I. INTRODUCTION AND GENERAL REMARKS
A number of metals have toxic effects on mammals.
The toxicity of metals is concerned with some 80 elements and their compounds. These compounds range from simple ionic salts to complex structures consisting of metal atoms and a set of ligands, and organometallic compounds. Pollution of the environment, food and drinking water may occur naturally as well as from human activities. The industrial and private uses of metal are continuously increasing in the world. New applications have been found for the less familiar elements. The modern chemical industry makes an ample use of catalysts, many of which are metals or metal compounds. The production of plastics such as PVC involves metal compounds, particularly as heat and U.V. stabilizers. All these activities increase the discharge of metals into the environment.
Metallic elements are found in all living organisms, where they may be structural elements, stabilizers, components of control mechanisms, and above all, enzyme activators, components of control mechanisms, and above all enzyme activators or components of redox systems. Some metals are therefore essential elements and deficiency results in impairment of biological functions. When present in excess essential elements become toxic.
For centuries it has been known that several metals are toxic for man and animals. Well-documented are the effects of Lead mining and smelting, Mercury mining, etc. on the health of workers in those industries.
What is it that makes exposure to metals a special toxicological problem? One important aspect is that metals are elements and as such they are intrinsic components of the environment to which man, animals, and plants are adapted. Natural exposure to all metals may thus be harmless to the human being. Some metals are even required for life (i.e. are essential elements).
Metals are not broken down in organisms or in the environment. Once absorbed, they stay (as various metal compounds) in the body until they are excreted. Some metals are transformed (e.g. by being methylated by micro-organisms) to much more toxic substances.
Several metals have a very long biological half-life and tend to accumulate in the body. For example, the half-life for Cadmium in humans is estimated to be two decades or more. With continuing exposure, accumulation will thus go on during the whole lifetime.
Metal toxicity can, in many cases, be explained by its interference with cellular biochemical systems, often interacting at important sites such as the SH-groups of enzyme systems. They may also compete with other (essential) metals - as enzyme cofactors. Thus the effects of a toxic metal can mimic the deficiency symptoms of an essential element.
Exposure may be by inhalation, through ingestion or absorption through the skin, although inhalation is the most important route for occupational situations. Ambient air, except in the vicinity of an emission source, does not usually significantly contribute to the total exposure (however. Lead may be found in city air due to the heavy traffic). There can be a secondary exposure from soil or water polluted via the air which can result in polluted (drinking) water, vegetables, and animals.
Ingestion via food and drinking water is the main way that the population gets exposed to metals in general.
Epidemiological studies of occupational groups as well as the general population have often been concerned primarily with well defined but rather late clinical symptoms. In future the aim should be to identify the effect of a metal on the critical organ; this can be observed when a critical organ first reaches its critical concentration of the metal in question. However, such a critical effect may or may not be of immediate importance to the health of the organism as a whole as occurs when there is an increased excretion of &-aminolevulinic acid (ALA) in the urine after critical exposure to lead, and an increased excretion of low-molecular weight proteins after exposure to critical levels of Cadmium. Once reliable data on critical organs, critical concentrations, and critical effects have been established, it may be possible to estimate the critical exposure (at least when enough information on the metabolism and the kinetics of that metal have been obtained).
Concentrations of metals in urine, blood or hair are often used for the evaluation of the exposure. When interpreting such data, an appropriate model, describing the behaviour of the metal in the body is necessary since it will depict the relationships between concentrations in indicator media (such as blood or hair) and concentrations in different organs, especially in the critical organ. For instance, blood levels of methyl-mercury are valuable for assessing metal concentrations in the nervous system. Urinary levels cannot be used since excretion of methyl-mercury is mainly via the bile into the faeces. For Cadmium, the situation is more complicated. In the long-term, under low exposure, urinary levels give an indication of the concentration in the kidneys and the total body burden. There is however, very wide variation among individuals. When the critical level has been reached in the kidneys, Cadmium excretion via the urine increases suddenly; simultaneously proteins appear in the urine (a situation referred to as tubular proteinurial). Levels of the metal in the blood can be useful to estimate recent exposure, but do not reflect the total body burden. The biological half-life of Cadmium in the blood is much shorter than that in the kidneys.
Metal concentrations in hair can be used to evaluate the exposure situations of groups (and not of individuals).
It is obvious that exposure to metals may be related to health risks. The crucial questions are which safety margins are needed and subsequently have them established. These questions are not easy to answer because of the lack of insufficient data (lack of adequate fundamental knowledge). Several factors (e.g. the age, occupation, food habits, the chemical forms of the metal) are of particular importance for an estimation of the risks associated with metal toxicity.
1.2. Metal Intoxications and their Treatment
The treatment of an intoxicated person or animal has to be done by a medical specialist with much experience in this field. Some of the antidotes in use to cure metal-intoxicated patients only serve to illustrate some of the toxicological characteristics of metals.
In case of a metal intoxication use can sometimes be made of the so called "chelating agents". Chelating agents are substances that form stable complexes with metals. When the affinity of the metal-iron to the chelator is stronger than the affinity to the tissue to which the metal is bound then this bond will be broken. Not every chelator in vitro will also be a good antidote in vivo. Therefore, some requirements must be fulfilled:-
The good chelator will have the following characteristics:-
(i) be water soluble;
(ii) not be transformed in the body;
(iii) not be (too) toxic itself;
The metal-chelator complex (the chelate) is:-
(i) stable at the pH in the tissues;
(ii) good for excretion by the kidneys;
(iii) less toxic than the metal itself;
(iv) not pass the blood-brain barrier better than the metal.
The following are a few good examples:-
> Pb, Cu
1.3. Some Acute Clinical Effects of Metals
· Gastro-intestinal effects
Gastro-intestinal effects caused by metals include the following:-
Soluble salts (in acidic food/drinks) can lead to 'food poisoning' i.e. vomiting, diarrhoea, cramps, and collapse; its causes include exposure to e.g. Antimony (Sb), Cadmium (Cd), Copper (Cu), Tin (Sn), and Zinc (Zn). Mercury (Hg) ions lead to bloody diarrhoea; while Pb ions lead to colic ('gripes').
· Respiratory effects
Respiratory effects resulting from metals include the following:-
Metal (oxide) fumes cause chemical pneumonia i.e. 'metal fume fever' and is caused by Cd, Arsenic (As), Ferric carbonate Fe (CO)5, Selenium dioxide (SeO2), Zinc chloride (ZnCl2), Mrecurous oxide (HgO), Zinc oxide (ZnO), and Cu.
· Cardiovascular effects
Cardiovascular effects from metal salts include arrhythmias (i.e. irregularity of the heart beat) and ventricular fibrillation and is caused by Antimony (Sb), Barium (Ba), Lithium (Li), and Cobalt (Co) salts.
Hypotension is caused by Sb, Cd, Co, Cu, and Fe; Fe salts can lead to shock.
· Effects on the central nervous system
When lead affects the central nervous system it can cause convulsive attacks, and other mental effects (especially in children). It can also cause coma and death. The same effects can be caused by Iron, Barium, Lithium, Thorium, organic tin and ethlylead leading to delusions, hallucinations, hyperactivity, and even coma and death.
· Renal effects
Renal effects include oliguria or anuria (little or no urine excretion) due to tubular necrosis, often preceded by the formerly mentioned effects Mercury and Iron salts. These effects sometimes occur after metal fume intoxication.
· Effects on the blood formation
Haemolysis is caused by soluble Copper salts.
1.4. Some Chronic Clinical Effects of Metals
Some of the chronic clinical effects of metals are given below.
· Gastro-intestinal effects
Gastro-intestinal effects such as prolonged diarrhoea can occur due to salts of copper and tin salts, or low level exposure to e.g. Lead, Selenium, Thallium. Occurs in industrial workers and children.
· Hepatic effects
Hepatic effects include jaundice; (due to Antimony, Arsenic, Bismuth, Copper, Chromium, Iron, Manganese and Selenium).
· Respiratory effects
There are different types of respiratory effects by metal dusts and fumes.
· Nervous system effects
Nervous system effects sometimes occur during the recovery period after acute Antimony or Thallium intoxication. Lead, on the other hand, can lead to permanent brain damage.
Methyl Mercury leads to cerebellum degeneration, and tremors of the hands, eyelids, and tongue.
Mercury vapour leads to personality changes.
· Renal effects
Renal effects are caused by Cadmium and Lead; and can also result in proximal tubular dysfunction, while Mercury and Bismuth salts can lead to proteinuria and edema.
The blood can also be affected by Antimony leading to anaemia (red cell destruction and its decreased formation). The effects of Lead are the same as in the above case. Cobalt can cause polycythemia (i.e. above normal increases in the number of red blood cells). Hair loss occurs when there are critical levels of Thallium.
1.5. Carcinogenic Metals
Metals proven to have carcinogenic effects in man are Nickel, Chromium, and Antimony although it is probable that Cadmium, Beryllium (Be), and Antimony. It is probable that other metals can also cause cancer. In animals, it has been experimentally proven that Beryllium, Iron, Cobalt, Zinc, Titanium (Ti) and Lead do have a carcinogenic effect. Specific metals and their carcinogenic effects on humans are given below:-
Nose, larynx and lung cancer has been found in Nickel refinery workers (mainly exposed to Nickel sulphide). Latency time is 10-40 years.
There is a general agreement that some hexavalent Chromium compounds are carcinogenic for humans. An increased risk of lung cancer has been found in chromate production and chromate pigment workers.
The relation between human exposure to inorganic Arsenic and lung and skin cancer and possibly leukemia in workers in the chemical industry, in Copper smelters and vineyards has been clearly demonstrated.
2. OCCURRENCES AND EFFECTS OF SELECT METALS
The negative effects that occur from exposure to the metals associated with the mining industry in Tanzania or used in their processing is given below.
For a metal, cadmium is a relative new comer. It became known as an element from the year 1817. Chemically, it is very similar to Zinc and occurs together with Zinc and Lead in minerals and soils. It is obtained as a by-product during the refining of Zinc. Only a minor part of the world's production is recycled, that's why it is called 'the dissipated element'.
Cadmium is used to coat metals (it protects them against corrosion) and in making Copper-Cadmium alloys and the soldering of Silver. Cadmium compounds are used as stabilizers in for example, plastics (Cadmium stearate) and pigments. It is also present in some phosphate fertilizers.
Human exposure is mainly by food (it is readily taken up by plants from the soil). Only 0.5% -15% of the Cadmium ingested is really absorbed. Cadmium and Iron in the food and also the Calcium and Iron levels in the body have an effect on the percentage absorbed. Uptake through the lungs can be very high (up to 50% for Cadmium present in cigarette smoke).
Absorbed Cadmium is transported in the blood cells bound to metallothionein and haemoglobin and bound to high molecular proteins in the blood plasma. Excretion is via faeces and urine. About 50% of the body's burden is found in the liver and the kidneys. After low level exposure the liver contains the highest amounts, but after high level exposure the kidneys contain the highest amounts. The excretion is slow: the biological half-life of Cadmium is more than 20 years for humans. The placental barrier is effective against Cadmium and the new-born baby is practically free from this metal. Ingestion of highly contaminated food or drinks results in acute gastro-intestinal effects. Excessive inhalation of Cadmium fumes and dusts in industries causes acute and chronic lung disease and chronic renal disease later on. After World War II there was a chronic low level exposure of the general population (by inhalation), but mostly by food. The concentrations in food are mostly less than 0.1 mg/gm fresh weight, but in some products like shellfish and liver often it is often higher than 10 ug/gm. The provisionally accepted weekly intake for human adults is 400-500 ug/person/week (WHO/FAO).
Chronic renal disease occurs after long-term exposure. The renal damage is primarily a defect of the reabsorption process in the proximal tubules. The first sign of chronic Cadmium intoxication is the appearance in the urine of low-molecular weight proteins ('proteinuria'). Later on, increased urinary excretion of amino acids, glucose and phosphates may occur. Disturbances in mineral metabolism may cause mineral depletion in bones. The effect of this has been found in industrially exposed workers and in women with the Itai-itai disease. Anaemia and disturbance in the liver functions may also result from Cadmium exposure. Some of the effects can be due to the interference of Cadmium with Zinc-containing enzymes. In order to detect renal tubular dysfunction at an early stage, examination of urine proteins and determination of certain low-molecular-weight proteins must be carried out. Once fully established, the renal dysfunction does not regress if exposure ceases. There is no specific therapy for chronic Cadmium poisoning.
Mercury can occur as element, as inorganic or as organic compound (e.g. Hg-vapour, salts, and alkyl Mercury compounds).
The toxicity of Mercury depends on the oxidation state. There are three oxidation states:
Hg°, Hg1+, and Hg2+.
Elementary Mercury (Hg°) gives rise to symptoms associated with damage of the central nervous, system.
Mercurous (Hg+) compounds are few in number, an example is the antiseptic calomel (i.e. Mercury chloride/HgCl.
Mercuric (Hg2+) compounds form a variety of inorganic salts, most of which have a high acute toxicity consisting of damage to the gastro-intestinal tract, kidneys and haemorrhages in the lower intestinal tract. The lethal dose in man is about 1 gram.
Inhaled Mercury vapour (a mono-atomic gas) crosses the alveolar membranes rapidly. A certain amount stays unchanged long enough in the blood to cross the blood brain barrier. Mercuric (Hg3+) ions do not cross this barrier. The element is poorly observed from the gastro-intestinal tract.
In nature methyl-mercury can be formed from inorganic Mercury by biochemical processes. It can be taken up by inhalation, skin penetration and by ingestion (in fish the major amount of Mercury is present in the form of methyl-mercury). In the blood, it is bound to plasma proteins and transported through the cell walls. It can be metabolized (back) to inorganic Hg. It crosses the blood-brain barrier as well as the placenta (giving prenatal exposure). The biological half-life is about 70 days, with excretion primarily via the bile.
Some organic Mercury compounds are used in medicine to increase the volume of urine for the treatment of edema (diuretics). Because of their toxicity, they are used to a lesser extent since the introduction of better diuretics.
Low level exposure to organic Mercury (0.05 mg/day) leads to neurological effects like bad vision, tickling sensations in the skin and physical weakness caused by a general neuron degeneration in parts of cerebral cortex accompanied by atrophy. It is possibly carcinogenic and teratogenic.
The accepted weekly intake of inorganic Mercury via water and food is 5ug/kg bodyweight (with a maximum of 3.3 ug as methyl-mercury).
Lead is used as a metal for cable sheetings, in storage batteries, etc. and as Lead compounds like pigments (white-lead), alkyl-lead (in automobile fuel, etc).
Lead poisoning was known from ancient times. The disease "plumbism" was described by a Greek poet-physician more than 200 years ago. As far as we know, Nutritionally, Lead is not an essential trace element.
The resorption in the gastro-intestinal tract depends on the chemical form (solubility) and on the circumstances (for instance, resorption is higher in the case of insoluble salts taken during meals). The resorption from food is on the average 5-10%. All the Lead resorbed via the stomach or the lungs arrives via the blood; 90%-95% of it being carried by the red blood cells. It can pass through the placenta (the concentration in the mother is almost equal to that found in the baby). During life, there is a build up of Lead in the bones.
The biological half-life for Lead in bones is about 20 years; while that for Lead in blood is 20 days. Excretion is mainly via the urine.
The primary source of exposure in cities is/was caused by automobile exhausts. Lead in drinking water (Lead tubes)) and in food is also important. Important sources for children are Lead paint, soil and dust. Young and unborn children are in the high-risk group. The established acceptable maximum level of 250 gms-300 gms Pb/l blood for adults is probably too high for children. The best measure for estimating health risk from Lead is the Lead in the blood level (this Lead is the biologically active part). The relations between e.g. Lead-air, Lead-food, etc remains uncertain.
Lead has many biochemical effects in the body, all probably related to the ability of Lead to combine with specific biochemical molecules containing SH-groups.
Four major systems are affected:-
(i) the haematopoietic system (disturbances in the blood formation, giving anaemia and porphyria);
(ii) the gastro-intestinal tract (anorexia and constipation, eventually leading to colic);
(iii) the kidneys (only after long-term exposure);
(iv) the central and the peripheral nervous system (giving loss of appetite, hyperkinesia, aggressiveness and in severe cases encephalopathy; in industrial workers symptoms like wrist and foot drop - 'palsy' - are seen).
There are probably no carcinogenic effects.
The acceptable daily intake (ADI), according to FAO/WHO 1972 of 430 ug Pb/day is toxicologically not well-founded.
Organic tetraethyl lead when added to gasoline during combustion in the engine, is converted to different solid an organic Lead compounds. The compound itself behaves completely different from inorganic lead. It can be inhaled, absorbed through the skin and through the intestines. The main organ affected is the central nervous system giving rise to, among others, insomnia, psychosis with hallucinations and excitement. Recovery is possible.
Copper is widely used as metal, metal-salts and organic metal compounds (pesticides, wood-preserving agents, etc.) It is an essential element, being part of enzymes like tyrosinase, cytochrome oxidase, etc. The daily requirement is estimated as 30 ug/kg bodyweight for adults, which can be obtained from meat, fish and vegetables (milk is poor in Copper). The absorption is normally regulated by homeostatic mechanisms.
Absorbed Copper is transported by albumin to the liver and mainly stored there, and also in the brain, the kidneys and muscles. In the tissues it is mainly bound to proteins, many of which are enzymes. Sheep store a very high amount in the liver, and are very susceptible to higher amounts of Copper in the food. Excretion is mainly via bile into the faeces. The biological half-life for Copper in humans is about 4 weeks. Copper deficiency can occur, especially in cattle, when the Molybdenum (Mo) intake is high.
Acute toxic effects are seen after exposure to copper fumes or dusts or by ingestion of Copper salts. The first type of exposure produces acute irritation of the upper respiratory tract and 'metal fume fever'; the second type. causes acute gastro-intestinal disturbances. Copper sulphate solutions induce vomiting.
Chronic Copper poisoning probably does not normally occur in human beings.
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