DiversityDiversity ofof TraceTrace ElementsElements andand ToxicToxic MetalMetal IonsIons inin EnvironmentalEnvironmental HealthHealth andand HumanHuman DiseasesDiseases JosJoséé A.A. CentenoCenteno U.S. ARMED FORCES INSTITUTE OF PATHOLOGY Washington, DC Email: [email protected] OutlineOutline

•• IntroductionIntroduction toto TraceTrace Elements,Elements, MetalsMetals andand MetalloidsMetalloids

•• TraceTrace ElementsElements andand KnownKnown Biological/ToxicologicalBiological/Toxicological ReactionsReactions

•• EnvironmentalEnvironmental HealthHealth andand DiseasesDiseases •• ConcludingConcluding RemarksRemarks

Suggested Reading: Essentials of Medical Geology (Selinus et al. 2005). Chapters on Nutrition (Gerald T. Combs), Biology of Trace Elements (Ulf Lindh)). Natural Non- deposits industrial

Drinking water Food

Industrial

Agriculture Mining/smelting Coal burning Micro-electronics Science, Vol 300, May 2003 From Harold H. Sandstead, MD collection University of Texas From Harold H. Sandstead, MD collection University of Texas GeochemistryGeochemistry ofof SomeSome EssentialEssential ElementsElements AffectsAffects HumanHuman HealthHealth

•• SomeSome essentialessential elementselements whosewhose geographygeography is,is, oror isis presumed,presumed, directlydirectly relatedrelated toto humanhuman health:health:

•• I,I, Se,Se, F,F, Cr,Cr, Mo,Mo, BB

•• SomeSome essentialessential elementselements whosewhose geographygeography isis apparentlyapparently notnot directlydirectly relatedrelated toto humanhuman health:health:

•• Fe,Fe, Zn,Zn, Cu,Cu, Ca,Ca, MgMg CriteriaCriteria forfor EssentialityEssentiality

•• WithdrawalWithdrawal oror absenceabsence ofof thethe metalmetal fromfrom thethe dietdiet producesproduces eithereither functionalfunctional oror structuralstructural abnormalities,abnormalities, andand thatthat thethe abnormalitiesabnormalities areare relatedrelated toto oror areare aa consequenceconsequence ofof specificspecific biochemicalbiochemical changeschanges thatthat cancan bebe reversedreversed byby thethe presencepresence ofof thethe essentialessential metal.metal. •• RoleRole:: AsAs catalystcatalyst inin cellularcellular functions.functions. •• Sources:Sources: MustMust bebe obtainedobtained fromfrom air(oxygen),air(oxygen), waterwater anan dietdiet •• Concentration:Concentration: neededneeded onon mcgmcg toto mgmg Sixteen trace elements are established as being essential for good health. These, collectively, have five general physiological roles:

•• bonebone andand membranemembrane structurestructure •• waterwater andand electrolyteelectrolyte balancebalance •• metabolicmetabolic catalysiscatalysis •• oxygenoxygen bindingbinding andand transporttransport •• hormonehormone effectseffects •• bonebone andand membranemembrane structurestructure •• waterwater andand electrolyteelectrolyte balancebalance •• metabolicmetabolic catalysiscatalysis •• oxygenoxygen bindingbinding andand transporttransport •• hormonehormone effects effects •• bonebone andand membranemembrane structurestructure •• waterwater andand electrolyteelectrolyte balancebalance •• metabolicmetabolic catalysiscatalysis •• oxygenoxygen bindingbinding andand transporttransport •• hormonehormone effects effects •• bonebone andand membranemembrane structurestructure •• waterwater andand electrolyteelectrolyte balancebalance •• metabolicmetabolic catalysiscatalysis •• oxygenoxygen bindingbinding andand transporttransport •• hormonehormone effects effects •• bonebone andand membranemembrane structurestructure •• waterwater andand electrolyteelectrolyte balancebalance •• metabolicmetabolic catalysiscatalysis •• oxygenoxygen bindingbinding andand transporttransport •• hormonehormone effects effects •• bonebone andand membranemembrane structurestructure •• waterwater andand electrolyteelectrolyte balancebalance •• metabolicmetabolic catalysiscatalysis •• oxygenoxygen bindingbinding andand transporttransport •• hormonehormone effects effects OutlineOutline

•• IntroductionIntroduction toto TraceTrace Elements,Elements, MetalsMetals andand MetalloidsMetalloids

•• TraceTrace ElementsElements andand KnownKnown Biological/ToxicologicalBiological/Toxicological ReactionsReactions

•• EnvironmentalEnvironmental HealthHealth andand DiseasesDiseases •• ConcludingConcluding RemarksRemarks ACTIONACTION OFOF MACRONUTRIENTSMACRONUTRIENTS Ca Strengthening of bones and teeth; muscular activity; blood coagulation; cellular permeability. Excess may originate liver and bladder stones and renal insufficiency. Cl Maintenance of blood pressure; vital as acid constituent during digestion.

K Maintenance of corporeal fluids; muscular contractions and nervous impulses.

Mg In bones, together with Ca; activation of muscular contractions; body temperature control; component of several enzymes.

Na Active in hydrosaline equilibrium; transmission of nervous impulses and transport of metabolites. P Bone constituent as apatite; participates in most body chemical reactions. Excess turns hair and bones brittle.

Scarpeli, William (personal communication) ACTIONACTION OFOF MICRONUTRIENTSMICRONUTRIENTS

Co Active in B12 and in chemical reactions. Deficiency causes anemia. Excess causes hearth failures. Cr Needed for metabolism of sugar. Deficiency may cause diabetes, intolerance to glucose etc. Excess may result in renal failures. Excess of Cr+6 is carcinogenic.

Cu Component of oxidizing enzymes during metabolism of energy sources; active in the synthesis of hemoglobin, in keratization and in skin and hair pigments. Deficiency leads to osteoporosis and low number of white blood cells.

F Give strength to teeth and bones, avoiding dental caries and osteoporosis. Excess causes fluorosis of teeth and bones. I Required by thyroidal hormones, temperature control, body growth, reproduction etc. Deficiency causes abnormal growth of the thyroid.

Scarpeli, William (personal communication) elementselements relatedrelated toto cardiaccardiac healthhealth antioxidant protection

antioxidant protection; insulin potentiation regulation of thymulin and IL-2

antioxidant protection antioxidant protection, regulation of PG metabolism TraceTrace ElementsElements inin EnvironmentalEnvironmental HealthHealth

•• ExposureExposure Routes:Routes: Inhalation Ingestion – Direct Absorption – Air (inhaling) – Drinking water – Diet (food chain) •• MetalMetal--InducedInduced Disease:Disease: – Carcinogenic Dermal contact – Teratogenic – Mutagenic CancerCancer andand SiteSite SpecificSpecific EffectsEffects AssociatedAssociated withwith ExposureExposure toto ToxicToxic TraceTrace MetalsMetals Examples:Examples: Element Target Organ and/or Sites → Cr Lung, Liver, Kidney → As Bladder, Liver, Lung, Skin, Vascular, Neurological changes → Cd Lung, Kidney, Bladder, Vascular, Hypertension, Neurological changes → Hg Neurological, lung, kidney, Brain → Pb Neurological, IQ(children), Anemia OutlineOutline

•• IntroductionIntroduction toto TraceTrace Elements,Elements, MetalsMetals andand MetalloidsMetalloids

•• TraceTrace ElementsElements andand KnownKnown Biological/ToxicologicalBiological/Toxicological ReactionsReactions

•• EnvironmentalEnvironmental HealthHealth andand DiseasesDiseases •• ConcludingConcluding RemarksRemarks Trace Element in Developing Countries

600 500 400 anemia, women goiter, all ages 300 Zn deficient 200 Se deficient

millions of people 100 0

Courtesy from Dr. Gerald T. Combs TRACETRACE ELEMENTSELEMENTS ANDAND TOXICTOXIC METALMETAL IONSIONS

HEALTHHEALTH EFFECTSEFFECTS DeficienciesDeficiencies IronIron (Fe):(Fe): TheThe mostmost widelywidely abundantabundant micronutrientmicronutrient • Essential constituent of: Hemoglobin, myoglobin, e-transport enzymes, oxidases;

• Human Body: 2-6 g or iron ; metabolic function is to transport oxygen and electrons (redox agent); • (ID): Anemia, fatigue, susceptibility to and impairment of cognitive development, increased risk of Pb poisoning; • Pregnancy: increases the risk of premature delivery, low birth weight and infant and maternal mortality • Iron Toxicity: Liver and increase risk of coronary heart diseases (adults), Iron-overload (children) • Clinical Signs (Fe > 10-fold excess): cirrhosis, diabetes, , arthritis, and sexual dysfunction. GlobalGlobal PrevalencePrevalence70ofof AnemiaAnemia 60 • >2.1 B affected – 43% of women, 34% of men in 50 developing countries % • multiple causes: 40 – malaria, intestinal parasites 30 – deficiencies of Fe, vit A, folate, vit B12 • reduced work capacity 20 • 20% of maternal deaths – hemorrhage, heart failure 10 • 1/3 of child deaths 0 • impaired cognitive learning Afr LAm Asia NAm

Courtesy from Dr. Gerald T. Combs ZnZn DeficiencyDeficiency (ZD)(ZD) GlobalGlobal PrevalencePrevalence • Similar to ID; likely widespread, but not well documented. • Infants, children, pregnant and premenopausal women, and elderly at higher risk. • impairs immunity, vit A utilization • Some clinical effects of ZD: – Abortion – Growth stunting (children) – Development delay – Decrease immunity – Dermatitis – Decrease neuropsychological functions – Behavior problems – Dementia SomeSome causescauses ofof zinczinc deficiencydeficiency

PrimaryPrimary SecondarySecondary

–– PoorPoor foodfood choiceschoices -- BloodBlood lossloss –– ReducedReduced bioavailabilitybioavailability -- GIGI diseasesdiseases –– GeophagiaGeophagia MalabsorptionMalabsorption InflammationInflammation -- LiverLiver diseasesdiseases -- RenalRenal losseslosses

TRACETRACE ELEMENTSELEMENTS ANDAND SELECTEDSELECTED ENDEMICENDEMIC DISEASESDISEASES OFOF SIGNIFICANCESIGNIFICANCE ININ MEDICALMEDICAL GEOLOGYGEOLOGY ElementElement DiseaseDisease Kaschin-Beck Disease Degenerative osteoarthropathic disease Keshan Disease Chronic heart disease () Iodine Goiter and Cretinism Fluorine Dental and Skeletal Metalloids:* Arsenic Skin lesions, cancer Disorders (IDD)

IDD and multi-causal disease involving factors such as: ! trace element deficiencies ! goiter-inducing substances in foodstuffs (known as goitrogens) ! genetics IDD disorders include: goiter (enlargement of the thyroid), cretinism (mental retardation with physical deformities), reduced IQ, miscarriages, birth defects.

GlobalGlobal PrevalencePrevalence ofof II DeficiencyDeficiency9 DiseasesDiseases 8 • >2 B at risk 7 • 740 M with goiter 6 • 20 M mentally retarded 5 % • 6 M infants with cretinism 4 (half in SE Asia) each yr 3 2 1 0 Afr Med LAm Asia Pac

Courtesy from Dr. Gerald T. Combs AbnormalitiesAbnormalities ofof SeleniumSelenium DeficiencyDeficiency ((SeDSeD)) •• FromFrom ExperimentalExperimental AnimalAnimal Studies:Studies: – SeD alone: reduce activity of Se-enzymes, but no clinical effects; – SeD + deficiency – lipid peroxidation, liver necrosis, cardiac necrosis – White muscle disease in sheep

•• Humans:Humans: – Keshan cardiomyopathy – Kashin-Beck osteoarthopathy

•• OtherOther effectseffects -- SeDSeD impairs:impairs: – thyroid hormone metabolism – T-cell function – resistance to RNA- GlobalGlobal PrevalencePrevalence ofof SeSe DeficiencyDeficiency

•• 400400 MM peoplepeople atat riskrisk inin ChinaChina –– children:children: cardiomyopathycardiomyopathy ((KeshanKeshan Disease)Disease) –– adolescents:adolescents: chondrodystrophychondrodystrophy ((KaschinKaschin-- BeckBeck Disease)Disease)

•• 500500--10001000 MM atat riskrisk worldwideworldwide SELENIUMSELENIUM A belt of low-Se rocks influences millions of people.

CHINA

low Se (<0,025 ppm)

Keshan disease

Kashin-Beck disease Keshan e Kashin-Beck diseases

Keshan disease – weakening of the heart muscle Kashin-Beck disease – muscular pains, other effects Kashin-Beck Disease

Photo: Courtesy of Prof. Wang Zhilun, China WorldwideWorldwide VariationVariation inin SeSe statusstatus

350 Venezuela 300 Venezuela 250 New Zealand USAUSA plasma Se 200 FinlandFinland ng/ml 150 ChinaChina 100 50 0 nutritional adequacy = 80ng/mL Nève, 1995 country SeP levels: Hill et al, 1996 Courtesy from Dr. Gerald T. Combs Mseleni Joint Disease

• Multiple epiphyseal displasia (long bones have malformed growth) • Polyarticular osteoarthritis (arthritis of several joints) Maputaland

• Protrusio acetabuli Botswana Namibia

Mozambique (hip disorder) Swaziland Maputaland South Africa

Lesotho • Dwarfism MJDMJD ResearchResearch

•• MedicalMedical

- Low PO4, F, Ca and Mg - Aflotoxins not present - Anemia due to parasites - Genetics inconclusive - Mg and Zn deficiency suspected •• ComparisonComparison withwith otherother diseasesdiseases - Keshan-Beck and Se - Dwarfism and Zn SoilSoil PropertiesProperties

•• NearNear neutralneutral pHpH 6.96.9

•• << 4%4% clayclay (kaolinite(kaolinite andand quartz)quartz) •• LowLow organicorganic CC ~1.6%~1.6% •• TraceTrace ElementElement Deficiency:Deficiency: F,F, I,I, V,V, SeSe ;; Others: Cu, Zn, B, N, P, K, S, Ca :

- Disease of children characterized by under-mineralization of growing bones, leading to physical deformities of the weight bearing bones most notably of the legs, wrists and arms

- A source of permanent disability

- Can be healed but not cured

his knees Photo Courtesy: Gerald F Combs, USDA RicketsRickets ...... causedcaused byby malnutritionmalnutrition ......

G deficienciesdeficiencies vitamin D (sunlight) Ca, P, Mg, B (?)

G imbalances/excessesimbalances/excesses P, Pb, Al, Sr, As(?) tachysterols (vit. D analogues) fat, oxalates, DDT (?)

Photo Courtesy: Dr. Gerald F Combs, USDA 0.7 ageage andand sexsex 0.6 0.5 distributiondistribution 0.4 0.3 ofof casescases cases/HH 0.2

0.1 12 10 -8 8-9 0-11 11- 0 -7 7 9- 1 6 4 5-6 4-5 -3 3- -2 2 1 0-1 age group, yrs.

80 male 70 female 60 50 40 cases 30 20

10 0 <5 y 5-10 y 10-18 y Courtesy from Dr. Gerald T. Combs Calcium-supplementation study (Combs et al. personal communication) PtPt 35A35A NovNov 9696 FebFeb 9898

Photos: Courtesy of Dr. Gerald F. Combs, USDA TRACETRACE ELEMENTSELEMENTS ANDAND TOXICTOXIC METALMETAL IONSIONS

HEALTHHEALTH EFFECTSEFFECTS ExcessExcess FLUORINEFLUORINE Fluorine is an essential component of phosphates, as the hydroxy-fluor- apatite, a constituent of teeth and bones.

It is essential for healthy and strong teeth and bones, and to avoid osteoporosis.

The excess causes fluorosis, with mottled and harder teeth and bone calcification.

Fluorosis is common where drainage water is high in fluorine, and is consumed without adequate treatment, as in large areas of China, Ghana, Sri Lanka and other places.

More than 100,000,000 people have fluorosis. Courtesy from Dr. William Scarpeli, Brazil FluorineFluorine inin DrinkingDrinking WaterWater

DoseDose--ResponseResponse RelationshipRelationship forfor Fluorine:Fluorine:

•• << 0.50.5 mg/Lmg/L :: dentaldental cavitiescavities maymay occuroccur (risk)(risk)

•• 0.50.5 –– 1.51.5 mg/L:mg/L: nono adverseadverse effectseffects •• >> 1.51.5 mg/Lmg/L :: fluorosisfluorosis riskrisk ARSENICARSENIC EXPOSUREEXPOSURE :: GLOBALGLOBAL IMPACTIMPACT PEOPLE AFFECTED BY NATURALLY CONTAMINATED WATER AND SOILS

Mongolia Cornwal, England up to 50,000 contaminated 2% As in soil

Taiwan up to 0.6 mg/L, Lagunera, Mexico, 20,000 30,000 affected; contaminated 0.5 millon at risk Bangladesh up to 2.0 mg/L, 200,000 affected; Antofagasta, Chile 0.8 50 million mg/L in water, 20,000 at risk affected Cordoba, Argentine 10,000 contaminated

Selinus O, Alloway B, Centeno JA et al. “Essentials of Medical Geology” (2005) Health Effects Associated with Arsenic Exposure • Cancer: skin, lung, bladder, liver, kidney • • Peripheral vascular disease • Developmental effects • Neurologic & neurobehavioral effects • Diabetes Mellitus • Hearing loss • Portal fibrosis of the liver • Lung fibrosis • Hematological effects (e.g., anemia)

Tchounwou PB, Patlolla AK, Centeno JA. Toxicologic Pathology 31:575-588 (2003).

Centeno et al. Environ Health Perspect 2002. OutlineOutline

•• IntroductionIntroduction toto TraceTrace Elements,Elements, MetalsMetals andand MetalloidsMetalloids

•• AnAn OverviewOverview ofof TissueTissue ReactionsReactions toto ToxicToxic TraceTrace MetalMetal ExposuresExposures

•• EnvironmentalEnvironmental HealthHealth andand DiseasesDiseases •• ConcludingConcluding RemarksRemarks SUMMARYSUMMARY

• Trace elements deficiency or excess contribute to a wide-spectrum of environmentally health-related problems. • Disorders related to trace element deficiency are treatable (dietary supplements, etc.) • Toxic metal ions may exhibit different toxicity depending on the chemical and physical form. • Toxic metal ions may affect more than one organ system. • Clinical and environmental health assessment (including risk assessment and risk management) studies of exposures to trace elements, toxic metals, and metalloids, must consider background exposure, natural modes of exposure, bioavailability, chemical/physical speciation, morphological characteristics, as well as dose-response relationships. CardiovascularCardiovascular effectseffects ofof CuCu deficiencydeficiency

•• cardiomyopathycardiomyopathy •• ventricularventricular aneurismsaneurisms •• impairedimpaired contractilecontractile functionfunction •• arrhythmiaarrhythmia •• hypertensionhypertension inin olderolder animals;animals; elevatedelevated BPBP inin responseresponse toto stressorsstressors •• depresseddepressed mitochondrialmitochondrial respirationrespiration •• myocardialmyocardial apoptosisapoptosis