, to form a potent methylating agent, similar to dimethylnitrosamine, which alkylates the DNA. Animals, especially cattle which have highly active populations of microflora in the rumen, can most readily effect the hydrolysis of cycasin and are, therefore, more susceptible than man to its toxic - - - - - - effects. --~~. -. I t is also mostly cattle that are affected by the poisons in bracken and Senecio. The poison(s) in bracken has been shown to be haemorrhagic, haemolytic, radiomimetic and carcinogenic and recently it has been suggested that the carcinogenic entity is shikimic acid. The carcinogenic chemical of bracken appears to be water-soluble and could be leached from the powdered ferns into the soil and thence into human drinking water. A world map of the bracken-growing areas shows a very close resemblance to a map of the areas of a high incidence of gastrointestinal and liver cancer, and it has been suggested that the incidence of human cancer, particularly in soft water areas, may be contributed to by the potent carcinogen present in bracken. The pyrrolizidine alkaloids are found in plants belonging to Senecio, a genus notorious for its toxic and carcinogenic effects upon the liver of the animals that consume this material. In certain areas of the world these alkaloids have also been associated with the formation of cyclops in cattle and sheep, and it is tempting to speculate that consumption by humans may, in the Grecian past, have been responsible for some of the allegories of cyclopian man. The occurrence of the fluorofatty acids in a variety of African plants has been associated with the toxicity of food containing these materials and also with certain African tribal practices. The fluorofatty acids are metabolised by P-oxidation to give rise to fluoroacetic acid or fluoroformic acid and the former enters the citric acid cycle resulting in lethal synthesis. I n this metabolic process, fluoroacetic acid is metabolised into fluorocitrate which subsequently blocks the citric acid cycle by inhibiting the enzyme aconitase. The result is the accumulation of citrate within the body's tissues and the lack of energy generation via the citric acid pathway. The high levels of citrate result in a reduction of ionic calcium and the poisoned subject dies in tetanic spasm. I n recent years fluoroacetate and fluoroacetamide, used as rat poisons, have found their way into pastures and streams and have resulted in the poisoning of sheep and cattle. These substances are extremely toxic, even in very small amounts, and it is exceedingly difficult to provide a n antidote.
Pesticide Residues The next category of toxic chemicals that find their way into our food, the fifth in importance with respect to hazard, are the pesticides. There is a con-
siderable degree of control over pesticide residues (Egan and Hubbard, 1975), which is exerted both at a national level and by international agreements, and the World Health Organisation has produced a list of acceptable daily intakes (ADI's) for most of the pesticides in current use. The chlorinated hydrocarbons are the most widely distributed pesticides, and these include DDT and its various metabolites, dieldrin, benzene hexachloride (y-BHC), chlordan, etc. (see Table 4). DDT and dieldrin have found disfavour in some countries because of their reported carcinogenicity in mice. Nevertheless, this finding of carcinogenicity in a rodent species may not have significance in man, and it has been suggested that DDT may be carcinogenic in the mouse because this species metabolises DDT to DDE, a pathway not common in other mammals. Similarly, dieldrin may be producing malignant tumours in mice because of its hepatic enzyme induction properties, the pesticide potentiating the level of natural carcinogenesis in this species. Nevertheless DDT is sometimes found in significant concentration in human milk and it is necessary to thoroughly examine this situation to ascertain if the enzyme induction effects of DDT and dieldrin in neonates presents any hazard to the human baby. Another class of pesticide residues is the organophosphate pesticides, such as parathion, malathion, etc. Some of these, such as parathion, are highly toxic not only to insects but also to humans, and the use of parathion as an insecticide has resulted in several deaths of agricultural workers, largely through errors in its application. This resulted in the development of more selective pesticides, such as malathion, which while having a very high toxicity for insects have a relatively low degree of toxicity for man. Malathion and similar safe pesticides are used to combat weevils and are added to grain stored in grain silos, as a result of which small amounts of these pesticides are consumed in our daily food, with no apparent harm. Residues of the herbicides 2,4-D and 2,4,5-T, used as defoliants in the recent Vietnam war have been claimed by various individuals to have resulted in considerable ill-health to the local inhabitants and to the birth of deformed babies. Although the two herbicides, 2,4-D and 2,4,5-T have been shown not to result in teratogenicity in experimental animals, they are associated with traces of a new class of compounds, namely the polychlorodibenzodioxins. These compounds may be impurities occurring during the manufacture of the herbicides, or are formed from these herbicides by the action of ultraviolet light in the environment.
Food Additives and Contaminants This is the last category of toxic chemicals in food and the category responsible for the least hazard to man, probably because there is the most rigorous control over the individual chemicals which comprise this group. As food additives we have antioxidants such as butylated hydroxytoluene (BHT), colourants such as the azo-dyes, sweeteners such as cyclamate and saccharin, and as contaminants we have the carcinogenic nitrosamines, polycyclic hydrocarbons, TABLE 4 ORGANOCHLORINE PESTICIDE RESIDUES IN THE TOTAL DIET IN THE UNITED KINGDOM Years 1966-67
1970-71
p,pf-DDT 0.003-0.038 (0.0125) 0.002-0.01 5 (0.0045)
p, p'-DDE 0.004-0.02 1 (0.009) 0.001-0.022 (0.004)
Dieldrit~ 0.002-0.01 1 (0.004) 0.001-0.003 (0.0015)
Values. given in mg/kg, are ranges with the mean value in parenthesis (From Egan and Hubbard, 1975)
.(-BHC 0.002-0.013 (0.004) 0.001-0.017 (0.0035)
and various drug residues, in addition of course to the three classes of chemicals previously dealt with. Most food additives constitute little or no hazard to man, although it i~ this category of compound which generally receives the widest public attention. Antioxidants such as butylated hydroxytoluene are known to cause liver hypertrophy in experimental animals, but this has been repeatedly shown not to constitute any hazard to experimental animals or to man. Of the various colourants used in foods many are azodyes and it is known that these can undergo reduction by the intestinal microflora to produce various aromatic amines. Several of the aromatic amines are known to be carcinogenic and there has been a very careful classification of these food colours to ensure that only those not constituting any carcinogenic risk are allowed to be added to our food. Similarly cyclamate and saccharin have been indicated as bladder carcinogens, but it is now believed that the real risk to humans is exceedingly small or even non-existent. However, cyclamate undergoes metabolism to cyclohexylamine, a metabolite which is known to be more toxic than the food sweetener. Recent work has shown that in both rats and man feeding of small amounts of cyclamate for long periods may change the intestinal microflora resulting in substantial increases in the metabolism of cyclamate to the more toxic chemical cyclohexylamine. The consequences of this adaptation to increased metabolic conversion, particularly in respect of the carcinogenic hazard of cyclamate, are as yet unknown. Of the food contaminants, probably the most important are the nitrosamines (Magee, 1971), products formed by the action of nitrite on secondary amines, although other amines and amides have also been shown similarly to give rise to these nitroso derivatives. The addition of nitrate and nitrite to meat pies and sausages, and their use in the production of bacon, to prevent the growth of the highly toxic bacterium Clostridium botulinum, have been considered to present a real risk from the formation of nitrosamines. However, it has been shown that the concentration of nitrosamines is highest in the rind of bacon and if this is removed, especially before cooking, a considerable amount of the carcinogenic hazard to the consumer is removed. Similarly, it was shown that the high nitrosamine content of the spices added to sausages and meat pies occurred because of the previous mixing of the herbs and spices with nitrite (Sen, et al., 1973) which was then left for a considerable period of time before adding to the sausage and pie meats. As the result of recent advice, sausage and pie manufacturers now mix their nitrite and spices just prior to adding to the meat, and the nitrosamine contents of these products are consequently very greatly reduced. I n this way simple changes of established manufacturing procedures can result in a considerable reduction of potential risk. Similarly, polycyclic hydrocarbons which are known to be very potent carcinogens, occur in smokes and smoked foods (see Table 5) (Malanoski, et al., 1968). Again it is the exterior of the foods which contain the highest concentrations of these polycyclic hydrocarbons, and removal of the outer layers of the food will considerably reduce the hazard. Most regulating TABLE 5 A R O M A T I C H Y D R O C A R B O N S IN S M O K E D F O O D Compound
Ham
Benz[a]anthracene Benzo[a]pyrene Benzo[g,h,i]perylene Fluoranthene Pyrene Chrysene
9.6 0.7
2.9 0.9 2.6
Values are expressed i n pg per kg (From Malanoski, et al., 1968)
Smoked Cod
Smoked Whitinp
4.0 2.2
6.6 2.4
0.6 1.4
g0.5
Barbecued Beef 13.2 3.3 4.3 2.0 3.2 9.6
Smoked Sousnge 0.5 0.4 1.5 1 .O
authorities allow the sale and consumption of smoked foods, where the food has been smoked with natural wood smoke. However, the practice of using tarred road blocks and old railway sleepers as the source of the wood smoke, with a consequent meteoric rise in the level of polycyclic hydrocarbons is a process to be condemned. New developments in this field have resulted in the use of the new smoke flavours (smoky bacon flavours) which are used to flavour foods yet are reputed to be low in content of polycyclic carcinogenic hydrocarbons. These smoke flavours are prepared by various processes, including the solvent extraction of smoke-flavour chemicals from animal offal treated with woodsmoke. With all the publicity that has recently been given to the hazards from smoking, it should be remembered that a kipper is equivalent, in its content of carcinogenic polycyclic hydrocarbons, to the smoking of many cigarettes. Various packaging materials also may present certain hazards in the way of food contaminants (Villeneuve, et al., 1973). The recent scares concerning the carcinogenicity of vinyl chloride monomer have ensured that the plastic food wrappings are relatively free from this dangerous material, and the hepatotoxic polychlorinated biphenyls and terphenyls which arise from plastic materials lining grain silos (Fries and Marrow, 1973), are also monitored to ensure that they do not reach significant levels in foods. The last category of food contaminants are drugs residues such as stilboestrol and antibiotics. Stilboestrol has recently been shown to be carcinogenic to humans and resurrects once again the possibility of hazard from its use in implantation in steers and cockerels for the more rapid production of meat. Nevertheless, there are statutory requirements to ensure that the level of this and other oestrogens remaining in the meat are acceptably low and constitute no risk to human consumers from cancer or other ill-effect. The presence of antibiotics in milk, resulting from the use of antibiotics to treat mastitis, and their presefice in meat, where they had been added to animal feedstuffs, presents a very real hazard because of the possible development of antibiotic-resistant human pathogens. The Swan Report (1971) has recently criticised the indiscriminate use of antibiotics in animal feedstuffs, and current veterinary and agricultural practice is eliminating this risk.
Gross Contamination of Food with Toxic Chemicals The real risk to man from poisoning by toxic chemicals in food comes from gross contamination, usually the result of accidents, adulteration, or ignorance. Such examples are the milllng of cereal grains for flour, when these have been specially treated with fungicides preparatory for sowing as seed. Grain treated with hexachlorobenzene, to prevent damage by wheat-bunt, was mistakenly consumed by peasants in Turkey in the 1960's leading to severe outbreaks of the liver disease, porphyria. More recently, in Iraq, seed grain treated with a mercury fungicide was sold and consumed as food, with even more disastrous consequences. I n Morocco in 1959 several hundred people were admitted to hospital suffering from the effects of a n acute virus disease. This 'viral epidemic' turned out to be the result of the presence of toxic chemicals in the food consumed by these people. An enterprising Moroccan had purchased engine oil from an American surplus store and had used this to adulterate vegetable cooking oil. Unfortunately, the engine oil contained triorthocresyl phosphate, a known nerve poison, similar to the organophosphate pesticides, which had been added to the mineral oil as a n antioxidant. Another such episode of gross contamination occurred in Epping in 1965 when some 84 people were stricken with jaundice, the result of eating wholemeal bread made from flour that had become contaminated with 4,4'-diaminodiphenylmethane, a n epoxy resin hardener which had contaminated the wholemeal flour during transport. Conclusion The potential contamination of our food with toxic chemicals is considerable,
but the vigilance of food manufacturers, food regulatory authorities and public analysts ensures that known contaminants and additives are kept to an absolute minimum, and the hazard to the public from these sources is consequently very small indeed. Moreover, the trace amounts of toxic chemicals present in our foods are quite adequately dealt with by the body's defence mechanisms against toxic chemicals (Parke and Williams, 1969). The real hazard comes from the occasional gross contamination of our food by toxic chemicals, the result of negligence, deliberate misuse, or accident. These events still occur resulting in epidemics of food poisoning, such as the episodes involving aflatoxin, methylmercury, triorthocresyl phosphate and hexachlorobenzene, which present the toxicologist and the forensic scientist with challenging situations. References AUSTWICK, P. K. C., 1975, Br. Med. Bull., 31, 222-229. CLAYTON, BARBARA E., 1975, Br. Med. Bull., 31, 236-240. CRAMPTON, R. F. and CHARLESWORTH, F. A., 1975, Br. Med. Bull., 31,209-213. A. W., 1975, Br. Med. Bull., 31, 201-208. EGAN,H. and HUBBARD, FRIES,G. F. and MARROW, G. S., 1973,J. Ass. Off. Anal. Chem., 56, 1002-1007. KAZANTZIS, G., 1974, Postgrad. Med. J., 50, 625-628. MAGEE,P. N., 1971, Fd. Cosmet. Toxicol., 9, 207-218. MAGOS, L., 1975, Br. Med. Bull., 31, 241-245. A. J., GREENFIELD, E. L., BARNES, C. J., WORTHINGTON, J. M. and MALANOSKI, JOE, F. L., 1968,J. Ass. Off. Anal. Chem., 51, 114-1 2 1. NEWBERNE, P. M., 1974, Clin. Toxicol., 7, 161-1 77. R. T., 1969, Br. Med. Bull., 25, 256-262. PARKE,D. V. and WILLIAMS, PHILLIPS, W. E. J., 1971, Fd. Cosmet. Toxicol., 9, 219-228. BARBARA, PANALAKS, T. and IYENGAR, SEN,N. P., MILES,W. F., DONALDSON, J. R., 1973, Nature, 245, 104-105. SWANREPORT,1971, Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine, H.M. Stationery Office. W. E. J., VILLENEUVE, D. C., REYNOLDS, L. M., THOMAS, G. H. and PHILLIPS, 1973,J. Ass. Off. Anal. Chem., 56, 999-1001.