PRINCIPLES OF TOXICOLOGY - Biology East Borneo

330 PROPERTIES AND EFFECTS OF METALSbarrier is compromised, such as with open wounds or burns. Skin sensitization may be a result ofexposure to some metals, resulting in irritation, discoloration, or rash.Dermal exposure is of greatest concern for those few metals in which significant toxicity iscombined with the ability to penetrate the skin. Inorganic mercury can enter the bloodstream throughthe skin in small amounts, where it may then be distributed to other tissues and cause a variety ofmercury poisoning symptoms. Nickel can be absorbed when handling nickel alloys, and among thegeneral population through handling coins, although the level of absorption is too low to be of concernin that case.Contact dermatitis and allergic skin reactions may be seen in individuals exposed dermally to somemetals. Nickel and its salts are among the most common causes of metal-induced allergic contactdermatitis, though silver and copper also have been associated with such reactions in highly sensitiveindividuals. Beryllium also is of concern, with necrotic granulomatous lesions or papulovesicularlesions often resulting from prolonged skin contact. Hexavalent chromium is an oxidizing irritant andcorrosive agent that may severely damage the skin on prolonged contact. Cobalt also causes allergicreactions in humans.Metabolism and StorageOnce metals have entered the bloodstream, they are available for distribution throughout the body. Therate of distribution to organ tissues is determined by blood flow to the particular organ. The eventualdistribution of a metal compound is largely dependent on the ability of the compound to pass throughcell membranes, coupled with its affinity for binding sites. Metals are often concentrated in a specifictissue or organ (e.g., lead in bone, cadmium in liver) and their metabolism within the body usuallyinvolves binding to proteins, such as enzymes, or changes in their speciation. Metals also may bind toother substrates and alter the bioavailability of important cell constituents.A common means by which the body defends itself against metal poisoning is by producingnonenzymatic proteins, which bind to and inactivate the metal, then transport it out of the body via theexcretory system. Lipoproteins located within renal lysosomes appear to function in this way, thusserving as some protection for the kidneys, which are particularly vulnerable to metal damage.Metallothioneins are a class of sulfur-containing, metal-binding proteins, which display a substantiallyincreased expression in response to cadmium, mercury, zinc, and several other metals.A number of antidotes to metal poisoning have been developed on the basis of knowledge of naturaldetoxification mechanisms. Chelation therapy involves systematic treatment of the patient with achelator, defined as a molecule with several electronegative groups able to form coordinate covalentbonds with metal cations, and thus render the metal unavailable and inactive. An example of a chelatoris ethylenediaminetetraacetic acid (EDTA), a flexible molecule with four binding sites capable ofnonspecifically binding metal ions and escorting them to the kidney for excretion. Calcium EDTA isparticularly effective against lead poisoning. British Anti-Lewisite (BAL, or dimercaprol) is anotherchelator which was developed during World War II as an antidote against a form of arsenic gas (BritishLewisite) and has since found application in therapy for chromium, nickel, cobalt, lead, and inorganicmercury poisoning. Dimercaptosuccinic acid (DMSA) is a water-soluble chelating agent similar toBAL, which is used to treat heavy-metal poisoning.Chelation therapy must be used with discretion. EDTA has the potential to produce kidney toxicity,possibly due to its action in preferentially mobilizing the metals and concentrating them in this organ.BAL may worsen the effects of selenium and methyl mercury intoxication. Since chelators are fairlynonspecific, they may attack essential cations as well.ExcretionThe simplest method of excreting metals is to exclude them before they achieve significant absorption.For instance, inhaled metal vapors may be immediately expired during subsequent breaths, whileinhaled particles may be trapped in the mucous and expelled by the cough reflex. Vomiting is a common