Pharmacology Chapter 56-58: Toxicology of Heavy Metals

Heavy Metals and Chelators

• Heavy metals can be toxic to humans and chelators are drugs used to prevent or reverse the toxic effects of heavy metals on enzymes or other cellular targets.
• Chelators accelerate the elimination of heavy metals from the body.

Inorganic Lead

• Poorly absorbed through the skin.
• Acute toxicity results from industrial inhalation of large quantities of lead oxide fumes or ingestion of a large oral dose of lead.
• Chronic toxicity signs and symptoms include:
  • Anorexia, fatigue, and malaise.
  • Neurologic complaints, including headache, difficulty in concentrating, and irritability or depressed mood.
  • Weakness, arthralgias, or myalgias.
  • Gastrointestinal symptoms.
  • Renal interstitial fibrosis and nephrosclerosis.
  • Saturnine gout, which is an alteration of uric acid excretion by the kidney, resulting in recurrent bouts of gouty arthritis.
  • Gingival lead lines, which are caused by lead sulfide at the gingival margin.

Mercury Poisoning

• Erethism is a syndrome resulting from mercury poisoning, characterized by insomnia, memory loss, excitability, and delirium.
• Plumbism is a range of toxic syndromes due to chronic lead poisoning, which may vary as a function of blood or tissue levels and patient age.

Pesticides

Organochlorine Pesticides

• Classified into four groups: DDT (chlorophenothane) and its analogs, benzene hexachlorides, cyclodienes, and toxaphenes.
• They are aryl, carbocyclic, or heterocyclic compounds containing chlorine substituents.
• The individual compounds differ widely in their biotransformation and capacity for storage in tissues; toxicity and storage are not always correlated.
• They have largely been abandoned because they cause severe environmental damage.
• They are now known to be endocrine disruptors in animals and humans.

DDT

• DDT in solution is poorly absorbed through the skin.
• Has very restricted use for domestic mosquito elimination in malaria-infested areas of Africa.
• Tremor may be the first manifestation, continuing to convulsions.

Cyclodienes

• Dieldrin absorption from the skin is very efficient.
• Interfere with inactivation of the Na+ channel in excitable membranes, causing rapid repetitive firing in most neurons.
• Ca2+ ion transport is inhibited, and the major effect is CNS stimulation.

Human Toxicity of Organochlorine Pesticides

• Interfere with inactivation of the Na+ channel in excitable membranes, causing rapid repetitive firing in most neurons.
• Ca2+ ion transport is inhibited, and the major effect is CNS stimulation.
• There is no specific treatment for the acute intoxicated state, and management is symptomatic.
• Recent studies suggest that the risk of testicular cancer and non-Hodgkin's lymphoma is increased in persons with elevated organochlorine levels.

Environmental Toxicology of Organochlorine Pesticides

• Organochlorine pesticides are considered persistent chemicals.
• Degradation is quite slow when compared with other pesticides.
• Bioaccumulation, particularly in aquatic ecosystems, is well-documented.

Organophosphorus Pesticides

• Based on compounds such as soman, sarin, and tabun, which were developed for use as war gases.
• They are absorbed by the skin as well as by the respiratory and GI tracts.
• Biotransformation is rapid, as compared to chlorinated hydrocarbon pesticides.

Human Toxicology of Organophosphorus Pesticides

• Inhibition of acetylcholinesterase through phosphorylation of the esteratic site.
• The signs and symptoms that characterize acute intoxication are due to inhibition of this enzyme and accumulation of acetylcholine.
• Some of the agents also possess direct cholinergic activity.
• Altered neurologic and cognitive functions, as well as psychological symptoms of variable duration, have been associated with exposure to these pesticides.

Neuropathy Target Esterase (NTE)

• Phosphorylation of this enzyme results in progressive demyelination of the longest nerves.
• Associated with paralysis and axonal degeneration, this lesion is sometimes called organophosphorus ester-induced delayed polyneuropathy (OPIDP).

Environmental Toxicology of Organophosphorus Pesticides

• Organophosphorus pesticides are not considered to be persistent pesticides.
• They are relatively unstable and break down in the environment as a result of hydrolysis and photolysis.