This article was downloaded by: [New York University] On: 16 July 2015, At: 10:20 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place, London, SW1P 1WG
Food Additives & Contaminants Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tfac19
Nutritional toxicology: Basic principles and actual problems John N. Hathcock
a
a
Food and Drug Administration , Center for Food Safety and Applied Nutrition , Washington, DC, 20204, USA Published online: 10 Jan 2009.
To cite this article: John N. Hathcock (1990) Nutritional toxicology: Basic principles and actual problems, Food Additives & Contaminants, 7:S1, S12-S18, DOI: 10.1080/02652039009373836 To link to this article: http://dx.doi.org/10.1080/02652039009373836
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sublicensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
FOOD ADDITIVES AND CONTAMINANTS, 1990, VOL. 7, SUPPLEMENT NO. 1, S 1 2 - S 1 8
Nutritional toxicology: basic principles and actual problems JOHN N. HATHCOCK Food and Drug Administration, Center for Food Safety and Applied Nutrition, Washington, DC 20204, USA
Downloaded by [New York University] at 10:20 16 July 2015
Basic principles
Many problems in food safety and adequacy occur at the interface between nutrition and toxicology, disciplines that study basically opposing influences on living organisms. Nutritional substances provide essential structural, catalytic and energetic support for life processes, and the science of nutrition studies how nutrients sustain expression of the genetic programme of an organism. Toxic substances disrupt life processes and structures and the science of toxicology studies effects of substances that disturb normal expression of the genetic programme. These fundamentally opposite actions of nutrients and toxicants cause extensive mutual modulation of effect. At high intakes, nutrients themselves become toxicants. The many interactions in nutritional toxicology may be categorized into three basic types of relationships: (1) influence of diet and nutrition on response to toxic substances; (2) effects of toxicants on nutritional functions and requirements; and (3) toxicities of nutrients at excessive intakes (Hathcock 1976, 1982). Effective research in these areas requires utilization of the information base, perspectives and experimental strategies of both nutrition and toxicology for optimal results (Ariens and Simonis 1982). The quantitative and statistical methods of toxicology relating to dose-response and time-response relationships, and toxicokinetics may be applied to nutrienttoxicant interactions and nutrient toxicities (Ariens and Simonis 1982, Hathcock, 1989a). Many methods of dose-body size extrapolation between or within species have been employed. The common dose/kg basis used in human pharmacology often gives large quantitative errors when used for extrapolation between species of very different body size. In toxicology, assessment of chemicals often involves dose characterization on the basis of nominal surface area (kg273) (Mantel and Schneiderman 1975, US Food and Drug Administration 1982). In human nutrition, recommended intakes are in amounts per person per day, with adjustments for differences in body size made only when there is a difference in age (National Research Council 1989). In animal nutrition, recommended intakes are made on a dietary concentration basis (National Research Council 1978). Because surface area is a major determinant of heat loss and thus energy need, there is a close correlation between the kg 2/3 basis (nominal surface area) and a dietary concentration basis for dosage with toxicants (Hathcock 1989a). Tables of equivalency between dose per kg and dietary concentration have been developed for species ranging in body size from the mouse to the horse (Lehman 1959). Dietary concentration is a good basis © US Government 1990
Downloaded by [New York University] at 10:20 16 July 2015
Nutritional toxicology
Si3
on which to determine the appropriate quantitative relationship between intake of a toxicant and the intake of a nutrient with which it interacts. Critical problems and questions that affect the public health and impact directly on food and health policy decisions may be grouped into categories similar to those of the basic relationships in nutritional toxicology. These include: (1) effects of specific diets or nutrients on degenerative diseases, including chemically induced diseases; (2) impact of dietary components, toxic substances and drugs on the functions and requirements of essential nutrients; and (3) adverse effects of excessive intakes of nutrients, imbalances of dietary nutrients or other dietary substances claimed to have specific health benefits. Understanding of such issues is fundamental to protecting and promoting public health and to providing a sound scientific basis for appropriate decisions. This basis of dose calculation can be used whether or not the diet is actually used as the vehicle for the toxicant. Nutritional well-being and diet alters susceptibility to many toxic substances including drugs, pesticides, heavy metals and carcinogens (Hathcock 1976, 1982). Adequate nutrition is necessary for the body to maintain its ability to eliminate these chemicals or to limit their toxic effects. The influence of diet on carcinogenesis is an important example of dietary modulation of response to toxicants, e.g., diets high in fibre and low in energy and fat decrease response to many carcinogens (Department of Health and Human Services 1988). Other dietary factors such as lipotropes also play an important role in resistance to chemical carcinogenesis (Rogers 1978). Nutrients play many structural and catalytic roles in foreign compound detoxification (Williams 1978, Hathcock 1985a). Nutritional deficiencies generally slow both phase I (oxidation, reduction, etc) and phase II (conjugation) of drug metabolism and enhance toxic potency of most xenobiotics (Meydani 1987). Nutritional requirements depend on the person's age, body size, sex, physical activity and many other factors. Some substances (e.g., certain drugs and heavy metals) can, because of the ways they are handled in the body, increase the amounts of specific vitamins, minerals, amino acids, or other nutrients needed for good health (Brin 1978, Hathcock 1982). Consequently, the dietary requirements for these particular nutrients may be higher in individuals exposed to these chemicals. Numerous toxicants including some drugs have adverse effects on nutritional functions, e.g., coumarins inhibit functions of vitamin K in blood clotting and acetaminophen conjugation depletes significant amounts of sulphate and glutathione, metabolites derived from methionine (Hathcock 1985a, 1990). Vitamins, essential minerals and other nutrients are required for reproduction, growth, disease resistance and longevity. Supplemental intakes of nutrients, sometimes in amounts much higher than the Recommended Dietary Allowance, are consumed by many persons (Stewart et al. 1985). These supplements may be consumed in an attempt to improve health or to be sure of avoiding nutritional deficiencies (Levy and Schucker 1987). Many nutrients are added to processed foods (Gilchrist 1981). This is usually done to increase the nutrient content but the nutrient may also have other functions. An example is the addition of vitamins C or E for their preservative effects. The increased addition of nutrients to foods together with deliberately increased intakes of many nutrients by a large portion of the population raises the questions of development of nutrient imbalances and the safety of very large intakes. Some nutrients, e.g., vitamin A and selenium, have relatively narrow margins of safety, thereby causing toxicity at intakes achieved by some persons (Hathcock 1985b, 1989b, Hathcock et al. 1990).
S14
J. N. Hathcock
Differences in diet composition cause much of the variability in toxicology experiments. Well-defined, standardized diets are needed to reduce variability in dose-response relationships and to improve the toxicological database for risk assessment and safety evaluation (Rader 1989). In general, natural-ingredient diets and those with high nutrient content produce relative resistance to the effects of xenobiotics. Actual problems
Downloaded by [New York University] at 10:20 16 July 2015
The extreme diversity of actual problems in nutritional toxicology is illustrated by the examples in the preceding discussion of basic principles. These examples were discussed only briefly in order to illustrate the principle involved. In this section, selected problems of emerging importance will be discussed in more detail. Adverse effects of soybean trypsin inhibitor Current interest in trypsin inhibitor results from the increasing use of soy protein products as human foods and increasing rate of pancreatic cancer in the United States (Mack 1982). This interest has led to research indicating that soybean trypsin inhibitor is procarcinogenic in several animal models of chemical carcinogenesis of the pancreas (Roebuck 1987). Raw soybean protein does not support normal growth of rats. This effect was at first attributed to the inhibition of trypsin and the resulting interference with the digestion of protein. This explanation, however, was contradicted by the observation that trypsin inhibitor also inhibited growth of rats fed free amino acid diets. A more likely explanation for the effect is the loss of the sufficient nitrogen to explain the effect through the increased flow of pancreatic juice stimulated by the trypsin inhibitor (Liener 1986). Trypsin inhibitor treatment also causes the exocrine acinar cells of the pancreas to become hypertrophic and hyperplastic (Smith et al. 1989). Although trypsin inhibitor produces pancreatic hypertrophy and hyperplasia in several common experimental animal species, several species are not responsive (Tudor and Dayan 1987). Pancreatic hypertrophy and hyperplasia in humans has not been demonstrated to result from trypsin inhibitor consumption but the feedback control mechanism that responds to trypsin inhibitor treatment by increasing output of four pancreatic enzymes, including trysin and chymotrypsin, has been observed (Liener et al. 1988). Enhanced secretion of pancreatic enzymes is associated with hypertrophy and hyperplasia which are related to increases in chemical carcinogenesis (Roebuck 1987, Liener 1986). The relationship between trypsin inhibitor and pancreatic carcinogenesis is still obscure, partly because many studies in this area have been inherently confounded by use of full-fat soybean flour, and high levels of dietary fat promote pancreatic carcinogenesis (Roebuck et al. 1981). Camostat [(N, Af-dimethylcarbamoylmethyl-/7-(/>-guanidobenzoyloxy) phenylacetate] is a synthetic compound with a molecular weight of 398-4 daltons. This compound has a powerful trypsin inhibitory action (Fujii 1977). Like soybean trypsin inhibitor (Liddle et al. 1984), it produces cholecystokinin (CCK) 8-sensitive pancreatic hypertrophy and hyperplasia (Miiller et al. 1988). The implication of the camostat studies is that trypsin inhibition may enhance pancreatic pathology associated with enhanced pancreatic carcinogenesis and that the origin and identity of the inhibitor is not a controlling factor. Nevertheless, if
Downloaded by [New York University] at 10:20 16 July 2015
Nutritional toxicology
S15
dietary soybean protein is a major dietary source of trypsin inhibitor, studies of soybean trypsin inhibitor are relevant to nutritional toxicology and food safety. Most evidence suggests that trypsin inhibitor is a promoter of pancreatic carcinogenesis, i.e., it is effective only if the animals are treated with an initiator such as azaserine (Roebuck 1987). Prolonged consumption of trypsin inhibitor without treatment with a recognized initiator such as azaserine may produce nodular hyperplastic foci in the rat pancreas but the effect is very weak compared with that observed when an initiator is also used (McGuinness et al. 1984). Evaluation of the health impact of dietary trypsin inhibitor on pancreatic cancer will require epidemiologic data to confirm or deny a relationship and experimental data to identify the mechanism in susceptible species and to determine whether the mechanism is present in humans. If both of these are confirmed, residual concentrations of various trypsin inhibitors in foods and the quantities of these foods in the diet must be determined. Whether or not trypsin inhibitor acts as an initiator (either direct-acting, which seems unlikely, or indirect) will need to be investigated. Also, data to describe the dose-response relationship will be required. If it is a promoter rather than an initiator, determination of whether background initiation is sufficient to make promotion important is essential for evaluation of the health impact. Alteration of methionine functions and requirements by acetaminophen Most studies of dietary methionine relationships with acetaminophen (ACAP) metabolism and toxicity have involved prolonged methionine (and cystine) treatment and acute ACAP administration (Reicks and Hathcock 1984, 1987). The decreases in available sulphate and GSH during sulphur amino acid deficiency cause decreased ACAP conjugation, increased adduct formation and increased hepatotoxicity (Reicks and Hathcock 1988a). Similar effects of decreased methionine/cystine intake have been observed for other toxicants (Meydani and Hathcock 1984, Meydani et al. 1984, Rowe et al. 1986). The dose partition for ACAP in humans is approximately 50% to the sulphate plus the glutathione derivatives but there is a large variability (Levy and Yamada 1971, Houston and Levy 1976). In animals, as the dose increases, the fraction excreted as the sulphate decreases but the total amount excreted as ACAP-sulphate increases. Also, with increasing dose, the amount and fraction excreted as GSHderived conjugates increases in mice (Reicks et al. 1988). Because ACAP is often ingested in multiple gram daily dosages, its prolonged consumption has the potential to induce methionine deficiency through depletion of sulphate and GSH (Reicks et al. 1987, McLean and Beales 1987). ACAP is recommended in daily dosages of up to 4 g (Physicians' Desk Reference 1989). This ACAP intake and its metabolic partition represents 13*2mmol/day of sulphate plus GSH depletion. The 25th percentile of protein intake in the 64-74 year-old female is 36 g/day (National Center for Health Statistics 1983) and the calculated total sulphur amino acid intake is 10-9 nmol/day, if the assumption is made that the protein sources are: meat, 50%; milk, 12-5%; egg, 12-5%; and wheat, 25%. Studies involving prolonged ACAP administration to rodents indicate that it can exaggerate methionine deficiency or induce it when dietary sulphur amino acid intake is marginal. Methionine deficiency in methionine-marginal animals with prolonged (dietary) ACAP administration is indicated by decreased growth (Reicks et al. 1987, McLean and Beales 1987, Reicks et al. 1988, McLean et al. 1989); inhi-
Downloaded by [New York University] at 10:20 16 July 2015
S16
J. N. Hathcock
bited protein synthesis, with decreases in plasma free cysteine; decreased excretion of creatinine and A'-methyl-nicotinamide (Reicks and Hathcock 1989); and prolonged decreases in tissue GSH levels (Reicks etal. 1988, Reicks and Hathcock 1988b, 1989, Reicks etal. 1989). Prolonged ACAP treatment decreased creatinine excretion but plasma levels of creatinine and muscle creatine were not affected (Reicks and Hathcock 1989). Also, dietary ACAP treatment increased the oxidation of 14C-phenylalanine, indicating its increased availability for oxidation due to ACAP-induced methionine deficiency (Reicks et al. 1989). These effects are prevent or substantially ameliorated by dietary methionine levels at 200% of the requirement (Reicks and Hathcock 1989). The altered biochemical indicators of methionine status at ACAP levels not causing hepatotoxicity demonstrate that methionine deficiency not confounded by direct ACAP toxicity can be induced by ACAP (Reicks and Hathcock 1989, Hathcock 1990). Chronic consumption of large amounts of ACAP may increase sulphate and GSH metabolic consumption by a sufficiently large amount to cause methionine deficiency in humans if methionine/cystine intakes are marginal. Summary Nutritional toxicology is a specialty that combines the backgrounds and research approaches of nutrition and toxicology. Many problems of substantial importance to health and food safety involve interactions of nutrition process and requirement with the effects of toxicologcal impact. Solution of these problems requires research that meets the procedural and design criteria of experimental nutrition and these of experimental toxicology. The relationships may be described in three basic categories: (1) influence of nutrition on toxicities; (2) influence of toxicants on nutrition; and (3) toxicities of nutrients. Trypsin inhibitor research, an example of diet impacting on toxicological response, illustrates the necessity of controlling nutritional composition aspects that can confound the results. Prolonged acetaminophen administration provides an example of the effects of toxicants on nutritional requirement and function which could be important for persons with marginal sulphur amino acid intake. References ARIENS, E. J., and SIMONIS, A. M., 1982, General principles of nutritional toxicology. Nutritional Toxicology, Vol. I, edited by J. N. Hathcock (New York: Academic Press), pp. 17-80. BRIN, M., 1978, Drugs and environmental chemicals in relation to vitamin needs. Nutrition and Drug Interrelations, edited by J. N. Hathcock and J. Coon (New York: Academic Press), pp. 131-150. DEPARTMENT OF HEALTH AND HUMAN SERVICES, 1988, The Surgeon General's Report on Nutrition and
Health. DHHS (PHS) Publication No. 88-50210 (Washington: US Government Printing Office). FUJII, S., 1977, Synthetic protease inhibitor. Metabolism and Disease, 14, 1087-1092. GILCHRIST, A., 1981, Foodborne, Disease & Food Safety. (Monroe, Wisconsin: American Medical Association). HATHCOCK, J. N., 1976, Nutrition: toxicology and pharmacology. Nutrition Reviews, 34, 65-70. HATHCOCK, J. N., 1982, Introduction. Nutritional Toxicology, Vol. I, edited by J. N. Hathcock (New York: Academic Press), pp. 1-15. HATHCOCK, J. N., 1985a, Metabolic mechanisms of drug-nutrient interactions. Federation Proceedings, 44, 124-129. HATHCOCK, J. N., 1985b, Quantitative evaluation of vitamin toxicities. Pharmacy Times, 51, 104—113. HATHCOCK, J. N., 1989a, High nutrient intakes—the toxicologist's view. Journal of Nutrition, 119, 1779-1784. HATHCOCK, J. N., 1989b, Risk/benefit analysis for vitamin supplements. Nutritional Toxicology, Vol. III, edited by J. N. Hathcock (Orlando: Academic Press), pp. 140-153. HATHCOCK, J. N. 1990, Nutrient depletion by drugs. Journal of Nutritional Biochemistry, 8, in press. HATHCOCK, J. N., HATTAN, D. G., JENKINS, M. Y., MCDONALD, J. T., SUNDARESAN, P . R. D.,
WILKENING, V. L., 1990, American Journal of Clinical Nutrition, 52, 183-202.
and
Nutritional toxicology
S17
HOUSTON, J. B., and LEVY, G., 1976, Drug biotransformation interactions in man VI: acetaminophen and ascorbic acid. Journal of Pharmaceutical Science, 65, 1218-1221. LEHMAN, A. J., 1959, Appraisal of the Safety of Chemicals in Foods. (Topeka: Association of Food and Drug Officials of the United States). LEVY, A. S., and SCHUCKER, R. E., 1987, Patterns of nutrient intake among dietary supplement users: attitudinal and behavioral correlates. Journal of the American Dietetic Association, 87, 754-760. LEVY, G., and YAMADA, H., 1971, Drug biotransformation interactions in man III: acetaminophen and salicylamide. Journal of Pharmaceutical Science, 60, 215-221. LIDDLE, R. H., GOLDFINE, I. D., and WILLIAMS, J. A., 1984, Bioassays of plasma cholecystokinin in
rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology, 87, 542-549. LIENER, I. E., 1986, Trypsin inhibitors: concern for human nutrition or not? Journal of Nutrition, 116, 920-923. MACK, T . M., 1982, Cancer Epidemiology and Prevention, edited by D. Schottenfield and J. Fraumeni (Philadelphia: W. B. Saunders), pp. 638-667.
Downloaded by [New York University] at 10:20 16 July 2015
LIENER, I. I., GOODALE, R. L., DESHMUKH, A., SATTERBERG, T. L., DIPIETRO, C. M., BANKEY, P . E.,
and BORNER, J. W., 1988, Effect of a trypsin inhibitor from soybeans (Bowman-Birk) on the secretory activity of the human pancreas. Gastroenterology, 94, 419-427. MANTEL, N., and SCHNEIDERMAN, M. A., 1975, Estimating 'safe' levels, a hazardous undertaking. Cancer Research, 35, 1379-1386. MCGUINNES, E. E., MORGAN, R. G. H., and WORMSLEY, K. G., 1984, Effects of soybean flour on the
pancreas of rats. Environmental Health Perspectives, 56, 205-212. MCLEAN, A. E. M., ARMSTRONG. G. R., and BEALES D., 1989, Effect of D- or L-methionine and
cysteine on the growth inhibitory effects of feeding 1% paracetamol to rats. Biochemical Pharmacology, 38, 247-352. MCLEAN, A. E. M., and BEALES, D., 1987, Paracetamol as a cause of dietary deficiency of sulphur amino acids. (Abstract) British Journal of Pharmacology, 90, 182p. MEYDANI, M., 1987, Dietary effects on detoxification processes. Nutritional Toxicology, Vol. II, edited by J. N. Hathcock (Orlando: Academic Press), pp. 1-39. MEYDANI, M., and HATHCOCK, J. N., 1984, Effect of dietary methionine on methylmercury and atrazine toxicities. Drug-Nutrient Interactions, 2, 217-233. MEYDANI, M., MEYDANI, S. N., and HATHCOCK, J. N., 1984, Effects of dietary methionine, methylmer cury, and atrazine on ex-vivo synthesis of prostaglandin E1 and thromboxane B 2 . Prostaglandins, Leukotrienes and Medicine, 14, 267-278. MÜLLER, M. K., GOEBELL, H., ALFEN, R., EHLERS, J., JÄGER, M., and PLÜMPE, H., 1988, Effects of
camostat, a synthetic protease inhibitor, on endocrine and exocrine pancreas of the rat. Journal of Nutrition, 118, 645-650. NATIONAL CENTER FOR HEALTH STATISTICS, 1983, Dietary Intake Source Data: United States, 1976-80. DHSS Publication No. (PHS)83-1681. (Hyattsville, Maryland: National Center for Health Statistics). NATIONAL RESEARCH COUNCIL, 1978, Nutrient Requirements of Laboratory Animals, 3rd revised edition (Washington: National Academy of Sciences). NATIONAL RESEARCH COUNCIL, 1989, Recommended Dietary Allowances, 10th edition (Washington: National Academy Press). Physicians' Desk Reference. 43nd Edition, 1989. (Oradel: Medical Economics Co.). RADER, J. I., 1989, Considerations in designing and using standardized diets in toxicology experiments. Nutritional Toxicology, Vol. III, edited by J. N. Hathcock (Orlando: Academic Press), pp. 123-139. REICKS, M., CALVERT, R., and HATHCOCK, J., 1987, Effects of chronic acetaminophen on glutathione functions in mice (Abstract) Federation Proceedings, 46, 959. REICKS, M., CALVERT, R. J., and HATHCOCK, J. N., 1988, Effects of prolonged acetaminophen ingestion and dietary methionine on mouse liver glutathione. Drug-Nutrient Interactions, 5, 351-363. REICKS, M.,
SATCHITHANANDAM,
S.,
and
HATHCOCK,
J.
N.,
1989, The
effects
of
prolonged
acetaminophen ingestion on the availability of methionine for its metabolic functions in mice (Abstract) FASEB Journal, 3, A1059. REICKS, M., and HATHCOCK, J. N., 1984, Effects of dietary methionine and ethanol on acetaminophen hepatotoxicity in mice. Drug-Nutrient Interactions, 3, 43-51. REICKS, M., and HATHCOCK, J. N., 1987, Effects of methionine deficiency and ethanol ingestion on acetaminophen metabolism in mice. Journal of Nutrition, 117, 572-579. REICKS, M., and HATHCOCK, J. N., 1988a, Effects of methionine and other sulphur compounds on drug conjugations. Pharmacology and Therapeutics, 37, 67-79. REICKS, M., and HATHCOCK, J. N., 1988b, Effects of prolonged acetaminophen ingestion on the growth requirement in weanling mice (Abstract) FASEB Journal, 2, A1573. REICKS, M., and HATHCOCK, J. N., 1989, Prolonged acetaminophen ingestion: Effects on the availability of methionine for metabolic functions. Journal of Nutrition, 119, 1042-1049. ROEBUCK, B. D., YAGER, J. D., and LONGNECKER, D. S., 1981, Dietary modulation of azaserine-induced
pancreatic carcinogenesis in the rat. Cancer Research, 41, 888-893.
S18
J. N. Hathcock
ROEBUCK, B. D., 1987, Trypsin inhibitors: Potential concern for humans? Journal of Nutrition, 117, 398-400. ROGERS, A. E., 1978, Dietary effects on carcinogenicity of drugs and related compounds. Nutrition and Drug Interrelations, edited by J. N. Hathcock and J. Coon (New York: Academic Press), pp. 505-542. ROWE, V. A., SERFASS, R. E., and HATHCOCK, J. N., 1986, Dietary methionine effects on interactions
of lead and lindane in rats. Drug-Nutrient Interactions, 4, 249-354. SMITH, J. C., WILSON, F. D., ALLEN, P. V., and BERRY, D. L., 1989, Hypertrophy and hyperplasia of
the rat pancreas produced by short-term dietary administration of soya-derived protein and soybean trypsin inhibitor. Journal of Applied Toxicology, 9, 175-179. STEWART, M. L., MCDONALD, J. T., LEVY, A. S., SCHUCKER, R. E., and HENDERSON, D. P., 1985,
Vitamin/mineral supplement use: A telephone survey of adults in the United States. Journal of the American Dietetic Association, 85, 1585-1590. TUDOR, R. J., and DAYAN, A. D., 1987, Comparative subacute effects of dietary raw soya flour on the pancreas of three species, the marmoset, mouse and rat. Food and Chemical Toxicology, 25, 739-745.
Downloaded by [New York University] at 10:20 16 July 2015
US FOOD and DRUG ADMINISTRATION, 1982, Toxicological Principles for the Safety Assessment of
Direct Food Additives and Color Additives Used in Food. (Washington: Bureau of Foods, US Food and Drug Administration). WILLIAMS, R. T., 1978, Nutrients in drug detoxication reactions. Nutrition and Drug Interrelations, edited by J. N. Hathcock and J. Coon (New York: Academic Press), pp. 303-318.
Food Additives & Contaminants Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tfac19
Nutritional toxicology: Basic principles and actual problems John N. Hathcock
a
a
Food and Drug Administration , Center for Food Safety and Applied Nutrition , Washington, DC, 20204, USA Published online: 10 Jan 2009.
To cite this article: John N. Hathcock (1990) Nutritional toxicology: Basic principles and actual problems, Food Additives & Contaminants, 7:S1, S12-S18, DOI: 10.1080/02652039009373836 To link to this article: http://dx.doi.org/10.1080/02652039009373836
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sublicensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
FOOD ADDITIVES AND CONTAMINANTS, 1990, VOL. 7, SUPPLEMENT NO. 1, S 1 2 - S 1 8
Nutritional toxicology: basic principles and actual problems JOHN N. HATHCOCK Food and Drug Administration, Center for Food Safety and Applied Nutrition, Washington, DC 20204, USA
Downloaded by [New York University] at 10:20 16 July 2015
Basic principles
Many problems in food safety and adequacy occur at the interface between nutrition and toxicology, disciplines that study basically opposing influences on living organisms. Nutritional substances provide essential structural, catalytic and energetic support for life processes, and the science of nutrition studies how nutrients sustain expression of the genetic programme of an organism. Toxic substances disrupt life processes and structures and the science of toxicology studies effects of substances that disturb normal expression of the genetic programme. These fundamentally opposite actions of nutrients and toxicants cause extensive mutual modulation of effect. At high intakes, nutrients themselves become toxicants. The many interactions in nutritional toxicology may be categorized into three basic types of relationships: (1) influence of diet and nutrition on response to toxic substances; (2) effects of toxicants on nutritional functions and requirements; and (3) toxicities of nutrients at excessive intakes (Hathcock 1976, 1982). Effective research in these areas requires utilization of the information base, perspectives and experimental strategies of both nutrition and toxicology for optimal results (Ariens and Simonis 1982). The quantitative and statistical methods of toxicology relating to dose-response and time-response relationships, and toxicokinetics may be applied to nutrienttoxicant interactions and nutrient toxicities (Ariens and Simonis 1982, Hathcock, 1989a). Many methods of dose-body size extrapolation between or within species have been employed. The common dose/kg basis used in human pharmacology often gives large quantitative errors when used for extrapolation between species of very different body size. In toxicology, assessment of chemicals often involves dose characterization on the basis of nominal surface area (kg273) (Mantel and Schneiderman 1975, US Food and Drug Administration 1982). In human nutrition, recommended intakes are in amounts per person per day, with adjustments for differences in body size made only when there is a difference in age (National Research Council 1989). In animal nutrition, recommended intakes are made on a dietary concentration basis (National Research Council 1978). Because surface area is a major determinant of heat loss and thus energy need, there is a close correlation between the kg 2/3 basis (nominal surface area) and a dietary concentration basis for dosage with toxicants (Hathcock 1989a). Tables of equivalency between dose per kg and dietary concentration have been developed for species ranging in body size from the mouse to the horse (Lehman 1959). Dietary concentration is a good basis © US Government 1990
Downloaded by [New York University] at 10:20 16 July 2015
Nutritional toxicology
Si3
on which to determine the appropriate quantitative relationship between intake of a toxicant and the intake of a nutrient with which it interacts. Critical problems and questions that affect the public health and impact directly on food and health policy decisions may be grouped into categories similar to those of the basic relationships in nutritional toxicology. These include: (1) effects of specific diets or nutrients on degenerative diseases, including chemically induced diseases; (2) impact of dietary components, toxic substances and drugs on the functions and requirements of essential nutrients; and (3) adverse effects of excessive intakes of nutrients, imbalances of dietary nutrients or other dietary substances claimed to have specific health benefits. Understanding of such issues is fundamental to protecting and promoting public health and to providing a sound scientific basis for appropriate decisions. This basis of dose calculation can be used whether or not the diet is actually used as the vehicle for the toxicant. Nutritional well-being and diet alters susceptibility to many toxic substances including drugs, pesticides, heavy metals and carcinogens (Hathcock 1976, 1982). Adequate nutrition is necessary for the body to maintain its ability to eliminate these chemicals or to limit their toxic effects. The influence of diet on carcinogenesis is an important example of dietary modulation of response to toxicants, e.g., diets high in fibre and low in energy and fat decrease response to many carcinogens (Department of Health and Human Services 1988). Other dietary factors such as lipotropes also play an important role in resistance to chemical carcinogenesis (Rogers 1978). Nutrients play many structural and catalytic roles in foreign compound detoxification (Williams 1978, Hathcock 1985a). Nutritional deficiencies generally slow both phase I (oxidation, reduction, etc) and phase II (conjugation) of drug metabolism and enhance toxic potency of most xenobiotics (Meydani 1987). Nutritional requirements depend on the person's age, body size, sex, physical activity and many other factors. Some substances (e.g., certain drugs and heavy metals) can, because of the ways they are handled in the body, increase the amounts of specific vitamins, minerals, amino acids, or other nutrients needed for good health (Brin 1978, Hathcock 1982). Consequently, the dietary requirements for these particular nutrients may be higher in individuals exposed to these chemicals. Numerous toxicants including some drugs have adverse effects on nutritional functions, e.g., coumarins inhibit functions of vitamin K in blood clotting and acetaminophen conjugation depletes significant amounts of sulphate and glutathione, metabolites derived from methionine (Hathcock 1985a, 1990). Vitamins, essential minerals and other nutrients are required for reproduction, growth, disease resistance and longevity. Supplemental intakes of nutrients, sometimes in amounts much higher than the Recommended Dietary Allowance, are consumed by many persons (Stewart et al. 1985). These supplements may be consumed in an attempt to improve health or to be sure of avoiding nutritional deficiencies (Levy and Schucker 1987). Many nutrients are added to processed foods (Gilchrist 1981). This is usually done to increase the nutrient content but the nutrient may also have other functions. An example is the addition of vitamins C or E for their preservative effects. The increased addition of nutrients to foods together with deliberately increased intakes of many nutrients by a large portion of the population raises the questions of development of nutrient imbalances and the safety of very large intakes. Some nutrients, e.g., vitamin A and selenium, have relatively narrow margins of safety, thereby causing toxicity at intakes achieved by some persons (Hathcock 1985b, 1989b, Hathcock et al. 1990).
S14
J. N. Hathcock
Differences in diet composition cause much of the variability in toxicology experiments. Well-defined, standardized diets are needed to reduce variability in dose-response relationships and to improve the toxicological database for risk assessment and safety evaluation (Rader 1989). In general, natural-ingredient diets and those with high nutrient content produce relative resistance to the effects of xenobiotics. Actual problems
Downloaded by [New York University] at 10:20 16 July 2015
The extreme diversity of actual problems in nutritional toxicology is illustrated by the examples in the preceding discussion of basic principles. These examples were discussed only briefly in order to illustrate the principle involved. In this section, selected problems of emerging importance will be discussed in more detail. Adverse effects of soybean trypsin inhibitor Current interest in trypsin inhibitor results from the increasing use of soy protein products as human foods and increasing rate of pancreatic cancer in the United States (Mack 1982). This interest has led to research indicating that soybean trypsin inhibitor is procarcinogenic in several animal models of chemical carcinogenesis of the pancreas (Roebuck 1987). Raw soybean protein does not support normal growth of rats. This effect was at first attributed to the inhibition of trypsin and the resulting interference with the digestion of protein. This explanation, however, was contradicted by the observation that trypsin inhibitor also inhibited growth of rats fed free amino acid diets. A more likely explanation for the effect is the loss of the sufficient nitrogen to explain the effect through the increased flow of pancreatic juice stimulated by the trypsin inhibitor (Liener 1986). Trypsin inhibitor treatment also causes the exocrine acinar cells of the pancreas to become hypertrophic and hyperplastic (Smith et al. 1989). Although trypsin inhibitor produces pancreatic hypertrophy and hyperplasia in several common experimental animal species, several species are not responsive (Tudor and Dayan 1987). Pancreatic hypertrophy and hyperplasia in humans has not been demonstrated to result from trypsin inhibitor consumption but the feedback control mechanism that responds to trypsin inhibitor treatment by increasing output of four pancreatic enzymes, including trysin and chymotrypsin, has been observed (Liener et al. 1988). Enhanced secretion of pancreatic enzymes is associated with hypertrophy and hyperplasia which are related to increases in chemical carcinogenesis (Roebuck 1987, Liener 1986). The relationship between trypsin inhibitor and pancreatic carcinogenesis is still obscure, partly because many studies in this area have been inherently confounded by use of full-fat soybean flour, and high levels of dietary fat promote pancreatic carcinogenesis (Roebuck et al. 1981). Camostat [(N, Af-dimethylcarbamoylmethyl-/7-(/>-guanidobenzoyloxy) phenylacetate] is a synthetic compound with a molecular weight of 398-4 daltons. This compound has a powerful trypsin inhibitory action (Fujii 1977). Like soybean trypsin inhibitor (Liddle et al. 1984), it produces cholecystokinin (CCK) 8-sensitive pancreatic hypertrophy and hyperplasia (Miiller et al. 1988). The implication of the camostat studies is that trypsin inhibition may enhance pancreatic pathology associated with enhanced pancreatic carcinogenesis and that the origin and identity of the inhibitor is not a controlling factor. Nevertheless, if
Downloaded by [New York University] at 10:20 16 July 2015
Nutritional toxicology
S15
dietary soybean protein is a major dietary source of trypsin inhibitor, studies of soybean trypsin inhibitor are relevant to nutritional toxicology and food safety. Most evidence suggests that trypsin inhibitor is a promoter of pancreatic carcinogenesis, i.e., it is effective only if the animals are treated with an initiator such as azaserine (Roebuck 1987). Prolonged consumption of trypsin inhibitor without treatment with a recognized initiator such as azaserine may produce nodular hyperplastic foci in the rat pancreas but the effect is very weak compared with that observed when an initiator is also used (McGuinness et al. 1984). Evaluation of the health impact of dietary trypsin inhibitor on pancreatic cancer will require epidemiologic data to confirm or deny a relationship and experimental data to identify the mechanism in susceptible species and to determine whether the mechanism is present in humans. If both of these are confirmed, residual concentrations of various trypsin inhibitors in foods and the quantities of these foods in the diet must be determined. Whether or not trypsin inhibitor acts as an initiator (either direct-acting, which seems unlikely, or indirect) will need to be investigated. Also, data to describe the dose-response relationship will be required. If it is a promoter rather than an initiator, determination of whether background initiation is sufficient to make promotion important is essential for evaluation of the health impact. Alteration of methionine functions and requirements by acetaminophen Most studies of dietary methionine relationships with acetaminophen (ACAP) metabolism and toxicity have involved prolonged methionine (and cystine) treatment and acute ACAP administration (Reicks and Hathcock 1984, 1987). The decreases in available sulphate and GSH during sulphur amino acid deficiency cause decreased ACAP conjugation, increased adduct formation and increased hepatotoxicity (Reicks and Hathcock 1988a). Similar effects of decreased methionine/cystine intake have been observed for other toxicants (Meydani and Hathcock 1984, Meydani et al. 1984, Rowe et al. 1986). The dose partition for ACAP in humans is approximately 50% to the sulphate plus the glutathione derivatives but there is a large variability (Levy and Yamada 1971, Houston and Levy 1976). In animals, as the dose increases, the fraction excreted as the sulphate decreases but the total amount excreted as ACAP-sulphate increases. Also, with increasing dose, the amount and fraction excreted as GSHderived conjugates increases in mice (Reicks et al. 1988). Because ACAP is often ingested in multiple gram daily dosages, its prolonged consumption has the potential to induce methionine deficiency through depletion of sulphate and GSH (Reicks et al. 1987, McLean and Beales 1987). ACAP is recommended in daily dosages of up to 4 g (Physicians' Desk Reference 1989). This ACAP intake and its metabolic partition represents 13*2mmol/day of sulphate plus GSH depletion. The 25th percentile of protein intake in the 64-74 year-old female is 36 g/day (National Center for Health Statistics 1983) and the calculated total sulphur amino acid intake is 10-9 nmol/day, if the assumption is made that the protein sources are: meat, 50%; milk, 12-5%; egg, 12-5%; and wheat, 25%. Studies involving prolonged ACAP administration to rodents indicate that it can exaggerate methionine deficiency or induce it when dietary sulphur amino acid intake is marginal. Methionine deficiency in methionine-marginal animals with prolonged (dietary) ACAP administration is indicated by decreased growth (Reicks et al. 1987, McLean and Beales 1987, Reicks et al. 1988, McLean et al. 1989); inhi-
Downloaded by [New York University] at 10:20 16 July 2015
S16
J. N. Hathcock
bited protein synthesis, with decreases in plasma free cysteine; decreased excretion of creatinine and A'-methyl-nicotinamide (Reicks and Hathcock 1989); and prolonged decreases in tissue GSH levels (Reicks etal. 1988, Reicks and Hathcock 1988b, 1989, Reicks etal. 1989). Prolonged ACAP treatment decreased creatinine excretion but plasma levels of creatinine and muscle creatine were not affected (Reicks and Hathcock 1989). Also, dietary ACAP treatment increased the oxidation of 14C-phenylalanine, indicating its increased availability for oxidation due to ACAP-induced methionine deficiency (Reicks et al. 1989). These effects are prevent or substantially ameliorated by dietary methionine levels at 200% of the requirement (Reicks and Hathcock 1989). The altered biochemical indicators of methionine status at ACAP levels not causing hepatotoxicity demonstrate that methionine deficiency not confounded by direct ACAP toxicity can be induced by ACAP (Reicks and Hathcock 1989, Hathcock 1990). Chronic consumption of large amounts of ACAP may increase sulphate and GSH metabolic consumption by a sufficiently large amount to cause methionine deficiency in humans if methionine/cystine intakes are marginal. Summary Nutritional toxicology is a specialty that combines the backgrounds and research approaches of nutrition and toxicology. Many problems of substantial importance to health and food safety involve interactions of nutrition process and requirement with the effects of toxicologcal impact. Solution of these problems requires research that meets the procedural and design criteria of experimental nutrition and these of experimental toxicology. The relationships may be described in three basic categories: (1) influence of nutrition on toxicities; (2) influence of toxicants on nutrition; and (3) toxicities of nutrients. Trypsin inhibitor research, an example of diet impacting on toxicological response, illustrates the necessity of controlling nutritional composition aspects that can confound the results. Prolonged acetaminophen administration provides an example of the effects of toxicants on nutritional requirement and function which could be important for persons with marginal sulphur amino acid intake. References ARIENS, E. J., and SIMONIS, A. M., 1982, General principles of nutritional toxicology. Nutritional Toxicology, Vol. I, edited by J. N. Hathcock (New York: Academic Press), pp. 17-80. BRIN, M., 1978, Drugs and environmental chemicals in relation to vitamin needs. Nutrition and Drug Interrelations, edited by J. N. Hathcock and J. Coon (New York: Academic Press), pp. 131-150. DEPARTMENT OF HEALTH AND HUMAN SERVICES, 1988, The Surgeon General's Report on Nutrition and
Health. DHHS (PHS) Publication No. 88-50210 (Washington: US Government Printing Office). FUJII, S., 1977, Synthetic protease inhibitor. Metabolism and Disease, 14, 1087-1092. GILCHRIST, A., 1981, Foodborne, Disease & Food Safety. (Monroe, Wisconsin: American Medical Association). HATHCOCK, J. N., 1976, Nutrition: toxicology and pharmacology. Nutrition Reviews, 34, 65-70. HATHCOCK, J. N., 1982, Introduction. Nutritional Toxicology, Vol. I, edited by J. N. Hathcock (New York: Academic Press), pp. 1-15. HATHCOCK, J. N., 1985a, Metabolic mechanisms of drug-nutrient interactions. Federation Proceedings, 44, 124-129. HATHCOCK, J. N., 1985b, Quantitative evaluation of vitamin toxicities. Pharmacy Times, 51, 104—113. HATHCOCK, J. N., 1989a, High nutrient intakes—the toxicologist's view. Journal of Nutrition, 119, 1779-1784. HATHCOCK, J. N., 1989b, Risk/benefit analysis for vitamin supplements. Nutritional Toxicology, Vol. III, edited by J. N. Hathcock (Orlando: Academic Press), pp. 140-153. HATHCOCK, J. N. 1990, Nutrient depletion by drugs. Journal of Nutritional Biochemistry, 8, in press. HATHCOCK, J. N., HATTAN, D. G., JENKINS, M. Y., MCDONALD, J. T., SUNDARESAN, P . R. D.,
WILKENING, V. L., 1990, American Journal of Clinical Nutrition, 52, 183-202.
and
Nutritional toxicology
S17
HOUSTON, J. B., and LEVY, G., 1976, Drug biotransformation interactions in man VI: acetaminophen and ascorbic acid. Journal of Pharmaceutical Science, 65, 1218-1221. LEHMAN, A. J., 1959, Appraisal of the Safety of Chemicals in Foods. (Topeka: Association of Food and Drug Officials of the United States). LEVY, A. S., and SCHUCKER, R. E., 1987, Patterns of nutrient intake among dietary supplement users: attitudinal and behavioral correlates. Journal of the American Dietetic Association, 87, 754-760. LEVY, G., and YAMADA, H., 1971, Drug biotransformation interactions in man III: acetaminophen and salicylamide. Journal of Pharmaceutical Science, 60, 215-221. LIDDLE, R. H., GOLDFINE, I. D., and WILLIAMS, J. A., 1984, Bioassays of plasma cholecystokinin in
rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology, 87, 542-549. LIENER, I. E., 1986, Trypsin inhibitors: concern for human nutrition or not? Journal of Nutrition, 116, 920-923. MACK, T . M., 1982, Cancer Epidemiology and Prevention, edited by D. Schottenfield and J. Fraumeni (Philadelphia: W. B. Saunders), pp. 638-667.
Downloaded by [New York University] at 10:20 16 July 2015
LIENER, I. I., GOODALE, R. L., DESHMUKH, A., SATTERBERG, T. L., DIPIETRO, C. M., BANKEY, P . E.,
and BORNER, J. W., 1988, Effect of a trypsin inhibitor from soybeans (Bowman-Birk) on the secretory activity of the human pancreas. Gastroenterology, 94, 419-427. MANTEL, N., and SCHNEIDERMAN, M. A., 1975, Estimating 'safe' levels, a hazardous undertaking. Cancer Research, 35, 1379-1386. MCGUINNES, E. E., MORGAN, R. G. H., and WORMSLEY, K. G., 1984, Effects of soybean flour on the
pancreas of rats. Environmental Health Perspectives, 56, 205-212. MCLEAN, A. E. M., ARMSTRONG. G. R., and BEALES D., 1989, Effect of D- or L-methionine and
cysteine on the growth inhibitory effects of feeding 1% paracetamol to rats. Biochemical Pharmacology, 38, 247-352. MCLEAN, A. E. M., and BEALES, D., 1987, Paracetamol as a cause of dietary deficiency of sulphur amino acids. (Abstract) British Journal of Pharmacology, 90, 182p. MEYDANI, M., 1987, Dietary effects on detoxification processes. Nutritional Toxicology, Vol. II, edited by J. N. Hathcock (Orlando: Academic Press), pp. 1-39. MEYDANI, M., and HATHCOCK, J. N., 1984, Effect of dietary methionine on methylmercury and atrazine toxicities. Drug-Nutrient Interactions, 2, 217-233. MEYDANI, M., MEYDANI, S. N., and HATHCOCK, J. N., 1984, Effects of dietary methionine, methylmer cury, and atrazine on ex-vivo synthesis of prostaglandin E1 and thromboxane B 2 . Prostaglandins, Leukotrienes and Medicine, 14, 267-278. MÜLLER, M. K., GOEBELL, H., ALFEN, R., EHLERS, J., JÄGER, M., and PLÜMPE, H., 1988, Effects of
camostat, a synthetic protease inhibitor, on endocrine and exocrine pancreas of the rat. Journal of Nutrition, 118, 645-650. NATIONAL CENTER FOR HEALTH STATISTICS, 1983, Dietary Intake Source Data: United States, 1976-80. DHSS Publication No. (PHS)83-1681. (Hyattsville, Maryland: National Center for Health Statistics). NATIONAL RESEARCH COUNCIL, 1978, Nutrient Requirements of Laboratory Animals, 3rd revised edition (Washington: National Academy of Sciences). NATIONAL RESEARCH COUNCIL, 1989, Recommended Dietary Allowances, 10th edition (Washington: National Academy Press). Physicians' Desk Reference. 43nd Edition, 1989. (Oradel: Medical Economics Co.). RADER, J. I., 1989, Considerations in designing and using standardized diets in toxicology experiments. Nutritional Toxicology, Vol. III, edited by J. N. Hathcock (Orlando: Academic Press), pp. 123-139. REICKS, M., CALVERT, R., and HATHCOCK, J., 1987, Effects of chronic acetaminophen on glutathione functions in mice (Abstract) Federation Proceedings, 46, 959. REICKS, M., CALVERT, R. J., and HATHCOCK, J. N., 1988, Effects of prolonged acetaminophen ingestion and dietary methionine on mouse liver glutathione. Drug-Nutrient Interactions, 5, 351-363. REICKS, M.,
SATCHITHANANDAM,
S.,
and
HATHCOCK,
J.
N.,
1989, The
effects
of
prolonged
acetaminophen ingestion on the availability of methionine for its metabolic functions in mice (Abstract) FASEB Journal, 3, A1059. REICKS, M., and HATHCOCK, J. N., 1984, Effects of dietary methionine and ethanol on acetaminophen hepatotoxicity in mice. Drug-Nutrient Interactions, 3, 43-51. REICKS, M., and HATHCOCK, J. N., 1987, Effects of methionine deficiency and ethanol ingestion on acetaminophen metabolism in mice. Journal of Nutrition, 117, 572-579. REICKS, M., and HATHCOCK, J. N., 1988a, Effects of methionine and other sulphur compounds on drug conjugations. Pharmacology and Therapeutics, 37, 67-79. REICKS, M., and HATHCOCK, J. N., 1988b, Effects of prolonged acetaminophen ingestion on the growth requirement in weanling mice (Abstract) FASEB Journal, 2, A1573. REICKS, M., and HATHCOCK, J. N., 1989, Prolonged acetaminophen ingestion: Effects on the availability of methionine for metabolic functions. Journal of Nutrition, 119, 1042-1049. ROEBUCK, B. D., YAGER, J. D., and LONGNECKER, D. S., 1981, Dietary modulation of azaserine-induced
pancreatic carcinogenesis in the rat. Cancer Research, 41, 888-893.
S18
J. N. Hathcock
ROEBUCK, B. D., 1987, Trypsin inhibitors: Potential concern for humans? Journal of Nutrition, 117, 398-400. ROGERS, A. E., 1978, Dietary effects on carcinogenicity of drugs and related compounds. Nutrition and Drug Interrelations, edited by J. N. Hathcock and J. Coon (New York: Academic Press), pp. 505-542. ROWE, V. A., SERFASS, R. E., and HATHCOCK, J. N., 1986, Dietary methionine effects on interactions
of lead and lindane in rats. Drug-Nutrient Interactions, 4, 249-354. SMITH, J. C., WILSON, F. D., ALLEN, P. V., and BERRY, D. L., 1989, Hypertrophy and hyperplasia of
the rat pancreas produced by short-term dietary administration of soya-derived protein and soybean trypsin inhibitor. Journal of Applied Toxicology, 9, 175-179. STEWART, M. L., MCDONALD, J. T., LEVY, A. S., SCHUCKER, R. E., and HENDERSON, D. P., 1985,
Vitamin/mineral supplement use: A telephone survey of adults in the United States. Journal of the American Dietetic Association, 85, 1585-1590. TUDOR, R. J., and DAYAN, A. D., 1987, Comparative subacute effects of dietary raw soya flour on the pancreas of three species, the marmoset, mouse and rat. Food and Chemical Toxicology, 25, 739-745.
Downloaded by [New York University] at 10:20 16 July 2015
US FOOD and DRUG ADMINISTRATION, 1982, Toxicological Principles for the Safety Assessment of
Direct Food Additives and Color Additives Used in Food. (Washington: Bureau of Foods, US Food and Drug Administration). WILLIAMS, R. T., 1978, Nutrients in drug detoxication reactions. Nutrition and Drug Interrelations, edited by J. N. Hathcock and J. Coon (New York: Academic Press), pp. 303-318.
