toxins, and ot her contaminants in food. H ow m uch risk to health do these represent? This is what we will be hearing about t o d a y from a distinguished array o f speakers.
B F o o d regulations in the U.K. and the impact on t hem o f membership o f the EEC -- P.S. Elias, Department of Health and Social Security, London
(Great Britain) The advances in f o o d t e c hnol ogy eventually necessitated the devel opm ent o f controls in the interest o f public health and for the p r o t e c t i o n of the consumer, a d e v e l o p m e n t seen in almost every c o u n t r y in the world. Various legislative measures in Britain since 1836 were eventually incorporated in the Sale o f F o o d and Drugs Act, 1875 which began a series of f o o d standard legislation. However, only the F o o d and Drugs Act of 1955 gave pow er to Ministers to make the regulations which now control our food. The Act covers such things as fraud, f ood safety, f o o d hygiene and f o o d composition. Danger to health from foodstuffs m a y arise from a variety of sources i.e. microbiological or parasitic contamination, intentional food additives, unintentional contaminants, irradiation and naturally occurring toxins. Examples of each of these sources are discussed and the appropriate regulations mentioned. Advice about f o o d additives b o t h as regards need and safety is given to Ministers by several com m i t t ees of i n d e p e n d e n t experts. The control over certain unintentional contaminants such as pesticide residues or residues of veterinary substances is partially by voluntary agreement with industry and partially by s t a t u t o r y licensing. E n t r y into the EEC has involved the U.K. in a programme of harmonization of legislation in the food field. Essentially it depends on the devel opm ent of C o m m u n i t y Directives which are then translated into national legislation to remove barriers to i n t e r - c o m m u n i t y trade. O t he r legislative instruments are C o m m u n i t y Regulations which are directly assimilated into national legislation. There is a complex machinery which is controlled by the Commission of the European C o m m u n i t y as a policy-making b o d y and which submits legislative proposals to the Council of Ministers and its subsidiary bodies for acceptance. This has implications for our existing f ood laws, resulting either in significant changes as regards the composition of or in alterations in the permitted additives which may in f ut ur e appear in our food. Some of these changes have already been foreshadowed because of the participation of the U.K. and all EEC m e m b e r states in the Codex Alimentarius food standards programme. C The experimental evaluation o f f o o d safety - - K.W.G. Shillam, Huntingdon
Research Centre, Huntingdon (Great Britain) The safety of chemicals t hat are added to food and of new foods t hat are unconventional either in their origin or processing technique is equally as
386
i m p o r t a n t to the c o n s u m e r as is the s a f e t y o f p h a r m a c e u t i c a l c o m p o u n d s . M e t h o d s o f t o x i c o l o g i c a l evaluation are just as stringent. An absolute g u a r a n t e e o f s a f e t y can o n l y be d e t e r m i n e d b y tests o n humans themselves. This practice w o u l d be impracticable, d a n g e r o u s and illegal. E x p e r i m e n t s with animals, p r o v i d e d t h e y are well-designed, w e l l - c o n d u c t e d and the results well-interpreted, can p r o v i d e a high degree o f assurance over h a z a r d t o h u m a n s . Such tests are usually m a d e in at least t w o u n r e l a t e d species o f animals, one o f which is a r o d e n t (rat, m o u s e , rabbit) and the o t h e r a n o n - r o d e n t (dog, p r i m a t e , pig). With the e x c e p t i o n o f primates, the animals used are bred specifically f o r the p u r p o s e i n t e n d e d and are o f certain p u r e breeds or strains. A c c o m m o d a t i o n is o f high standard, p a r t i c u l a r a t t e n t i o n being paid t o density o f stocking, t e m p e r a t u r e , ventilation, h u m i d i t y and n u t r i t i o n a l r e q u i r e m e n t s . B e f o r e animals are a c c e p t e d o n long-term studies, t h e y are given a detailed v e t e r i n a r y , clinical and b i o c h e m i c a l e x a m i n a t i o n to ensure n o r m a l i t y . T h e aim is to use a u n i f o r m p r o d u c t in which the n o r m a l can be a p p r e c i a t e d and the a b n o r m a l d e t e c t e d . Much n o r m a l b a c k g r o u n d d a t a on clinical, b i o c h e m ical, physiological and pathological p a r a m e t e r s o f the species a n d breeds u n d e r investigation will already be k n o w n t o the toxicologist. T h e actual p r o g r a m m e o f safety tests o n a new f o o d or f o o d additive is n o t rigid. Much d e p e n d s on its i n t e n d e d use, its chemical s t r u c t u r e and its similarity to o t h e r c o m p o u n d s t h a t are in use or have b e e n tested, and o n inf o r m a t i o n t h a t is acquired during the early stages o f the investigation. Invariably o n e begins with a d e t e r m i n a t i o n o f acute t o x i c i t y -- the LD50 -- in r o d e n t s , which is t h e a m o u n t o f c o m p o u n d , given as a single dose, t h a t results in a 50% m o r t a l i t y rate. T h e value provides a guide to the i n h e r e n t t o x i c i t y o f the chemical and it m a y also p r o v i d e some early i n d i c a t i o n o n the mode of toxicity. Sub-acute studies vary in d u r a t i o n f r o m 1--3 m o n t h s . T h e c o m p o u n d is a d m i n i s t e r e d daily to t w o species with the objectives o f d e t e r m i n i n g the n a t u r e o f the t o x i c response and t o find the m a x i m u m n o - e f f e c t level and also t h a t at which the m o s t sensitive p a r a m e t e r gives adverse change. These studies p e r m i t p r o p e r selection o f the dose levels to be used in the longer or chronic toxicity study. A c h r o n i c t o x i c i t y s t u d y is n o r m a l l y o f 2 y e a r s ' d u r a t i o n b u t m a y be less, d e p e n d i n g o n the t y p e o f c o m p o u n d u n d e r investigation. T h r e e dose levels are e m p l o y e d : the m a x i m u m n o - e f f e c t level, a level which p r o d u c e s definite adverse effects and a level i n t e r m e d i a t e b e t w e e n the two. T h e l o w e r dose level m a y serve to assess the a c c e p t a b l e daily intake (ADI) b y man, o n e being c o n f i d e n t o n a s a f e t y p r e d i c t i o n t o set the ADI at 1 / 1 0 0 o f the m a x i u m n o - e f f e c t level in animals. A t intervals during the s t u d y b o d y weights are rec o r d e d and clinical observations m a d e , h a e m a t o l o g i c a l and b l o o d b i o c h e m ical p a r a m e t e r s d e t e r m i n e d , organ f u n c t i o n tests m a d e t o g e t h e r with analysis o f urine. A t t e r m i n a t i o n , a detailed p o s t - m o r t e m e x a m i n a t i o n is m a d e , organ weights r e c o r d e d and m i c r o s c o p i c e x a m i n a t i o n m a d e on up t o s o m e 50 organs and tissues. Specific e x a m i n a t i o n f o r t u m o u r s m a y also be m a d e at the
387
end o f a 2-year rat study or a separate 1.5-year carcinogenicity study in the mouse may be made. Life span studies for carcinogenic effects are n o t normally made in non-rodents. Studies to reveal possible effects on r e p r o d u c t i o n or foetal development are highly desirable. A multigeneration r e p r o d u c t i o n study in rats permits evaluation of an ef f ect on several reproductive cycles, and a separate study in rats, rabbits or mice, in which the c o m p o u n d is administered during the period of organogenesis, is necessary to find any effect on the developing e m b r y o . If the additive is used in baby foods, a neonatal study in which the c o m p o u n d is given to hand-reared y o u n g through to normal weaning age is desirable. At the present time scientific opinion is divided on the relevance of mutagenicity studies. Three studies involving examination for mutations or chrom o s o m e observations are relevant: host-mediated assay, d o m i n a n t lethal test and cytogenetic studies. A study of the metabolic fate of a c o m p o u n d within the animal b o d y is of considerable value. Such a metabolism study would include investigations on absorption, the organ which metabolises the c o m p o u n d , identification of any metabolites, distribution and storage in various tissues, and excretion in urine, faeces and bile. In the case of major metabolites which are n o t excreted rapidly, and depending on their chemical structure, it m ay be necessary to c o n d u c t t oxi ci t y tests on these also. Having established the absence o f toxic s y m p t o m s in animals, it is o f great value to investigate the metabolism in man and to compare this with the animal species. Two persons only are used and a small a m o u n t of the c o m p o u n d given in radio-actively labelled form. Finally, carefully controlled, medically supervised studies may be cond u cted in h um a n volunteers provided the risk involved is negligible. Because the testing programme is n o t rigid it is difficult to estimate the total cost o f a toxicological evaluation. Moreover in the current inflationary period, costs do n o t remain valid for very long. If all the tests described in this paper were c o n d u c t e d , it is t h o u g h t the current cost might be of the order o f £ 1 5 0 - - 2 0 0 000.
D Natural hazards occurring in foods -- N.R. Jones and J. Nabney, Tropical
Products Institute, London (Great Britain) The role of f o o d control measures in assessing the potential hazards of natural toxins and antimetabolites was discussed, and control of application o f tech n o lo gy emphasised. The types of problems encountered, and solutions which have been developed were illustrated by a n u m b e r of examples.
Fish poisons This section, dealing with marine toxins and ichthyosarcotoxicism, dis-
388
B F o o d regulations in the U.K. and the impact on t hem o f membership o f the EEC -- P.S. Elias, Department of Health and Social Security, London
(Great Britain) The advances in f o o d t e c hnol ogy eventually necessitated the devel opm ent o f controls in the interest o f public health and for the p r o t e c t i o n of the consumer, a d e v e l o p m e n t seen in almost every c o u n t r y in the world. Various legislative measures in Britain since 1836 were eventually incorporated in the Sale o f F o o d and Drugs Act, 1875 which began a series of f o o d standard legislation. However, only the F o o d and Drugs Act of 1955 gave pow er to Ministers to make the regulations which now control our food. The Act covers such things as fraud, f ood safety, f o o d hygiene and f o o d composition. Danger to health from foodstuffs m a y arise from a variety of sources i.e. microbiological or parasitic contamination, intentional food additives, unintentional contaminants, irradiation and naturally occurring toxins. Examples of each of these sources are discussed and the appropriate regulations mentioned. Advice about f o o d additives b o t h as regards need and safety is given to Ministers by several com m i t t ees of i n d e p e n d e n t experts. The control over certain unintentional contaminants such as pesticide residues or residues of veterinary substances is partially by voluntary agreement with industry and partially by s t a t u t o r y licensing. E n t r y into the EEC has involved the U.K. in a programme of harmonization of legislation in the food field. Essentially it depends on the devel opm ent of C o m m u n i t y Directives which are then translated into national legislation to remove barriers to i n t e r - c o m m u n i t y trade. O t he r legislative instruments are C o m m u n i t y Regulations which are directly assimilated into national legislation. There is a complex machinery which is controlled by the Commission of the European C o m m u n i t y as a policy-making b o d y and which submits legislative proposals to the Council of Ministers and its subsidiary bodies for acceptance. This has implications for our existing f ood laws, resulting either in significant changes as regards the composition of or in alterations in the permitted additives which may in f ut ur e appear in our food. Some of these changes have already been foreshadowed because of the participation of the U.K. and all EEC m e m b e r states in the Codex Alimentarius food standards programme. C The experimental evaluation o f f o o d safety - - K.W.G. Shillam, Huntingdon
Research Centre, Huntingdon (Great Britain) The safety of chemicals t hat are added to food and of new foods t hat are unconventional either in their origin or processing technique is equally as
386
i m p o r t a n t to the c o n s u m e r as is the s a f e t y o f p h a r m a c e u t i c a l c o m p o u n d s . M e t h o d s o f t o x i c o l o g i c a l evaluation are just as stringent. An absolute g u a r a n t e e o f s a f e t y can o n l y be d e t e r m i n e d b y tests o n humans themselves. This practice w o u l d be impracticable, d a n g e r o u s and illegal. E x p e r i m e n t s with animals, p r o v i d e d t h e y are well-designed, w e l l - c o n d u c t e d and the results well-interpreted, can p r o v i d e a high degree o f assurance over h a z a r d t o h u m a n s . Such tests are usually m a d e in at least t w o u n r e l a t e d species o f animals, one o f which is a r o d e n t (rat, m o u s e , rabbit) and the o t h e r a n o n - r o d e n t (dog, p r i m a t e , pig). With the e x c e p t i o n o f primates, the animals used are bred specifically f o r the p u r p o s e i n t e n d e d and are o f certain p u r e breeds or strains. A c c o m m o d a t i o n is o f high standard, p a r t i c u l a r a t t e n t i o n being paid t o density o f stocking, t e m p e r a t u r e , ventilation, h u m i d i t y and n u t r i t i o n a l r e q u i r e m e n t s . B e f o r e animals are a c c e p t e d o n long-term studies, t h e y are given a detailed v e t e r i n a r y , clinical and b i o c h e m i c a l e x a m i n a t i o n to ensure n o r m a l i t y . T h e aim is to use a u n i f o r m p r o d u c t in which the n o r m a l can be a p p r e c i a t e d and the a b n o r m a l d e t e c t e d . Much n o r m a l b a c k g r o u n d d a t a on clinical, b i o c h e m ical, physiological and pathological p a r a m e t e r s o f the species a n d breeds u n d e r investigation will already be k n o w n t o the toxicologist. T h e actual p r o g r a m m e o f safety tests o n a new f o o d or f o o d additive is n o t rigid. Much d e p e n d s on its i n t e n d e d use, its chemical s t r u c t u r e and its similarity to o t h e r c o m p o u n d s t h a t are in use or have b e e n tested, and o n inf o r m a t i o n t h a t is acquired during the early stages o f the investigation. Invariably o n e begins with a d e t e r m i n a t i o n o f acute t o x i c i t y -- the LD50 -- in r o d e n t s , which is t h e a m o u n t o f c o m p o u n d , given as a single dose, t h a t results in a 50% m o r t a l i t y rate. T h e value provides a guide to the i n h e r e n t t o x i c i t y o f the chemical and it m a y also p r o v i d e some early i n d i c a t i o n o n the mode of toxicity. Sub-acute studies vary in d u r a t i o n f r o m 1--3 m o n t h s . T h e c o m p o u n d is a d m i n i s t e r e d daily to t w o species with the objectives o f d e t e r m i n i n g the n a t u r e o f the t o x i c response and t o find the m a x i m u m n o - e f f e c t level and also t h a t at which the m o s t sensitive p a r a m e t e r gives adverse change. These studies p e r m i t p r o p e r selection o f the dose levels to be used in the longer or chronic toxicity study. A c h r o n i c t o x i c i t y s t u d y is n o r m a l l y o f 2 y e a r s ' d u r a t i o n b u t m a y be less, d e p e n d i n g o n the t y p e o f c o m p o u n d u n d e r investigation. T h r e e dose levels are e m p l o y e d : the m a x i m u m n o - e f f e c t level, a level which p r o d u c e s definite adverse effects and a level i n t e r m e d i a t e b e t w e e n the two. T h e l o w e r dose level m a y serve to assess the a c c e p t a b l e daily intake (ADI) b y man, o n e being c o n f i d e n t o n a s a f e t y p r e d i c t i o n t o set the ADI at 1 / 1 0 0 o f the m a x i u m n o - e f f e c t level in animals. A t intervals during the s t u d y b o d y weights are rec o r d e d and clinical observations m a d e , h a e m a t o l o g i c a l and b l o o d b i o c h e m ical p a r a m e t e r s d e t e r m i n e d , organ f u n c t i o n tests m a d e t o g e t h e r with analysis o f urine. A t t e r m i n a t i o n , a detailed p o s t - m o r t e m e x a m i n a t i o n is m a d e , organ weights r e c o r d e d and m i c r o s c o p i c e x a m i n a t i o n m a d e on up t o s o m e 50 organs and tissues. Specific e x a m i n a t i o n f o r t u m o u r s m a y also be m a d e at the
387
end o f a 2-year rat study or a separate 1.5-year carcinogenicity study in the mouse may be made. Life span studies for carcinogenic effects are n o t normally made in non-rodents. Studies to reveal possible effects on r e p r o d u c t i o n or foetal development are highly desirable. A multigeneration r e p r o d u c t i o n study in rats permits evaluation of an ef f ect on several reproductive cycles, and a separate study in rats, rabbits or mice, in which the c o m p o u n d is administered during the period of organogenesis, is necessary to find any effect on the developing e m b r y o . If the additive is used in baby foods, a neonatal study in which the c o m p o u n d is given to hand-reared y o u n g through to normal weaning age is desirable. At the present time scientific opinion is divided on the relevance of mutagenicity studies. Three studies involving examination for mutations or chrom o s o m e observations are relevant: host-mediated assay, d o m i n a n t lethal test and cytogenetic studies. A study of the metabolic fate of a c o m p o u n d within the animal b o d y is of considerable value. Such a metabolism study would include investigations on absorption, the organ which metabolises the c o m p o u n d , identification of any metabolites, distribution and storage in various tissues, and excretion in urine, faeces and bile. In the case of major metabolites which are n o t excreted rapidly, and depending on their chemical structure, it m ay be necessary to c o n d u c t t oxi ci t y tests on these also. Having established the absence o f toxic s y m p t o m s in animals, it is o f great value to investigate the metabolism in man and to compare this with the animal species. Two persons only are used and a small a m o u n t of the c o m p o u n d given in radio-actively labelled form. Finally, carefully controlled, medically supervised studies may be cond u cted in h um a n volunteers provided the risk involved is negligible. Because the testing programme is n o t rigid it is difficult to estimate the total cost o f a toxicological evaluation. Moreover in the current inflationary period, costs do n o t remain valid for very long. If all the tests described in this paper were c o n d u c t e d , it is t h o u g h t the current cost might be of the order o f £ 1 5 0 - - 2 0 0 000.
D Natural hazards occurring in foods -- N.R. Jones and J. Nabney, Tropical
Products Institute, London (Great Britain) The role of f o o d control measures in assessing the potential hazards of natural toxins and antimetabolites was discussed, and control of application o f tech n o lo gy emphasised. The types of problems encountered, and solutions which have been developed were illustrated by a n u m b e r of examples.
Fish poisons This section, dealing with marine toxins and ichthyosarcotoxicism, dis-
388
![[Gastrointestinal absorption in the rat of anisole, trans-anethole, butylhydroxyanisole and safrole].](/assets/img/hold.png)
