cadmium

Total slids : 96 1April 10, 2023

Cadmium Metabolism & Pathogenesis EffectsIsfahan University of Medical Science, School of Pharmacy

Department of Clinical Biochemistry

Cadmium Biology

(An Overview)

By: A.N. Emami Razavi


Cadmium Metabolism & Pathogenesis Effects

Outlines

Introduction Pharmacokinetics Molecular mechanism of toxicity Pathogenesis effects Detoxification Summery

Cadmium

Introduction



silver ← cadmium → indiumn

Zn

↑

Cd↓

Hg

Periodic Table - Extended Periodic Table



Cadmium: A Co-product of Zinc Smelting



Notable characteristics

Cadmium is a soft, malleable, ductile, toxic, bluish-white bivalent metal. It is similar in many respects to zinc but reacts to form more complex compounds.

The most common oxidation state of cadmium is +2, though rare examples of +1 can be found.



Properties of cadmium

Boiling point=765° C

Melting point=320.9° C

Silvery metal soft enough to be easily cut with a knife

Density=8.65g/cm³



Cadmium facts

Date of discovery = 1817

Discoverer = Fredrich Stromeyer

Atomic number = 48

Atomic mass = 112.41

1776 - 1835



Sources:

Natural rock weatheringCopper, lead and zinc smelting auto exhaustCigarette smoke (a cigarette contains 1-2 ug Cd)



Small rocks - Cadmium (Cd)



Cadmium base, Cd



Industrially produced cadmium



Cadmium sifide



Cadmium smithsonite contains cadmium impurities and is yellow to yellow-green.



The Name 'Smithsonite

Smithsonite was named after James Smithson in 1832. James Smithson was an English scientist, often referred to as the best chemist and mineralogist of his year. He was an active member of many scientific organizations that benefited society and advanced scientific research. James published at least 27 papers with topics in chemistry, geology, and mineralogy. In 1802 James Smithson proved that zinc carbonates were true carbonate minerals, not zinc oxides. This discovery lead to the breakdown of calamine into two separate minerals hemimorphite and smithsonite. After James Smithson's death in 1829 the bulk of his estate was given to his nephew. Since his nephew died without any heirs the Smithson Estate was then given to the United States of America to found the Smithsonian Institution.



Cadmium Production



Cadmium Consumption



The Application of Cadmium

metal plating nickel-cadmium batteries solders paint pigments plastic stabilizers photographic chemicals fungicides



Cadmium Plating

COMMERCIAL

Cadmium has long been used for its superior corrosion protection. Cadmium as deposited is bright silver finish to which a clear or yellow chromate can be applied. The deposit is soft, ductile and solderable. Here at DeTray Plating Works we have both rack and barrel capabilities depending on your needs.



Nickel Cadmium Batteries



Cadmium in paints



Chrome yellow and Cadmium yellow



Cadmium Orange Poppies Art Print

Cadmium

pharmacokinetics



Inhalation

Smelters, cigarette smoke 15-50% absorbed

Shenyang Copper Smelter



Cigarette smokers, however, typically sustain significantly higher exposure. Cadmium inhaled through cigarette smoke is more easily taken up by the body than cadmium in food or water. From 40 to 60 percent of the cadmium inhaled in smoke is absorbed into the bloodstream as opposed to the 5 to 10 percent absorbed through foods. Each cigarette contains roughly 1 to 2 micrograms of cadmium, and smokers absorb an additional 1 to 3 micrograms of cadmium into their systems daily for every pack they smoke. Studies have shown that smoking more than 20 cigarettes daily can increase cadmium levels in the body tenfold.



Ingestion

Main source is liver and kidney of meats

6% absorbed, greater if deficient in calcium, zinc or iron



Distribution

bound to albumin in plasma and red blood cells

transported to liver, pancreas, prostate and kidney, with eventual transfer to kidney

50-75% of total body Cd is found in liver and kidney



Metallothionein

protein rich in cysteine

Traps Cd esp. in kidney

Synthesis induced by Cd



Elimination

Urine half-life in humans is 20 - 30 years

Cadmium

Molecular mechanism of toxicity



Classification of metals

Class AClass A (oxygen-seeking)

BorderlineBorderline Class BClass B

(sulphur- or nitrogen-seeking)

Calcium

Magnesium

Manganese

Potassium

Strontium

Sodium

Zinc

Lead

Iron

Chromium

Cobalt

Nickel

Arsenic

Vanadium

CadmiumCadmium

Copper

Mercury

Silver



Borderline and Class B metals and metalloids are important pollutants

Nitrogen- and sulphur-seeking

High affinity to proteins and other biological ligands



Cadmium is a heavy metal

Heavy metals are chemical elements that have a specific gravity (a measure of density) at least five times that of water.



Basis of toxicity of metals

Substitution of essential metals in active centers of enzymes

Interference with intracellular signaling pathways and Ca2+ metabolism

Oxidative stress (excessive production of free radicals)

Interference with DNA transcription, translation and repair



Toxic effects of heavy metals

Heavy metals (HM) exert their toxic effects by combining with one or more reactive groups (ligands) essential for normal physiological functions

Nearly all organ systems are involved in heavy metal toxicity; however, the most commonly involved organ systems include the CNS, PNS, GI, hematopoietic, renal, and cardiovascular (CV).



Mechanisms of uptake and transport of metals

Lipid route Plays limited role in metal transport Hg may diffuse through the membrane in the form of neutrally charged

chlorocomplexes Hg2++2Cl- ↔ HgCl2

Aqueous routes Simple diffusion

Yes Facilitated diffusion

Very much so Active transport

Little or no role



Simple and facilitated diffusion

Ion channels Ca2+ channels

can transport Zn2+, Cd2+, Hg2+, Pb2+

SH-rich Zn2+ channels can transport Cd2+

Carrier proteins Divalent cation transporter 1 (DCT1)

Major carrier protein for uptake of Fe2+, Zn2+ but can also transport Cd2+, Hg2+, Pb2+



Endocytosis

Receptor-mediated endocytosis Iron-binding proteins - transferrin, ferritin,

lactoferrin can bind other metals

Fe3+

Apotransferrin

Out In Out In Out In



Take-home messages

There are multiple pathways of metal uptake into the cell

No specific pathways of uptake exist for “toxic” metals

Toxic metals use uptake routes, which have evolved for uptake of essential metals such as iron, copper and zinc



General mechanisms of metal toxicity

Metals have multiple intracellular targets Proteins

Substitution of essential metals in active centers of enzymes Binding to thiol (SH) groups Oxidative damage

Membranes Membrane permeability Oxidative stress

DNA Interference with transcription, translation and repair Oxidative damage

Interference with intracellular signaling pathways and Ca2+ metabolism



Oxidative damage

A hallmark of heavy metal toxicity

Free radical (ROS,Free radical (ROS,RNS)RNS)

Increase in free radicalproduction

Decrease in antioxidants



Heavy metals increase ROS production

Direct effectsHaber-Weiss reactions

Meox+O2•-→ Mered+O2

Mered+H2O2→ Meox+ OH• +OH-

Net: H2O2+O2•-→ O2+OH• +OH-

Indirect (inhibition of the mitochondrial electron transfer chain)



Oxidative damage to DNA

Single Cell Comet Assay (single cell gel electrophoresis)

SCGE

Detects DNA fragmentation



Oxidative damage to DNA

TUNEL (TdT-mediated X-dUTP nick-end labeling) assay

Detects free –OH groups created by strand breakage

Terminal uridine deoxynucleotidyl transferase

dUTP nick end labeling (TUNEL) is a common

method for detecting DNA fragmentation that

results from apoptotic signaling cascades. The

assay relies on the presence of nicks in the

DNA which can be identified by terminal

deoxynucleotidyl transferase, an enzyme that

will catalyze the addition of dUTPs that are

secondarily labeled with a marker. It may also

label cells undergoing necrosis or cells that

have suffered severe DNA damage.



TUNEL-detected DNA damage in Cd-exposed zebra fish embryos

ControlControl

100 100 M CdM Cd

Chan & Cheng (2002)



Cd-induced apoptosis in zebrafish

Chan & Cheng (2002)

Control embryo

Cd-exposed embryos

Cd-exposed embryo



Oxidative DNA damage may lead to mutations

AT –GC transitions Deamination of adenine or cytosine

G—C → G - - U (deamination) → G—C + A - -U (replication) → G—C+ A—T (replication)

GC-TA transversions 8-hydroxyguanine

G—C → 8HOG—C → 8HOG - - A + G—C → T—A + G—C (replication)



Oxidative damage to proteins and lipids

LipidsMalondialdehyde (MDA)Lipofuscin

ProteinsCarbonylationLoss of iron from



Mutagenicity of cadmium

Jin et al., 2003 Nature Genetics



Inhibition of DNA repair

Isolated human cells exposed to Cd in vitro

Jin et al., 2003 Nature Genetics



Toxic metal can affect function of zinc-finger proteins

Hartwig (2001)



Take-home messages

Heavy metals affect a wide variety of intracellular molecules and functions.

Two major mechanisms of heavy metal toxicity are: Binding to –SH and nitro-groups of biomolecules

Cofactor substitution, conformational changes, etc. Oxidative damage due to direct catalysis of ROS

production and/or to inhibition of ETC in mitochondria

Cadmium

Pathogenesis effects



Cadmium and renal effects

Cadmium accumulates especially in the kidneys leading to dysfunction of the kidney with increased secretion of e.g. proteins in urine (proteinuri) and other effects.

The proximal renal tubular dysfunction creates low phosphate levels in the blood hypophosphatemia, causing muscle weaknesses and coma. The dysfunction also causes Gout, a form of arthritis due to the accumulation of sodium urate crystals in the joints because of high blood levels of uric acid (hyperuricemia). Another side effect are increased levels of chloride in the blood (hyperchloremia). The kidneys can also shrink up to 30%.



Markers of kidney function:

tubular function:

Urinary excretion of

NAG RBP ß2-microglobulin AA Ca



Cadmium and liver toxicity

Intraperitoneal injection of CdCl2 in animals cause:

Elevation of hepatic enzymes Morphological changes in mitochondry and

endoplasmic reticulum of hepatocytes Decrease of intracellular pH from 6.8 to 6.6

due to:Cadmium interaction with Cl-/HCO3 channels



Cadmium and fractures Chronic exposure to cadmium may

promote urinary calcium loss

Cadmium may interfere with the metabolism of calcium, vit. D, collagen

Severe cadmium poisoning is associated with ostemalacia or osteoporosis



Cadmium and fractures

In postmenopausal women, urinary cadmium correlated negatively with bone density.

The population-based risk for fractures in districts near the smelters was 35%.

Conclusion: cadmium may promote skeletal demineralisation, which may lead to increased bone fragility and raised risk of fractures.



Cadmium and placenta

Cadmium induces placental necrosis at lower doses than renal toxicity

Deposited in placenta, little into fetus

Blocks nutrient and blood flow: growth retardation, fetal death

Interferes with zinc

Responsible for the growth retardation caused by smoking



Cadmium and lung toxicity

edema and emphysema by killing lung macrophages



Cadmium and cancer risk Several occupational studies have reported an excess risk of

lung cancer in humans from exposure to inhaled cadmium.

Animal studies have reported cancer resulting from inhalation exposure to several forms of cadmium, while animal ingestion studies have not demonstrated cancer resulting from exposure to cadmium compounds.

EPA(Environmental Protection Agency) considers cadmium

to be a probable human carcinogen (cancer-causing agent) and has classified it as a Group B1 carcinogen



Itai itai

Itai itai

Itai itai

Itai itaiItai itai

Itai itai

Itai itai

Itai itai



itai-itai disease The itai-itai disease (Japanese: イタイイタイ病 , literally: ouch-ouch-

disease) From 1939 to 1954, some two hundred people near Fuchu, Japan suffered from a condition termed 'Itai-itai‘

There are a number of symptoms associated with cadmium poisoning. The

two main organs affected are the bones and the kidneys. The bones get soft (osteomalacia) and lose bone mass and become weaker (Osteoporosis). This causes the pain in the joints and the back, and also increases the risk of fractures. In extreme cases of cadmium poisoning the body weight alone might cause a fracture.

The second affected organ is the kidney, which loses its function to remove acids from the blood, a so called proximal renal tubular dysfunction. The kidney damage due to cadmium poisoning is irreversible and does not heal over time, and the victims of the itai-itai disease still have this disorder.



Is there a test for cadmium exposure?

There are several tests that indicate if someone has been exposed to or been harmed by cadmium exposure. Urine or blood samples can be tested to indicate current and past exposure and may even be useful in determining if kidney damage has occurred. Hair and fingernails or toenails are also excellent biomarkers — biological indicators — for cadmium exposure and can reveal past exposure to the metal



Cadmium health effects

Long-term exposure to cadmium at levels around 0.1 milligrams per cubic meter of air may cause kidney stones and lung damage, and have been linked to lung cancer and high blood pressure.

Short-term exposure at ten times that level may irritate the lungs. Our everyday diet, however, only gives one-tenth the amount that could possibly affect long-term health, but if you eat large amounts of shellfish, liver and kidneys, or if you smoke, you may consume more cadmium than you should.



Cadmium health effects

The EPA has set a limit of 5 parts of cadmium per billion parts of drinking water (5 ppb). EPA doesn't allow cadmium in pesticides.

The Food and Drug Administration (FDA) limits the amount of cadmium in food colors to 15 parts per million (15 ppm).

The Occupational Safety and Health Administration (OSHA) limits workplace air to 100 micrograms cadmium per cubic meter (100 µg/m³) as cadmium fumes and 200 µg cadmium/m³ as cadmium dust.

Cadmium

Detoxification



Detoxification of metals

Biotransformation Not possible for most metals Biotransformation (methylation) of Hg makes it more toxic

Binding to intracellular ligands Reduces the amount of biologically active form (free ion)

Deposition of insoluble metal granules

detoxification



Intracellular ligands for metal binding

Metallothioneins

Glutathione

CRP(cysteine rich proteins)

Histidine

detoxification



Metallothioneins

Low molecular weight (60-68 aa, 6-7 kDa)

Cysteine-rich

In mammals – 20 Cys, bind eqiuvalent of 7 bivalent metals

Cys positions are highly conserved

detoxification



Rat MT I

Blue crab MT II

detoxification



Cadmium bound to metallothionein subunit

detoxification



Metallothionein is induced by exposure to heavy metals

Leung & Furness (1998)

Nucella lapillus

detoxification



Metallothionein protects from Cd toxicity

Experimental exposure to toxic Cd levels

Survival: Cd-pretreated>control

Liver damage:Control>Cd-pretreated

Klaasen & Liu (1998)

detoxification



MT-knockout mice studies support protective role of MT against Cd toxicity

Liu et al., 1999

5 weeks 10 weeks

detoxification



MT-knockout mice studies support protective role of MT against Cd toxicity

Liu et al., 1999

detoxification



Cellular functions of metallothionein

Storehouse for Zn

Protection against Cd-toxicity

Free-radical scavenger

detoxification



Short peptide metal chelators

Glutathione

Phytochelatins

detoxification



Phytochelatines

detoxification



Cysteine-rich (intestinal) protein

Zn2+

Zn2+

detoxification



Deposition of insoluble granules (invertebrates only)

Lysosome-derived granule in a snail Littorina littorea Marigomez et al. (2002)

detoxification



Take-home messages

Specialized proteins (metallothioneins) and polypeptides can protect cells from heavy metal toxicity by binding metals

Cysteine has high affinity for metals and therefore is a key amino acid in metal-binding proteins

Some invertebrates (mollusks, crustaceans, annelids) can detoxify metals by deposition and excretion of insoluble metal-containing granules

Cadmium

Summery



discoverer=Fredrich Stromeyer

boiling point=765°C

date ofdiscovery

=1817

atomicnumber

=48

crystal structure=hexagonal

color=bluish white

oxidation state=2density=8.65g/cm³atomicmass=112.41

paint pigments

solders

poisonous

compoundsAretoxic

nickel-cadmiumbatteries

Cadmium properties & application



Cadmiumeffects

Respiratory SystemPneumonitis, destruction of

mucous membranes

KidneyProteinuria, kidney stones,

glomerular & tubulardamage

PlacentaDeposition & necrosis

Block nutrient & blood flowGrowth retardation & fetal death

Skeletal SystemLoss of bone density and

mineralisation, Itai-Itai disease

Reproductive SystemTesticular necrosis,

estrogen-like effects,affection of steroid-hormon

synthesis

Cancer Excess risk of lung cancer

Classified in group B1 carcinogens



Do we need cadmium for health?

Though trace amounts of many metals are essential for the health of living things, there is no scientific evidence showing a nutritional role for cadmium.



The First Cadmium Enzyme – Carbonic Anhydrase 2 from the Marine Diatom Thalassiosira weissflogii

Cadmium is generally thought to be toxic and was not thought to be used by nature in anyway. X-ray absorption experiments on a marine diatom showed that Cadmium is not only of biological importance, but plays an important role in the global carbon cycle.

Lane, T.; Saito, M. A.; George, G. N.; Pickering, I. J.; Prince, R. C.; Morel, F. F. M. "Isolation and Preliminary Characterization of a Cadmium Carbonic Anhydrase from a Marine Diatom" Nature, 2005, 435, 42

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