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Cadmium toxicity in human


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presented on 28/10/2012

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Cadmium toxicity in human

  1. 1. Presented ByShashi Shekhar Singh SES,JNU New Delhi
  2. 2. INTRODUCTION Encountered in earth’s crust combined with chlorine (CdCl2), oxygen (CdO),sulphur (CdS) Exists as small particles in air, result of smelting, soldering or other high temp. industrial processes By-product of smelting of zinc, lead, copper ores Used mainly in metal plating, producing pigments, batteries, plastics and as a neutron absorbent in nuclear reactors
  3. 3. CADMIUM POISONING Caused by excessive exposure to cadmium No constructive purpose in the human body. Extremely toxic even in low concentrations, and will bioaccumulation in organisms and ecosystems The McDonalds Shrek Glasses are contaminated with Cadmium
  4. 4. EXPOSURE SOURCES Tobacco smoke (a one pack a day smoker absorbs roughly 5 to 10 times the amount absorbed from the average daily diet) Tobacco smoke is an important source of cadmium exposure Cadmium a component of chuifong tokwan , sold illegally as a miracle herb in china. Low levels are found in grains, cereals, leafy vegetables, and other basic foodstuffs
  5. 5. Toxicity Primary effects on lungs & kidneys Lung, Emphysema, Kidney, Calcium metabolism, Possible lung carcinogen. Secondary effects on skeletal system Mechanisms Binds to sulfhydryl groups, displacing other metals from metalloenzymes, disrupting those enzymes competing with calcium for binding sites (calmodulin) Kidney toxicity  Free Cd binds to kidney glomerulus  Proximal tubule dysfunction
  6. 6. Contd… Lung toxicity:  Edema and Emphysema by killing lung macrophagesSkeletal effects:  Osteoporosis and osteomalacia (pseudofractures) Cancer:  Carcinogenic in animal studies  Approx.8% of lung cancers may be attributable to Cd
  7. 7. A Model: Major mechanism involved in Cd+2 Carcinogenesis Enhancement of DNA Inhibition of DNA repair damage DNA Gene damage Mutation Preneoplastic Decrease of Antioxidants Oxidative stress lesionCd+2 Activation of cellular Induction of Proto- Promotion of signals Oncogenes proliferation Inhibition of DNA Methylation Malignant E-cadherin dysfunction Disruption Cell Adhesion Cancer Cell damage Induction of Apoptosis
  8. 8. Cadmium epidemics/case studies Japan (1950s) “Itai-Itai” is Japanese for “ouch-ouch”-refers to bone pain related to calcium loss Renal failure,Anemia, severe muscle pain River polluted with waste from factory, water used on rice fields for many years Rice accumulated high level of Cd Community was poor (and therefore malnourished with respect to calcium)
  9. 9. Metabolism, storage and excretion of cadmium in human body Journal of Occupational Medicine and Toxicology 2006
  10. 10. Mechanism Two mechanisms are involved in cadmium mutagenicity, Induction of reactive oxygen species and Inhibition of DNA repair Cystein is a precursor to the anti-oxidant protein glutathione and is also required for metallothionein which is a protein that binds to cadmium specifically Intracellular, cadmium binds to metallothionein Cadmium is released into the plasma after haemolysis or when the erythrocytes lifetime has expired Cadmium is transported in blood plasma initially bound to albumin Cadmium bound to albumin is preferentially taken up by the liver
  11. 11. Contd.. In the liver, cadmium induces the synthesis of metallothionein After a few days exposure metallothionein-bound cadmium appears in the blood plasma Plasma metallothionein play an important role in transport of cadmium Bound to sulfhydryl groups of cystein residues After chronic exposure, cadmium accumulates in the liver then redistributed slowly to the kidney
  12. 12. MechanismMechanism responsible for the selective accumulation of cadmium in proximal tubular cells
  13. 13. Cadmium-induced apoptosis involves two main pathways• Extrinsic pathway Fas- FADD caspase-8 pathway initiated by ligand-induced activation of the death receptors (such as Fas) at the plasma membrane resulting in the activation of caspase-8 or caspase-10• Intrinsic pathway triggered by cellular stress signals (such as DNA damage) activating caspase-9. Caspase-8 and caspase-9 cleave and activate the effector caspases caspase-3 and caspase-7, which kill the cells by cleaving a wide range of protein substrates• cadmium induced cell death seems to be associated with caspase-8 activation (via FAS receptor) followed by BID cleavage and induction of mitochondria caspase cascade after release of cytochrome C .• Apoptosis may also be induced by caspase-independent events after intoxication, maybe by Ca2+-calpain coupled processes or by translocation to the nucleus of apoptosis-inducing factor (AIF)
  14. 14. Cadmium-induced apoptosis involves two main pathways
  15. 15. Cadmium induces ROS production Cadmium exposure causes oxidative stress, which is not due to direct involvement of cadmium in the production of ROS but through indirect processes like decrease of cellular anti-oxidants and exhalation of ROS from mitochondria Surprisingly, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) are reduced after 4 h but increased again after 8 h of intoxication The reduction of glutathione levels after cadmium administration is also shown to occur in mice. The reduction of the activities of antioxidants may lead to the production of ROS species like H202, OH and O2–. This overproduction of ROS is partly responsible for the DNA damage.
  16. 16. Proposed pathways for ROS in Cd toxicology and carcinogenesis following acute and chronic exposures
  18. 18. SYMPTOMS Food poisoning (ingestion) Bronchitis (inhalation) Interstitial pneumonitis (inhalation) Pulmonary edema (inhalation)MEDICAL CONDITIONS Osteoporosis Osteomalacia Hyperuricemia Hypophosphatemia Itai-itai disease Renal failure
  19. 19. DIAGNOSISDIRECT EVALUATION 24 hour urine cadmium – reflects exposure over time Blood cadmium-estimatedINDIRECT EVALUATION Urinary ß 2 -microglobulin – evaluate urine levels > 300 g/g creatinine Urinary retinol-binding protein(RBP)Urinary Metallothionein (MT) Critical levels: blood cadmium: 10 micrograms/l Urinary cadmium: 10 micrograms/g creatinine Urinary beta 2-microglobulin: 2000 micrograms/g creatinine Urinary retinol-binding protein: 200 micrograms/g creatinine
  20. 20. TREATMENT Elements like calcium and selenium are shown to have protective effect against cadmium-induced toxicity Adequate levels of zinc in the body helps to displace cadmium from the tissues Potent antioxidants like Vitamin C, E,glutathione, methionine, glycine, cysteine has great protective efficiency.
  21. 21. TREATMENT: Smoking should be avoided and do check your house products for compounds which contain cadmium Render gastric lavage or make the infected person vomit within an hour if the person has consumed cadmium salts Chelation therapy