ERYTHROCYTE (RED BLOOD CELL) ELEMENTS

Introduction:
The evaluation of plasma or erythrocyte trace elements for clinical or nutritional purposes has been a matter of debate. Copper and zinc have been routinely determined in plasma which is an easier specimen to analyze than whole blood or erythrocytes due to the absence of cells. The advantages and disadvantages of using erythrocytes for these elements are reviewed (1). Their findings suggest that inflammation increases serum copper with only a slight influence in erythrocyte copper. In true copper deficiency, the serum copper may give misleading results due to the inflammatory reaction. Although erythrocyte zinc may not be as useful in deficiency states, it is shown to be more useful to monitor pathophysiology in dysgeusia (taste impairment), cancer and hyperthyroidism (1). Plasma is a more transient medium for the trace elements as they are transported bound to albumin and other plasma proteins to organs and tissues or are excreted from the kidneys and bile. Erythrocytes actively absorb trace elements which are required in enzymatic reactions or are bound to membrane proteins, and with a 120 day life cycle can be a useful index of nutritional or disease status. In our studies comparing the levels of plasma and erythrocyte trace elements in patients on total parenteral nutrition, and in the general population, we noted the various amounts of the essential elements in these subjects. Discussion on the individual elements are presented below, but in general, erythrocytes appear to be more useful to monitor steady-state levels of the nutritional elements.

Essential Elements - Erythrocytes

Chromium (Cr)-Of the major chemical forms of chromium, chromium (III) is considered an essential element and forms part of the complex, the glucose tolerance factor (GTF). This factor is believed to enhance the action of insulin at its receptor site in promoting glucose uptake. A deficiency of chromium can result in an increase in insulin requirement. Chromium (III) is provided as a supplement in total parenteral nutrition (TPN), and the measurement of erythrocytes provides a better index of body content than the measurement of plasma. Some intravenous fluids have been shown to contain chromium as a contaminant from its manufacture (ie. in steel vats). We have reported on elevated serum chromium in patients on TPN (2). Exposure to chromium (VI) through the air which is produced in industry can result in damage to the nose, lungs, and is a carcinogen.

Cobalt (Co)-Cobalt is an essential metal for humans and is part of the enzyme cyanocobalamin (vitamin B12). A deficiency of cobalt is accompanied by all the signs and symptoms of a vitamin B12 deficiency, and is often due to absorption problems (ie. lack of intrinsic factor or malnutrition). It is also used as cobalt alloys in orthopedic prosthesis. Cobalt chloride had been used as a foam stabilizer in beer, and had induced cardiomyopathy among heavy beer consumers. This is no longer used, and such sources of toxicity do not occur.

Occupational workers can still be exposed to cobalt dust with resulting illnesses as contact dermatitis, cardiomyopathy, liver and kidney damage. Deficiency or toxicity to cobalt can be monitored with erythrocyte, urine or hair analysis.

Copper (Cu)- As an essential trace metal, it is an active component of several proteins such as ceruloplasmin and important enzymes such as cytochrome oxidase, superoxide dismutase and metallothionein. Determination of this metal in biological samples is used to diagnose metabolic diseases due to deficiencies or excessive accumulation of Cu. Deficiency of Cu results in anemia as 90% of plasma copper is bound to ceruloplasmin which is an oxidase required for the binding of iron to transferrin. Dietary Cu malnourishment can result in neutropenia, diarrhea, and bone changes. In nutritional copper deficiency, the serum copper may give misleading results due to the inflammatory reaction which increases serum Cu (1). Erythrocyte copper may be a better index to determine Cu deficiency in patients with inflammation. Genetic defect in copper absorption can result in Menke's (kinky hair ) syndrome or excessive accumulation of Cu in the liver, brain, cornea and kidney due to an inborn error of Cu metabolism (Wilson's disease).

Magnesium (Mg)- Magnesium plays an essential role in ATP activation, muscle contraction, and the synthesis of several amino acids, RNA and DNA. In erythrocytes, magnesium is over twice the concentration found in plasma with over 55% in the ionized form. As the intracellular Mg is bound to ATP, it may be a better index of the bio-energetic activity on a long-term basis. It has been reported to be significantly lower in women with premenstrual tension syndrome, hypertension, and chronic fatigue syndrome (3).

Manganese-(Mn) is an essential trace element which is required for a number of enzymes which include glycosyl transferase, superoxide dismutase, pyruvate kinase and arginase required for the metabolism of carbohydrate, protein, lipid and free radicals. Deficiency of manganese can result in convulsive disorders such as epilepsy, myasthenia gravis, and impaired insulin activity. Excess levels may result in iron-deficiency anemia due to its interference of dietary iron absorption. Manganese poisoning can occur in workers in battery manufacturing, and from well water with excessive content. Increased erythrocyte concentrations have been reported in patients with rheumatoid arthritis (4). Measurement of erythrocyte Mn may provide a better index of nutritional intake than plasma or urine levels.

Molybdenum (Mo)-Molybdenum is an essential element required for several enzymes including aldehyde oxidase, xanthine oxidase, and sulfite oxidase (5). Diseases associated with Mo deficiency include gout with uric acid accumulation, cancer susceptibility as it plays a role in its prevention, and in sulfur metabolism. High exposure to Mo is toxic as it is an antagonist to copper. Urine and hair Mo are useful for the biological monitoring from occupational or environmental exposure. Erythrocyte Mo is a more sensitive for the detection of deficiency in patients on TPN with findings of 60% below normal values compared to 4% using plasma (6).

Potassium (K)- Potassium is mainly an intracellular cation with important functions in nerve impulses, muscle contractions, maintenance of osmotic pressure, regulation of acid-base balance, and kidney function among other roles. Plasma K measurements provide little information as to the K nutritional status. The homeostasis of K is regulated by its excretion by the kidneys. RBC potassium is a more useful index of nutritional and tissue content than plasma measurement. In a study of elderly men and women, low erythrocyte K were found in 20%, but only 2% in plasma (7).

Selenium (Se)-Selenium is found in the inorganic (selenite, selenate), and organic (selenomethionine, selenocysteine) forms. Due to its varied geographical soil content world-wide, the amounts which occur in our food (meat is rich in selenium), and its dietary intake affect our body's content. Deficiency of selenium has been documented in humans in China named Keshan's disease in the form of myocardiopathy, and as an endemic degenerative osteoarthropathy, named Kaschin-Beck's disease. Deficiency can also occur in patients on long-term total parenteral nutrition (8). Selenium is an essential component of glutathione peroxidase which plays a role as an antioxidant. Other key functions include immune regulation, and reduced cancer mortality (ie. lung, prostate, and colorectal). Toxicity from overdoses has resulted in several metabolic and physical changes such as impaired bone development, liver disease, hair loss, and fatigue. High selenium intake, especially in children can cause stunting of growth. This element can be monitored in plasma, erythrocytes, urine and hair.

Vanadium (V)-Vanadium may be an essential element, but signs of nutritional deficiency has not been reported. Pharmacological effects show that it has a strong insulin mimetic action, and vanadium can result in the reduction of blood glucose. As with many other elements, toxicity to vanadium has resulted in skeletal abnormalities, fetal toxicity, and teratogenicity. Its toxic effects results from its ability to interfere with biological functions of amino acids, peptides, nucleotides, ATP and carbohydrates. Industrial inhalation of vanadium dust can produce respiratory, cardiac and central nervous system problems. Erythrocyte vanadium appear to be a more sensitive index to detect deficiency (RBC 14% versus plasma 0%) than plasma as found in TPN patients (6).

Zinc (Zn)- An essential trace metal which influences the activity of over 300 enzymes such as lactate dehydrogenase, alkaline phosphatase, and alcohol dehydrogenase. Deficiencies can result in growth retardation and delayed sexual development in children, and impaired wound healing and T-cell function at all ages. Erythrocyte zinc have potential application in which deficiency relates to taste and smell dysfunction (dysgeusia) and in relationship to neural tube defects in the early stages of pregnancy (1). The higher concentration of Zn in RBC appear to be a more sensitive index to detect cellular deficiency (42%) than in plasma (32%) sample comparisons (6).

References:
1. Vitoux D, Arnaud J, Chappuis P. Are copper, zinc and selenium in erythrocytes valuable biological indexes of nutrition and pathology? J Trace Elements Med Biol 1999;13:113-128.
2. Leung FY, Galbraith LV. Elevated serum chromium in patients on total parenteral nutrition and the ionic species of contaminant chromium. Biol Trace Elem Res 1995;50:221-228.
3. Elin RJ. Magnesium: the fifth but forgotten electrolyte. Am J. Clin Pathol 1994;102:616-622.
4. Milne, DB. Laboratory assessment of trace element and mineral status. In Clinical Nutrition of the essential trace elements and minerals. Bogden JD, Klevay LM [Eds], Human Press, NJ, 2000; 82-83.
5. Rajagopalan KV. Molybdenum: an essential trace element in human nutrition. Ann Rev Nutr 1988;8:401-427.
6. Leung F, Gupta S, Bradley C, Edmond P. Comparative use of plasma versus erythrocytes to monitor essential trace elements in patients on total parenteral nutrition. Presented at the VIth ISTERH Conference, Quebec City, Sept. 11, 2002.
7. Touitou Y, Godard J-P, Ferment O, et al. Prevalence of magnesium and potassium deficiencies in the elderly. Clin Chem 1987;33:518-523.
8. Hatanaka N, Nakaden H, Yamamoto Y, et al. Selenium kinetics and changes in glutathione peroxidase activities in patients receiving long-term parenteral nutrition and effects of supplementation with selenite. Nutrition 2000;16:22-26.

Toxic Elements - Erythrocytes

Antimony (Sb)-The element antimony is found in the periodic table directly below arsenic, and shares many of the characteristics of arsenic, but is less toxic. It exerts its activity by binding to sulfhydryl (SH) groups on many enzymes, and exists in a tri- and pentavalent ionic form within compounds. As it is associated in ores with arsenic, lead and copper, toxic exposure occurs in the mining and ore extraction industries. Acute exposure can result in heart, liver and kidney damage, while chronic exposure results in skin, mucus membrane and lung conditions. Unlike arsenic, antimony is not methylated in vivo, but is excreted in the bile and in the urine. In normal subjects, Sb is four-fold higher in erythrocytes than in plasma. Elevated RBC indicates recent or chronic exposure.

Arsenic (As)- In humans, acute severe arsenic poisoning result in paralytic symptoms of shock, vasodilation, cyanosis, coma and death from circulatory failure. Chronic intoxication from exposures such as from arsenic pesticides or herbicides can result in skin, lung and lymphatic cancers. As arsenic is largely excreted through the urine as methylated derivatives, urine is used to monitor acute toxic exposure while hair can be used to assess longer term arsenic accumula-tion. Approximately equal amounts of As are distributed into the plasma and the RBC (1), but the resident time is short (<2 hr). Blood is not a good sample for assessing arsenic poisoning due to its relative rapid clearance.

Cadmium (Cd)- Industrial exposure such as from steel production, pigment and battery manufacturer are occupational hazards. Dietary sources from rice, wheat, oysters and other seafoods, as well as from smoking cigarettes contribute to our body burden. Acute air exposure can result in respiratory distress while chronic exposure results in kidney tubular damage. In blood, 90% of the cadmium is bound to erythrocytes, and has a half-life of 70-120 days (2). Depending upon the rate of exposure, the body burden increases during the first 4 months, and is reflected in the blood concentration. Both whole blood or erythrocytes and urine concentrations should be used to monitor chronic Cd exposure.

Lead (Pb)- This metal is particularly hazardous to children and mothers of child-bearing age. Exposure can occur from lead paints in old houses, from pottery glaze, lead battery, and lead solder in water pipes. Development of mental retardation, encephalopathy, and anaemia are some of the clinical effects of lead toxicity. Over 93% of the lead is bound to hemoglobin in the blood such that erythrocyte lead is a very sensitive marker of lead exposure. This represents about 5% of the exchangeable pool distributed between blood and soft tissues. The majority of the lead is sequestered in bone with a half-life of 20-30 years (2).

Mercury (Hg) - Exposure to this highly volatile metal can occur from the air, but the main sources are from contaminated seafood, industrial wastes, and fungicides. Damages from overexposure presents as proximal kidney tubule damage, and sensory nervous disturbances in the brain. Methylmercury is more toxic than inorganic Hg due to its lipid solubility, and bio-accumulation effect. The central nervous system is its target organ, and since Hg can cross the placenta freely, normal development of the fetal brain can be highly affected. Release of Hg from dental amalgam fillings is also of concern to pregnant mothers (3).

Nickel (Ni)-Environmental and occupational exposure to nickel can result in diseases of the respiratory system, the nasal cavities and sinuses, the immune system, and the skin. Nickel carbonyl is the most toxic compound and is a carcinogen found in cigarette smoke. Occupational workers in the mining, alloy production, battery, electronic and rubber industries are more exposed to this toxin. Dithiocarb has been shown to be an effective antidote for acute nickel carbonyl exposure. Ni concentrations in serum reflects recent exposure (4), and its upper content of 25 nmol/L in normal subjects is about half of that found in erythrocytes (51 nmol/L). RBC levels may reflect more extended exposure.

Thallium (Tl)-Thallium is obtained as a byproduct from smelting of other metals. It is used in the semiconductor industry, for special glass, as radioactive thallium-201 in medical procedures, and as thallium-salts, a rodent poison. Exposure to high levels can result in harmful health effects of the nervous system (numbness of fingers and toes), the lungs, heart, liver and kidneys. Blood thallium is not as good an indicator because of its short half-life. Erythrocyte Tl levels (up to 0.39 nmol/L) are higher than that found in plasma (up to 0.14 nmol/L) in the general population. Urine is usually monitored for excessive exposure (5).

Reference:

1. Pott WA, Benjamin SA, Yang RSH. Pharmacokinetics, metabolism and carcinogenicity of arsenic. Rev Environ Contam Toxicol 2001;169:165-214.
2. Baldwin DR, Marshall WJ. Heavy metal poisoning and its laboratory investigation. Ann Clin Biochem 1999;36:267-300.
3. Mimy MJ, Hooper DE, King WW, Lorscheider FL. Mercury from maternal "silver" tooth fillings in sheep and human breast milk. A source of neonatal exposure. Biol Trace Elem Res 1997;56:143-152.
4. Sunderman FW Jr. in Biological Monitoring of Toxic Metals, Clarkson, Friberg, et al [eds], Rochester Ser Environ Toxicity, Plenum Press, New York ,1988;265.
5. Van der Voet GB, De Wolff FA. Human exposure to lithium, thallium, antimony, gold and platinum. in Toxicology of metals, [Chang LW ed] CRC Press, Boca Raton, Florida 1996;456-457.

Trace Element Laboratory London Laboratory Services Group

HAIR ANALYSIS

Introduction:
The use of multielement hair analysis to assess an individual's nutritional health or predispositon to disease has been controversial, and even denounced over the years. Part of the difficulty has been due to the lack of studies which can correlate low concentrations of essential elements in hair to deficiencies in tissue and body levels. More evidence is available which document the presence of toxic elements such as Arsenic, Cadmium, Lead and Mercury in hair to excess exposure, and serves as a useful diagnostic index of toxic elements. The analysis of hair for the determination of heavy metals is recommended by the U.S. Environmental Protection Agency provided the hair sample is properly collected, cleaned and analyzed by the best analytical methods.

A recent article by Seidel et al.(1) published in 2001 in JAMA compared the findings of 6 commercial laboratories which performed hair mineral analysis. They concluded that hair mineral analysis from these laboratories was unreliable, and that health care practitioners refrain from using such analyses to assess individual nutritional status or suspected environmental exposures. One of these laboratories (2) have disputed these findings, and rightly point out that not all of the labs can be considered wrong, and that the best sample preparation or best instruments for analysis were used. The use of atomic emission spectrometry has been reported to be not suitable for several elements (3).

Our laboratory have applied standardized sample preparation (4) which include washing the hair in Triton X-100, and rinsing in de-ionized water to remove external contamination. The hair is digested in ‘in-house' redistilled nitric acid which is trace metal free. The analysis is performed using high-resolution ICP-MS which is ‘state-of-the-art' technology, and monitored using ‘in-house' prepared quality controls, commercial hair standards, and tested using CAP and Le Centre de Toxicologie due Quebec proficiency testing programs. Reference ranges are established for 38 hair elements and are comparable to a laboratory which uses equivalent instrumentation and methods (5).

Toxic Panel - Hair

Aluminum (Al)-The determination of aluminum was initiated over 20 years ago from the finding that dialysis patients who consumed aluminum hydroxide to reduce serum phosphate, and from contaminated dialysis fluids developed encephalopathy, osteomalacia and anemia. Some other sources for aluminum toxicity can result from excessive exposure to intravenous fluids, cosmetics, aluminum cookware, deodorants, and antacids. Aluminum is eliminated by the digestive and urinary tract, and is considered harmless, unless elevated ingestion with compounds such as citric acid increases its absorption. Hair is easily contaminated with Al from hair treatment, by wash water if it contains a high content of Al, and from dust. Elevated hair Al can reflect chronic exposure or intake of Al. Symptoms of elevated Al may include fatigue, headache, and CNS disturbances.

Antimony (Sb)-The element antimony is found in the periodic table directly below arsenic, and shares many of the characteristics of arsenic, but is less toxic. It exerts its activity by binding to sulfhydryl (SH) groups on many enzymes, and exists in a tri- and pentavalent ionic form within compounds. As it is associated in ores with arsenic, lead and copper, toxic exposure occurs in the mining and ore extraction industries. Acute exposure can result in heart, liver and kidney damage, while chronic exposure results in skin, mucus membrane and lung conditions. Unlike arsenic, antimony is not methylated in vivo, but is excreted in the bile and in the urine. Hair Sb levels in scalp hair is positively correlated with 24-h excretion of urine (5,6). Antimony containing drugs for treatment of leishmaniasis produced increased hair Sb levels in patients (7).

Arsenic (As)-Poisoning with arsenic trioxide and the derivatives arsenite and arsenate are the main causes for their environmental and occupational toxic activity. They inactivate SH groups of many enzymes which leads to cell death. Exposure occurs from contaminated water supplies (>50 ug/L), seafood (> 2 ug/kg body weight), and industries (wood preservatives, glass production, gold, copper and zinc smelting, pesticides, and coal burning). The organically bound forms of arsenic exit as arsenobetaine and arsenocholine which are mainly nontoxic as it is excreted unchanged in the urine. Tests require speciation to determine the amount of the toxic content of inorganic arsenic. Hair arsenic has also been used to assess chronic exposure. Hair arsenic is correlated with levels in the kidney-cortex (8), and with drinking water exposure (9).

Barium (Ba)-A barium compound such as barium sulfate that do not dissolve well in water is generally not harmful, and is used as an X-ray contrast medium. Other salts such as barium chloride which are water soluble are poisons which result in breathing problems, increased blood pressure, heart rhythm, brain swelling, liver-, kidney-, heart- and spleen damage. It displaces potassium to induce muscle weakness and heart dysfunctions. It can inhibit calcium absorption, and has properties similar to lead and cadmium. Exposure can result from drinking contaminated water, or from industry which produces paint, bricks, tiles, glass, pesticides, fuel additives and rubber. Significant correlation is reported between the trace element content of hair and exposure to Ba (and other elements) in dust (10).

Beryllium (Be)-This is a naturally occurring metallic element found in rocks, coal and oil, and has found wide usage in the industries as metal alloys with copper and aluminum for its strength. They are used in such products as dental appliances, golf clubs, computer microprocessor connectors, optical laser, and missile/radar navigation systems. Workers who handle compounds such as beryllium oxide, phosphate and sulfate are exposed to these extremely toxic agents which can result in chronic lung inflammation (beryllosis and pneumonitis). It is also a suspected human carcinogen, and trace amounts exits in tobacco smoke. Biochemically it blocks several hepatic enzymes, and binds chromatin to interfere with DNA synthesis.

Bismuth(Bi)-Medical uses of bismuth compounds are largely responsible for excessive exposure to bismuth. These compounds include formulations which are used as antiseptics, astringents, and antacids, and preparations for the treatment of duodenal ulcers and peptic diseases (Helicobacter pylori infections). Some compounds include bismuth subsalicylate (Pepto-Bismol) to control GI upset, diarrhea, and irritable bowel syndrome, and bismuth subgallate (Colo-fresh) to control fecal odours associated with colostomies, ileostomies and fecal incontinence. Toxicity results in renal damage, encephalopathy and peripheral neuropathy. As bismuth is also used in paint pigments, exposure of occupational workers in this industry can occur. Levels in plasma, urine, hair and nails (5) have been used to monitor excessive exposure.

Cadmium (Cd)- Industrial exposure such as from steel production, pigment and battery manufacturer are occupational hazards. Dietary sources from rice, wheat, oysters and other seafoods, as well as from smoking cigarettes contribute to our body burden. Acute air exposure can result in respiratory distress while chronic exposure results in kidney tubular damage. The determination of Cd in hair is positively correlated with kidney and liver Cd concentrations (11) and urine excretion (12,13). Hair analysis of children has been used as a monitor for detecting toxic effects from ambient air cadmium exposure (14).

Lithium (Li)- Lithium is a monovalent cation which can compete with ions such as sodium to alter neurotransmitters of nerve and muscle cells. It is used in the treatment of manic-depression and bipolar illness. Plasma lithium levels are used to adjust therapy, but high hair levels may reflect long-term intake with tissue accumulation. Low hair lithium should not be used to indicate lithium deficiency or should be used to alter therapy. Hair lithium may be low in some pathological conditions such as learning-disabled subjects, and incarcerated violent criminals (15).

Lead (Pb)- This metal is particularly hazardous to children and mothers of child-bearing age. Exposure can occur from lead paints in old houses, from pottery glaze, lead battery, and lead solder in water pipes. Development of mental retardation, encephalopathy, and anaemia are some of the clinical effects of lead toxicity. Hair lead has been correlated to both blood and teeth concentrations (16,17). Increased lead levels in the livers and kidneys of smelter workers correlated with higher hair lead concentrations (18). The lead content in bone has also been correlated with hair concentrations (19). Pb concentrations in hair is useful as an environmental marker of chronic lead exposure (20), and level of exposure in children (21).

Mercury (Hg)- Exposure to this highly volatile metal can occur from the air, but the main sources are from contaminated seafood, industrial wastes, and fungicides. Mercury dental amalgam has been considered a predominant source of mercury exposure of non-occupationally exposed persons (22-23). Damages from overexposure presents as proximal kidney tubule damage, and sensory nervous disturbances in the brain. Methylmercury is more toxic than inorganic Hg due to its lipid solubility. Hair Hg is significantly correlated to blood (17), urine (24), and tissue (25) mercury concentrations.

Nickel (Ni)-Environmental and occupational exposure to nickel can result in diseases of the respiratory system, the nasal cavities and sinuses, the immune system, and the skin. Nickel carbonyl is the most toxic compound and is a carcinogen found in cigarette smoke. Occupational workers in the mining, alloy production, battery, electronic and rubber industries are more exposed to this toxin. Dithiocarb has been shown to be an effective antidote for acute nickel carbonyl exposure.
Urine and hair analysis can reliably detect early and chronic exposure to nickel (26,27).

Palladium (Pd)-This relatively unknown element may be more toxic than mercury which is also used in dental fillings since 1986. It is mixed with gold and can contain up to 78% Pd. Its biological toxicity results from its cell blocking action which results in muscle, joint pain, cardiac arrhythmia, nervous disorders and memory loss. Allergic contact dermatitis has also been reported with jewelry containing Pd. Hair analysis can be used to detect early toxicity and chronic exposure (28).

Platinum (Pt)-Pure platinum is relatively nontoxic, but as complex salts such as cisplatin is highly toxic to both cancerous and healthy cells. Its use can result in cumulative nephrotoxicity, GI symptoms and neurotoxicity. Pt is rapidly distributed to most tissues of the body, and mainly excreted into the urine. Pt can give rise to allergic symptoms, dermatitis, platinum asthma, and rhinorrhea.. Urine and hair analysis can be used to monitor renal toxicity in chemotherapy patients (28).

Silver (Ag)-Silver is poorly absorbed, and not considered toxic to humans in its elemental form. It is used to make jewelry, electronic equipment, dental fillings, and in photography as silver nitrate, silver chloride in plating or silver oxide in the glass industry. Silver is a dietary copper antagonist which can result in copper deficiency. As it also binds to selenium, it has been used to alleviate selenium toxicity. Excessive exposure to silver can result in its deposition in the skin and organs causing gray discolouration (argyreia). It has been taken in colloidal form as an alternative treatment for bacterial infection, and as silver nitrate in eye drops for newborns to prevent blindness caused by gonorrhea. Blood, urine and hair can be used for its analysis.

Thallium (Tl)-Thallium is obtained as a byproduct from smelting of other metals. It is used in the semiconductor industry, for special glass, as radioactive thallium-201 in medical procedures, and as thallium-salts, a rodent poison. Exposure to high levels can result in harmful health effects of the nervous system (numbness of fingers and toes), the lungs, heart, liver and kidneys. Blood thallium is not as good an indicator because of its short half-life. Tests for exposure are best monitored with urine and hair analysis (29,30).

Titanium (Ti)-Due to the low absorption of titanium in humans, it is considered nontoxic, but has been reported to cause soft-tissue sarcoma from a titanium-covered pulse generator (Thorac Cardiovasc Surg 1984;32:67-69). Its use in surgical implants have not been associated with cancers. Toxicities have been reported in workers from lung inhalation to result in subpleural fibrosis. Levels are detectable in RBC, urine and hair from environmental and occupational exposure. Elevated levels of titanium were found in hair six years after hip implantation (31), and in patients recently diagnosed with naso-pharyngeal cancer (32).

Uranium (U)-Natural uranium consists of a mixture of three radioactive isotopes which are U238 (99.27%), U235 (0.72%) and U234 (0.0054%). Depleted uranium (DU) contains less U235 (0.2%), has a higher density and is used in projectiles and armour of tanks. Soldiers are in danger of inhaling airborne, ingesting or have wound contamination by DU particles. Concerns from long term exposure of uranium which have kidney, lung and skin cancer effects. Population concerns to uranium exposure can result from nuclear power plants, factories which process ceramics, fertilizers, and from well water in specific geographic locations. Monitoring with urine for current, and hair to monitor long-term uranium exposure (33).

References:

1. Seidel S, Kreutzer R, Smith D, McNeel S and Gilliss D. Assessment of commercial laboratories performing hair mineral analysis, JAMA 2001;285:67-72.
2. Doctor's Data. Initial response to the recent JAMA article on hair analysis. http:www.doctorsdata.com/response.htm, 2002.
3. Miekeley N, Dia Carneiro MTW, Porto da Silveira CL. How reliable are human hair reference intervals for trace elements? The Science of the Total Environ. 1998;218:9-17.
4. International Atomic Energy Agency. Standardized hair sample preparation, RL/50, Vienna.
5. Rodushkin, IA. Application of double focusing sector field ICP-MS for multielemental characterization of human hair and nails. Part II. A study of the inhabitants of northern Sweden. Sci Total Environ 2000;262:21-36.
6. Gebel T, Suchenwirth RH, Behmke C, Plessow A, Claussen K, Schulze E, Dunkelberh H. Biological monitoring in persons of areas with increased soil mercury, arsenic, and antimony content [German]. Gesundheitswesen 1998;60:580-585.
7. Dorea, JG, Costa HM, Holzbecher J, Ryan DE, Marsden PD. Antimony accumulation in hair during treatment of leishmaniasis. Clin Chem 1987;33:2081-2082.
8. Zhuang GS, Wang YT, Tan MG, Zhi M, Pan WQ, Cheng YD. Preliminary study of the distribution of the toxic elements As, Cd and Hg in human hair and tissues by NNAA. Biol Trace Elem Res 1990;26-7:729-736.
9. Kurttio P, Komulainen H, Hakala E, Kahelin H, Pekkanen J. Urinary excretion of arsenic species after exposure to arsenic present in drinking water. Arch Environ Contam Toxicol 1998;34:297-305.
10. Creason JP, Hinners TA, Bumgarner JE, Pinkerton C. Trace elements in hair, as related to exposure in metropolitan New York. Clin Chem 1975;21:603-612.
11. Oleru UG. Epidemiological implications of environmental cadmium. I. The probable utility of human hair for occupational trace metal (cadmium) screening. Am Ind Hyg Assoc J 1975;36:229-233. Oleru UG. Kidney, liver, hair and lungs as indicators of cadmium exposure. Am Ind Hyg Assoc J 1976;37:617-621.
12. Lie XJ. Cadmium concentrations in hair, urine and blood among residents in a cadmium-polluted area. Nagasaki, Japan: A 18 year follow-up after soil replacement. [Japanese] Nippon Eiseigaku Zasshi 1999;54:544-551.
13. Bustueva KA et al. Cadmium in the environment of three Russian cities and in human hair and urine. Arch Environ Health 1994;49:284-288.
14. Stewart-Pinkham SM. The effect of ambient cadmium air pollution on the hair mineral content of children. Sci Total Environ 1989;78:289-296.
15. Schrauzer GN, Shrestha KP, Flores-Arce MF. Lithium in scalp hair of adults, students, and violent criminals. Effect of supplementation and evidence for interactions of lithium with vitamin B12 and with other trace elements. Biol Trace Elem Res 1992;34:161-176.
16. Bergomi M, Borella P, Fantuzzi G. Blood, teeth and hair: 3 different material used to evaluate exposure to lead and cadmium in children living in an industrial zone [Italian]. Ann IG 1989;1:1185-1196.

17. Foo SC, Khoo NY, Heng A, Chua LH, Chia SE, Ong CNN, Ngim CH, Jeyaratnam J. Metals in hair as biological indices for exposure. Int Arch Occup Environ Health 1993;65(suppl):S83-86.
18. Gerhardsson L, Englyst V, Lundstrom NG, Nordberg G, Sandberg S, Steinvall F. Lead in tissues of deceased lead smelter workers. J Trace Elem Med Biol 1995;9:136-143.
19. Hac E, Czarnowski W, Gos T, Krechniak J. Lead and fluoride content in human bone and hair in the Gdansk region. Sci Total Environ 1997;206:249-254.
20. Nowak B, Chmielnicka J. Relationship of lead and cadmium to essential elements in hair, teeth and nails of environmentally exposed people. Ecotoxicol Environ Saf 2000;46:265-274.
21. Tuthill RW. Hair lead levels related to children's classroom attention-deficit behavior. Arch Environ Health 1996;51:214-220.
22. Begerow J, Zander D, Freier I, Dunemann L. Long-term mercury excretion in urine after removal of amalgam fillings. Int Arch Occup health 1994;66:209-212.
23. Bjorkman L, Sandborgh-Englund G, Ekstrand J. Mercury in saliva and feces after removal of amalgam fillings. Toxicol Appl Pharmacol 1997;144:156-162.
24 Ludwicki JK, Waidrowska B, Palut D, Tyrkiel E. The evaluation of urine and hair total mercury content in occupationally exposed and non-exposed people [Polish] Rocz Panstw Zakl Hig 1998;49:447-455.
25. Hac E, Krzyzanowski M, Krechniak J. Total mercury in human renal cortex, liver, cerebellum and hair. Sci Total Environ 2000;248:37-43.
26. Spruit D, Bongaarts PJ. Nickel content of plasma, urine and hair in contact dermatitis. Dermatalogica 1977;154:291-300.
27. Bencko V. Nickel:A review of its occupational and environmental toxicology. J Hyg Epidemiol Microbiol Immunol 1983;27:237-247.
28. Johnson DE, Tillery JB, Prevost RJ. Levels of platinum, palladium and lead in populations of Southern California. Environ Health Perspect 1975;12:27-33.
29. Hirata M, Taoda K, Ono-Ogasawara M, Takaya, M, Hisanaga N. Aprobable case of chronic occupational thallium poisoning in a glass factory. Ind Health 1998;36:300-303.
30. Yoshinaga J, Shibata Y, Morita M. Trace elements determined along single stands of hair by inductively coupled plasma mass spectrometry. Clin Chem 1993;39:1650-1655.
31. Trinchi V, Nobis M, Cecchele D. Emission spectrophotometric analysis of titanium, aluminum and vanadium levels in the blood, urine and hair of patients with total hip arthroplasties. Ital J Orthop Traumatol 1992;18:331-339.
32. Leung PL, Huang HM. Analysis of trace elements in the hair of volunteers suffering from naso-pharyngeal cancer. Biol Trace Elem Res 1997;57:19-25.
33. Byrne AR, Benedik L. Uranium content of blood, urine and hair of exposed and non-exposed persons determined by radiochemical neutron activation analysis, with emphasis on quality control. Sci Total Environ 1991;107:143-157.

Trace Element Laboratory London Laboratory Services Group

Essential Elements - Hair

Boron (B)-Boron is considered an essential trace element with roles as a homeostatic regulator in carbohydrate and lipid metabolism (1). It may also play a role in the prevention and treatment of osteoporosis through estradiol effects. Boron is distributed throughout the tissues and organs, and stored in bones. Deficiencies can trigger skin allergies such as eczema, acne, and enteritis. Boron is rapidly absorbed, and excreted mainly in the urine. Renal problems can result in accumulation of boron in the heart, lungs, kidneys, brain and reproductive organs. Oral boron has low toxicity, but doses >3.5 mg of boron can be lethal in humans. Whole blood, plasma, urine and hair can be used to monitor deficiencies or excess exposure.

Calcium (Ca)-Hair calcium is determined as part of the panel of 38 elements available in hair. Reference values have been established (400-1500 ug/g) which show a wide range, in contrast to serum calcium which have tight limits except in serious pathologies. Calcium accumulation in hair can reflect its chronic mobilization from bone with calcium loss. High hair calcium can be seen in older women with indications of osteoporosis. Hair calcium concentrations are inversely correlated to that of the aorta (2). In adults, low calcium in hair has been seen in cases of myocardial infarction, with increased aortic calcium levels (Trace Elem Res 1981;12:383-7). During the active growing years in children, there is a rapid uptake by osteocytes of bone with a lower hair calcium. This may not directly be related to dietary intake of calcium. Calcium and magnesium supplements may be indicated as an adjunctive treatment of fibromyalgia (3).

Chromium (Cr)-Of the major chemical forms of chromium, chromium (III) is considered an essential element and forms part of the complex, the glucose tolerance factor (GTF). This factor is believed to enhance the action of insulin at its receptor site in promoting glucose uptake. A deficiency of chromium can result in an increase in insulin requirement. Chromium (III) is provided as a supplement in total parenteral nutrition, and the measurement of erythrocytes provides a better index of body content than the measurement of plasma. Some fluids have been shown to contain chromium as a contaminant from its manufacture (ie. in steel vats). Exposure to chromium (VI) through the air which is produced in industry can result in damage to the nose, lungs, and is a carcinogen. A good correlation between chromium levels in hair, sweat, urine and serum concentrations (4).

Cobalt (Co)-Cobalt is an essential metal for humans and is part of the enzyme cyanocobalamin (vitamin B12). A deficiency of cobalt is accompanied by all the signs and symptoms of a vitamin B12 deficiency, and is often due to absorption problems (ie. lack of intrinsic factor or malnutrition). It is also used as cobalt alloys in orthopedic prosthesis. Cobalt chloride had been used as a foam stabilizer in beer, and had induced cardiomyopathy among heavy beer consumers. This is no longer used, and such sources of toxicity do not occur. Occupational workers can still be exposed to cobalt dust with resulting illnesses as contact dermatitis, cardiomyopathy (5), liver and kidney damage. Deficiency or toxicity to cobalt can be monitored with blood, urine or hair analysis.

Copper (Cu)- As an essential trace metal, it is an active component of several proteins such as ceruloplasmin and important enzymes such as cytochrome oxidase, superoxide dismutase and metallothionein. Determination of this metal in biological samples is used to diagnose metabolic diseases due to deficiencies or excessive accumulation of Cu. Hair copper usually reflects tissue levels except in copper transport diseases such as Menke's and Wilson's disease which may present with low copper concentrations. Contamination of hair may occur from the copper containing purification agents added to swimming pool water, from acidified water leached from copper pipes, and from certain dyes and hair bleaching agents.

Iodine (I)-Iodine is an essential component of the two thyroid hormones, thyroxine and triiodothyronine. Deficiency of iodine can result in miscarriages, still births, congenital anomalies, goiter, hypothyroidism, cretinism, and delayed development. Excess iodine intake can also produce teratogenetic effects in the newborn. Iodine can be monitored in plasma and hair with hair concentrations correlating with exposure levels. Iodine in hair are lower in most diseases of the thyroid, but is elevated in cases of thyroid cancer (6).

Iron (Fe)-Daily requirements for iron vary depending on sex, age, and physiological status such as during adolescence, pregnancy, nursing or menstruation. Deficiency is relatively common with blood loss the most common cause such as during menstrual bleeding. Iron deficiency anemia can be related to cofactor deficiencies which include pyridoxine, vitamin B12, and folic acid. Iron overload can occur from excess intake or from genetic causes (hemochromatosis). Determination of liver iron is used to diagnose hemochromatosis. Lower hair iron were noted in patients with inflammatory bowel syndrome (7), and liver cancer (8).

Magnesium (Mg)- Magnesium plays an essential role in ATP activation, muscle contraction, and the synthesis of several amino acids, RNA and DNA. In erythrocytes, magnesium is over twice the concentration found in plasma with over 55% in the ionized form. As the intracellular Mg is bound to ATP, it may be a better index of the bio-energetic activity on a long-term basis. It has been reported to be significantly lower in women with premenstrual tension syndrome, hypertension, and chronic fatigue syndrome (Am J Clin Pathol 1994;102:616-22). In hair, low magnesium have been found with long-term insufficient dietary intake, malabsorption syndromes or chronically-increased magnesium losses. Lower Mg in hair is reported in children with attention deficit hyperactivity disorder (ADHD)(9).

Manganese-(Mn)-Manganese is an essential trace element which is required for a number of enzymes which include glycosyl transferase, superoxide dismutase, pyruvate kinase and arginase required for the metabolism of carbohydrate, protein, lipid and free radicals. Deficiency of manganese can result in convulsive disorders such as epilepsy, myasthenia gravis, and impaired insulin activity. Excess levels may result in iron-deficiency anemia due to its interference of dietary iron absorption. Manganese poisoning can occur in workers in battery manufacturing, and from well water with excessive content. Hair Mn is significantly correlated with urinary Mn (10).

Molybdenum (Mo)-Molybdenum is an essential element required for several enzymes including aldehyde oxidase, xanthine oxidase, and sulfite oxidase. Diseases associated with Mo deficiency include gout with uric acid accumulation, cancer susceptibility as it plays a role in its prevention, and in sulfur metabolism. High exposure to Mo is toxic as it is an antagonist to copper. Urine and hair Mo are useful for the biological monitoring from occupational or environmental exposure (11).

Phosphorus (P)-Although phosphorus is a major structural element of the bones and teeth, about 20% is present in other macromolecules such as proteins, nucleic acids and phospholipids. Most metabolic processes are driven by high energy bonds in adenosine triphosphate (ATP) and other phosphate compounds. Most of the phosphorus is in the form of phosphate (PO4). It is required for the formation of bone mineral with calcium, and is needed during rapid growth. When the skeleton matures, phosphorus continues to be needed more than calcium for metabolic activities.
Common causes of hypophosphatemia are: malabsorption, alcoholism, and chronic antacid abuse. Deficiency symptoms in combination with calcium deficiency occurs in rickets, arthritis, osteomalacia, and poor teeth and bone formation. High levels occur in renal failure and increased phosphate or vitamin D intake. Low hair concentrations reflects a poor dietary intake, protein digestive problems or inadequate calcium/magnesium intake (12).

Potassium (K)- Potassium is mainly an intracellular cation with important functions in nerve impulses, muscle contractions, maintenance of osmotic pressure, regulation of acid-base balance, and kidney function among other roles. In hair analysis, a significant increase has been related to patients with acute celiac disease and cystic fibrosis (13), and is decreased after prolonged alcohol abuse.(Lab Delo 1989;2:42-4).

Selenium (Se)-Selenium is found in the inorganic (selenite, selenate), and organic (selenomethionine, selenocysteine) forms. Due to its varied geographical soil content world-wide, the amounts which occur in our food (meat is rich in selenium), and its dietary intake affect our body's content. Deficiency of selenium has been documented in humans in China named Keshan's disease in the form of myocardiopathy, and as an endemic degenerative osteoarthropathy, named Kaschin-Beck's disease. Deficiency can also occur in patients on long-term total parenteral nutrition. Selenium is an essential component of glutathione peroxidase which plays a role as an antioxidant. Other key functions include immune regulation, and reduced cancer mortality (ie. lung, prostate, and colorectal). Toxicity from overdoses has resulted in several metabolic and physical changes such as impaired bone development, liver disease, hair loss, and fatigue. High selenium intake, especially in children can cause stunting of growth. This element can be monitored in plasma, erythrocytes, urine and hair. With hair analysis, there is good correlation with blood and urine levels (14).

Sodium (Na)-Hair sodium generally do not reflect dietary status, but very high levels may be diagnostic in cystic fibrosis (Pediatrics 1972;49:620). Retention of sodium in hair tissue may be caused by disturbances in renal function and electrolyte balance. Chronic stress syndrome can result in depressed hair sodium as a result of inadequate renal response to adrenal hormones.

Strontium (Sr) - There is not evidence that strontium is an essential mineral. Humans contain about 350 mg of the element, 99% in the bones and teeth. Since it closely resembles calcium chemically it can displace it in the bones, and may increase the strength in teeth to prevent tooth decay. Radioactive strontium-90 is a hazardous by-product of nuclear fission. The use of non-radioactive strontium-88 may protect the body from exposure to the radioactive form. Strontium-89 has been used for palliation of painful bone metastasis from prostate, breast or lung cancers. Blood and urine strontium is depressed in patients with cholecystitis, and elevated in liver cancer. Hair is useful to monitor strontium exposure and correlates well with bone levels (15).

Sulfur (S)-Sulfur is essential to human life, and is found in all cells, especially the skin, connective tissues, and hair. It is part of the SH- amino acids of cysteine, cystine, taurine, and methionine. Deficiencies have resulted in skin and nail diseases due to an inadequate intake of the sulfur essential amino acids. Sources such as meat and egg yolk are high in sulfur with lack of adequate intake seen in some vegetarians. Allergic reactions to sulfite used as food preservatives have been reported in asthmatics. Sulfur metabolism have also been reported to be impaired in patients with systemic lupus erythrematosus (Lancet 1992;339:25-6). Levels can be monitored in urine and hair specimens.

Tin (Sn)-The essential role for tin has not been well established in humans, but has been shown to be needed for growth in riboflavin-deficient rats. In humans, tin accumulates in the liver, kidney, and bones. Its generally has a low level of toxicity due to its low tissue accumulation, poor absorption and rapid tissue turnover. Tin has been shown to affect heme metabolism, and suppress iron absorption. In tin mining, excessive inhalation of tin oxide has resulted in pneumoconiosis (stannosis). Divalent tin has been reported to be carcinogenic as it induces DNA damage (Mutat Res 1983;119:195-201). Urine and hair levels can be used to monitor occupational exposure.

Vanadium (V)-Vanadium may be an essential element, but signs of nutritional deficiency has not been reported. Pharmacological effects show that it has a strong insulin mimetic action, and vanadium can result in the reduction of blood glucose. As with many other elements, toxicity to vanadium has resulted in skeletal abnormalities, fetal toxicity, and teratogenicity. Its toxic effects results from its ability to interfere with biological functions of amino acids, peptides, nucleotides, ATP and carbohydrates. Industrial inhalation of vanadium dust can produce respiratory, cardiac and central nervous system problems. Blood, urine and hair samples can be used to monitor vanadium body burden. Significantly elevated hair levels were reported in manic patients in comparison to controls (16).

Zinc (Zn)- An essential trace metal which influences the activity of over 300 enzymes such as lactate dehydrogenase, alkaline phosphatase, and alcohol dehydrogenase. Deficiencies can result in growth retardation and delayed sexual development in children, and impaired wound healing and T-cell function at all ages. Low intake of zinc correlated with low zinc in plasma and in hair (17). Hair zinc values are a good indicator of nutritional status (18), and supplementation with zinc (19, 20).

References:
1. Nielsen FH. Possible essential trace elements. In Clinical Nutrition of the Essential Trace Elements and Minerals. (Bogden JD, Klevay LM eds). Humana Press, New Jersey 2000;17-19.
2. MacPherson A, Balint J, Bacso J. Beard calcium concentration as a marker for coronary disease as affected by supplementation with micronutrients including selenium. Analyst 1995;120:871-875. MacPherson A, Bacso J. Relationship of hair calcium to incidence of coronary heart disease. Sci Total Environ 2000;255:11-19.
3. Ng SY. Hair calcium and magnesium levels in patients with fibromyalgia: A case center study. J Manipulative Physiol Ther 1999;22:586-593.
4. Randall JA, Gibson RS. Hair chromium as an index of chromium exposure of tannery workers. Br. J Ind Med 1989;46:171-175. Stupar J, Vrotovec M, Kocijancic A, Gantar A. Chromium status of tannery workers in relation to metabolic disorders. J App Toxicol 1999;19:437-446.
5. Jarvis JQ, Hammond E, Meier R, Robinson C. Cobalt cardiomyopathy. A report of two cases from mineral assay laboratories and a review of the literature. J Occup Med 1992;34:620-626.
6. Mende T, Wiesener W, Franke WG, Domschlke S, Gorner W. Isotopenpraxis 1984;20:301-303.
7. Bisse E, Renner F, Sussmann S, Scholmerich J, Wieland H. Hair iron content: Possible marker to complement monitoring therapy of iron deficiency in patients with chronic inflammatory diseases? Clin Chem 1996;42:1270-1274.
8. Wang YX, Qin JF, Wu SM, Yan LB. Study on the relation of Se , Mn, Fe, Sr, Pb, Zn, Cu, and Ca to liver cancer mortality from analysis of scalp hair. Sci Total Environ 1990;91:191-198.
9. Kozielec T, Starobrata-Hermelin B. Assessment of magnesium levels in children with attention deficit hyperactivity disorders (ADHD). Magnes. Res 1997;10:143-148. Starobrat-Hermelin B, Kozielec T. The effects of magnesium physiological supplementation on hyper-activity in children with attention deficit hyperactivity disorder (ADHA). Positive response to magnesium oral loading test. Magnes Res 1j997;10:149-156.
10. Foo SC. Khoo NY, Heng A, Chua LH, Chia SE, Ong CN, Ngim CH, Jeyaratnam J. Metals in hair as biological indices for exposure. Int Arch Occup Environm Health 1993;65 (Suppl):S83-S86.
11. Tsalev DL, Zaprianov ZK. Atomic absorption spectrometry in occupational and environmental health practice. Volume 1: Analytical aspects and health significance. Boca Raton (FL): CRC Press, Inc, 1983;95.
12. Blaurock-Busch E, Griffin V. Mineral and trace element analysis. TMI/MTM Books, Boulder, Co. 1996;145.
13. Varkonyi A, Boda M, Szokefalvi-Nagy Z, Nyilasi B. Determination of hair trace elements in childhood celiac disease and in cystic fibrosis. Acta Paediatr Hung 1992;32:159-165.
14. Valentine JL, Kang HK, Spivey GH. Selenium levels in human blood, urine, and hair in response to exposure via drinking water. Environ Res 1978;17:347-355.
15. Vatonova VA, Shvydko NS. Sr90 in the hair as an indicator of its content in human bone tissue [Russian]. Gig Sanit 1970;35:43-45.
16. Naylor GJ, Smith AH, Bryce-Smith D, Ward NI. Elevated vanadium content of hair and mania. Biol Psychiatry 1984;19:759-764.
17. Hambidge KM, Hambidge C, Jacobs M, Baum JD. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediatr Res 1972;12:868-874. Gibson RS, Huddle JM. Suboptimal zinc status in pregnant Malawian women: Its association with low intakes of poorly available zinc, frequent reproductive cycling and malaria. Am J Clin Nutr 1998;67:702-709.
18. Weber CW, Nelson GW, Vasquez de Vaquere M, Pearson PB. Trace elements in the hair of healthy and malnourished children. J Trop Pediatr 1990;36:230-234.
19. Cavan KR, Gibsone RS, Grazioso CF, Isalgue AM, Ruz M, Solomons NW. Growth and body composition of periurban Guatemalan children in relation to zinc status: A longitudinal zinc intervention trial. Am J Clin Nutr 1993;57:344-352.
20. Leung PL, Huang HM, Sun DZ, Zhu MG. Hair concentrations of calcium, iron, and zinc in pregnant women and effects of supplementation. Biol Trace Elem Res 1999;69:269-282.

Trace Element Laboratory London Laboratory Services Group

URINE TRACE ELEMENTS
	Toxic Element Panel - Urine

Aluminum (Al)-The determination of aluminum was initiated over 20 years ago from the finding that dialysis patients who consumed aluminum hydroxide to reduce serum phosphate, and from contaminated dialysis fluids developed encephalopathy, osteomalacia and anemia. Some other sources for aluminum toxicity can result from excessive exposure to intravenous fluids, cosmetics, aluminum cookware, deodorants, and antacids. Aluminum is eliminated by the digestive and urinary tract, and is considered harmless, unless elevated ingestion with compounds such as citric acid increases its absorption. Routine monitoring of serum, urine and water (dialysis use) is used to assess the risk from chronic aluminum exposure in dialysis patients, occupational workers, and the general population..

Antimony (Sb)-The element antimony is found in the periodic table directly below arsenic, and shares many of the characteristics of arsenic, but is less toxic. It exerts its activity by binding to sulfhydryl (SH) groups on many enzymes, and exists in a tri- and pentavalent ionic form within compounds. As it is associated in ores with arsenic, lead and copper, toxic exposure occurs in the mining and ore extraction industries. Acute exposure can result in heart, liver and kidney damage, while chronic exposure results in skin, mucus membrane and lung conditions. Unlike arsenic, antimony is not methylated in vivo, but is excreted in the bile and in the urine. Urine and erythrocytes (trivalent Sb is bound to RBC with lower amounts in plasma) are used to monitor antimony in occupational workers or subjects suspected of toxic poisoning. Elevated levels have been found in heart tissue of uremic patients, and in patients with myocardial infarction.

Arsenic (As)-Poisoning with arsenic trioxide and the derivatives arsenite and arsenate are the main causes for their environmental and occupational toxic activity. They inactivate SH groups of many enzymes which leads to cell death. Exposure occurs from contaminated water supplies (>50 ug/L), seafood (> 2 ug/kg body weight), and industries (wood preservatives, glass production, gold, copper and zinc smelting, pesticides, and coal burning). The organically bound forms of arsenic exit as arsenobetaine and arsenocholine which are mainly nontoxic as it is excreted unchanged in the urine. Tests require speciation to determine the amount of the toxic content of inorganic arsenic. As arsenic is rapidly cleared from the blood, urine provides a better index of recent exposure to inorganic arsenic. Hair arsenic has also been used to assess chronic exposure. Urine arsenic is used to monitor chelation therapy, and is important to determine its removal from the therapy.

Barium (Ba)-A barium compound such as barium sulfate that do not dissolve well in water is generally not harmful, and is used as an X-ray contrast medium. Other salts such as barium chloride which are water soluble are poisons which result in breathing problems, increased blood pressure, heart rhythm, brain swelling, liver-, kidney-, heart- and spleen damage. It displaces potassium to induce muscle weakness and heart dysfunctions. It can inhibit calcium absorption, and has properties similar to lead and cadmium. Exposure can result from drinking contaminated water, or from industry which produces paint, bricks, tiles, glass, pesticides, fuel
additives and rubber.

Beryllium (Be)-This is a naturally occurring metallic element found in rocks, coal and oil, and has found wide usage in the industries as metal alloys with copper and aluminum for its strength. They are used in such products as dental appliances, golf clubs, computer microprocessor connectors, optical laser, and missile/radar navigation systems. Workers who handle compounds such as beryllium oxide, phosphate and sulfate are exposed to these extremely toxic agents which can result in chronic lung inflammation (beryllosis and pneumonitis). It is also a suspected human carcinogen, and trace amounts exits in tobacco smoke. Biochemically it blocks several hepatic enzymes, and binds chromatin to interfere with DNA synthesis.

Cadmium (Cd): Widespread environmental contamination did not occur until it was mined from zinc deposits, and used in steel production, cement manufacture, pigment, plating and the battery industries. Further emissions to air, water, and land resulted from ashes from oil, waste, coal and phosphate fertilizer combustions. Individual intake increased with tobacco smoking such that one cigarette results in the inhalation of 0.1-0.2 g Cd which increases the blood Cd by 1.6%. Sources of intake from foods include: shellfish, saltwater fish, pork liver, black tea, and coffee.
Cd is toxic to many human systems, and is known to cause renal disease, prostatic carcinoma, hypertension, anemia, and bone disease with joint aches and pains (itai-itai or ouch-ouch disease in Japan). Its harmful action may result from its competition with zinc, and interference with its essential enzyme functions. Cd toxicity is worse during zinc deficiency, and is reduced with zinc intake. Cd binds to metallothionin and is transported by the blood to the liver, kidneys, and other tissues. Long-term exposure results in accumulation in the body of levels up to 30 mg by age 50 with levels of 200 to 500 g/g wet wt. being toxic to the kidneys. Being firmly bound to tissue sites, excretion is very slow in the urine with a T½ = 20-30 yrs.

Lead (Pb): In our century, the use of Pb in paints, leaded gasoline, pottery glazing, tin can solder, cosmetics and lead plumbing is being recognized to produce similar toxicity as seen in the earlier civilizations, particularly in children. Many of these sources have been reduced or removed, but the amount of lead in our environment is still significant, and monitoring is still required.
The toxic effects of Pb results from its ability to interfere with other essential elements such as calcium, iron, copper and zinc. In the formation of heme, the prosthetic group for hemoglobin, peroxidase and cytochromes, Pb inhibits the enzymes, -aminolevulinic dehydratase and ferrochelatase. Pb affects the function of the brain and peripheral nerves through its action on zinc, copper and iron-dependent as well as cysteine-containing enzymes. Its ability to displace calcium in bones are noted as "lead lines" on X-rays. Other widespread toxic effects includes an effect on the immune system with greater infections to bacteria and viruses, and a reduced ability to remove free radicals with enhanced cancer risks. Treatment for Pb burden includes removing the environmental source, and then determining if chelation therapy should be used. This would involve chelation with EDTA or other agents such as dimercaprol, or oral D-penicillamine. A high calcium diet or supplement will reduce the lead toxicity effect. Other therapeutic considerations would include providing increased intakes of phosphorus, multi-vitamins and elements such as magnesium, iron, copper and zinc. Biological monitoring of Pb exposure may require a combination of tests which would include blood, 24 h urine and hair analyses. Blood reflects a current Pb status, urine helps to indicate the subject's ability to excrete the Pb (good renal function) while the hair helps to indicate the tissue storage or longer term exposure.

For example, a person showing a high blood, normal urine and normal hair Pb content would indicate a very recent exposure or an acute situation with reduced renal function. Another person with normal blood Pb, but high urine and hair content would suggest a chronic exposure or longer term exposure with good renal function.

Mercury (Hg): Acute toxicity can occur with (0.2-1 g is lethal) of corrosive sublimate (HgCl2), calomel (Hg2Cl2), or methyl mercury (100 mg is lethal). Elemental mercury is volatile at room temperature, but also forms an alloy with other metals such as tin, copper, zinc, and silver, called amalgams. These alloys are used in dental filling with minute quantities released as vapours into the body. The Hg affects T-lymphocytes and inhibits immune function. Further effects on red blood cells and chromosomal damage suggest that Hg may be harmful to the fetus, and to pregnant women. At the prenatal stage of the developing brain, Hg inflicts the most damage during neuronal cell division and the migration of neuronal cells. Its mode of toxicity also results from its binding to sulfhydryl, amine, phosphoryl, and carboxyl groups to inhibit the enzyme system as well as damage the cell membranes. Detoxification procedures include the use of sulfur amino acids (lysine and methionine) to support the sulfhydryl groups, vitamin B6 to support kidney function, and selenium to bind Hg and reduce its absorption and toxicity. Chelation therapy with EDTA and D-penicillamine have been used to remove the body's burden. Acute toxicity from exposure to Hg within the first day, can be determined by measuring whole blood Hg (drawn in heparinized vacutainers). A 24 h urine collection is used to confirm its excretion with normal renal function. If a reduced excretion occurs, the blood level remains high, and a low urine content will be observed with the danger that the Hg can be deposited into the tissues.

Nickel (Ni): It exists in several oxidation states, but the predominant forms are as the metal (0) and the (2+) inorganic salts such as oxides and sulfides. In animals, Ni is necessary for certain metabolic processes, but in humans it is considered a toxic heavy metal. Sources from cigarette smoke such as Ni carbonyl are carcinogenic, and lethal in high doses. Food sources with high Ni content include cocoa powder (1000 mg/100g), chocolate (250 mg/100g) and tea (300 mg/100g). Occupational workers with higher Ni exposure with increased risks of nasopharyngeal and lung cancers include casting, chemical, mining, alloy production, battery and electronic industries
Early symptoms of Ni toxicity manifests as frontal headaches, fever, vertigo, vomiting, diarrhea, gastroenteritis, dermatitis, eczema, and cancer of the lungs and nasal cavity. Elimination of Ni is predominantly by the urine, but other sites include the bile, sweat, and milk in lactating mothers. Removal from the source of the exposure is required, and some therapeutic considerations include greater intake of sulfur containing amino acids and proteins.

Silver (Ag)-Silver is poorly absorbed, and not considered toxic to humans in its elemental form. It is used to make jewelry, electronic equipment, dental fillings, and in photography as silver nitrate, silver chloride in plating or silver oxide in the glass industry. Silver is a dietary copper antagonist which can result in copper deficiency. As it also binds to selenium, it has been used to alleviate selenium toxicity. Excessive exposure to silver can result in its deposition in the skin and organs causing gray discolouration (argyreia). It has been taken in colloidal form as an alternative treatment for bacterial infection, and as silver nitrate in eye drops for newborns to prevent blindness caused by gonorrhea. Blood, urine and hair can be used for its analysis.

Thallium (Tl): These compounds are extremely toxic, and because they are colourless and tasteless they have been used in criminal poisonings. A fatal dose of Tl is about 0.2 to 1 g absorbed by the GI system. Acute symptoms include diarrhea, nausea, abdominal pain and vomiting. This would be followed by neurological effects of neuropathy, neuritis, and cardiovascular symptoms of tachycardia with hypertension. A characteristic sign of Tl poisoning is alopecia about 2 weeks post-ingestion. Other signs include white bands on the nails, and atrophic changes of the skin. Most ingested Tl is excreted by the kidneys, but a portion is stored in many tissue sites. The toxicity of Tl results from its ability to substitute for potassium in the red blood cells, and thus inhibit the activity of the enzyme, Na/K ATPase. It can also bind onto sulfhydryl group sites of active enzymes. It may cause teratogenic effects in pregnant women as Tl is able to pass through the placenta to the fetus. In acute episodes of Tl toxicity, blood may be used, but urine monitoring is usually used. Chelating agents such as EDTA and dimercaprol (BAL) can cause a severe redistribution phenomena, and are not effective for treatment. Activated charcoal has been used, and slow intravenous potassium chloride infusions enhance Tl diuresis.

Uranium (U): Uranium with an atomic weight of 238.03 can exits in three isotopic forms: U-234, U-235 and U-238. The latter form contains 99% of natural uranium as trace amounts in rocks, soil, and water with weak background radiation. The decay process is very slow with a half-life of 4.5 billion yrs. The process of decay forms thorium and then lead (Pb). In this decay process, other radioactive by-products include radium and radon. Radioactive radon can pollute the air and water in homes with carcinogenic effects. Well water should be tested for uranium content. The amount of uranium in drinking water is 0.4 to 1.4 g/L. Amounts found in food such as root vegetables (beets and potatoes) can range from 0.08 to 70 g/kg. Those who live near uranium mines or industries have greater exposure levels. The toxicity of uranium is monitored in urine which can show detectable levels several months after exposure. Uranium can produce kidney disease and lung cancer from chronic exposure. For chronic exposure, hair analysis can reflect the tissue levels. Urine monitoring can be used with chelation therapy to follow the amount of U removed.