I.2.2. METALS (Cadmium, Lead, Mercury, etc.) (Meyers, R.A. & Dittrich, D.K., 1999)
Andrei Florin DǍNEŢ
I.2.2.1. Metal Toxicity
The greatest concerns in heavy metal usage and releases into the environment are industrial sources, agricultural usage, food products and chemical wastes. Metal toxicity is modified by various environmental factors, such as light, temperature, humidity, and pH (e.g. in soil and water). The most important factors that influence the metabolism and effects of metals are: age, sex, diet, species and dose/duration of exposure.
The toxic effects of metals could be very different: renal toxicity, neurotoxicity, genotoxicity, developmental toxicity, etc. (Chang, L.W., 1996)
Cadmium causes toxic injury to the renal, pulmonary, skeletal, testicular and nervous system (Chang, L.W., 1981). The toxicity of cadmium may be explained by the production of metallothionein. The breakdown of the Cd-metallothionein complex within cells releases free cadmium within cells for the induction of cell damage. Hemorrhagic lesions are hallmarks of cadmium toxicity in the testis, lung and neonatal brains (Chang, L.W., 1981; Murphy, V.A., 1996).
Mercury vapors and organomercury (alkyl mercury) enter the central nervous system (by crossing the blood-brain barrier) very readily and are considered highly neurotoxic. The neurotoxic mechanisms of mercury are extremely complex. Combinations of the following mechanism of actions occur: (a) inhibition of protein and macromolecule (e.g. RNA) syntheses; (b) modified post-translation phosphorylation; (c) defective calcium homeostasis and ion flux; (d) abnormal neurotransmitter homeostasis; (e) oxidative injury; (f) cytoskeletal disaggregations; (g) mitochondrial dysfunction (Chang, L.W. & Verity, M.A., 1985; Verity, M.A., 1996). Since the outbreak of methylmercury poisoning in Japan (Minamata), methyl mercury poisoning is also known as Minamata disease.
Inorganic mercury ions (Hg2+) are not a potent neurotoxic substance because they do not cross the blood-brain barrier effectively. Inorganic mercury salts, however, are very nephrotoxic, producing necrotizing damage to the renal proximal tubules (Chang, L.W., 1979).
One of the best known effects of inorganic lead is its impact on hemoglobin synthesis resulting in stippling of the erythrocytes and anemia. Two mitochondrial enzymes are inhibited leading to reduced insertion of Fe2+ into the heme and the synthesis of protoporphyrin (Hammond, P.B. & Bililes, R.P., 1980).
Chronic lead exposures of most concern are for children who are exposed to low levels of lead via contaminated drinking water, lead-containing paint, or lead-containing environment. Significant neurobehavioral changes and learning disabilities are reported in animals and children following lead exposure at a young age. The mechanisms of action for lead neurotoxicity are multifaceted including alteration in calcium homeostasis, ion channels and neurotransmitters, signal transduction and the calcium messenger system (Cory-Slechta, D.A. & Pounds, J.G., 1995). Organolead, as an additive to gasoline, was a serious environmental concern (Seawright, A.A. et al, 1984).
Aluminum is considered a neurotoxic metal inducing significant biochemical changes and cytoskeletal neuropathology. Motor neurons, anterior thalamic nuclei and neurons of the para subiculum are especially sensitive to aluminum. The mechanistic base of aluminum neurotoxicity involves alterations in calcium homeostasis, energy metabolism, RNA synthesis, etc. (Lukiw, W.J. & McLachlan, D.R., 1995).
Arsenic is a general cytotoxicant causing injury to most cells and organ systems. Arsenic chelates with α-lipoic acid which is an essential cofactor for pyruvate dehidrogenase, an enzyme critical in mitochondrial production of ATP. Arsenic forms also an oxyanion, which mimics phosphate oxyanion and thus disrupts a variety of biological processes requiring phosphate, including ATP synthesis (Clarkson, T.W., 1991).
Although manganese is an essential trace element in the biological systems, overexposure to manganese results in toxicity. In chronic situations, the neurological signs of manganism resemble Parkinson’ disease and dystonia (Chu, N.S et al, 1995). The toxicity of manganese is related to biological transformation of Mn2+ to Mn3+ with autoxidation of dopamine and the production of cytotoxic free radicals (Chu, N.S et al, 1995).
I.2.2.2. Biotransformation of metals
It is assumed that biometabolism of inorganic species are, practically, in all cases enzymatically mediated (Ochiai, Ei-O, 1987). For carcinogenic metals, it is assumed that Phase I enzymes (including P450 isoenzymes) are involved; if a metal is an anticancer agent, Phase II enzymes (including the glutathione-S-transferase) play a role. Current research is devoted to the role of metals as precursors of active oxygen and the effect on lipid peroxidation (Wetterhahn, E.K. & Dudek, E.J., 1996).
Metallic, liquid inorganic mercury has a high vapor pressure and is quite soluble in lipids. The lungs are the most important area for absorption. After absorption, the lungs retains as much as 80%, in contrast with gastrointestinal absorption, which retains less than 0.01%. The free mercury, which circulates in the bloodstream, crosses the blood-brain barrier easily. Within a minute, the free mercury oxidizes to Hg2+ and is no longer strongly lipid soluble. This oxidation is done by catalase in the biological system (Clarkson, T. et al, 1984). Microorganisms transform free mercury to the +1 or +2 state; these microorganisms also methylate mercury to monomethyl mercury chloride or dimethylmercury. These lipid soluble compounds ingested by fish are stored in the liver (Von Berg, R. & Greenwood, M.R. 1991).
Within biological systems, arsenic cycles easily between As3+ and As5+. In a number of systems, arsenic is methylated to mono-, di- and even to the trimethylated metabolite. All postulations invoke the interaction with GSH-S-t and hence GSH, and the cytosolic enzymes requiring methyl donors, S-adenosylmethionine (ADO MET), metylcobalamin (vitamin B12) and Mg2+ (Styblo, M. et al, 1995). Microorganisms including bacteria, fungi, yeasts, molds and algae have common bio-pathways.
Much effort has been made to evaluate the carcinogenicity of nickel by directly implanting the nickel compound in specific organ and tissue. Nickel and its compounds are carcinogenic agents. Currently many investigators are working on the carcinogenicity of nickel compounds (Kasprzak, K.S. et al, 1987; Hass, B.S. et al, 1996).
Of all the inorganic compounds, chromium as Cr6+ is most active as a carcinogen and mutagen. This ion is genotoxic in almost every system tested. Cr6+ is also considered a human carcinogen by the World Health Organization.
Copper as Cu2+ initiates lipid peroxidation with high, low or very low-density human lipoprotein (Kontush, A., 1996). During this reaction, copper is rapidly reduced to Cu+.
Many tin compounds are neurotoxins, especially the alkyltin compounds (Chang, L.W., 1995).