METALS

Lead, Pb Unique properties - used since antiquity Mostly anthropogenic sources (Greenland snow pack data, 1954) Banned as paint additive –Europe 1921 –USA 1978 Sources: smelters, refineries, power plants, incinerators, manufacturing and recycling operations

Exposure to Pb Pb in air NAAQS level =1.5ug/m 3 (quarterly) –Mostly (90%) from leaded gasoline, until 1978 (400t/day worldwide) –Industrial emissions Pb in water Action water level =15ppb (0.015ppm) –Airborne Pb deposition in water –Water supply pipes –Lead shots in lakes (Whatcom county, WA) Pb in food –From water to plants --> animals --> food –Pb-based glaze for pottery –Pica for children - leaded paint flakes Pb in soil –From industrial emissions, home paint disposal, gasoline (~600,000t/year) –Pica for children Annual US air emissions: ,000t ,100t

Pb Health effects Young animals and humans more susceptible Aquatic organisms and birds affected (directly or by water acidification)

Human health effects of Pb In blood - 25 days Half life In soft tissue - 40 days In bone - 25 years ! Accumulates (95% in bone and teeth) - remobilized Possible human carcinogen (IARC) (phosphate and acetate forms) Systemic poison –Inhibits hematopoiesis - anemia (heme synthesis) –Causes renal tubular dysfunction –Lung function (asthma, bronchitis, tissue damage) –Muscle and joint pains, skeletal growth effects –Immune system damage –Miscarriage, stillbirth Action blood level =25ug/dl (2.5ug/ml)

Children more vulnerable Pb poisoning is the most common and serious environmental disease Primary target CNS –Retardation and brain damage –Behavioral changes –Cognitive development Levels dropped since 1974 from to 2- 3ug/dl - still 2.2% US children are above the 10ug/dl limit CNS effects from blood level =10ug/dl (1ug/ml) - CDC

Mechanism of action Binds to -SH groups on enzymes (inactivation) –adenyl cyclase (ATP to AMP), –aminotransferase (protein metabolism) Competition with Ca ++ –Mitochondria respiration –Synaptic regulation –Skeletal calcium substitution –tRNA interaction with aminoacids and ribosomes Heme synthesis inhibition –  -aminolevulinic acid dehydratase (Zn ++ ) ( serum ALA levels) –Ferrochelatase (Fe ++ ) Nutritional factors affect Pb absorption (Fe deficiency)

Cadmium, Cd Itai-itai byo disease (Japan 1945) –Irrigation of rice fields with contaminated water from Zn-Cd-Pb mine Bone fractures, deformations, decalcification, pains Persistent (t 1/2 =10-25y), one of the most toxic trace metals Byproduct of smelting, fossil fuel combustion, phosphate fertilizers Used with other metals as anticorrosive, multiple other uses Similar to Zn ++ (binds proteins), and to Ca ++

Exposure to Cd - t 1/2 = y Air % retention –Mostly occupational –Ambient air 1ng/m 3 (20-50ng/day) –Tobacco smoke major inhalation source (1.5-2ug/cig) Water (naturally at <10ng/l) –In salt waters as CdCl 2, in fresh waters as CdCO 3 Soil –Deposition from air –Municipal sewage on agricultural soil –Phosphate fertilizers Food % retention (10-50ng/d to ug/d) –Main source of human exposure (plants bioaccumulate Cd) –Leafy vegetables, grains, cereals –Some seafoods EPA max 0.01mg/l, (goal 5ug/l) OSHA air 200ug/m 3

Cd Health effects Known human carcinogen (lung cancer) (air 1ug/m 3 ) Accumulation in liver, kidney (t 1/2 =10-20y), and skeleton over lifetime - Very low excretion (0.005 % /day) Nephrotoxicity due to Ca ++ ion uptake inhibition (free intracellular Cd ions; Metallothionein) Mechanisms: Enzyme inhibition, metal co-factor displacement, oxidative damage (lipid peroxidation) Antagonist of nutritional metal intake (role of deficiencies in toxicity, protein in diet, vit. C) Newborns and children most sensitive

Mercury - Hg Unique properties and rare on earth crust, but also ubiquitous Multiple uses (thermometers, UV light lamps, catalyst, batteries, electrical apparatus) US sources: chloralkali industry and coal fired power plants (40%); also pulp and paper industry, incineration, smelters, gold mining (Amazon) Also natural sources (volcano eruptions) Elemental Hg is oxidized to Hg ++ and biotransformed to organic forms (mostly methyl) Bioaccumulates in fat tissue - fish intake

Hg Health effects Brain is target organ: Neurotoxicity, psychomotor effects, brain damage (fetus) Poisonings –Minamata Bay acute toxicity (Japan) (11mg/g) –Iraq , bread - MeHg as fungicide Women of childbearing age and children are subpopulations of highest concern Enzyme inhibition (-SH binding) Na+ and K+ membrane permeability Nephrotoxicity Se protective? FDA guideline for fish 0.5ug/g Critical daily dose 300mg

Nickel - Ni Occupational toxicity - inhalation - Ni(CO) 4 Water contamination through leakage Carcinogenic forms - Ni, Ni 2 S 3, NiO x –DNA and protein crosslinking –Chromosomal aberrations –Oxidative processes Competition with essential metals Skin contact exposure Crosses the blood-placenta barrier Mg protective? OSHA air level 7ug/m 3 (occupational) No drinking water safety level

Arsenic -As Oxides, AsO 3, H 3 AsO 3, H 3 AsO 3 Uses: Insecticides, rodenticides, herbicides, fungicides, preservatives, pigments, vet med. Sources: Natural processes, fossil fuel combustion (fly ash particulates), smelting (AsH 3 ) Microorganismal oxidation, methylation (organic forms) Groundwater and surface water contamination –350,000 US residents above safe level –Mostly in Asia (India, China), South America (Chile) Urban air (0.02ug/m 3 ), soil (0.2-40ug/g) Food - fish EPA safe level 50ug/l (drinking water)

Arsenic Health Effects Inhalation, ingestion, skin contact –Liver, kidneys, spleen, intestine (lung), skin, hair, nails Toxicity higher for water soluble forms (As 3+ ), metabolic transformation (methylation detox) CNS effects (motor activity) Carcinogen (bladder, kidney, skin, liver, blood, lung and colon (inorganic forms) ( mg/l) Capillary injury - “Blackfoot” (gangrene) Teratogen Reacts with -SH: enzyme inhibitor (antidote BAL) Uncouples oxidative phosphorylation Oxidative processes (SOD, CAT, GPX, GST inhibition)