Heavy Metals in the Environment - Chapter 1 pot

The book provides a critical review and analy-sis of the current state of knowledge of heavy metals in the environment.The volume begins with a chapter on the essentiality and toxicity o

Heavy Metals in

the Environment

edited by Bibudhendra SarkarThe Hospital for Sick Children and University of Toronto

Toronto, Ontario, Canada

M A R C E L

nD E C K E R

MARCEL DEKKER, INC NEW YORK • BASEL

Copyright © 2002 Marcel Dekker, Inc

ISBN: 0-8247-0630-7

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Our global environment now consists of numerous natural and artificial metals.Metals have played a critical role in industrial development and technologicaladvances Most metals are not destroyed; indeed, they are accumulating at anaccelerated pace, due to the ever-growing demands of modern society A finebalance must be maintained between metals in the environment and humanhealth It is with this view in mind that this book has been written to addressdiverse issues surrounding heavy metals in the environment Nineteen chaptershave been contributed by 50 experts from around the world, known for theirexpertise and outstanding research The book provides a critical review and analy-sis of the current state of knowledge of heavy metals in the environment.The volume begins with a chapter on the essentiality and toxicity of metals.The widespread distribution of metals in the environment is of great concernbecause of their toxic properties; however, some metals are also essential fornormal growth and development This chapter provides a critical assessment ofnutritional and toxicological information based on available data on humans Theevaluation has used information available on speciation and bioavailability toidentify the critical effects and clinical manifestations of metal deficiency andtoxicity New principles and basic concepts are presented to define the acceptablerange of oral intake (AROI) at which no adverse effects occur and the correspond-ing safe range of population mean intake (SRPMI) of essential trace metals such

as selenium, iron, manganese, zinc, and copper The interdependence of various

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elements is discussed with regard to metabolic and functional interactions ing storage and metabolism.

involv-Analytical measurements of heavy metals in the environment are an integralcomponent of monitoring and assessing their toxic effects They are required forregulatory purposes and routine monitoring to ensure compliance with allowedlevels to determine hazardous conditions Clean-ups of contaminated locationsare commenced on the basis of measurements indicating the site and extent ofcontamination Chapter 2, on analytical methods for quantitative determination

of heavy metals discusses various analytical tools and speciation analyses ofheavy metals as well as their microscopic analyses Techniques used for specia-tion analyses are discussed for individual metals such as chromium, arsenic, mer-cury, lead, and cadmium This chapter also describes recent developments in theuse of microprobe beamline to monitor intracellular distribution of elements in

A large spectrum of radionuclides was produced after the creation of thecosmos Their radioactive half-lives are very long, and they remain ubiquitouscomponents of the environment Additionally, as a result of the development ofnuclear weapons and nuclear technology, a number of artificial radionuclideshave become a part of the human environment Chapter 4 discusses the distribu-tion and concentration of both natural and manmade radionuclides and the mecha-nism of their transfer to plants, animals, and humans Possible long-term effects

of their distribution in human tissue in terms of health implications are discussed.Metallic agents, as a class, make up a substantial portion of known human carcin-ogens Chapter 5 reviews the topic of metal carcinogenesis, following the Interna-tional Agency for Research on Cancer (IARC) classification system, with particu-lar emphasis on known human carcinogens

In recent years, both carcinogenic and noncarcinogenic potential of arsenichave been intensely studied Chapters 6 and 7 review the global perspective onarsenic in the environment and aspects of arsenic toxicity Chapter 6 exploresthe environmental behavior of arsenic with special reference to the abundanceand distribution of arsenic in the lithosphere, sediments, soil environment, andgroundwater It also discusses various pathways of arsenic emission into the envi-ronment, methods for arsenic determination in drinking water, and techniques

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for remediation of arsenic-contaminated soil and groundwater systems Chapter

7 discusses the sources of human exposure and aspects of human toxicology withspecial emphasis on chronic arsenic poisoning and its general effects related todermatological manifestations, cardiovascular diseases, neurological impair-ments, and cancer effects

Individual chapters are devoted to selected metals in the environment, cluding cadmium, chromium, aluminum, nickel, lead, mercury, and molybdenum.Chapter 8 reviews the pertinent literature of cadmium toxicology, with discus-sions of the health effects in humans of cadmium exposure and the molecularmechanisms underlying these effects The connection between inhalation of chro-mium (VI) compounds and the causation of cancers of the airways and lungs

in-is well establin-ished Chapter 9 describes epidemiological studies along with thetoxicokinetics and molecular mechanisms underlying the carcinogenicity of chro-mium (VI) It is followed by an in-depth consideration of approaches to the bio-logical monitoring of chromium (VI)–exposed subjects Chapter 10 presents anassessment of the hazards of aluminum exposure to humans, animals, and plants.Chapter 11, on nickel, reviews its distributions in the environment, human expo-sure, metabolism, systemic and molecular toxicology, and carcinogenesis Thischapter also includes a discussion on the interaction of nickel with other essentialmetals such as magnesium, calcium, iron, zinc, and manganese Chapter 12 dis-cusses the release of lead in the environment, human body burdens, and the popu-lation at risk Special emphasis is given to analytical methods for the assessment

of lead exposure and its metabolism, treatment of lead poisoning, in vitro andanimal studies, molecular mechanisms, reproductive outcome, risk assessmentand human epidemiological studies

It is believed that the global cycling of mercury of natural and genic sources is responsible for the transport and deposition of mercury in areasremote from the original source Chapter 13 takes a detailed look at mercury inthe environment and its toxic actions, including a discussion on epidemiologicalstudies of prenatal exposure Molybdenum is essential to a variety of organisms,and is distributed widely in the environment owing to its diverse chemistry andits technological and agricultural applications Chapter 14 provides a balancedpicture of the complex environmental chemistry of molybdenum, including itsinteractions with copper, which can be either antagonistic or beneficial from theinterplay of individual components in the biogeosphere

anthropo-The intracellular concentration of heavy metals is kept in balance by avariety of metal-transporters Many of the metals are toxic in excess Bacterialmetal resistance probably arose early in evolution owing to widespread geochem-ical sources of metals Chapter 15, devoted to the microbial resistance mechanism

of heavy metals, discusses the mechanisms of resistance to zinc, cadmium, lead,copper, arsenic, and antimony in bacteria The exposure to metal that is harmless

to some bacteria may be destructive to others with specific genetic changes

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ter 16 examines genetic susceptibility to heavy metals in the environment, notinghow each metal is expected to have its own series of transporters Transport ofseveral metals is highly dependent upon the concentration of the other metals.This balance can be disrupted when any gene within the balanced system is non-functional The interaction between genes and environment—considered criticalfor avoiding metal toxicity not only for humans but also for a wide variety ofanimal species—is described in detail Selenium has multiple biological actions

as an essential trace element, a modifier of other toxic elements, an genic agent, and a toxicant These are all discussed in Chapter 17, which provides

anticarcino-an overview of the entire profile of biological actions of selenium in nutritionand toxicology

Over the past three decades, elements such as arsenic, antimony, gallium,and indium have been used in the manufacture of semiconductors for computerchips, cellular telephones, and light-emitting diodes Many tons of these elementshave been incorporated into these devices, either as dopants for silicon-basedcomputer chips or in higher-speed semiconductors, such as gallium arsenide andindium arsenide With the increased demand for higher-speed devices, older de-vices have been discarded, generating a large stockpile of electronic equipmentcontaining these elements known collectively as ‘‘e-waste.’’ This is a new phe-nomenon, and the magnitude of this growing problem has been recognized onlyrecently, since there are no well-established recycling programs for such item.Chapter 18, on semiconductors, provides an assessment of the present state ofknowledge of the role and biological effects of metal/metalloids utilized in thesemiconductor industry The potential human health and environmental effects

of these elements, either alone or as mixtures, are discussed in relation to areas

of future studies

There is a growing need for methods of assessing the amount of heavymetals pollution in our natural and industrial environments While it is relativelystraightforward to use the techniques of analytical chemistry to detect heavymetal concentrations in a particular location, they do not indicate how much ofthis metal is a ‘‘biological hazard.’’ Chapter 19 describes biosensors for monitor-ing heavy metals, and how researchers are exploiting various biological mecha-nisms to determine the amount of ‘‘bioavailable’’ heavy metal in the natural andindustrial environments These methods are still in their infancy compared withthe techniques of analytical chemistry, but they clearly offer advantages in terms

of ease of use, and biological relevance The recent progress made in the ment of whole-cell and protein-based biosensors is encouraging and holds muchpromise for the future

develop-The book was written by contributors in close collaboration with me Ivisited some of their laboratories, intensively discussed their work with them,and made a few field trips to environmentally affected areas to obtain first-handknowledge Despite conscientious efforts by all concerned, the chapter authors,

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the editor, and the publisher cannot assume any liability for errors that this bookmay contain Every effort has been made to keep the error rate as low as possible.

Heavy Metals in the Environment will be an invaluable resource for

toxicol-ogists; biochemists; bioinorganic, inorganic, environmental, and medicinal ists; immunologists; oncologists; physiologists; pharmacologists; geneticists;bacteriologists; molecular biologists; environmental scientists; and upper-levelundergraduate and graduate students in these disciplines

chem-I thank many of my international colleagues who provided valuable tions in the selection of topics and other advice Special thanks are due to LorettaLeBlanc for preparing the manuscript and to Suree Narindrasorasak, Ping Yao,and Negah Fatemi for their assistance in the preparation of the index

sugges-Bibudhendra Sarkar

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Preface

Contributors

Gunnar F Nordberg, Brittmarie Sandstro¨m, George Becking, Robert A Goyer

Quantitative Determination, Speciation, and MicroscopicAnalysis

Richard Ortega

Intracellular Mechanisms of Toxicity

Wendy E Parris and Khosrow Adeli

6 Arsenic in the Environment: A Global Perspective

Prosun Bhattacharya, Gunnar Jacks, Seth H Frisbie, Euan Smith, Ravendra Naidu, and Bibudhendra Sarkar

J Thomas Hindmarsh, Charles O Abernathy,

Gregory R Peters, and Ross F McCurdy

Monica Nordberg and Gunnar F Nordberg

Montserrat Casadevall and Andreas Kortenkamp

Edward I Stiefel and Henry H Murray

Metalloids

Mallika Ghosh and Barry P Rosen

Diane W Cox, Lara M Cullen, and John R Forbes

Seiichiro Himeno and Nobumasa Imura

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18 Semiconductors

Bruce A Fowler and Mary J Sexton

Biosensors for Monitoring of Heavy Metals

Ibolya Bontidean, Elisabeth Cso¨regi, Philippe Corbisier, Jonathan R Lloyd, and Nigel L Brown

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George Becking World Health Organization, Research Triangle Park, NorthCarolina

Prosun Bhattacharya Department of Land and Water Resources Engineering,Royal Institute of Technology, Stockholm, Sweden

Ibolya Bontidean Department of Biotechnology, Lund University, Lund,Sweden

Nigel L Brown School of Biosciences, The University of Birmingham, baston, Birmingham, United Kingdom

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Montserrat Casadevall Centre for Toxicology, The School of Pharmacy, don, England

Lon-Thomas W Clarkson Department of Environmental Medicine, University ofRochester School of Medicine, Rochester, New York

Philippe Corbisier Joint Research Centre of the European Commission, tute for Reference Materials and Measurements, Geel, Belgium

Insti-Max Costa Department of Environmental Medicine, New York UniversitySchool of Medicine, Tuxedo, New York

Diane W Cox Department of Medical Genetics, University of Alberta, ton, Alberta, Canada

Edmon-Elisabeth Cso¨regi Department of Biotechnology, Lund University, Lund,Sweden

Lara M Cullen Department of Medical Genetics, University of Alberta, monton, Alberta, Canada

Ed-John R Forbes Department of Biochemistry, McGill University, Montreal,Quebec, Canada

Bruce A Fowler Department of Epidemiology, Laboratory of Cellular andMolecular Toxicology, University of Maryland, Baltimore, Maryland

Seth H Frisbie Better Life Laboratories, Inc., Plainfield, Vermont

Mallika Ghosh Department of Biochemistry and Molecular Biology, WayneState University School of Medicine, Detroit, Michigan

Othman Ghribi Department of Pathology, University of Virginia, ville, Virginia

Charlottes-Robert A Goyer University of Western Ontario, London, Ontario, Canada

Mary M Herman National Institute of Mental Health, National Institutes ofHealth, Bethesda, Maryland

Seiichiro Himeno School of Pharmaceutical Sciences, Kitasato University,Tokyo, Japan

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J Thomas Hindmarsh Department of Pathology and Laboratory Medicine,The University of Ottawa and The Ottawa Hospital, Ottawa, Ontario, Canada

Nobumasa Imura School of Pharmaceutical Sciences, Kitasato University,Tokyo, Japan

Gunnar Jacks Department of Land and Water Resources Engineering, RoyalInstitute of Technology, Stockholm, Sweden

Andreas Kortenkamp Centre for Toxicology, The School of Pharmacy, don, England

Lon-Jonathan R Lloyd School of Biosciences, The University of Birmingham,Edgbaston, Birmingham, United Kingdom

Emily F Madden Center for Devices and Radiological Health, U.S Food &Drug Administration, Rockville, Maryland

R Bruce Martin Department of Chemistry, University of Virginia, ville, Virginia

Charlottes-Ross F McCurdy InNOVAcorp., Dartmouth, Nova Scotia, Canada

Henry H Murray Corporate Strategic Research, ExxonMobil Research andEngineering Co., Annandale, New Jersey

Ravendra Naidu CSIRO Land and Water, Commonwealth Scientific & trial Research Organization, Glen Osmond, South Australia, Australia

Indus-Gunnar F Nordberg Department of Environmental Medicine, Umea˚ sity, Umea˚, Sweden

Univer-Monica Nordberg Institute of Environmental Medicine, Karolinska Institute,Stockholm, Sweden

Richard Ortega Chimie Nucle´aire Analytique Bioenvironnementale, sity of Bordeaux, Gradignan, France

Univer-Wendy E Parris Division of Clinical Biochemistry, Department of LaboratoryMedicine and Pathology, and Program in Structural Biology and Biochemistry,The Hospital for Sick Children and University of Toronto, Toronto, Ontario,Canada

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Gregory R Peters Philip Analytical Services Inc., Bedford, Nova Scotia,Canada

Barry P Rosen Department of Biochemistry and Molecular Biology, WayneState University School of Medicine, Detroit, Michigan

Brittmarie Sandstro¨m Research Department of Human Nutrition, The RoyalVeterinary and Agricultural University, Copenhagen, Denmark

Bibudhendra Sarkar Program in Structural Biology and Biochemistry, TheHospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

John Savory Department of Pathology, Biochemistry and Molecular Genetics,University of Virginia, Charlottesville, Virginia

Mary J Sexton Department of Epidemiology and Preventive Medicine, School

of Medicine, University of Maryland, Baltimore, Maryland

Donald R Smith Department of Environmental Toxicology, University of ifornia, Santa Cruz, California

Cal-Euan Smith CSIRO Land and Water, Commonwealth Scientific & IndustrialResearch Organization, Glen Osmond, South Australia, Australia

Edward I Stiefel Department of Chemistry, Princeton University, Princeton,New Jersey

Jessica E Sutherland Department of Environmental Medicine, New YorkUniversity School of Medicine, Tuxedo, New York

David M Taylor Department of Chemistry, Cardiff University, Cardiff, Wales

Michael P Waalkes Laboratory of Comparative Carcinogenesis, NationalCancer Institute and National Institute of Environmental Health Sciences, Na-tional Institutes of Health, Research Triangle Park, North Carolina

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been partly in conflict with those issued with an aim of protecting from deficiency.There is an obvious need for an approach including a balanced consideration ofnutritional as well as toxicological data for these metals.

These new principles of evaluation take into account some basic concepts

of interindividual variability in sensitivity to deficiency and toxicity Such tion translated into one interval of (low) daily intake, at which there is a risk ofdeveloping deficiency, and another interval of (high) dietary intake, at whichtoxicity may occur In between there is a set of intakes that represent the accept-able range of oral intakes (AROI), at which no adverse effects occur While it

varia-is possible to define such a range that will protect most people, a range willnot usually be found that protects all persons from adverse effects Those withgenetically determined sensitivity may require higher intakes to avoid deficiency

or lower intakes to avoid toxicity than those defined by the acceptable range.AROI is defined as protecting 95–98% of healthy individuals in specified genderand life stage population groups from even minimal adverse effects of deficiency

or toxicity While AROI is defined for intakes by individuals in a populationgroup, the corresponding range for mean intakes is the safe range of populationmean intakes (SRPMI)

This chapter reviews principles and methodologies that may be applied indefining limits of safety for nutritionally essential metals Excessive intake ofthese metals can give rise to toxicity There is increasing use of various standardsworldwide that express the maximum acceptable limits for human exposures forvarious substances present in the environment including nutritionally essentialtrace elements In some instances, the methodology applied to standard settingfor these nutritionally essential substances has been the same as applied to toxicmetals In the case of zinc, RDA (recommended daily allowances set by the U.S.National Research Council) and RfD (reference dose, set by the U.S Environ-mental Protection Agency) were found to be almost identical and, for certain agegroups, the RDA was higher than the Rfd (1,2) It is becoming apparent thatstandard setting for nutritionally essential trace elements requires considerationbeyond approaches traditionally applied to metals that have no biological require-ment for good health

Recognition of this problem has prompted a number of conferences on thistopic that have resulted in publications and discussions of potential approaches

as well as potential problems These activities include a workshop sponsored bythe U.S Environmental Protection Agency, the Agency for Toxic Substances andDisease Registry, and the International Life Sciences Institute’s Risk SciencesInstitute held in March 1992 in Herndon, Virginia, which reviewed the problemand identified a number of topics that had been inadequately considered to date(1) Similarly, a Nordic Working Group on Food and Nutrition and the NordicGroup on Food Toxicology have prepared a report (3), and a conference on

‘‘Trace Elements in Human Health’’ held in Stockholm in May 1992 has also

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been reported (2) The conceptual framework for the preparation of a WHO/IPCS methodology document was based on discussions from a WHO planningmeeting held in Washington in April 1996 (4) and on IPCS Workshop held inSantiago de Chile in 1998 The methodology [reviewed in part also by Nordberg

et al (5)] proposed in the present chapter has evolved from the activities.Metals have been classified as essential, beneficial, or detrimental Traceelements recognized as essential for human health include iron, zinc, copper,chromium, iodine, cobalt, molybdenum, and selenium (6) For the purpose ofthis chapter all metallic elements in this listing will be considered in discussions

of methodology Later in the chapter, the methodology described will be applied

to a few of these as examples There is also a second group of elements thought

to be beneficial to life (e.g., silicon, manganese, nickel, boron, and vanadium).Some of these elements may be essential to vegetative life and perhaps beneficial

to human health but, generally, they are not yet accepted as essential for humanhealth If any of these or other elements become accepted as essential for humansand quantitative nutritional requirements are established, the approaches outlined

in this chapter should be applicable for setting an acceptable range of oral intakes(AROI)

The methodology described for determining the AROI is not intended to

be applied to detrimental metals or metals that are regarded as purely toxic metalssuch as lead, cadmium, and mercury, which are not known to provide any essen-tial or potentially beneficial health effect at any level of exposure Also this meth-odology, in its present form, is not intended to assess risk for carcinogenicity,although at present this is only of concern for one essential element, chromium,and is probably limited to inhalation and not oral exposure While the essentialelements are not by themselves known to be carcinogenic by the oral route, sev-eral play important roles as modulators of carcinogens by promoting or protectingfrom oxidative damage For example, selenium deficiency and excess iron intakemay act synergistically to enhance oxidative damage of macromolecules, nucleicacids, and lipid membranes

Presently recommended dietary intakes of essential trace metals are based

on estimates of amounts needed to prevent clinical or biochemical deficiency It

is increasingly recognized that higher intakes of some of the trace elements mayhave beneficial health effects in relation to risk reduction of degenerative diseasessuch as cardiovascular disease and cancer These suggested higher levels areusually not met by ordinary foods but require supplements, often administered

in a more available form than dietary minerals Long-term intake of high but notimmediately toxic doses of trace elements may lead to interaction with othertrace elements and/or other changes not identified with a classical toxicologicalapproach Thus the safety of essential trace elements is a subtle issue and as newcriteria for estimates of requirements are emerging there may be a need to redefinealso the criteria used to estimate adverse-effect levels

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For essential metals health risk assessment requires consideration of bothtoxicity from excess exposures and health effects as a consequence of deficienciesfrom severe restriction of intake Such an approach involves principles from nutri-tion as well as toxicology The objective is to make recommendations that result

in a range of recommended intakes that recognizes consequences of both tional deficiency and toxicity

nutri-The approach described in this chapter outlines the principles that supportthe concept of AROI, or a ‘‘homeostatic model’’ for determining the distribution

of intakes for essential trace metals (ETM) that meet nutritional requirements of

a healthy population as well as preventing toxicity The methodology presented

in this document recognizes the importance of variability in exposure and netics arising from age, gender, physiological conditions, and nutritional status

bioki-In addition it should be noted that dietary/food intake is only part of oral intake.Oral intake also includes intake from water, dietary supplements, and a fraction

of inhalation exposures that are subsequently ingested after coughing and lowing

swal-1.1 Nutritionally Essential Trace Metals (ETM)

The traditional criteria for human health are that absence or deficiency of theelement from the diet produces either functional or structural abnormalities andthat the abnormalities are related to, or a consequence of, specific biochemicalchanges that can be reversed by the presence of the essential metal (6).The criteria for identifying ETM have evolved over the past 50 years andmay be expected to expand as the result of future research New end points re-flecting effects of deficiency have been considered in recent investigations ofessentiality of ETMs in experimental animals (7) These have included mild re-ductions in growth rate, impairment of reproductive performance, decreased lifespan, sudden unexpected death, and some anatomical lesions

absorp-of these ETMs there may be a specific chain absorp-of protein carriers and receptors toeffect uptake into cells Anionic ETMs, like molybdenum and selenium, are more

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soluble and systemic absorption is less regulated than for cationic ETMs Theyare absorbed very efficiently and subsequent control, tissue deposition, and excre-tion are managed by oxidation state Total body burden is regulated by renalexcretion A third category of homeostatic mechanism is illustrated by cobalt,which is a highly reactive element with several oxidation states The physiologi-cal role for this metal is as one of highly regulated form in cobalamin and there

is no evidence that humans require inorganic cobalt Whether or not an analogoussituation applies to chromium and the ‘‘glucose tolerance factor’’ is unclear par-ticularly since inorganic chromium has been effective in alleviating chromiumdeficiency in patients on total parenteral nutrition However, there is a wide diver-sity within populations and individuals as to the efficiency of these mechanisms

2 CONCEPTS OF EVALUATION—CONSIDERATION

OF TOXICITY AND ESSENTIALITY

Interindividual variation that occurs in human populations is considerable Thisapplies to the expression of toxicity from higher doses of an ETM as well as forthe expression of deficiency symptoms as a result of too low intakes of the sameessential element

2.1 Acceptable Range of Oral Intake (AROI)

InFigure 1the interindividual distribution of sensitivity is shown for nutritionalrequirements and for expression of toxicity For a specific adverse effect of defi-ciency, individuals exist in a population who display average sensitivity to devel-oping symptoms (mean nutrient requirement, Fig 1) as well as more sensitiveindividuals, i.e., those developing deficiency symptoms at somewhat higher in-takes (⫹1.5–2.5 D nutrient requirement), and individuals with less sensitivity,i.e., those that develop deficiency symptoms first when intakes are lower (⫺1.5–2.5 D nutrient requirement) A similar situation applies for a specific toxic effect;i.e., some individuals display symptoms at doses lower than those giving rise tosymptoms in the individuals of average sensitivity and there are also individualswho are less than average sensitive and they require higher doses to developsymptoms The situation can be depicted as two bell-shaped curves describingthe distribution of sensitivity to deficiency and toxicity In most cases an intervalbetween these curves describes the AROI in which no adverse effects occur inthe large majority (95–98%) of subjects (cf Fig 1) If these conditions are insteaddepicted with curves in cumulative forms, a U-shaped curve is formed and theAROI appears at the bottom of the U (Fig 2) Further aspects and examples ofhow AROI for specific essential metals can be derived will be given in latersections

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F IGURE 1 Theoretical model describing distribution of intakes to meet tional requirements (left) and distribution of intakes giving rise to toxicity(right), with the acceptable range of oral intakes (AROI) in between Lowerlimit to the AROI should cover the requirements of most (97.5%) of the popu-lation; the higher limit if AROI should protect a similar proportion of the popu-lation from toxic effects.

nutri-2.2 Groups with Special Sensitivity/Resistance

2.2.1 Genetically Determined

InFigure 3, the same model for distribution of intakes to meet nutritional ments and to prevent toxicity is displayed as in Figure 1 The low limit of theAROI covers the requirement of most of the population and the high limit of theAROI should protect most of the population from toxic effects Special popula-tion subgroups, such as persons with Wilson’s disease, may exhibit toxicity atrelatively low intakes of copper, lower than the acceptable range for normal per-sons On the other hand, some population subgroups such as B may have require-ments higher than the upper limit of acceptable range (for example, zinc intake

require-in subjects with acrodermatitis enteropatica) Further aspects on genetically mined variation in sensitivity have been given by WHO 1996 (6) and will begiven in a future document on ‘‘Principles of Risk Assessment for Essential TraceElements’’ by IPCS/WHO

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F IGURE 2 Percent of population subjected to deficiency or toxicity to oralexposure/intake This is the same model as inFigure 1, but in a cumulativeform As intake drops below A (lower limit of AROI), risk for deficiency in-creases; at extremely low intakes all subjects will manifest deficiency As in-takes increase beyond B, a progressively larger proportion of subjects willexhibit effects of toxicity.

2.2.2 Nongenetically Determined

Many diseases are genetically determined but this is not considered here if thedisease is not known to involve a specific metabolic defect related to essentialelements In celiac disease, there is a deficient uptake of several nutrients in-cluding essential elements such as iron (9) and zinc (10) In addition, gastrointes-tinal losses of trace elements can be increased due to diarrhea If the disease isnot well controlled by exclusion of gluten from the diet, and/or the decreaseduptake is not compensated by an increased intake of these elements, iron and/

or zinc deficiency may develop Increased urinary losses of zinc are observed inpatients with alcoholic cirrhosis (11) and diabetes (12) It has been shown thatiron deficiency gives rise to an increased uptake of manganese from the diet (13)

It can therefore be assumed that there would be an increased risk of manganesetoxicity if persons with iron deficiency were exposed to high oral intakes of man-ganese

Sensitivity to manifestations of zinc deficiency is known to be dependent

on certain metabolic situations When discussing effects of deficiency or toxicity

of an essential element it is therefore of fundamental importance to specify the

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F IGURE 3 Theoretical model for distribution of intakes to meet nutritional quirements of healthy population and prevent toxicity The lower limit toAROI should cover the requirements of most (97.5%) of the population; thehigher limit should protect most of the population from toxic effects Specialpopulation subgroups, such as A, may exhibit toxicity at intakes lower thanthe acceptable range (e.g., Wilson’s disease and copper intake), or in contrast,some population subgroups, such as B, may have requirements higher thanthe upper limit of acceptable range (e.g., zinc intakes in subjects with acroder-matitis enteropathica).

re-background conditions of the group of persons under consideration Such ground conditions can be all-determining for the dose-response relationships Forexample, at a certain low zinc intake (e.g., under conditions of total parenteralnutrition) clinical symptoms of zinc deficiency may not develop in a group ofindividuals who are in metabolic balance, but may be clinically manifest in per-sons who undergo growth or who are in an anabolic phase (14) Dose-responserelationships for zinc deficiency thus can be quite different depending on meta-bolic state

back-2.3 Nutritional Requirement and Safe Range of Population

Mean Intake (SRPMI)

Public health aspects concerning adverse effects as a result of deficiency from

an essential element have been discussed in many documents Definitions relating

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to the needs of individuals were defined by the Joint FAO/IAEA/WHO ExpertConsultation on Trace Elements in Human Nutrition (6).

Requirement This is the lowest continuing level of nutrient intake that,

at a specified efficiency of utilization, will maintain the defined level ofnutriture in the individual

Basal requirement This refers to the intake needed to preventpathologically relevant and clinically detectable signs of impaired func-tion attributable to inadequacy of the nutrient

Normative requirement This refers to the level of intake thatserves to maintain a level of tissue storage or other reserve that is judged[by the Expert Consultation] to be desirable

Ideally the establishment of estimates of requirement of essential elementshould be based on functional criteria for adequacy For many trace elementssensitive and specific criteria are lacking and other approaches have to be

adopted The factorial technique, i.e., the sum of the obligatory endogenous

losses of the element via skin, kidney, and intestine with the addition of ments for synthesis of new tissue in periods of growth, has been the basis forthe estimates of zinc requirement in the WHO 1996 report (6) This approachwas originally used for estimates of protein requirements The obligatory lossesare usually determined in balance studies at different intakes The principal prob-lem in relation to zinc has been to account for the ability to adapt to differentintakes by changes in endogenous losses

require-Most early reports on recommended intakes of essential elements have vided estimates of the requirements of individuals and the ‘‘recommended’’ or

pro-‘‘safe’’ level of intake has been defined as the average requirement⫹ 2 SD inrequirement Thus for an individual consuming this amount of element therewould be a very low probability that the individual’s requirement was not met.The WHO 1996 report is concerned with population (group) mean intakes ratherthan intakes of individuals The lower limit of population mean intake is set sothat very few individuals in the population (group) would be expected to haveintakes below their requirement; i.e., the population mean intake corresponds tothe estimates of average individual requirement ⫹ 2 SD in intakes The term

‘‘population’’ in the WHO 1996 report refers to a group that is homogeneous interms of age, sex, and other characteristics believed to affect requirement andnot, for example, to demographically or culturally defined groups The variability

in usual intakes within a population group is usually larger than estimates ofvariability of requirements and it has empirically been demonstrated that the eval-uation of the prevalence of inadequate intakes is relatively insensitive to the vari-ability in requirements

WHO/FAO/IAEA Expert Consultation (6) identified the need to work withrecommendations of mean population intakes, since it is difficult in practice to

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