Toxicity of Metals

How metals are different to other material

They are neither created nor destroyed (found in environment naturally)

Potential for metal health effects

• Altering environmental transport

• Altering biochemical form (mercury)

Major excretory pathways for metals

• Many metals go to the KIDNEY (urine)

• Feces if not absorbed

• Sweat or hair if external contamination

Half-life of Cadmium

20-30 years in kidney

Half-life of Lead

In bone for 20-30 years

In blood for 36 days

Useful assessment tool for alkyl/methyl mercury

HAIR: long hair allows you to see exposure over time

Metallothioneins

Inducible low molecular weight proteins containing thiols (sulfur) in the golgi apparatus

Functions of metallothioneins

Protection against metal toxicity, metal homeostasis

Ligands of metallothioneins

Cd, Cu, Hg, Ag, and Zn

Transferrin

Glycoprotein in plasma that binds ferric IRON, transport across membrane for oxidation and carrying oxygen by hemoglobin

How is iron separated from transferrin?

Acidification in endosomes

Ferritin

Stores iron in liver, spleen, and bone

Chelation Therapy

Treating toxic metal poisoning with chelators that form metal-ion complexes with a metal

Chelation

Formation of ringed structure between chelator and ligand (metal)

Requirements for Chelators

Oppositely charged to metal (metals are ALWAYS POSITIVE, so chelators must be negative)

Often contain O, N, or S (LONE PAIRS!)

Examples of Chelators

• BAL (British anti-lewisite)

• DMPS

• DMSA

• EDTA

British anti-lewisite (BAL)

Chelating agent (first used for chemical warfare) that increases excretion of cadmium by kidneys

Contains sulfur and oxygen

Danger of using BAL

• May be toxic to kidney because it brings more cadmium to kidney

• Enhances toxicity of selenium and tellurium

DMPS

• Chelator developed because BAL was toxic

• Water-soluble, orally administered

• Conains S and O

Excretion of DMPS

ACTIVE excretion by organic anion transport system in the kidney

EDTA

• Important chelator that is POORLY ABSORBED by GI tract

• Removes lead from soft tissue

• Binds calcium, allowing bubbles, preventing coagulation

• Common preservative in food

• Contains O, and N

What is hard water?

Calcium

Where is EDTA found?

• Many food products as a preservative

• Carbonated drinks

• Shampoo and detergents

Arsenic

Ubiquitous metalloid often found in food (seafood) and water

Arsenic Poisoning Symptoms

• Hyperpigmentation

• Gangrene of lower extremities

• Skin cancer

• GI damage, vomiting, diarrhea in high doses

Cadmium

Natural metal found in lead/zinc ores released from mines/smelting

Uses of Cadmium

• Electroplating (preventing corrosion)

• Alloys (dull finish)

• Alkali storage batteries

Exposure to Cadmium

• Grains/cereal main source

• Cigarette smoke (pack a day doubles intake)

• Liver, kidney, shellfish

Acute Cadmium Toxicity

Nausea, vomiting, abdominal pain

Chronic Cadmium Toxicity

COPD (usually in smokers), emphysema, chronic renal tubular disease

Lead absorption

• Respiratory and GI tract

  • Industrial lead especially by respiratory system

• Poorly absorbed by the skin

• 99% bound to RBCs, distributed to bone, kidney, brain, liver, muscle, gonads

Factors affecting lead absorption

• Children absorb more than adults

• Low calcium

• Iron deficiency

• Empty stomach

Leaded Gasoline

Discovered by GM in Ohio, trying to stop engine knock, lead used as an additive to increase octane rating

Five workers went insane in 1924, no longer used

What do we use for gasoline now?

Ethanol from corn instead of octane

Picher, Oklahoma

Ghost town that was a Zinc and lead mining town

Superfund site due to lead

Why are lead levels higher in children?

They are smaller, and lead is sweet-tasting so kids were more likely to try to ingest it (white lead paint chips)

Highest lead levels were…

Before 1970s due to white lead paint and emissions from leaded gasoline

Where is lead mainly found?

Mostly in soil, smaller amounts in ground water

Uses for Lead

• Fuel additives

• Paint pigment

• Storage batteries (lead-acid car battery with sulfuric acid)

• Lead pipes

• Glazed ceramic foodware

Lead toxicity

• Inhibits heme synthesis enzymes → Anemia

• Cerebral edema

• Neuronal degradation

• Stupor, coma, and death

Systemic and neural toxicity

Lead toxicity in children

Hyperactivity, decreased attention, lowered IQ scores

Chromium

Most abundant in the trivalent and hexavalent forms (+3/+6)

Uses of Chromium

• Tanning leather

• Wood preservatives

• Anticorrosive

• Chrome plating (shiny)

Where do we mostly get chromium?

From food

Chromium Toxicity

• Acute tubular and glomerular damage

• Allergic skin reaction

• Carcinogenic genotoxic

Hazard Identification

Scrutinize all relevant toxicological and related data to identify the hazard

Dose-response assessment

Relationship between magnitude of exposure and probability of effects

Exposure assessment

Extent of human exposure (routes, temporary and permanent effects)

Risk Characterization

Nature and magnitude of human risk and the uncertainty of the estimate

Used for high risk groups, with a built-in safety feature

Acrylamide

Found in starchy (fried/breaded) foods

Do we prefer NOEL or LOAEL?

NOEL! Gives us more confidence that humans won’t be affected

RfD/ADI =

NOAEL/(UF * MF)

UF

Uncertainty factor

MF

Modifying factors

Interspecies Uncertainty Factor (UFA)

Accounts for uncertainty extrapolating animal data to humans

Intraspecies Uncertainty Factor (UFH)

Accounts for uncertainty/variation in sensitivity between humans (elderly/children)

Uncertainty factor subchronic to chronic (UFS)

Used if deriving a chronic RfD from subchronic data

Uncertainty factor from LOAEL to NOAEL (UFL)

Used if no NOAEL can be directly determined

Database Uncertainty Factor (UFDB)

Accounts for absence of key data in the database for a certain toxin

Modifying Factor

Applied when scientific uncertainties exist within the study or database

PPM (part per million)

1 mg/kg

1/1,000,000

ppb (part per billion)

1 ug/kg

1/1,000,000,000

ppt (part per trillion)

1 ng/kg

1/1,000,000,000,000

Dioxin-like chemicals

• Dioxin (most toxic manmade chemical)

• PCBs

• Furans

LONG LASTING ENVIRONMENTAL CHEMICALS

History of PCBs

• 1865 - first discovered from coal tar

• 1881 - first synthesized

• 1927 - first manufactured commercially

• 1937 - link PCB to liver disease

• 1977 - stopped manufacturing

Uses of PCBs

• Dielectric fluids in transformers, capacitors, light ballasts

• Plasticizers in paints, sealants, etc.

  • ALL buildings 1950-1970 had PCBs

• Carbonless copy paper

PCB Properties

Very stable, don’t conduct electricity, lubricating, high heat capacity (coolant)

Chlorination of PCB

• Chlorine can attach at any position of biphenyl

  • 209 possible combos

• Allows use in complex mixtures for desired properties

Toxicity of PCBs

• Cancer, hormonal, reproductive, biochemical

• Similar to Dioxin’s toxicity due to similar structure (biphenyl)

Why are Dioxin-like chemical persistent?

Strong bonds between chlorine and biphenyl

How do we determine toxicity of all 209 PCBs?

Compare to Dioxin with a toxic equivalence factor (Dioxin = 1)