Metal poisoning – mercury, lead, cadmium

Lecture No. 9

Copyright © Mgr. Zuzana Široká, PhD.

Mercury - Hg

• Only metal which is liquid at room temperature • Both organic and inorganic compounds, all toxic • Sources: earth’s crust and industry, burning of fosil fuels, waste • Cummulation in water environment • Water microorganisms transform pure or inorganic mercury into methylmercury – most common source of poisonings – incorporation into food chain (fish) • Other cases of intoxication usually occupational, mistakes – Iraq (wheat seed with antifungal phenylmercury compound – exchanged for food), Minamata disease (fishermen)

Elemental mercury

• Liquid • Almost no absorption in GIT • Vapours are more dangerous, perfect absorption via lungs • Once in the blood circulation, the target organ are kidneys, where it can cummulate and be deposited for several months • Also crosses blood-brain barrier (change to inorganic mercury with longer deposition times) and placental barrier • Excreted via urine, faeces and milk

Inorganic mercury compounds:

• HgCl 2 , Hg(CN) 2 , Hg(NO 3 ) 2 • Transported bound to blood peptides, they do not cross barriers much • Mercury binds with covalent bond to -SH, -COOH and – His • This influences function of many enzymes and cell processes • Water soluble salts moreover coagulate peptides and are corrosive • They damage kidney tubules and GIT mucosa • Only traces excreted to milk

Organic mercury compounds:

• Methoxyethylmercury and arylmercury compounds (e.g. phenylmercury) – release mercuric ions – act like inorganic compounds • Methyl- and ethylmercury – firm bond, whole compound toxic • Bind with –Cys and –SH, block enzymes, destroy haematoencephalic (blood-brain) barrier, increase permeability • Don't have corrosive effect on mucosas • In blood transported bound to erythrocytes • They have high affinity to neural tissue (change to inorganic mercury with longer deposition times) , cummulate also in kidneys

• Cross the placenta and have fetotoxic effect • Excretion to faeces, urine, milk, sweat, saliva • Deposition in hair and skin, excretion very slow

• Clinical signs: - in dogs, cats and young cattle – more stimulation of CNS - in cattle, pigs and poultry – more depression of CNS in dogs: blindness, involuntary chewing in cats: weakness, ataxia, rigidity of hind limbs, convulsions, glass-like gaze, miaowing, hypersalivation in calves: ataxia, limping, stumbling, clonuses of eyelids and ears, hypersensitivity, malfunction of swallowing, disturbance of vision, convulsions, opistotonus, coma, death in cattle: anorexia, loss of weight, weakness, loss of coordination, salivation, lacrimation, diarrhoea and colic, loss of teeth, swollen lymphatic nodes, disturbances in EKG, cough, dyspnoe, eczema, hyperkeratosis. Convulsions very rare in pigs: inappetence, colic, diarrhoea, hypermotility, tremors, loss of coordination, they are hunched, paralysis of hind limbs in poultry: ataxia, loss of coordination, pale cere and lobes

 Acute intoxication: more often in inorganic poisoning, mainly GIT signs, oliguria, uraemia, typical mercury bluish gum line, decrease of blood pressure, sometimes CNS disturbances  Chronic intoxication: typical for methylmercury, not GIT signs, damage of CNS, kidneys, again bluish margin on gingiva, loss of teeth, tremor • Pathoanatomical examination: - reduction of cerebellum, leptomeningitis in cats, congestion and haemorhagia in brain, stomatitis, enteritis, petechias - histology – swollen axons, demyelinisation, vacuolisation on neurons, hyperplasia of epithelium • Treatment: chelate agents – DMSA, penicilamin (only in inorganic forms!), vitamin E and Se – antioxidants, spironolacton – blocks binding of organic mercury compounds to erythrocytes in acute poisoning, thiosulfate – increases elimination of mercury by kidneys

Lead - Pb

• Soft, grey metal • Known since ancient times • Absolutely abiogenic to organisms • Used in pipes, tetraethyl-lead as a petrol additive, red-lead (minium) primer paintings • Most poisonings in cattle (lead paintings, batteries in silage), but also dogs, wild animals • Both inorganic and organic compounds – like in mercury, different characteristics

•

Absorption and elimination

: - Inorganic lead: toxic after ingestion - Organic lead: toxic after skin contact, ingestion, inhalation - Absorption is promoted by calcium, zinc and iron deficit and by fats in food, higher in young animals - Transported bound to erythrocytes (90 %) - High deposition in tissues – first in liver, then redistributed to bones (inorg.), kidneys, muscles and hair - Bone-lead becomes mobilized through pregnancy or fracture healing - Excretion via bile to faeces, also to urine and milk - Inorganic compounds acummulate more and elimination is very slow, organic compounds excreted much quicker - Normal blood level of lead cca 0,1 mg/kg, above 0,4 it is considered as toxic

•

Mechanism of action

: - Inorganic lead (mainly): - Disturbs saccharide metabolism, metabolism of haem inhibits Ala-D (Delta-aminolevulinic acid dehydratase) – increased concentration of aminolevulinic acid in urine, and other enzymes involved in haem formation - The toxicity comes from its ability to mimic other biologically important metals - calcium, iron and zinc and to interact with proteins - Organic lead (mainly): - interferes with excitatory neurotransmission by glutamate - it is a potent inhibitor of the NMDA receptor, a protein playing an important role in brain development and cognition (also in development of schizophrenia) - doesn't influence synthesis of haem much

•

Clinical signs of intoxication

: - Acute intoxication: - from 12 – 92 hours after absorption - apathy, atonia of rumen, anorexia, CNS disturbances and brain oedema – tremor of head, neck, loss of coordination, salivation, gnashing of teeth, aggressiveness, convulsions, blindness, death due to respiration collapse - Subacute intoxication: - similar symptoms, but more severe GIT damage, changing of constipation and severe diarrhoea, strong colic pains (Saturnine or Poitou colic), mydriasis, opistotonus - Chronic intoxication: - inappetence, anorexia, paresis, paralysis of n. recurens in horse – whistling, typical greyish gum line (Burton line), CNS disturbances

•

Pathological examination

: - Typical smell from cadaver, petechias - Green-grey colour of muscles - Corrosive changes on GIT mucosa - Dystrophic kidneys •

Diagnostics

: - Samples of blood, urine, muscle, liver etc.

- Assessment of lead in these samples + assessment of aminolevulinic acid in blood and urine •

Treatment

: - Usually only in pets - Gastrolavage, administration of activated charcoal, laxatives - Chelating agents – EDTA, penicilamin, dimercaprol

Cadmium - Cd

• No constructive purpose in the body • Extremely toxic even in low concentrations, accumulates in organisms and ecosystems • Chemical properties similar to zinc – exchange in an organism (also can replace Cu, Fe, Ca) • Sources: earth crust, fossil fuels, plastic materials industry, electronic industry, tobacco fume • Absorption after ingestion (1-5%) or by inhalation (better bioavailability) • The first documented case of mass cadmium poisoning in the world - in Toyama Prefecture, Japan in 1950 –

Itai-Itai disease

(river polluted with waste from factory, water used on rice fields – poisoning from rice)

- In blood transported bound to proteins (formation of complexes), in higher concentrations bound to erythrocytes - Deposition in liver, kidneys and gonads. Slow excretion (up to 10 years). Does not go to milk and to foetus.

•

Mechanism of action

: - Inhibition of many enzymes, antagonist to many metals – Zn, Cu, Ca, Fe - Disturbance of cholecalciferol (vit. D) production, thus influences Ca metabolism - Inhibition of a specific testis hydrolase – affects activity of gonads - Xenoestrogennic element - Formation of complexes, which are digested in kidney – release of Cd - damage

•

Clinical signs

: - Acute exposure: -

Cadmium fumes may cause flu like symptoms including chills, fever, and muscle ache - More severe exposures can cause tracheo-bronchitis, pneumonitis, and pulmonary oedema. Symptoms of inflammation may start hours after the exposure and include cough, dryness and irritation of the nose and throat, headache, dizziness, weakness, fever, chills, and chest pain.

- Ingestion of any significant amount of cadmium causes immediate poisoning and damage to the liver and the kidneys. Also CNS disturbances occur and changes in blood count

- Chronic exposure: - Osteomalacia, osteoporosis – disturbance of vitamin D and calcium metabolism - Pain in the joints and the back, and also increased risk of fractures. In extreme cases of cadmium poisoning, the mere body weight causes a fracture - The kidneys lose their function to remove acids from the blood. The kidney damage is irreversible. - Gout, a form of arthritis due to the accumulation of uric acid crystals in the joints (hyperuricemia). - Some patients may lose their sense of smell (anosmia) - Damage of gonads, suspected carcinogen – tumours of testes

•

Pathological examination

: - gastritis, enteritis, nephritis, stomatitis, degeneration of liver, necrosis on testes •

Treatment

: - Chelating agents – EDTA, DMSA - Administration of calcium

More info: http://www.ilo.org/encyclopedia/?doc&nd=857200247&n h=0 http://enhs.umn.edu/hazards/hazardssite/mercury/merchea ltheffects.html

http://www.niehs.nih.gov/ http://www.ra.mahidol.ac.th/journal/index.php?command

=preview&selvol=27&selno=1&selids=156 http://www.nsc.org/library/facts/lead.htm

http://www.calpoison.org/public/lead.html

http://www.lead.org.au/au.html

http://www.atsdr.cdc.gov/toxprofiles/tp5.pdf

http://www.portfolio.mvm.ed.ac.uk/studentwebs/session2/ group29/introtox.htm