Chelation Treatment During Acute and Chronic Metal Overexposures: Experimental and Clinical Studies

Metal overexposures, ranging from nonsymptomatic, elevated body levels to life threatening acute or chronic poisonings, should in general be treated by eliminating the exposure source, by various decontamination procedures, and by supportive treatment. However, in a quite extensive number of cases, various chelation treatment schedules offer an efficient way of handling the adverse effects of overexposure to metals, either by reducing the toxicity of the metal by forming a less toxic complex, by changing the toxicodynamics of the metal thereby reducing the interaction of the metal with a vulnerable target, and/or reducing its uptake and/or enhancing its excretion. The present chapter offers a systematic review of the present state-of-the-art for chelation treatment of metal overexposures. Such exposures can be due to occupational, environmental, dietary, or lifestyle factors, or iatrogenic procedures. The review is ordered alphabetically citing animal experimental studies and epidemiological and clinical studies for each metal, if available. The general experience is that the metal (Lewis acid) and the chelator (Lewis base) should have high affinity for each other (high stability constant), thus soft metals should be chelated by chelators with soft ligands (eg, C-SH), and hard metals with chelators with hard ligands (eg, COOH, CR. O, CR2. OH). Intermediate metals prefer, for example, N-containing ligands, but can be chelated by both hard and soft bases. However, the pharmacokinetics of the chelating agent is highly important also, especially whether the chelator and the metal-chelator complex formed are hydrophilic with enhanced renal excretion as result, or lipophilic with enhanced biliary excretion and/or brain deposition as a potential result. Some important questions are: Can the chelator be administered orally, and will it enhance or prevent systemic uptake of toxic metal remaining in the gastrointestinal tract? Is the chelator metabolically stable to allow extended treatment with appropriate time lag between doses According to generally accepted ethical principles in pharmacology and medicine, experimental chelating agents proven efficient in animal experiments cannot be used in humans except in special cases, where the benefit clearly outweighs the potential toxicity of the agent. Based on the experimental and clinical work, optimal chelating agents for acute poisonings with selected metals are as follows: Deferoxamine for aluminum compounds. Dimercaptosulfonate (DMPS) for arsenic compounds, deferoxamine for iron compounds, with deferiprone and deferasirox as potential alternative chelators. Dimercaptosuccinic acid (DMSA) for lead compounds, DMPS for inorganic mercury compounds including mercury vapor, DMSA may be superior for organic mercury compounds. Today new chelators are being developed as decorporating agents for all classes of metals.