Table Of ContentNUTRITION: BASIC AND APPLIED SCIENCE
A SERIES OF MONOGRAPHS
WILLIAM J. DARBY, Editor
Professor of Biochemistry (Nutrition)
Vanderbilt University School of Medicine
Nashville, Tennessee
and
President, The Nutrition Foundation
New York, New York
Anthony W. Norman. Vitamin D: The Calcium Homeostatic Steroid Hor
mone, 1979.
Donald S. McLaren (Editor). Nutritional Ophthalmology, 1980.
John N. Hathcock (Editor). Nutritional Toxicology, Volume I, 1982.
Nutritional
Toxicology
VOLUME I
Edited by
JOHN N. HATHCOCK
Department of Food and Nutrition
Iowa State University
Ames, Iowa
1982
ACADEMIC PRESS
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COPYRIGHT © 1982, BY ACADEMIC PRESS, INC.
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United Kingdom Edition published by
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Library of Congress Cataloging in Publication Data
Main entry under title:
Nutritional toxicology.
(Nutrition, "basic and applied science)
Includes "bibliographies and index.
1. Nutritionally induced diseases. 2. Nutrition.
3. Food additives—Toxicology. I. Hathcock, John N.
II. Series. CDNLM: 1. Food contamination. 2. Food
additives—Adverse effects. 3. Food poisoning. WA 701
N976J f
RC622.N89U 66:l 6.399 82-1+036
ISBN 0-12-332601-X AACE2
PRINTED IN THE UNITED STATES OF AMERICA
82 83 84 85 9 8 7 6 5 4 3 21
List of Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Michael C. Archer (327), Department of Medical Biophysics, University of
Toronto, and Ontario Cancer Institute, Toronto, Ontario M4X 1K9,
Canada
E. J. Ariens (17), Institute of Pharmacology and Toxicology, Medical Faculty
and Faculty of Sciences, University of Nijmegen, 6500 HB Nijmegen, The
Netherlands
Murray Berdick (383), P.O. Box 245, Branford, Connecticut 06405
Frank Cordle (303), Epidemiology and Clinical Toxicology, Bureau of Foods,
Food and Drug Administration, Washington, D.C. 20204
John N. Hathcock (1), Department of Food and Nutrition, Iowa State Uni
versity, Ames, Iowa 50011
K. C. Hayes (81), Department of Nutrition, Harvard School of Public Health,
Boston, Massachusetts 02115, and New England Regional Primate
Center, Southborough, Massachusetts 01772
George W. Irving, Jr. (435), The Federation of American Societies for Ex
perimental Biology, Bethesda, Maryland 20814
Albert C. Kolbye (303), Epidemiology and Clinical Toxicology, Bureau of
Foods, Food and Drug Administration, Washington, D.C. 20204
Donald M. Kuhn (473), Hypertension-Endocrine Branch, National Heart,
Lung, and Blood Institute, Bethesda, Maryland 20205
Walter Lovenberg (473), Hypertension-Endocrine Branch, National Heart,
Lung, and Blood Institute, Bethesda, Maryland 20205
D. R. Miller (81), Department of Nutrition, Harvard School of Public Health,
xi
xii List of Contributors
Boston, Massachusetts 02115, and New England Regional Primate
Center, Southborough, Massachusetts 01772
/. Orvin Mundt (209), Department of Microbiology, University of Tennes
see, Knoxville, Tennessee 37916
Stata Norton (451), Department of Pharmacology, College of Sciences, Uni
versity of Kansas Medical Center, Kansas City, Kansas 66103
A. M. Simonis (17), Institute of Pharmacology and Toxicology, Medical Fa
culty and Faculty of Sciences, University of Nijmegen, 6500 HB Nijme
gen, The Netherlands
George V. Vahouny (135), Department of Biochemistry, School of Medicine
and Health Sciences, George Washington University, Washington D.C.
20037
P. D. Whanger (163), Department of Agricultural Chemistry, Oregon State
University, Corvallis, Oregon 97331
Benjamin J. Wilson (239), Center in Toxicology, Department of Biochemis
try, School of Medicine, Vanderbilt University, Nashville, Tennessee
37232
Preface
The levels of nutritional intake form a continuum from lethal deficiencies
to lethal excesses. Optimal nutrient requirements of all organisms are for the
level that will meet minimal nutrient needs and prove sufficient to accumu
late desirable stores, but not in quantities large enough to be detrimental to
health. Both nutritionally essential and nonessential substances can in excess
cause toxicity. Study of the full range of nutritional concerns cannot be
complete without careful examination of the toxic excesses of chemicals
that can be found in some diets at detrimentally high concentrations.
Toxicology has usually been considered a separate discipline or a subject
closely related to pharmacology; a nutritional perspective in toxicology is less
common. The increasing use in food production and processing of pesticides,
growth stimulants, preservatives, processing chemicals, and nutrient sup
plements has resulted in a need for increased toxicological awareness and
understanding by nutritionists and other professionals concerned with food
production, utilization, and health. Relevant information concerning nutri
tional toxicology is widely scattered in handbooks, manuals, monographs,
and research publications in nutrition, toxicology, pharmacology, and re
lated sciences.
The purpose of this book is to collate the essential information relating to
nutrition-associated toxicity problems of basic importance and current con
cern. The reader is assumed to be familiar with the fundamentals of
biochemistry; those who have studied nutrition, toxicology, or pharmacology
will find new outlooks and perspectives. It is hoped that the subject matter
and orientation of this book will prove useful to students and researchers in
nutrition and toxicology as well as to others needing a single-source treat
ment of these important topics in the expanding subject of nutritional tox
icology.
John N. Hathcock
xiii
1
Nutritional Toxicology: Definition and Scope
JOHN N. HATHCOCK
I. Introduction and Definitions 1
II. Diet as a Source of Toxicants 3
A. Nutrients 3
B. Natural Toxicants in Foods 4
C. Contaminants 4
D. Food Additives 5
III. Nutritional Effects of Toxicants 5
A. Nutrients in Detoxification Systems 5
B. Nutritional Alteration of Susceptibilities to Toxicants . .. 7
C. Nutrition and Drug Interrelations 7
D. Chemical Interactions of Nutrients and Toxicants . . .. 8
IV. Effects of Toxicants on Nutrition 9
A. Modification of Nutrient Contents of Foods 9
B. Modulation of Appetite 10
C. Inhibition of Digestion and Absorption 10
D. Alteration of Nutrient Metabolism and Function . . .. 11
V. Safety Evaluation, Risk Assessment, and Regulation of Chemicals
in Food 12
A. Safety Evaluation 12
B. Risk Assessment 13
C. Regulation of Chemicals in Foods 14
References 15
I. INTRODUCTION AND DEFINITIONS
Toxicology is the science dealing with poisons or toxicants. Nutritional
toxicology, then, as its name indicates, is the nutritional aspects of toxicol
ogy. Conversely, it may be considered a branch of nutrition as well. The
term nutritional toxicology is carefully chosen. It is not synonymous with
food toxicology, although the two are related and overlap. Nutritional tox-
l
NUTRITIONAL TOXICOLOGY, VOL. I Copyright © 1982 by Academic Press, Inc.
All rights of reproduction in any form reserved.
ISBN 0-12-332601-X
2 John N. Hathcock
icology is concerned with toxicants in the diet and their interrelations with
nutrition, whereas food toxicology deals with toxicants in foods. Nutritional
toxicology is the branch of toxicology and nutrition concerned with the diet
as a source of toxicants, the effects of toxicants on nutrients and nutritional
processes, the effects of nutrients and nutritional metabolism on toxicants,
and the scientific basis for regulatory decisions affecting toxicological safety
of dietary components.
Nutritional toxicology has many facets of extensive practical and theoreti
cal importance. Nutrients may act as toxicants when consumed in excess.
Some of these toxicities, especially of Vitamins A and D, sometimes cause
significant problems of human health. The diet may contain nonnutrients
which are cause for toxicological concern. The choice of a good diet with a
variety of foods included is important not only for assuring an adequate
supply of nutrients but also for limiting the intake of undesirable substances;
variety in the diet helps achieve both goals. Toxicants may alter nutrient
intake, digestion, absorption, transport, activation, function, metabolism, or
elimination. Conversely, food consumption, meal timing, nutrient intake,
and nutritional status alter the actions, potencies, and detoxification of toxi
cants. These actions may be quite indirect, e.g., the effects of dietary lipids on
drug metabolism by alteration of membranes of the smooth endoplasmic
reticulum. Some nutrients, or their products, are used more directly in
detoxification biochemistry, e.g., the sulfur amino acids are precursors of
glutathione, which is used to conjugate many toxicants. A few nutrients react
directly with toxicants and thereby limit their toxicity, e.g., selenium forms
a complex with mercury, and ascorbic acid reacts with nitrite. Finally, nutri
tional toxicology is concerned with the scientific basis and consequences of
regulatory decisions relating to control of toxicant residues in foods, e.g.,
setting legal tolerances or maximum residue limits for pesticide residues and
for the maximum permissible levels of natural toxicants such as aflatoxins.
The responses of organisms to toxic substances vary widely depending on
the organism and the identity of the substance, dose, route of administra
tion, timing, synergists or antagonists, and numerous other factors. Depend
ing on the substance and its specific effects, the response may be acute,
subacute, or chronic. The kinds of adverse effects which may be produced
involve histopathology, pathophysiology, metabolic aberrations, mutations,
oncogenesis, teratogenesis, and behavioral abnormalities.
The toxic characteristics of a chemical may be described in terms of its
qualitative type of toxicity, e.g., neurotoxins, hepatotoxins, carcinogens,
trypsin inhibitors, etc., and in terms of its potency, i.e., the quantitative
ability of the substance to produce its effects. When multiple effects are
involved, the potencies of the effects may be sirriilar or very different. For
example, aflatoxin Bi is a potent carcinogen and a potent hepatotoxin,
I. Definition and Scope 3
whereas benzo[a]pyrene is a potent carcinogen but virtually nontoxic in
other respects.
II. DIET AS A SOURCE OF TOXICANTS
A. Nutrients
Intakes of essential nutrients form a continuum from lethally deficient to
lethally excessive (Hathcock, 1976). Obviously, intakes at either extreme
cannot occur over prolonged periods. This may be visualized, in Fig. 1, as a
graph of nutritional well-being versus intake. Well-being may be defined
and measured in many ways; growth rate of young animals is a common
criterion. The plateau of optimal function may be very wide, as with the
water-soluble vitamins, or relatively narrow, as with vitamins A and D and
selenium.
The probability of actual hazard from intake of excessive amounts of nutri
ents is very different for the different nutrients. It is difficult to imagine any
probable diet which would lead to toxic intakes of biotin, whereas infrequent
vitamin A poisoning from eating livers of certain animals high in the food
chain, e.g., polar bears, sled dogs, and large fish, is well known. Certainly,
for the usual range of nutrients to have any possibility of posing a toxic
hazard, the nutrient must be extremely potent or capable of bioaccumula-
tion. This generalization does not hold for excessive dietary supplementa
tion, in which the intake of many nutrients may be many times higher than
could ever be achieved by eating an unsupplemented diet.
C
Concentration
Fig. 1. Impact of nutrient concentration on health. The concentration referred to may be in
diet or tissues. A, lethally low concentration; B, minimum concentration compatible with good
health; C, concentration for optimal health; D, maximum concentration compatible with good
health; E, lethally high concentration.
4 John N. Hathcock
With naturally occurring concentrations of nutrients in foods, toxicity
problems are primarily restricted to vitamins A and D and, in some loca
tions, to selenium or fluoride. With excessive nutrient supplementation,
however, the list can be expanded to include niacin, pyridoxine, ascorbic
acid, sodium, and many other nutrients that normally involve no hazard.
B. Natural Toxicants in Foods
Natural toxicants in foods include inorganic elements, oxyanions, toxic
proteins, peptides and amino acids, vaso- and psychoactive substances, goit-
rogens and other sulfur-containing compounds, mycotoxins and toxic stress
metabolites, bacterial toxins, plant-produced toxins of many types, and
bioaccumulated substances (Table I; Natl. Acad. Sci., 1973). Some toxins,
e.g., those in poisonous mushrooms, affect very few people but occasionally
do produce dramatic and sometimes lethal intoxications. Other toxins, e.g.,
aflatoxins, may rarely produce easily visualized intoxications but may still be
responsible for a substantial fraction of the total rate of primary hepatocar-
cinoma in some countries. Marginal toxicants such as tyramine usually pro
duce dramatic results only in persons who are taking monoamine oxidase
inhibitor drugs. Toxins may occur naturally in the plant or animal matter
taken as food, or they may be produced by contaminating microorganisms.
Botulinum toxin and aflatoxin are examples.
C. Contaminants
Contaminants may enter the food chain at many different stages. Natural
soil constituents, fertilizer ingredients and contaminants, irrigation water
contaminants, and pesticides can enter through the roots of food crops.
TABLE I
Toxicants Occurring Naturally in Foods
1. Inorganic substances
A. Cationic elements:3 Pb, Cd, Hg, etc.
B. Anions: CN", As04~, SeCV", VO/", etc.
2. Compounds of microbial origin
A. Bacterial toxins
B. Mycotoxins and toxic stress metabolites
3. Compounds of plant origin or accumulation
Hundreds of different compounds, including proteins, amino acids, cyanoglycosides,
phytates, oxalates, polyphenols, and selenium
4. Compounds of animal origin or accumulation
Many different compounds, including shellfish toxins, pufferfish toxin, thiaminase,
and avidin
