General Principles of Metal Toxicity

Mechanism of Action -- Metals may exert a toxic effect by one of two primary mechanisms.
1) They may substitute for metals required by the body, effectively acting as an antagonist to the essential metal.  This type of toxicity may be seen with lead antagonising the effects of calcium in nerves and bone and in the substitution of lead and zinc for iron in heme.

2) They may directly damage tissue (direct irritation) by mechanisms described previously.

Metal toxicity is unique in that the toxic agent may not be metabolised.  Compounds containing metals may certainly be metabolised to hasten their excretion and the properties of metals may change, but the body cannot reduce a toxic metal to a non-toxic metal.  One mechanism that may reduce the toxicity of metals is a metal carrier protein, METALLOTHIONEIN, which may complex with the metal, preventing it from exerting a toxic effect, and transport it to the kidney where it may be filtred and excreted.  The affinity of metals for metallothionein differs, with cadmium, zinc, and copper having some of the highest affinity (it is probably for copper that metallothionein exists).   However, as described below, this may also contribute to the specific toxic effect of certain metals.

Typically, children and the elderly are more prone to toxic responses to metals than young and middle-aged adults.  Also, the life-style of the individual may influence their response to metal toxicity (smokers are at much greater risk of cadmium toxicity, since cadmium may be found in cigarette smoke).

Treatment of Metal Toxicity -- Chelation Therapy -- In addition to supportive and symptomatic treatment, the primary goal of metal toxicity is to decrease the risk of toxic damage by the metal.  This is best accomplished by hastening the excretion of the metal.  The therapeutic approach to increase excretion of metals is through the use of chelating agents that bind to the metal, effectively inactiving it and allowing its excretion.

BAL -- British Anti-Lewisite, 2,3 dimercaptopropanol, Dimercaprol -- This chelating agent was developed as an antidote to arsenical gases designed for use as chemical warfare agents.  Is it especially useful for arsene gas, arsenic, lead, and mercury.  It may also be used for numerous other metals, although the binding affinity is not as great.

DMPS -- 2,3 dimercapto-1-propane sulphonic acid -- This is a water soluble version of BAL and may be administered orally.  It may be used in mercury, methylmercury, cadmium, copper, nickel, and arsenic poisoning.

EDTA -- ethylenediaminetetra-acetic acid -- This chelator is most often given as the calcium salt (to reduce the incidence of side effects and to increase solubility). This dosage form makes it especially useful for the treatment of lead toxicity.  In chronic lead toxicity there is a state of hypocalcæmia.  Lead has a greater affinity for EDTA than calcium does, so the calcium is displaced and the lead bound to EDTA and excreted.  This also helps to restore the body load of calcium.

Penicillamine -- This drug is a metabolite of the antibiotic penicillin (is has no clinically relevant anti-bacterial actions).  It was initially used in the treatment of Wilson's disease, which is characterised by a state of hypercupræmia (excess copper levels).  It chelates and removes copper, lead, mercury, and iron.

DTPA -- diethylenetriaminepenta-acetic acid -- Is used primarily in the treatment of cadmium toxicity (as an adjunct to BAL therapy).

Desferrioxamine -- Binds to iron and is used primarily in cases of iron overload.

DDC -- diethyldithiocarbamate, dithiocarb -- Is used primarily for nickel carbonyl toxicity.

Arsenic -- has been used in insecticides, herbicides, paint, manufacture of wall paper, ceramics, and glass.  Arsenical compounds were used as a treatment for venereal disease, tuberculosis, and other infections around the turn of the century.  Trivalent arsenic appears to be more toxic than other forms of the metal.
Acute Arsenic Poisoning -- Presents as severe gastroenteritis with violent vomiting, bloody and/or mucous diarrhœa, cold/clammy skin, and hypotension progressing to convulsions, coma, and death by circulatory failure.

Chronic Arsenic Toxicity -- Has numerous organ effects

Nerves -- polyneuritis involving the optic nerve (visual disturbances) and sensory nerves (paræsthesias)
Skin -- bronzing of the skin, alopecia, and dermatitis
Gastrointestinal/Hepatic -- cirrhosis, anorexia, weight loss
Hæmatological -- anæmia
Cadmium -- is used in plating metals, bearing alloys, batteries, and in silver solders.
Acute Cd toxicity --
oral ingestion may produce nausea, vomiting, diarrhœa, headache, muscle aches, and salivation

inhalation causes a metallic taste, shortness of breath, chest pain, and cough with a bloody or foamy sputum

Chronic toxicity --
inhalation -- loss of sense of smell, cough, dyspnœa

ingestion -- nephrotoxicity (Cadmium bound to metallothionein is filtered through the glomerulus for excretion.  However, it may be reabsorbed and once in the tubular epithelium may cause direct irritation and cell damage, resulting in necrosis and tubular occlusion as described in the renal toxicity section.  Thus, metallothionein, by presenting the kidney with cadmium, may contribute to its nephrotoxicity.), testicular toxicity, calcium displacement from bones (This causes osteoporosis and the bones may become brittle and can be quite painful.  Cases of chronic cadmium ingestion of contaminated fish and rice in Japan gave rise to an epidemic of cadmium toxicity called itai-itai disease (ouch-ouch disease) because of the pain experienced by affected individuals.  NOTE that chelation therapy is relatively ineffective in chronic cadmium toxicity.  Once the cadmium has been bound to metallothionein, chelators have little effect in hastening excretion (the affinity of cadmium for metallothionein is greater that than for the chelating agent).  Chelators are effective in acute cadmium toxicity (before complexation with metallothionein has occurred).

Lead -- used in batteries, paint, solder, and pottery glaze and crystalware (although lead may leach from leaded crystal, especially with alcoholic beverages, the risk of lead toxicity is considered small with the use of crystalware)
Acute Pb toxicity (Rare) -- metallic taste, abdominal pain, vomiting, diarrhœa (black stools), oliguria, coma, and death

Chronic toxicity -- may be divided into three distinct phases, dependent upon how chronic the exposure is

early -- anorexia, weight loss, constipation, apathy, irritability, appearance of lead line on gums

middle -- intermittent vomiting, incoordination, vague pain in extremities and joints, paræsthesias, paralysis of extensor muscles (foot and wrist drop), menstrual irregularities, abortion

late -- persistent vomiting, ataxia, stupor, lethargy, encephalopathy, hypertension, papillœdema, cranial nerve paralysis, delirium, convulsions, coma, decreased bone density

The progression of chronic toxicity begins with mild gastric disturbances and continues to present as more severe gastric damage and progressive nerve damage, ultimately causing mental impairment that may often be mis-diagnosed as learning disorders in children.

Organic lead toxicity -- insomnia, vivid weird and bizarre dreams, psychoses, convulsions
Zinc -- fumes may be produced during welding, metal cutting, used in galvanising iron
Primarily presents as acute inhalational toxicity -- muscle aches, pain, fever, chills, nausea, vomiting, pulmonary œdema with cyanosis, and dyspnœa.

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