Reviews in Food and Nutrition Toxicity, Volume 4 (CRC, 2005)

REVIEWS IN FOOD AND NUTRITION TOXICITY Volume 4

REVIEWS IN FOOD AND NUTRITION TOXICITY Edited by Victor R. Preedy and Ronald R. Watson

Volume 1 Volume 2 Volume 3 Volume 4

REVIEWS IN FOOD AND NUTRITION TOXICITY Volume 4

Edited by Victor R. Preedy and Ronald R. Watson

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© 2005 by Taylor & Francis Group CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3519-1 (Hardcover) International Standard Book Number-13: 978-0-8493-3519-8 (Hardcover) Library of Congress Card Number 2004047814 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data Reviews in food and nutrition toxicity / edited by Victor R. Preedy and Ronald Watson. p. cm. Includes bibliographical references and index. ISBN 0-8493-3519-1 (alk. paper) 1. Nutrition policy. I. Preedy, Victor R. II. Watson, Ronald R. (Ronald Ross). III. Title. TX359.A56 2004 363.8'561–dc22

2004047814

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Preface In this fourth volume of reviews, we present state-of-the-art chapters pertaining to the potential and actual harm that arises as a consequence of consuming food substances and other components in the diet. We emphasize the terms potential and actual, as very often there are threshold boundaries that need to be crossed before an innocuous substance becomes toxic and/or induces a cascade of cellular and pathological changes. However, as evidenced from the present chapters, there is some debate as to what these thresholds are, and this illustrates the fundamental need for constant scientific dialogue. The chapters in Reviews in Food and Nutrition Toxicity fulfill these scientific, academic, and intellectual needs. The first part of the present volume can be considered thematic in that five chapters cover chemical elements: heavy metals (mercury, lead, cadmium, and arsenic), selenium, arsenic, sulfur, and fluoride. The chapters on arsenic, sulfur, and fluoride are general and may be considered as overviews, whereas the two chapters on heavy metals and arsenic specifically pertain to their occurrence in breast milk and fish, respectively. There follows three chapters on bacterial and fungal components. These include contamination of ready-to-eat foods, T-2 mycotoxin, and aflatoxin B1. Finally, there are two very comprehensive reviews on cycad consumption and dietary lectins. As with previous volumes in Reviews in Food and Nutrition Toxicity, we believe that the present coverage will stimulate broad-based interests as well as specific applicability to other food or nutritional substances. It is difficult to highlight a single chapter for meritous mention, as they are all equally well focused and scientific stimulating. The present chapters are written by nationally and internationally recognized experts and essentially complement the previous three volumes to give wide coverage of food nutrition and toxicity in a holistic manner.

Editors Victor R. Preedy, Ph.D., D.Sc., F.R.C.Path., is a professor in the Department of Nutrition and Dietetics, King’s College, London. He directs studies regarding protein turnover, cardiology, nutrition, and, in particular, the biochemical aspects of alcoholism. Dr. Preedy graduated in 1974 from the University of Aston with a combined honors degree in biology and physiology with pharmacology. He received his Ph.D. in 1981 in the field of nutrition and metabolism, specializing in protein turnover. In 1992, he received membership in the Royal College of Pathologists based on his published works, and in 1993 a D.Sc. degree for his outstanding contribution to the study of protein metabolism. At the time, he was one of the university’s youngest recipients of this distinguished award. Dr. Preedy was elected a fellow of the Royal College of Pathologists in 2000. He has published more than 475 articles, which include more than 150 peer-reviewed manuscripts based on original research, and 70 reviews. His current major research interests include the role of alcohol in enteral nutrition and the molecular mechanisms responsible for alcoholic muscle damage. Ronald R. Watson, Ph.D., attended the University of Idaho but graduated from Brigham Young University in Provo, Utah, with a degree in chemistry in 1966. He earned his Ph.D. in biochemistry from Michigan State University in 1971. His postdoctoral schooling in nutrition and microbiology was completed at the Harvard School of Public Health, where he gained 2 years of postdoctoral research experience in immunology. From 1973 to 1974, Dr. Watson was assistant professor of immunology and performed research at the University of Mississippi Medical Center in Jackson. He was assistant professor of microbiology and immunology at the Indiana University Medical School from 1974 to 1978 and associate professor at Purdue University in the Department of Food and Nutrition from 1978 to 1982. In 1982, Dr. Watson joined the faculty at the University of Arizona Health Sciences Center in the Department of Family and Community Medicine of the School of Medicine. He is currently professor of health promotion sciences in the Mel and Enid Zuckerman Arizona College of Public Health. Dr. Watson is a member of several national and international nutrition, immunology, cancer, and alcoholism research societies. He is presently funded by the National Heart Blood and Lung Institute to study nutrition and heart disease in mice with AIDS. Dr. Watson has edited more than 35 books on nutrition and 53 scientific books and has contributed to more than 500 research and review articles.

Contributors Gabriella Augusti-Tocco Department of Cellular and Developmental Biology “La Sapienza” University Rome, Italy

Willy Baeyens Brussels Research Unit of Environmental, Geochemical and Life Sciences Department of Analytical and Environmental Chemistry Vrije Universiteit Brussel Brussels, Belgium

Tapan K. Basu Department of Agricultural, Food and Nutritional Science The University of Alberta Edmonton, Alberta, Canada

Marjan De Gieter Brussels Research Unit of Environmental, Geochemical and Life Sciences Department of Analytical and Environmental Chemistry Vrije Universiteit Brussel Brussels, Belgium Tony J. Fang Department of Food Science National Chung Hsing University Taiwan, Republic of China Hanne Frøkiær Biocentrum-DTU Biochemistry and Nutrition Technical University of Denmark Lyngby, Denmark Claudia Gundacker Center for Public Health Medical University of Vienna Vienna, Austria

Emanuele Cacci Department of Cellular and Developmental Biology “La Sapienza” University Rome, Italy

Erin L. Hawkes Graduate Program in Neuroscience University of British Columbia Vancouver, British Columbia, Canada

Thomas F.X. Collins Center for Food Safety and Applied Nutrition U.S. Food and Drug Administration Laurel, Maryland

Ziad W. Jaradat Department of Biotechnology and Genetic Engineering Jordan University of Science and Technology Irbid, Jordan

Tanja Maria Rosenkilde Kjær Biocentrum-DTU Biochemistry and Nutrition Technical University of Denmark Lyngby, Denmark Lioudmila A. Komarnisky Department of Agricultural, Food and Nutritional Science The University of Alberta Edmonton, Alberta, Canada

Christopher A. Shaw Graduate Program in Neuroscience Departments of Ophthalmology, Physiology, and Experimental Medicine University of British Columbia Vancouver, British Columbia, Canada Robert L. Sprando Center for Food Safety and Applied Nutrition U.S. Food and Drug Administration Laurel, Maryland

Ruggero Ricordy Institute of Molecular Biology and Pathology CNR Rome, Italy

Ujang Tinggi Centre for Public Health Sciences Queensland Health Scientific Services Brisbane, Australia

Jeff D. Schulz Graduate Program in Neuroscience University of British Columbia Vancouver, British Columbia, Canada

Bettina Zödl Center for Physiology and Pathophysiology Medical University of Vienna Vienna, Austria

Table of Contents Chapter 1 Heavy Metals in Breast Milk: Implications for Toxicity .........................................1 Claudia Gundacker and Bettina Zödl Chapter 2 Selenium Toxicity and Its Adverse Health Effects .................................................29 Ujang Tinggi Chapter 3 Arsenic in Fish: Implications for Human Toxicity.................................................57 M. De Gieter and W. Baeyens Chapter 4 Biological and Toxicological Considerations of Dietary Sulfur ............................85 Lioudmila A. Komarnisky and Tapan K. Basu Chapter 5 Fluoride – Toxic and Pathologic Aspects: Review of Current Literature on Some Aspects of Fluoride Toxicity..................................................................105 Thomas F.X. Collins and Robert L. Sprando Chapter 6 Bacterial Contamination of Ready-to-Eat Foods: Concern for Human Toxicity .....................................................................................................143 Tony J. Fang Chapter 7 T-2 Mycotoxin in the Diet and Its Effects on Tissues..........................................173 Ziad W. Jaradat Chapter 8 Aflatoxin B1 and Cell Cycle Perturbation.............................................................213 Ruggero Ricordy, Emanuele Cacci, and Gabriella Augusti-Tocco Chapter 9 Cycad Consumption and Neurological Disease....................................................233 Jeff D. Schulz, Erin L. Hawkes, and Christopher A. Shaw

Chapter 10 Dietary Lectins and the Immune Response ..........................................................271 Tanja Maria Rosenkilde Kjær and Hanne Frøkiær Index ......................................................................................................................297

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Heavy Metals in Breast Milk: Implications for Toxicity Claudia Gundacker and Bettina Zödl

CONTENTS Abstract ......................................................................................................................2 Abbreviations .............................................................................................................2 Introduction................................................................................................................2 Sources of Heavy Metals and Transfer in the Environment ........................3 Exposure Routes and Biological Half-Life...................................................4 Heavy Metals in Breast Milk ....................................................................................5 Exogenous and Endogenous Sources............................................................5 The Process of Milk Production ...................................................................7 Transfer of Heavy Metals into Milk .............................................................8 Mercury ................................................................................................9 Lead ......................................................................................................9 Cadmium ............................................................................................13 Arsenic ...............................................................................................14 Metal Concentrations in Breast Milk..........................................................14 Factors Influencing Milk Metal Contents ...................................................14 Mercury ..............................................................................................15 Lead ....................................................................................................15 Cadmium ............................................................................................15 Arsenic ...............................................................................................16 Toxicological Implications ..........................................................................16 Mercury ..............................................................................................17 Lead ....................................................................................................19 Cadmium ............................................................................................20 Arsenic ...............................................................................................20 Exposure Guidelines....................................................................................20 Conclusions..............................................................................................................21 References................................................................................................................22

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Abstract

Breast milk is unique as a matrix for biomonitoring, providing information about the metal body burden of women as well as the exposure of infants. The heavy metals mercury, lead, cadmium, and arsenic are widespread and persistent agents with significant dose-related toxicological implications at high exposure levels. However, the interrelationships under conditions of chronic exposure are not fully known. Metal in breast milk originates from exogenous sources, i.e., uptake via contaminated air, food, and drinking water, and endogenous release along with essential trace elements, which is characteristic for the reproductional period. Metal transfer into breast milk depends on the chemical form and the distribution of the metal in maternal blood fractions. Methylmercury is strongly bound to erythrocytes. A small quantity of methylmercury passes into breast milk and is easily absorbed by the suckling infant. Inorganic mercury is readily transferred into breast milk, but is not well absorbed by infants. Lead transfer is associated with casein. Human milk has a very low casein content; therefore, the excretion rate of lead is low. Because cadmium binds to metallothioneins, the mammary gland, like the placenta, is considered to serve as a barrier for cadmium and to protect the infant. Inorganic arsenic is not excreted in breast milk to any significant extent. The suckling infant may be exposed to toxic influences in a period of highest susceptibility. Metal toxicity is dependent on the chemical form involved, which determines the bioavailability, absorption rate, and retention time. The brain is regarded as the most important target organ of toxic impairment even at low doses. There is some epidemiological evidence that prenatal metal exposure (in particular, methylmercury exposure) correlates with neurodevelopmental deficits. Yet, it remains unclear whether and to what extent postnatal metal exposure through breastfeeding impairs the infant’s health. The toxicokinetics of arsenic among neonates and infants has been scarcely reported. As environmental and maternal conditions lead to significant differences in milk metal levels, all measures must be taken to avoid additional metal exposure of infants via breastfeeding.

Abbreviations

As: arsenic; Ca: calcium; Cd: cadmium; Hg: mercury; K: potassium; Mg: magnesium; Na: sodium; Pb: lead; Po4: phosphate; Zn: zinc

INTRODUCTION The American Academy of Pediatrics (AAP) firmly adheres to the position that breastfeeding ensures the best possible health as well as the best developmental and psychosocial outcomes for the infant. It is recommended that breastfeeding continue for at least 12 months, and thereafter for as long as mutually desired (AAP, 1997). There is no doubt that exclusive breastfeeding is ideal nutrition; yet it has to be considered that breast milk may contain pollutants, which implies the need to evaluate breast milk contents. Analyses of breast milk metal concentrations provide data about the metal burden in the woman’s body on the one hand, and metal exposure of neonates and infants via breastfeeding on the other. Therefore, breast milk is “unique as a matrix for biomonitoring, and analyses of breast milk for

Heavy Metals in Breast Milk: Implications for Toxicity

3

environmental chemicals as well as for nutrients are of wide scientific interest” (Needham and Wang, 2002). Among diverse environmental pollutants, heavy metals belong to the most harmful xenobiotics, as they are widespread and persistent agents with significant doserelated toxicological implications. The persistence of metals, i.e., that they are not degradable, is one of their most problematic features and a major factor in the ecotoxicological relevance of heavy metals. The toxicology of metals is related to approximately 80 elements, including those heavy metals that, per definition, exceed a density of 5 g/cm3. Heavy metals of relevance in this context are mercury, lead, and cadmium. Arsenic is usually regarded as a hazardous heavy metal although it is actually a semimetal. Humans are routinely exposed to environmental metal concentrations and accumulate metals accordingly, which results in a variety of health impacts. Heavy metals are known, or at least suspected, to possess an immunotoxic, mutagenic, carcinogenic, embryotoxic, and teratogenic potential. Their dose–effect relationships, however, are not fully known, especially under chronic exposure. Long-term, low-level metal exposure results in elevated metal burdens for the body. Such burdens are considered nontoxic as long as they are below health-based exposure guidelines; nonetheless they may impair human health. Women of reproductive age are subject to a process known as body clearance, which may be defined as the loss of essential and nonessential elements during pregnancy and lactation due to the high nutrient demand at this stage. Lactating women (and subsequently their offspring) are affected by heavy metal exposure not only via exogenous sources, i.e., environmental exposure, but also through endogenous metal release. Hence the infant may be exposed to toxic influences in a period of highest susceptibility due to rapid growth, immaturity of kidneys and liver, and the unique vulnerability of the myelinizing central nervous system (CNS) to neurotoxic exposure. Furthermore, in cases of maternal element deficiency, the risk of toxic effects for both the infant and mother may be higher (Vahter et al., 2002); yet very few data are available on the interrelationships of essential and nonessential trace elements in breast milk. Data on mercury, lead, cadmium, and arsenic transfer into and concentrations in breast milk are described in the following, as are the factors apparently responsible for increasing milk metal levels. Very few studies have been carried out on the distinct effects of metal exposure via breastfeeding, illustrating the difficulties in this concern: effects of postnatal exposure do not clearly separate from those of prenatal exposure.

SOURCES

OF

HEAVY METALS

AND

TRANSFER

IN THE

ENVIRONMENT

Heavy metals spread through natural and anthropogenic sources. Heavy metals are natural constituents of Earth’s crust, emitted by volcanic activity, forest fires, and rock weathering. Anthropogenic sources of heavy metals include various processing and manufacturing industries, mining, foundries and smelters, piping, waste disposal, and diffuse sources such as combustion of fossil fuels and by-products, constituents of products, and corrosion. Human activities throughout the last century have

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dramatically altered the biochemical and geochemical cycles of some heavy metals. Stumm and Keller (1984) presumed that, on a global scale, the anthropogenic emissions significantly exceed the natural emissions. Once released into the environment, metals move between the atmosphere, land, and water. Physical properties determine whether an element is predominantly transported by the atmosphere or the lithosphere, which is particle-bound aquatic transport for the latter. Relatively volatile heavy metals and those that become attached to airborne particles can be widely dispersed on a very large scale. The biosphere absorbs and accumulates various quantities of metals at certain trophic levels, depending on the environmental metal concentration, metal bioavailability, the feeding behavior, and the physiological state of organisms. In addition, some organic metal forms tend to accumulate along the food chain, e.g., methylated mercury. As a consequence, metallic elements are found in all living organisms and have potential toxicological implications for humans if the latter frequently consume species known to be accumulators of heavy metals, such as predatory fish, sea mammals, crustaceans, or shellfish.

EXPOSURE ROUTES

AND

BIOLOGICAL HALF-LIFE

The main exposure routes for humans are (1) inhalation of metal aerosols and metal vapor, (2) metal uptake through food and drinking water, (3) dermal metal absorption, and in case of the fetus, (4) uptake via the placenta. After a metal has been taken into the lung or into the gastrointestinal tract, it will be deposited on the walls of the airways or will be taken up in the mucosa of the gastrointestinal tract, and a certain fraction of the deposited amount will be transferred to the systemic circulation and distributed among tissue compartments throughout the body (Camner et al., 1986). Several chemical and physical characteristics of metals in exposure media, such as air, water, and food, are important for absorption, excretion, and retention of metals by humans, and determine the specific biological half-life of metals. Mercury is readily absorbed (especially methylmercury in the gastrointestinal tract) and distributed throughout the body. Biological half-life varies from a few days to months; the organs with the longest retention times are the brain and kidneys (Figure 1.1). Vahter et al. (2000) presumed that the half-life of methylmercury is longer in fetal blood than in maternal blood, about 2 months in the latter. About 10% of ingested lead is absorbed in the gastrointestinal tract. Infants and children may absorb as much as 50% of dietary lead. The main target organ of lead is the skeleton. The half-life varies among different tissue types. Lead retention in soft tissues is about 3 weeks, but in bone it may range from a few years to a few decades (Figure 1.2). Raghunath et al. (1997) reported retention times of 20 and 9 days for blood-lead and blood-cadmium in 6- to 10-year-old children, respectively. Gulson et al. (1999) described a longer lead half-life for infants than for mothers: 91 vs. 59 days. Cadmium predominantly accumulates in the kidney. On account of its low excretion rate, cadmium has a very long half-life of 10 to 30 years in the muscle, kidney, and liver (Figure 1.3). Organic and inorganic arsenic have been shown to be readily absorbed via the gastrointestinal tract, and also by inhalation (Figure 1.4).

Heavy Metals in Breast Milk: Implications for Toxicity

Invasion:

Hg:

Anorganic

•Anorganic •Organic

•Ingestion •Inhalation •Dermal

Organic

5

Absorption: Anorganic •1–7% •80–95%

Organic

•Ingestion •Inhalation •Dermal

Distribution via blood and lymph (mostly bound to plasma proteins)

Excretion: •Urine (60% of total elimination) •Feces (methyl-Hg) •Sweat •Saliva •Exhalation •Breast milk

Body Depots: •CNS (organic Hg) •Liver •Pancreas •Kidney

Target Organs: •Kidney •CNS (organic Hg-Minamata disease)

T1/2: •70–90 d •1–18 a in CNS (metallic Hg)

FIGURE 1.1 Mercury distribution and half-life in the human body. (Modified from Oehlmann and Markert, 1997.) Note: a = annus; d = days.

Absorbed arsenic is widely distributed in the body; the highest levels are found in the hair, nails, and skin. The major part of arsenic in humans is eliminated within 10 days.

HEAVY METALS IN BREAST MILK EXOGENOUS

AND

ENDOGENOUS SOURCES

Metals circulating in the maternal bloodstream originate from endogenous (metals released from storage organs and tissues) as well as exogenous sources (metal uptake via inhaled air, food, and drinking water). It is assumed that the chemical similarity of nonessential and essential elements, for example, calcium and lead, leads to the incorporation of nonessential elements via the same routes into the same storage organs available for essential element uptake, e.g., the skeleton for calcium and lead. This is true also for the extraction process taking place in phases of high nutrient demand, which is characteristic of the reproduction period. During this time, metals are eliminated along with essential trace elements from the target organs. Mobilization of lead from bone is likely to occur during periods of altered mineral metabolism. Because calciotropic factors determine the uptake and storage of lead in this compartment, changes in calcium-related regulatory factors are likely to affect lead compartmentation (Silbergeld, 1991).

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Pb:

Invasion:

•Anorganic •Organic

Absorption

Anorganic

Anorganic •5–10% (children up to 50%) •50–80%

•Ingestion •Inhalation

Organic •Ingestion •Inhalation •Dermal

Organic •>90% •>90% •>90%

Distribution via blood (90% bound to erythrocytes)

Body Depots: •Bone [Pb3(PO4)2] (90–95% of body burden)

Target Organs:

Excretion: •Urine (75– 80% of absorbed Pb) •Feces (90% of oral uptake) •Breast milk •Sweat

•Kidney •CNS •Smooth muscle •Peripheral nervous system •Red bone mark

T1/2: •20–30 a in bone •20 d in soft tissues

FIGURE 1.2 Lead distribution and half-life in the human body. (Modified from Oehlmann and Markert, 1997.)

Cd:

Invasion:

Absorption:

•Ingestion •Inhalation

•1–7% •25–50%

Distribution via blood (95% bound to erythrocytes -most likely complexed to metallothioneins)

Excretion: •Urine •Feces •Breast milk •Placenta

Body Depots: •Kidney (50–75% of body burden) •Liver (metallothioneins) •Pancreas •Thyroid gland

Target Organs:

T1/2: >10 a

•Kidney •Lung (cancer) •Bone (Itai Itai disease) •Gonads

FIGURE 1.3 Cadmium distribution and half-life in the human body. (Modified from Oehlmann and Markert, 1997.)

Heavy Metals in Breast Milk: Implications for Toxicity

As:

Invasion:

Absorption:

•Ingestion •Inhalation •Dermal

•95% •30–60% •1–40%

Distribution via blood (95–99% in erythrocytes bound to globin)

7

Body Depots: •Hair, nails (keratin) •Erythrocytes •Thyroid gland •Liver, kidney •Epididymis

Excretion:

Target Organs:

•Urine •Feces •Sweat •Exhalation

•Skin (hyperpigmentary, cancer) •Lung (cancer) •Heart muscle •Liver •Kidney •

T1/2: 5d (except hair, nails, bone)

FIGURE 1.4 Arsenic distribution and half-life in the human body. (Modified from Oehlmann and Markert, 1997.)

Both endogenous and exogenous metal concentrations are responsible for the actual metal content in milk. Which of these sources is the more important, especially for lead, is under discussion (see, e.g., Gulson et al., 2003). Oskarsson et al. (1998) presume that the clearance of chemicals during lactation is the major factor. In fact, between 45 and 70% of blood-lead in adult females arises from long-term lead stores in the tissue (Gulson et al., 1995) and the mobilization of lead from the skeleton during the postnatal period is greater than that during pregnancy; this might be attributed to an inadequate calcium intake. Breast milk lead levels were related to a 5.6% bone loss and to significant bone turnover in a study conducted by Sowers et al. (2002).

THE PROCESS

OF

MILK PRODUCTION

Lactation, i.e., the production of milk by the mammary gland, is a highly complex procedure. It can occur only after a series of developmental processes have taken place in the breast of the pregnant woman. Interaction between the mother and the child is an essential aspect of the process. Unless the child starts suckling or the breast is emptied artificially, the secretion of milk will stop within a few days (Philip and WHO Working Group, 1988). The production of milk varies according to the infant’s demands, age, and ability to suckle. The normal output of mature milk ranges from 600 to 1000 ml per day, but may vary between 300 and 1200 ml per day. The process of milk production and ejection is triggered by the hormones progesterone, estrogen, prolactin, and oxytocin. Lactogenesis begins about 40 h after the birth. The foremilk colostrum is produced within 3 to 5 days after delivery; it is low in volume and fat content (2.9%). Over the next 2 to 6 weeks, the transitional milk matures and increases in fat content to about 4%; the major class of milk lipids

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are the triglycerides. Breast milk is composed of several other components including carbohydrates, proteins, and minerals, especially calcium (Needham and Wang, 2002). Milk is synthesized in the mammary alveolar gland, prior to which the components of milk and their precursors have to pass through a membrane that separates the blood flowing in capillaries from the alveolar epithelial cells of the breast. Alveolar secretory cells are involved in four processes that occur simultaneously: exocytosis; fat synthesis and excretion; secretion of ions, water, and proteins; and the transfer of milk components across the cell. Oskarsson et al. (1998) presumed that the exocrine pathway is quantitatively the most important. The major milk proteins casein and lactose, along with calcium and phosphate, form the so-called micelles, which are transported via Golgi vesicles to the apical membranes and then released into the milk alveoli. Small molecules such as sodium, potassium, chloride, and glucose can pass across the apical membrane.

TRANSFER

OF

HEAVY METALS

INTO

MILK

The transport of xenobiotics into milk is supposed to follow the same pathways as milk components and to proceed according to the principles of cellular metal uptake (Table 1.1). In general, there is a low transfer of toxic metals through milk when maternal exposure levels are low. However, knowledge concerning the lactational transport of metals and the potential effects of metals on milk secretion and composition is scarce (Oskarsson et al., 1998).

TABLE 1.1 Cellular Uptake of Heavy Metals Passive Transport

Active Transport

Diffusion Energy (ATP)-dependent via carrier-proteins Channel-mediated diffusion (e.g., Na+, K+, Ca2+) 2+ Carrier-mediated diffusion (e.g., Ca ) Simple diffusion Filtration Depends on: Similarity to essential metals (e.g., Ca-Pb, Zn-Cd) (chemical mimicry) Size and molecular weight Chemical bonding Lipophilic character Grade of ionization Transport through epithelial cells can take place: Transcellular (active or passive) Paracellular (passive through tight junctions of epithelial cells) Source: Data from Merian, 1984; Oehlmann and Markert, 1997.

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9

Experimental data have shown that each metal is distributed in a characteristic way between the milk fractions. Lead is almost exclusively found in the casein fraction, while cadmium and methylmercury are found in fat, and inorganic mercury is largely found in whey fractions (Oskarsson et al., 1998). In human milk, mercury is mainly bound to caseins (Mata et al., 1997). Thus, mercury possesses a greater ability to interact with milk proteins than with low-weight molecules. In contrast, it appears that cadmium and lead are equally distributed among milk components with high and low molecular weights (Coni et al., 2000). Mercury Findings of Sundberg et al. (1999b) showed serum albumin is a major mercurybinding protein in whey and plasma fractions of mice for both methylmercury and inorganic mercury. The authors suggested passive transfer from plasma into milk using albumin as a passive carrier. Following the administration of lead and mercury to lactating and nonlactating mice, metal elimination from plasma was significantly greater in lactating mice, while about 30, 8, and 4% of the administered dose of lead, inorganic mercury, and methylmercury, respectively, was excreted in milk (Oskarsson et al., 1998; Sundberg et al., 1998). The transfer of mercury from plasma to milk was found to be higher in dams exposed to inorganic mercury than to methylmercury. In contrast, the uptake of mercury from milk was higher in the sucklings of dams exposed to methylmercury than to inorganic mercury (Oskarsson et al., 1995). Almost all methylmercury delivered via milk was absorbed and the suckling pups had a very low elimination rate until lactational day 17. Sundberg et al. (1999a) concluded that, on account of differences in kinetics, lactational exposure to methylmercury is a greater hazard for the breastfed infant than is inorganic mercury. However, both inorganic and organic mercury can be excreted in breast milk and the demethylation that takes place in vivo is thought to play an important role in the lactational transfer (Abadin et al., 1997). In contrast to lipophilic chemicals such as the persistent organic pollutants, metals do not bind to fat and usually do not accumulate at higher concentrations in breast milk than in blood. Oskarsson et al. (1995) established that milk mercury levels are approximately 30% of the levels in blood. On account of the placental transfer of mercury, it may be concluded that prenatal mercury exposure is generally more important than lactational exposure. In contrast, Drexler and Schaller (1998) and Ramirez et al. (2000) found lower maternal blood-mercury levels compared to milk mercury concentrations (Table 1.2). Lead It has been suggested by Palminger Hallen et al. (1996) that lead is transported into milk via the same pathway as calcium because of its high affinity to casein. In lactating mice, lead was found to be associated with casein micelles inside the alveolar cells and the milk lumen, indicating that lead is excreted into milk, bound to casein, via the Golgi secretory system. Oskarsson et al. (1995) reported that tissue

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TABLE 1.2 Mercury, Lead, Cadmium, and Arsenic Concentrations in Breast Milk Country

μg/l Hg

SD/Range

Austria

7.70

11

Austria

0.85