Toxic metals


Toxic metals


Toxic metals


Toxic metals

11.1 Laboratory investigation of toxic metals

Lothar Thomas

11.1.1 Heavy metals

According to reference /1/, heavy metals are naturally occurring elements that have a high atomic weight and a density at least 5 times greater than that of water. Their multiple industrial, domestic, agricultural, medical and technological applications have led to their wide distribution in the environment; raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the U.S. Environmental Protection Agency, and the International Agency for Research on Cancer.

Toxic metals are not usually found in elemental form, but occur ubiquitously in nature as more or less soluble salts or hydroxide compounds. High concentrations can be found in water, in sediments, and in foods derived from plants or animals. This chapter includes the following group of elements that are toxic to humans: aluminum (Al), arsenic (As), lead (Pb), cadmium (Cd), mercury (Hg), and thallium (TI). Their physiological function is largely unknown.

Toxic metals accumulate in the organs to varying degrees following high-dose exposure as a result of differences in absorption, distribution, and excretion. The toxicologic kinetics of these metals vary from element to element, but are based mainly on the properties of individual compounds, such as their water solubility /2/.

11.1.2 Indication for the determination of toxic metals

Suspected acute or chronic intoxication:

  • Absorption of a high dose of a toxic element (e.g., in a pesticide, dye, or cleaning product) either accidentally or with suicidal or criminal motives
  • Occupational-related exposure in areas metal production and metal processing
  • Chronic exposure in highly contaminated regions.

11.1.3 Specimen

Intoxication can be measured by determining the blood concentration and the urinary excretion of the metal. Occupational and environmental medicine take only an upper threshold but not the toxic limit into account when evaluating exposure. Deficiencies are not clinically relevant. Because metals accumulate in red cells, their concentrations are usually higher in whole blood than in serum or plasma. Plasma should be used in preference to serum to avoid the risk of contamination by elements that have accumulated within cells being released during coagulation. Blood should be collected using metal-free, lithium heparinate blood collection tubes.

The analysis of hair and nail samples can be of some use in toxicological or forensic investigations since toxic elements accumulate in these samples to varying degrees.

11.1.4 Method of determination

In the routine laboratory setting, arsenic, lead, cadmium, mercury, and thallium are often analyzed using direct electrothermal atomic emission spectrometry (ETAES). When ETAES is used to determine the concentration of mercury or arsenic, mercury is first enriched using the cold vapor technique and arsenic is first enriched using the hydride technique. Inductively-coupled mass spectroscopy (ICP-MS) is highly sensitive.

11.1.5 Clinical significance

Each toxic metal has unique features and physic-chemical properties that confer to its metal-induced toxicity and carcinogenicity. Because toxic metals accumulate in organs, organ biopsies and renal excretion respectively provide the most powerful and second most powerful confirmation of exposure. However, organ biopsies are seldom ethically acceptable.

Well regulated uptake and excretion mechanisms for essential trace elements are sometimes also used by toxic metals. In aluminum, lead, nickel, or cobalt intoxication, the divalent metal ion transporter of the enterocytes and/or its internal transport and storage protein metallothionein are used, which can reduce the absorption of iron and copper and lead to anemia /1/. The presence of lead inhibits the incorporation of iron into the heme molecule. The injury caused by toxic doses of metals with unknown functions can therefore be due to interactions with essential trace elements.

The direct effects of toxic metals are due to the triggering of oxidative reactions, the formation of complexes with proteins (e.g., via sulfhydryl groups) or the binding to active sites of enzymes and inhibition of enzyme activity. Pathological effects appear primarily in the form of micro angiopathies that cause typical toxic symptoms such as glomerular nephropathies, encephalopathies, stomatitis, and intestinal disturbances (Tab. 11.1-1 – Pathophysiological effects of toxic metal doses).

The degree of tissue damage depends on whether the element is absorbed by an organ, whether it is excreted again quickly or stored, and where it is stored. Mercury and cadmium accumulate primarily in the kidneys, whereas lead accumulates in the bones and arsenic accumulates in the liver. Fertility disorders associated with exposure to heavy metals are also becoming increasingly common /3/.

Hair analysis is not recommended for the determination of toxic elements since the correlation between the hair concentration and organ content is low for many elements. Furthermore, validated reference methods and generally accepted reference intervals do not exist for hair analysis and the results show limited reproducibility. Therefore, hair analysis is only useful for obtaining a rough estimate of exposure /4/.


1. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metals toxicity and the environment. EXS 2012; 101: 133–64.

2. Brätter P, Heseker H, Kruse-Jarres JD, Liesen H, Negretti de Brätter V, Pietrzik K, Schümann K. Mineralstoffe, Spurenelemente und Vitamine: Leitfaden für die ärztliche Praxis. Gütersloh; Bertelsmann Stiftung 2002: 88.

3. Gerhard I, Runnebaum B. Schadstoffe und Fertilitätsstörungen durch Schwermetalle und Mineralstoffe. Geburtsh Frauenheilk 1992; 52: 383–96.

4. Kruse-Jarres JD. Limited usefulness of essential trace element analyses in hair. Ann Clin Lab 2000; 19: 8–10.

5. Köppel C, Hallbach J, von Clarmann M, Ibe K. Klinische Interpretation. In: Gibitz HJ, Schütz H (eds). Einfache toxikologische Laboratoriumsuntersuchungen bei akuten Vergiftungen. Mittlg DFG Senatskommission für klinisch-toxikologische Analytik 1995/XXIII: 135–9.

6. Deutsche Forschungsgemeinschaft. Maximale Arbeitsplatzkonzentrationen und biologische Arbeitsstofftoleranzwerte. DFG-Senatskommission zur Prüfung gesundheitsschädigender Arbeitsstoffe, Mittlg XXI, Weinheim: Verlag Chemie, 1985.

7. Emsley J. Die Elemente. Berlin: Walter de Gruyter, 1994.

11.2 Aluminum (Al)

Lothar Thomas

Al is a ubiquitous element, comprising 8.1% of the earth’s crust. It is the third most abundant element, following oxygen and silicon, and the most abundant metal (even more abundant than iron).

Al tends to donate its three valence electrons to form colorless Al3+cations. These cations are hydrated in water [Al(H2O)6]3.. Al reacts quickly with air and water to form aluminum oxide and hydrogen. The elemental Al does not exist in pure state but is always combined with other compounds such as hydroxide, silicate, sulphate, and phosphate. The most important Al-containing silicon minerals are potassium feldspar (orthoclase) K(AlSi3O8), sodium feldspar (albite) Na(AlSi3O9), calcium feldspar (anorthite) Ca(Al2Si2O8), potassium mica (muscovite) KAl2(AlSi3O10)(OH,F)2 and cryolite Na3AlF6. The wide distribution of Al ensures the potential for causing human exposure and harm.

11.2.1 Indication

Suspected Al toxicity:

  • Evaluation of occupational exposure in the context of diseases affecting the lower respiratory tract and lungs
  • Monitoring individuals exposed to Al, such as workers in aluminum-processing plants
  • Monitoring dialysis patients on Al medications (phosphate binders).

11.2.2 Method of determination

Direct electrothermal atomic emission spectrometry (ETAES) /1/

11.2.3 Specimen

  • Serum, plasma: blood collection with metal-free collection devices: 1 mL
  • 24 h collection of urine or random specimen of urine with reference to creatinine excretion: 5 mL

11.2.4 Reference interval

Serum, Plasma /2/

< 5 μg/L (0.19 μmol/L)

24 h collection of urine /2/

< 15 μg/L (0.57 μmol/L)

Biological tolerance value for occupational exposure /2/

< 50 μg/g creatinine

Conversion: μg/L × 0.0371 = μmol/L

11.2.5 Clinical significance

Al occurs naturally in the environment, foodstuffs, and drinking water, but it is also used in processed foods, materials (aluminum containing food packaging, aluminum foils, cooking utensils and banking trays), cosmetic products and drugs /2/.

Aluminum exposition in the general population

Only about 0.1% of orally ingested Al is absorbed from the gastrointestinal tract. The tolerable weekly intake set by the European Food Safety Authority /3/ is 1 mg aluminum/kg body weight in adults and up to 2.3 mg/kg in children. Exceeding these values does not mean that there is an acute health hazard. The levels are designed to be precautionary and long-term values for the general population /2/.

Although Al has no biological function, a correlation exists between its local concentration in tissues and the degree of dysfunction it causes. In clinically healthy individuals with normal exposure to Al, the highest concentrations of Al are found in the spleen, lungs, liver, and bones. Other tissues contain 0.3–0.8 mg/kg wet weight, which is around 100–300 times higher than the Al concentration in the plasma /4/.

If renal function is normal, Al does not accumulate in the body even following increased intake. Plasma concentrations of up to 10 μg/L are still considered normal; however, the typical signs of Al intoxication can be absent at significantly higher concentrations.

The US Food and Drug Administration published a recommendation in 2004 regarding the contamination of parenteral nutrition. According to this recommendation, patients receiving parenteral nutrition should receive no more than 5 μg Al/kg body weight per day.

The clinical significance of the Al concentration in plasma and urine as an indicator of the body Al burden is shown in Tab. 11.2-1 – Plasma and urine aluminum concentration as a measure of aluminum exposure.

The urine accounts for > 95% of excreted Al. Reduced renal function increases the risk of Al accumulation in the very young, elderly and diseased individual. Occupational aluminum exposure

Urinary Al is the main criterion used to evaluate occupational Al exposure. A concentration of 300 μg/L (11.1 μmol/L) is the biological tolerance value. It is evaluated in combination with a clinical evaluation of neurotoxic symptoms. Workers can be exposed to high levels of Al in the workplace in the following situations, for example:

  • Extraction of metallic Al from bauxite or kaolin
  • Production of corundum from bauxite with inhalation of Al dust and vapor
  • Al processing in many branches of industry (e.g., Al welding). Aluminum intoxication

The plasma Al concentration can be used as a criterion for assessing the Al burden (Tab. 11.2-1 – Plasma and urine aluminum concentration as a measure of aluminum exposure). Toxicity is known to occur at concentrations > 100 μg/l, although neurotoxic symptoms may occur at > 50 μg/L. Studies on Al welders revealed that the content in welding fumes correlated with Al concentrations in plasma and urine.

There is no correlation of Al exposition and the urinary Al excretion in patients with decreased renal function. In dialysis patients, for example, there is no correlation between the accumulation of Al in the bones, neurotoxicity and the plasma concentration /6/. High acute exposure to Al is basically due to the use of Al compounds in medicines (antacids, phosphate binders, buffered aspirin, vaccines, allergen injections). Inadvertent Al contamination has been reported in infusion solutions, mainly human albumin /4/. In addition to occupational exposure, chronic Al exposure can result from:

  • Storing and preparing acidic foods in Al-containing cooking utensils
  • Feeding infants with soy-based formula
  • Regularly drinking water from Al-rich soils.

The toxic dose of Al is 5 g; the lethal dose is unknown /7/. The accumulation of Al is in the order liver > kidney > brain when mice were exposed to Al sulphate in drinking water. The most important toxic effects of Al are neurotoxicity, bone disease, anemia, and pulmonary fibrosis /8/. Ingestion of aluminum phosphide causes acute fatal poisoning. Diseases and symptoms associated with Al intoxication are listed in Tab. 11.2-2 – Diseases and conditions associated with toxic plasma Al concentrations.

11.2.6 Comments and problems

Blood sampling

Blood should be collected using plastic heparin monovettes. Specimens collected in glass tubes must be processed and transferred to plastic containers within 1 h of collection to minimize alteration of Al concentration /9/. Contamination from other sources of this ubiquitous element when collecting, storing, and processing samples must be avoided.


Chronic excessive intake of Al is also reflected in the hair. When hair is used as a specimen, however, contamination during sample preparation cannot be distinguished from toxic Al concentrations.


In a study /10/ many serum Al concentrations in the toxic range were not confirmed after retesting. Serum Al concentrations of 60 μg/l or greater were considered false positives and not indicative of chronic toxicity if another specimen retested within 45 days had a concentration below 20 μg/l.

11.2.7 Pathophysiology

Because Al occurs mainly in silicon compounds as water-insoluble complexes, its bio availability is greatly reduced. At pH 3–8, its amphoteric character allows it to be transformed from free Al3+ into [Al(OH)4]. At pH 7.4, Al exists as barely soluble Al(OH)3, which is significantly more soluble at acidic pH. Because it can bind to oxygen, nitrogen, and phosphate atoms, Al reacts well with biological macromolecules such as proteins.

The body stores 30–50 mg of Al: 50% in the bones, 25% in the lungs, and 1% in the brain /8/. The oral bio availability of Al is around 0.3% from water and 0.1% from the diet. The main absorption site for Al is the proximal part of the small intestine. The absorption of Al, including Al(OH)3, is inhibited by phosphates in food. Al bound to citrate, on the other hand, is absorbed more easily. This is why using antacids and drinking fruit juice at the same time can lead to a significant acute Al burden.

In the plasma, Al competes with iron to bind to the transport protein apotransferrin. Up to 90% of the Al is bound to transferrin; the rest is bound to citrate. Like iron, Al is taken up by cells via the transferrin receptor and bound to proteins in the cytoplasm. The tissue Al concentration is 0.3–0.8 mg/kg wet weight and increases with age. Al not incorporated into the tissues is eliminated by the kidneys. Uremic hemodialysis patients have increased plasma Al concentrations and increased amounts of Al in the bones and liver.

The brain has a lower Al concentration than many other tissues, because Al transport out of brain extracellular fluid occurs by mono carboxylate transporter or transferring mediated endocytosis and glutamate transporter /4/. However, this system can become overburdened due to a Al intake, which leads to increased accumulation of Al in the brain (normal brain concentration is no more than 0.25–0.75 mg/g wet weight).

At cellular level, Al accumulates in mitochondrial membranes, in the reticuloendothelial system of the liver and spleen, and in lysosomes.

Al can displace iron from its functional bonds in enzymes and coenzymes. There is some overlap between the symptoms of Al intoxication and the symptoms of iron intoxication (hemosiderosis).

The toxic effects of Al exposure are thought to be due to reduced mitochondrial function caused by oxidative stress. This has a negative impact on the respiratory chain, in particular, complex I and ATP synthesis. Nucleotide content is also reduced by the inhibition of nucleotide translocase and the increased lipid peroxidation in Al intoxication causes mitochondrial swelling.


1. Tahán JE, Granadillo VA, Romero RA. Electrothermal atomic absorption spectrometric determination of Al, Cu, Fe, Pb, V and Zn in clinical samples and certified environmental reference materials. Anal Chim Acta 1994; 295: 187–97.

2. Klotz K, Weistenhöfer W, Neff F, Hartwig a, van Thriel C, Drexler H. The health effects of aluminum exposure. Dtsch Arztebl Int 2017; 114: 653–9.

3. European Food Safety Authority. Safety of aluminum from dietary intake, scientific opinion of the panel of food additives, flavourings, processing aids and food contact materials. ESFA J 2008; 1–34.

4. Kumar V, Gill KD. Aluminium neurotoxicity: neurobehavioural and oxidative aspects. Arch Toxicol 2009; 83: 965–78.

5. Rükgauer M. Aluminium. In Thomas L, ed. Labor und Diagnose. Frankfurt 2008; TH-Books, 507–9.

6. Macdonald TL, Martin RB. Aluminium ion in biological systems. Trends Biochem Sci 1988; 13: 15.

7. Emsley J. Die Elemente. Berlin: Walter de Gruyter 1994: 14–5.

8. Yokel RA, McNamara PJ. Aluminium toxokinetics: an updated minireview. Pharmacology and Toxicology 2001; 88: 159–67.

9. Frank EL, Hughes MP, Bankson DD, Roberts WL. Effects of anticoagulants and contemporary blood collection containers on aluminium, copper and zinc. Clin Chem 2001; 47: 1109–12.

10. Schifman RB, Luevano DR. Aluminum toxicity. Arch Pathol Lab Med 2018. doi: 10.5858/arpa.2017-0049-OA.

11. Sedman AB, Wilkening GN, Warady BA, Lum GM, Alfrey AC. Encephalopathy in childhood secondary to aluminium toxicity. J Pediatr 1984; 105: 836–48.

12. Hellstroem HO, Mjöberg B, Mallmin H, Michaelsson K. No association between aluminium content of trabecular bone and bone density, mass or size of the proximal femur in elderly men and women. BMC Muskuloskelet Disord 2006; 7: 69.

13. Boukhari LV, Nacher M, Goulle JP, Roudier E, Elguindi W, Laquerriere G. Plasma and urinary aluminium concentrations in severely anemic geophagous pregnant women in the Bas Maroni region of French Guiana: a case control study. Am J Tro Med Hyg 2010: 83: 1100–5.

14. Kiesswetter E, Schäper M, Buchta M, Schaller KH, Rossbach B, Kraus T, Letzel S. Longitudinal study on potential neurotoxic effects of aluminium: II. Assessment of exposure and neurobehavioral performance of Al welders in the automobile industry over 4 years. Int Arch Occup Environ Health 2009; 82: 1191–1210.

15. Fritschi L, Hoving JL, Sim MR, Del Monaco A, MacFarlane E, McKenzie D, et al. All cause mortality and incidence of cancer in workers in bauxite mines and alumina refineries. Int J Cancer 2008; 123: 882–7.

16. Mathai A, Bhanu MS. Acute aluminium phosphide poisoning: Can we predict mortality? Indian J Anaesth 2010; 54: 302–7.

17. Mehrpour O, Alfred S, Shadnia S, Keyler DE, Soltaninejad K, Chalaki N, Sedaghat M. Hyperglycemia in acute aluminium phosphide poisoning as a potential prognostic factor. Human & Experimental Toxicology 2008; 27: 591–5.

11.3 Arsenic (As)

Lothar Thomas

As is a metallic element that occurs naturally in the earth’s surface at 1.5 to 2 ppm, mostly in inorganic form. However, As is not uniformly distributed throughout the world. Arsenic generally exists in low concentrations in many rock types but is frequently associated with metal ore deposits (e.g., Au, Ag, Cu and Fe) /1/. Because surface and ground water are often in contact with ores or tailings, waters near former melting or smelting sites often contain elevated As concentrations. Although most As compounds have no smell or taste, heat can cause As to sublimate to a gas with a garlic odor.

Depending upon environmental conditions inorganic As exists in the valence states –3, 0, +3, and +5 /1/:

  • In oxidizing conditions As will usually exist as compounds of H3AsO4 called arsenates (+5)
  • In mildly reducing conditions, As is generally present as H3AsO3 compounds called arsenites (+3)
  • In moderate reducing conditions, As often combines with S and Fe to form As sulfides or FeAs, which are virtually insoluble in water and immobilized in the environment
  • In strongly reducing environments, elemental As (0) or H3As (–3) can exist, but such conditions are rare.

11.3.1 Indication

Suspected acute or chronic As toxicity: www.atsdr.cdc.gov/spl.

  • Exposition to As containing drinking water
  • Inhalation of arsine gas
  • Oral intake of As compounds either accidentally or with suicidal or criminal motives
  • Suspected intoxication due to occupational exposure.

11.3.2 Method of determination

  • Atomic absorption spectrophotometry with flame less hydride technique.
  • Neutron activation analysis is scientifically the most suitable method because it does not require any special sample preparation and it has very low detection limit.
  • The IC-ICP-MS method using a Dionex 5000 with ion chromatography for separation and iCAP Q for detection is used for detection and separation of arsenic in urine. Toxic arsenite (AsIII) and toxic arsenate (AsV) and the less toxic metabolites monomethyl arsenic acid (MMA) and dimethylarsenic acid (DMA) are determined /27/.

11.3.3 Specimen

  • Whole blood: 3 mL
  • 24 h urine specifying the collected volume: 5 mL

11.3.4 Reference interval

Whole blood /3/

< 160 nmol/L

< 12.0 μg/L

Urine /3/

< 618 nmol/24 h*

< 47.0 μg/24 h*

* Expressed for 1,5 L/24 h; Conversion: μg/l × 13,3 = nmol/l

11.3.5 Clinical significance

Exposure to arsenic (As) can occur through ingestion, inhalation, and contact with the skin. In As-prone areas, many people suffer from skin disorders, respiratory diseases, disorders of the nervous system, obstetric disorders, diabetes, cardiovascular diseases, as well as cancers of various organs /4/.

Arsenobetaine and arsenocholine are organic forms created through biotransformation in seafood and are considered as nontoxic. Distribution of arsenic

The US Agency for Toxic Substances and Disease Registry ranked As top among hazardous substances in their 2015 priority list (www.atsdr.cdc.gov/spl). As is widely dispersed around the world. As is released into the environment through anthropogenic pollution. As contamination in groundwater occurs in more than 107 countries worldwide and is major contributor to inorganic As intake for the global population, especially for Asians, who consume rice as a staple food. Large populations in America, Bangladesh, China and India are exposed to arsenite and arsenate via drinking water /1/.

As in air, soil, water and diet /1/

Diet and drinking water together usually account for 99% of the total human intake. The calculated tolerable daily intake for inorganic As from all sources is 0.45 μg/kg body weight per day /5/.

Air: As concentrations of 1 to 3 ng/m3 has been detected in remote areas, yielding estimated daily As intakes of 20–200 ng. In urban areas without substantial industry emissions were 20–30 ng/m3, yielding estimated daily As intakes of 400–600 ng /1/.

Soil: As may consist in numerous forms in soil. It may be complexed with organic material, it may be bound as an inorganic oxyanion to soil cations, or it may exist in its mineral form. If the soil overlays an ore deposit rich in sulfides, the arsenic level may reach several hundred mg/kg, but more typical values tend to be in the range of 0.1 to 40 mg/kg in most soils /6/.

Diet: the As content of various foods per kg dry weight are as follows: apples 0.04–1.72 mg, rice up to 3.53 mg, potatoes up to 1.25 mg, beef 0.008 mg, pork 0.22–0.32 mg, crabs 27–52.5 mg. The large amounts of arsenic in seafood are due to organically bound arsenic in the form of harmless arsenobetaine and arsenocholine /5/.

Arsenic in water: inorganic As occurs in drinking water as arsenite or arsenate. The mean As concentration in surface water is 0.001 mg/L. In Germany, and subsequently, in the WHO guidelines for drinking water, an upper limit of 0.01 mg/L was specified for the As concentration in water, to ensure that a potentially carcinogenic daily dose of 0.2 mg is not exceeded /5/. Surface water contains mainly arsenate, whereas groundwater contains mainly arsenite. Many regions of the world, such as Bangladesh, have higher water As concentrations. Here, water is mostly extracted from groundwater through 4 million shallow tube-wells from deep rock layers, and 8%, 35%, and 58% of water samples contain 0.3 mg, more than 0.05 mg, and more than 0.01 mg of As per liter of water respectively. In Bangladesh, As occurs mainly as arsenite. More than 20,000 deaths occur each year and the health of 50 million people is threatened as a result of these elevated As concentrations /7/. In the USA, 5% of water sources exceed the upper limit specified by the WHO. More than 350 thousand people are exposed to As concentrations of more than 0.05 mg/L and more than 2.5 million are exposed to concentrations of more than 0.025 mg/L /8/. Toxic effects of arsenic

The toxicity of As is highly influenced by its oxidation state, solubility, exposure dose, frequency and duration, the biological species, age and gender, as well as on genetic and nutritional factors /18/. In general, trivalent As compounds are more toxic than their pentavalent equivalents and inorganic compounds are more toxic than organic compounds such as methylated arsenic compounds. Although arsenites (AS+3) have a higher affinity than arsenates (As+5) for binding to disulfide, which plays an important role in the toxicity of the arsenites, a positive correlation also exists between toxicity and solubility. Arsenates are more soluble than arsenites. To eliminate the more toxic arsenites from groundwater, for example, these must first be oxidized using oxygen. Arsenic trioxide, arsenic hydride (colorless, with a garlic-like odor), and 2-chlorovinyldichloroarsine are highly toxic /9/. Arsenic hydride does not occur in the natural environment but is intentionally or unintentionally produced as a result of human activities. It is also produced by bacteria.

Elemental As and organic As compounds are only mildly toxic, e.g. arsenobetaine, which exists in appreciable quantities in marine organisms.

The following doses (in mg/kg body weight) of different forms of As have been shown to be lethal in rats: arsenites 1.5, arsenates 5, monomethylarsinate 50, dimethylarsinate 500 /8/.

In the environment, As+3 is converted into (As+5) and vice versa chemically or biologically. Bacteria and phytoplankton transform arsenate to arsenite and vice versa. Many organisms also form organic As compounds by methylation, which takes place mainly in soil and water. In the human body, (As+5) compounds are converted into (As+3) compounds, which in turn are methylated to form less toxic metabolites and excreted renally.

In groundwater, As exists as arsenite or arsenate. Arsenate that is ingested in drinking water is converted relatively quickly into arsenite. This either takes place non-enzymatically, with glutathione as an electron donor, or is catalyzed by the enzyme glutathione S-transferase.

Arsenic exerts its toxic effects through impairment of cellular energy regeneration by the inhibition of mitochondrial enzymes, and through uncoupling of oxidative phosphorylation. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorous in a variety of biochemical reactions /7/. Laboratory diagnostics

The determination of As in the blood and urine can be used to evaluate both acute and chronic As intoxications. Repeated measurements of these indices can be used to depict long-term exposure level and changes in exposure over time. The Health Effects of Arsenic Longitudinal Study (HEALS) found a high degree of correlation between urine values and blood values in individuals with chronic As exposure. Urinary arsenic concentration was a useful biomarker for tracking arsenic exposure and did not fluctuate greatly over time /10/.

Acute As toxicity is usually diagnosed by increased urinary As in excess of 50 μg/L (665 nmol/L) or 100 μg (1,330 nmol) in a 24-hour urine, and a shorter time span before examination, if no seafood has been ingested /11/. As speciation of inorganic or organic forms of As is often as important as total quantification, because of their different toxicity and mobility. As speciation in biological samples is an essential tool to gain insight into its distribution in tissues and its specific toxicity to target organs /11/. Many organic As compounds that are present in appreciable amounts in marine organisms are only mildly toxic. Consumption of this “fish arsenic” does not cause intoxication /11/. The diet in the days before the examination must also be taken into consideration, because a diet high in marine organisms can lead to relatively high urinary As, which may be mistaken for chronic intoxication. For example, the urinary As concentration following a seafood meal was 291 ± 267 μg/L, while a few days later, it was only 9 ± 12 μg/L /13/.

At low exposure levels, changes in the blood As concentration are so slight or transient that it is easier to make a diagnosis using a urine sample /14/.

Acute intoxication

If intensive treatment is not started immediately, oral doses of As2O3 of 70–180 mg are fatal within 1 hour /15/. When an individual is exposed to sub fatal doses, the length of time frame for the appearance of symptoms depends on the dose involved, the route of exposure, and the health of the individual /1/. The clinical symptoms are vomiting, abdominal pain, and diarrhea. Neurological effects of As may develop within a few hours after ingestion, but usually are seen 2–8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain-Barré syndrome. The predominant clinical features of neuropathy are paresthesia, numbness and pain, particularly in the soles of feet /11/.

Chronic intoxication

In chronic long-term exposures, individuals begin to display characteristic signs of As toxicity at oral intakes of about 20 μg/kg per day of body weight, but some humans can ingest over 150 μg/kg per day without any apparent illness /16/. Chronic As intoxication can result from drinking water, industrial accidents, occupational exposure, or environmental exposure.

The initial clinical symptoms of long-term exposure to low levels of As (arsenicosis) are skin discolorations, chronic indigestion, and stomach cramps. Longer-term effects include skin, lung, kidney, liver, cardiovascular system, peripheral vascular system, and reproductive system, as well as neurological diseases and carcinomas. The European Chemicals Bureau and US Environmental Protection Agency classified As as a carcinogen in 2007.

Although the deleterious effects of high As concentrations in drinking water (over 300 μg/L) have been documented, the chronic disease-causing effects of low to moderate concentrations (10–300 μg/L) cannot be attributed to As alone. Lifestyle factors such as smoking, body mass index, and genetic factors that influence arsenic metabolism must also be taken into consideration /10/. Diseases caused by acute and chronic As intoxication are listed in Tab. 11.3-1 – Diseases and conditions associated with acute and chronic arsenic intoxication.


The treatment of As intoxication focuses mainly on accelerating elimination while reactivating blocked enzymes by administering an antidote (dimercaptopropanol, BAL).

11.3.6 Comments and problems


Chronic high As intake is also reflected in the hair. Since the determination of As in hair samples has not yet been sufficiently validated, measured values cannot be used to reliably determine As levels in the organs.


Samples can be stored for up to 2 months at 4 °C or deep-frozen (–20 °C). No additives are required /17/.

11.3.7 Pathophysiology

Following intake, soluble As salts are absorbed rapidly in the small intestine with an absorption rate of 95% (this percentage is probably lower for mono methylated and dimethylated compounds). As is then distributed rapidly throughout the body and can be found in different organs, in particularly, the liver. As undergoes hepatic bio methylation to form mono methyl arsenic (MMA) and dimethyl arsenic acids (DMA). The uptake of trivalent arsenic compounds is mediated by aquaglyceroporin and pentavalent arsenates are transported into cells by phosphate transporters. As accumulates in hair, nails, and skin and also reaches the placenta, breast milk, and brain (via the cerebrospinal fluid) /1517/.

As is detoxified in the liver by the transformation of inorganic As into organic As and the reduction of pentavalent As into trivalent As. The reduction is catalyzed by glutathione and other thiols, which are reducing agents or can be catalyzed by the enzyme glutathione S-transferase. Methylation of the trivalent arsenic compounds then occurs, catalyzed by As (III) methyl transferase, which uses S-adenosyl methionine (SAM) as a methyl donor. A methyl group is added to arsenite, which leads to the synthesis of pentavalent MMA. Pentavalent MMA is immediately reduced again by glutathione to form trivalent MMA. Trivalent MMA is then methylated to form DMA. Not all methylation steps end with DMA; other metabolites such as trimethyl arsenite or trimethyl arsinoxide are also produced.

As-containing compounds are excreted by the kidney. DMA is the main metabolite. Typically, 60–80% of As is excreted in the urine as DMA, 10–20% is excreted as MMA, and 10–30% is excreted as inorganic As. Specific single nucleotide polymorphisms of As(III) methyl transferase lead to a 50% reduction in the excretion of DMA.

Many metals, such as As, cadmium, lead, and mercury, have an affinity for sulfhydryl groups and can change the protein structure. This reduces the activity of enzymes that are involved in energy metabolism, DNA synthesis, and DNA repair.

As, instead of phosphate, is incorporated into energy-rich compounds such as ATP, which reduces the amount of energy available for metabolic processes (e.g. for glucose uptake by cells, gluconeogenesis, fatty acid oxidation, and glutathione synthesis).


1. Jones FT. A broad view of arsenic. Poultry Science 2007; 86: 2–14.

2. Schlemmer G. Welz B. Grundlagen atomspektrometrischer Analytik. Lab Med 1986; 10: 160–5.

3. Arnold W. Arsenic. In: Seiler HG, Sigel H, Sigel A (eds). Toxicity of inorganic compounds. New York; Marcel Dekker: 1988: 79–93.

4. Deng F, Yamaji N, Feng Ma J, Lee S-K, Jeon JS, Martinoia E, Lee Y, et al. Engineering rice with lower grain arsenic. Plant Biotechnol J 2018. doi: 10.1111/pbi.12905

5. Schuhmacher-Wolz U, Dieter HH, Klein D, Schneider K. Oral exposure to inorganic arsenic: evaluation of its carcinogenic and non-carcinogenic effects. Crit Rev Toxicol 2009; 39: 271–98.

6. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metals toxicity and the environment. EXS 2012; 101: 133–64

7. Chaudhuri A. Dealing with arsenic contamination in Bangladesh. MIT Undergrad Res J 2004; 11: 25–30.

8. Nordstrom DK. Worldwide occurrences of arsenic in ground water. Science 2002; 296: 2143–5.

9. Miller WH, Schipper HM, Lee JS, Singer J, Waxmam S. Mechanism of action of arsenic trioxide. Cancer Research 2002; 62: 3893–903.

10. Chen Y, Parvez F, Gamble M, Islam T, Ahmed A, Argos M, et al. Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurologic functions, and biomarkers for respiratory and cardiovascular diseases: Review of recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Toxicology and Applied Pharmacology 2009; 239: 184–92.

11. Vahidnia A, van der Voet GB, de Wolff FA. Arsenic neurotoxicity – a review. Hum Exp Toxicol 2007; 26: 823–32.

12. Mückter H. Arsen. In: Biesalski HK, Köhrle J, Schümann K (eds). Vitamine, Spurenelemente und Mineralstoffe. Stuttgart; Thieme 2002: 210–7.

13. Kales SN, Huyck KL, Goldman RH. Elevated urine arsenic: un-speciated results lead to unnecessary concern and further evaluations. J Anal Toxicol 2006; 30: 80–5.

14. Daldrup T, Franke JP, eds. Metallscreening aus Urin bei akuten Vergiftungen. Mittlg DFG Senatskommission für klinisch-toxikologische Analytik 1993; XXII: 8–12.

15. New Hampshire Department of Environmental Services. 2004. Arsenic environmental fact sheet ARD-EHP-1. www.des.nh.gov/organization/commissioner/pip/factsheets/ard/documents/ard-ehp-1.pdf. Accessed May 2006.

16. Ontario Ministry of Environment. 2001. Arsenic in the environment. https://collections.ola.org/mon/1000/10294039.pdf. Accessed February 2006.

17. Feldmann J, Lai VWM, Cullen WR, Ma M, Lu X, Le XC. Sample preparation and storage can change arsenic speciation in human urine. Clin Chem 1999; 45: 1988–97.

18. Druwe Il, Vaillancourt RR. Influence of arsenate and arsenite on signal transduction pathways: an update. Arch Toxicol 2010; 84: 585–96.

19. Pakulska D, Czerczak S. Hazardous effects of arsine: a short review. Int J Occup Med Environ Health 2006; 19: 36–44.

20. Sengupta SR, Das NK, Datta PK. Pathogenesis, clinical features and pathology of chronic arsenicosis. Indian J Dermatol Venereol Leprol 2008; 74: 559–70.

21. Ashan H, Chen Y, Zablotska L, Argos M, Hussain AI, Momotaj H, et al. Arsenic exposure from drinking water and risk of premalignant skin lesions in Bangladesh: baseline results from the Health Effects of Arsenic Longitudinal Study. Am J Epidemiol 2006; 163: 1138–48.

22. Tseng CH. Cardiovascular disease in arsenic-exposed subjects living in the arseniasis-hyperendemic areas in Taiwan. Atherosclerosis 2008; 199: 12–8.

23. Wang CH, Hsiao CK, Chen CL, Hsu LI, Chiou HY, Chen SY, et al. A review of the epidemiologic literature on the role of environmental arsenic exposure and cardiovascular diseases. Toxicol Appl Pharmacol 2007; 222: 315–26.

24. Rahman MM, Ng JC, Naidu R. Chronic exposure of arsenic via drinking water and its adverse health impacts on humans. Environ Geochem Health 2009; 31: 189–200.

25. Chou WC, Chung YT, Chen HY, Wang CJ, Ying TH, Chuang CY, et al. Maternal arsenic exposure and DNA damage biomarkers, and the associations with birth outcomes in a general population from Taiwan. PLOS one 2014; 9: issue 2, e86398.

26. Karagas MR, Stukel TA, Morris JS, Tosteson TD, Weiss JE, Spencer SK, et al. Skin cancer risk in relation to toenail arsenic concentrations in a US population-based case-control study. Am J Epidemiol 2001; 153: 559–65.

27. Wegwerth PJ, Erdahi SA, Wermers ML, Hanley M, Eckdahl AJ, Jannetto PJ. Reliable, rapid, and robust speciation of arsenic in urine by IC-ICP-MS. JALM 2021; July; 846–57.

11.4 Lead (Pb)

Lothar Thomas

Lead is a soft metal that is white and shiny when freshly cut. Pb occurs naturally in the earth’s crust at 2 × 10–4 percent. Pb forms divalent or tetravalent compounds and its predominant oxidation state is +2. Pb(IV) derivatives are strong oxidizing agents. The most important mineral is PbS (lead glance). Pb also exists in the form of carbonate, chromate, molybdate, phosphate, and tungstate.

11.4.1 Indication

Suspected acute or chronic lead intoxication:

  • Accidental oral ingestion of lead compounds
  • Workers with high levels of occupational exposure, for example, workers in smelting plants, lead refineries, and the lead-processing industry
  • Inhabitants of highly contaminated regions
  • Patients with clinical symptoms suggestive of acute or chronic lead intoxication

11.4.2 Method of determination

Electrothermal atomic emission spectrometry (ETAES) /1/.

11.4.3 Specimen

11.4.4 Reference interval

Refer to Tab. 11.4-2 – Lead reference intervals.

11.4.5 Clinical significance

As a result of environmental protection measures in the workplace and the ban on leaded fuel, environmental and blood Pb concentrations have decreased significantly in western industrialized nations. This is supported by data from the German Environmental Survey and the National Health and Nutrition Examination Survey in the USA. German Environmental Survey 1998

Blood Pb concentrations of below 4 to 380 μg/L (0.02 to 1.82 μmol/L) were measured, with a geometric mean of 30.7 μg/L (0,15 μmol/L). Reference values were lowered based on this survey. The following factors influenced the Pb concentration in the survey /2/:

  • Age (increased concentrations were measured in the age groups 18–19 years to 50–59 years)
  • Hematocrit (a positive correlation was found between blood Pb concentration and hematocrit)
  • Frequency of consumption of beer, sparkling wine, and fruit wine (Pb concentrations increased with frequency of consumption)
  • Pb concentration in domestic drinking water.

Threshold Pb levels above which chronic intoxication can occur:

  • For women of childbearing age and children: Values ≥ 100 μg/L (0.48 μmol/L).
  • For men and women over 45 years of age: values ≥ 150 μg/L (0.72 μmol/L). National Health and Nutrition Examination Survey in the USA

Data from the National Health and Nutrition Examination Survey study in the United States show a decline in the geometric mean Pb blood level in the general population from 131 μg/L (0.63 μmol/L) in 1976–1988 to 16 μg/L (0.08 μmol/L) in 1999–2002. Factors linked to higher Pb concentrations were older age, male sex, smoking, Pb in old paint and water pipes, drinking, lower socioeconomic status, urban residence, and housing in older buildings. According to the Bio monitoring Study of Lead in New York City, the geometric mean of the blood Pb in the general population was 17.9 μg/L (0.09 μmol/L). Smokers had a concentration of 24.9 μg/L (0.12 μmol/L), construction workers had a level of 28.6 μg/L (0.14 μmol/L), and Chinese immigrants had mean values of 24.9 μg/L (0.12 μmol/L). Lead metabolism

Pb dust and Pb compounds are absorbed primarily via the respiratory tract (70–100%) and, to a lesser extent, via the gastrointestinal tract (5–20%) /6/. If the particle size is less than 1 μm, inhalation accounts for around 90% of absorption. Enteral absorption depends on the physicochemical characteristics of the Pb (metallic, inorganic or organic compound) and whether it contains other cations such as Ca2+, Fe2+ , and Zn2+. The absorption rate of Pb is 11% for adults. Lipophilic Pb, such as the antiknock agent tetraethyl lead, is absorbed well by the skin. The Pb concentration rises fast after Pb exposure, but within 100 days Pb is redistributed to soft tissues and bones.

The absorbed Pb is accumulated in the body in three compartments:

  • About 95% is stored in the bones of adults. The half-life is 4–20 years. Pb is stored for longer in cortical bone than in trabecular bone.
  • Below 5% of Pb is free in plasma, and the rest is bound within the erythrocyte to the enzyme δ-aminolevulinic acid dehydrogenase (ALAD). The half-life of Pb in the blood is 35 days.
  • Below 5% of Pb is localized in soft tissues. The half-life of Pb in soft tissues is about 30 days and in the brain 2 years.

Metallic Pb is eliminated by the kidneys (75%), in the bile (15%), and via the hair and nails (10%). Clinical symptoms

The clinical symptoms of Pb intoxication are anemia, neuropathy, nephropathy, gastrointestinal disorders, reproductive disorders, and cardiovascular effects. In the Nurses’ Health Study, early menopause (< 45 years) was more common in women with the highest tibial Pb concentrations than those with the lowest Pb concentrations (odds ratio 5.3) /7/.

Clinical findings due to increased blood Pb concentration and elevated urinary Pb excretion are listed in Tab. 11.4-3 – Clinical disorders due to increased lead concentration in the blood and urine.

Diseases and symptoms associated with Pb intoxication are listed in Tab. 11.4-4 – Diseases and conditions associated with lead intoxication. Laboratory diagnostics

Determination of Pb in whole blood

Because of the short mean biological half-life in blood the Pb concentration reflects an ongoing exposure. However, if exposure to Pb has been going on for a long period of time, giving rise to a high body burden of Pb, blood level of Pb will remain elevated for an extended period of time. Normal blood Pb concentrations do not rule out Pb intoxication /6/.

Supplementary investigations and findings

Pb inhibits three important enzymes in hemoglobin synthesis (ALAD, coproporphyrinogen oxidase, and ferrochelatase), which show the following results in lead intoxication /6/:

  • Reduced ALAD activity in erythrocytes (less than 10% of normal)
  • Increase in free erythrocyte protoporphyrin (over 500 mg/L whole blood)
  • Increase in renal excretion of δ-aminolevulinic acid (over 20 mg/L urine)
  • Increased renal excretion of coproporphyrin III (over 0.5 mg/L urine)
  • Basophilic stippling of erythrocytes (more than 100 stippled cells per 1 million erythrocytes)
  • Abnormalities in complete blood count: hypochromic anemia, anisocytosis, poikilocytosis /8/.

Pb mobilization test

To measure the Pb burden, one can perform a mobilization test using a chelating agent /6/. Urine examinations do not provide information about exposure quantity, unless a Pb mobilization test is performed. Blood Pb and the EDTA-test are correlated under steady-state circumstances, especially if the exposure is recent. This is because most of the chelatable Pb comes from the blood-soft tissue compartments, and to a lesser extent from trabecular bone with higher bio availability compared with the cortical bone. The exchange of Pb is greater during increased bone turnover such as pregnancy, immobilization, or hyperparathyroidism /6/.

Non-invasive measurement of lead: Due to the high contamination risk, hair analyses cannot be used for diagnostic purposes. A non-invasive way to measure stored Pb is by in-vivo X-ray fluorescence of the bone. Stored Pb can be estimated by determining the Pb concentration in exfoliated milk teeth.

Recommended treatment

Forced Pb excretion using chelating agents such as CaNa2EDTA, dimercaptopropane sulfonate (DMPS), or 2,3 dimercaptosuccinic acid (Succimer) increases renal Pb excretion by a factor of 25–30. The chelating agents are used for Pb intoxication when the blood concentration is above 400 μg/L (1.9 μmol/L) /9/. The German Society for Occupational and Environmental Medicine recommends forced excretion if the blood concentration of Pb exceeds 150 μg/L (0.72 μmol/L) for women or 250 μg/L (1.2 μmol/L) for men /10/. The United States Centers for Disease Control and Prevention recommends forced Pb excretion in children for Pb concentrations ≥ 450 μg/L (2.16 μmol/L).

11.4.6 Comments and problems

Blood sampling

Metal-free blood collection devices that contain lithium heparin or EDTA should be used.

Hair mineral analysis

Chronic high Pb intake is reflected in the hair. However, contamination during sample preparation cannot be distinguished from toxic Pb concentrations in the hair.

Influence factors

The blood Pb concentration increases in exsiccosis with increased hematocrit.

Urine determination

Incomplete collection, contamination, precipitation of Pb salts, and absorption of Pb onto vessel walls with polar properties lead to falsely low results.

11.4.7 Pathophysiology

Non-occupational Pb exposure occurs as a result of oral ingestion or inhalation of contaminated food or air. Pb is absorbed by the lungs and the intestine, depending on the food component. Calcium, zinc, phosphate, and phytate inhibit its uptake. Fasting, for example, can increase the absorption rate of Pb by up to 60% /6/. Children can absorb 30–75% of the Pb ingested, while adults absorb about 11% of ingested Pb.

One of the major mechanisms by which lead exerts its toxic effect is through biochemical processes that include lead’s ability to inhibit or mimic the actions of calcium and to interact with proteins. Within the skeleton, lead is incorporated into the mineral place of calcium. Pb has a high affinity for the sulfhydryl group of cysteine, the amino group of lysine, the carboxyl group of glutamate and aspartate, and the hydroxyl group of tyrosine. Of all the cellular structures, the mitochondria are most sensitive to Pb.

Circulating Pb is quickly taken up from the plasma into erythrocytes and bound to δ-aminolevulinic acid dehydrogenase (ALAD). The binding capacity of erythrocyte ALAD for Pb is so high that it cannot be saturated, even in severe Pb intoxication. From the red blood cells, Pb is distributed to the liver, kidneys, and brain. With a half life of around 30 days, Pb is released from these tissues and is eliminated by the kidneys or deposited in the skeleton as Pb phosphate. The Pb content of the skeletal system increases with age and constitutes 70% of the total Pb burden in children and 90% in adults.

Renal excretion of Pb is delayed in severe renal insufficiency; this must be taken into account during forced Pb elimination using chelating agents. The movement of Pb out of bones is increased when bone metabolism is activated by hyperparathyroidism, immobility, or pregnancy, for example.

Enteral and red blood cell uptake of Pb are decreased in the presence of iron, probably because both elements are transported into the cell using the same metal ion transporter. For this reason, iron deficiency potentiates Pb absorption.

Pb inhibits the synthesis of heme, mainly due to the effect of Pb on the mitochondrial membrane. Heme acts as both an oxygen carrier in the red blood cells and a respiratory pigment in the cytochrome c system of all cells. Heme synthesis begins and ends in the mitochondria; intermediate steps take place in the cytoplasm. Pb disrupts heme synthesis by inhibiting ALAD and ferrochelatase /22/. ALAD is a cytoplasmic enzyme, while ferrochelatase is a mitochondrial enzyme.

Inhibition of ALAD

In the first step of heme synthesis, this enzyme catalyzes the condensation of two molecules of δ-aminolevulinic acid (δ-ALAS) to porphobilinogen (see also Fig. 14.6-1 – First step of heme synthesis). The half maximal inhibition of ALAD takes place at a blood Pb concentration of 160 μg/L (0.77 μmol/L) and 90% inhibition at a concentration of 550 μg/L (2.64 μmol/L) /24/. As a metabolic consequence of ALAD inhibition, δ-ALAS accumulates and its urinary excretion increases. The increased δ-ALAS concentration in the tissues causes neurological symptoms. ALAD activity depends on the integrity of the sulfhydryl groups and on the availability of zinc, because each molecule of ALAD contains one molecule of zinc. The inhibition of ALAD can be reversed by increasing the availability of zinc.

Inhibition of ferrochelatase

This enzyme catalyzes the final step in heme synthesis, the incorporation of iron into the protoporphyrin ring (see Fig. 14.6-2 – Heme biosynthesis: enzyme disorders in porphyrias). If this step is inhibited, iron-free protoporphyrin is incorporated into the heme-binding pockets in the red blood cells. If insufficient iron is available, zinc protoporphyrin is incorporated. Because protoporphyrin binds relatively firmly to hemoglobin, it does not diffuse out of the red blood cells into the plasma and skin. In contrast to patients with erythropoietic protoporphyria, therefore, patients with Pb intoxication do not develop skin photosensitivity /21/. The increase in protoporphyrin in the erythrocytes depends on the blood Pb concentration. If the Pb concentration exceeds 500 μg/L (2.4 μmol/L), the protoporphyrin concentration exceeds 2,500 μg/L erythrocytes /25/.

Inhibition of red cell osmotic resistance

The reduction in the osmotic resistance of the erythrocytes is due to inhibition of Na+/K+–ATPase in the erythrocyte membrane by Pb, which leads to a significant efflux of K+ from the erythrocytes. Their basophilic stippling results from the precipitation of mitochondrial remains and ribosomal DNA. This occurs because Pb inhibits pyrimidine 5’-nucleotidase in red blood cells. After the cell nucleus is ejected, the enzyme cleaves the remaining nucleotide chains into small fragments /26/.


1. Schlemmer G, Welz B. Grundlagen atomspektrometrischer Analytik. Lab Med 1986; 10: 160–5.

2. Stellungnahme der Kommission Human-Biomonitoring des Umweltbundesamtes. Aktualisierung der Referenzwerte für Blei, Cadmium und Quecksilber im Blut und Urin von Erwachsenen. Bundesgesundheitsbl, Gesundheitsforsch, Gesundheitsschutz 2003; 46: 1112–3.

3. Leckie WJH, Tompsett SL. The diagnostic and therapeutic use of edathamil calcium disodium (EDTA, versene) in excessive inorganic lead absorption. Quarterly J Med 1958; 105: 65–82.

4. Lin JL, Lin-Tan DT, Li YJ, Chen KH, Huang YL. Low -level environmental exposure to lead and progressive chronic kidney diseases. Am J Med 2006; 119: 707–23.

5. Mc Kelvey W, Gwynn RC, Jeffery N, Kass D, Thorpe LE, Garg RE, et al. A biomonitoring study of lead, cadmium, and mercury in the blood of New York city adults. Environ Health Perspect 2007; 115: 1435–41.

6. Evans M, Linder CG. Chronic renal failure from lead. Kidney Int 2010. doi: 10.1038/ki.2010.394.

7. Eum KD, Weisskopf MG, Nie LH, Hu H, Korrick SA. Cumulative lead exposure and age at menopause in the Nurses’ Health Study Cohort. Environmental Health Perspectives 2014; 122: 229–34.

8. Rossi E, Costin KA, Garcia-Webb P. Effect of occupational lead exposure on lymphocyte enzymes involved in heme biosynthesis. Clin Chem 1990; 36: 1980–3.

9. Kosnett MJ, Wedeen RP, Rothenberg SJ, et al. Recommendations for medical management of adult lead exposure. Environ Health Perspect 2007; 115: 463–71.

10. DGAUM, Gesellschaft für Arbeitsmedizin und Umweltmedizin e.V. Leitlinien der Deutschen Gesellschaft für Arbeitsmedizin und Umweltmedizin e.V. AWMF online: https://leitlinien.net/2005

11. Lommel A, Dengler D, Janßen U, Fertmann R, Hentschel S, Wessel M. Bleibelastung durch Trinkwasser. Teil 1: Einfluss auf den Blutbleispiegel junger Frauen. Bundesgesundheitsbl, Gesundheitsforsch, Gesundheitsschutz 2002; 45: 605–12.

12. Lommel A, Dengler D, Janßen U, Fertmann R, Hentschel S, Wessel M. Bleibelastung durch Trinkwasser. Teil 2: Effekte verschiedener Präventionsstrategien. Bundesgesundheitsbl, Gesundheitsforsch, Gesundheitsschutz 2002; 45: 613–7.

13. Vaidyanathan A, Staley F, Shire J, Muthukumar S, Kennedy C, Meyer PA, et al. Screening for lead poisoning: a geospatial approach to determine testing of children in at-risk neighborhoods. J Pediatr 2009; 154: 409–14.

14. Lidsky TI, Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 2003; 126: 5–19.

15. Dietrich KN, Ware JH, Salganik M, Radcliffe J, Rogan WJ, Rhoads GG, et al. Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry. Pediatrics 2004; 114: 19–26.

16. Neal AP, Guilarte TR. Molecular neurobiology of lead (Pb2+): effects on synaptic function. Mol Neurobiol 2010; 42: 151–60.

17. Li Pj, Sheng YZ, Wang QY, Gu Ly Wang YL. Transfer of lead via placenta and breast milk in human. Biomed Environ Sci 2000; 13: 85–9.

18. Brätter P, Heseker H, Kruse-Jarres JD, Liesen H, Negretti de Brätter V, Pietrzik K, Schümann K. Mineralstoffe, Spurenelemente und Vitamine: Leitfaden für die ärztliche Praxis. Gütersloh; Bertelsmann Stiftung 2002: 107–9.

19. Karimooy HN, Mood MB, Hosseini M, Shadmanfar S. Effects of occupational lead exposure on renal and nervous system of workers of traditional tile factories in Mashad (northeast of Iran). Toxicology and Industrial Health 2010; 26: 633–8.

20. Mason LH, Harp JP, Han DY.Pb neutotoxicity: neuropsychological effects. Biomed Res Int 2014;Article ID 840547. doi: 10.1155/2014/840547

21. Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease – a systematic review. Environ Health Perspect 2007; 115: 472–8.

22. Piomelli S. Childhood lead poisoning. Pediatr Clin North Am 2002; 49: 1285–1304.

23. Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E. Blood lead below 0.48 μmol/L (10 μg/dL) and mortality among US adults. Circulation 2006; 114: 1388–94.

24. Hernberg S, Nikkanen J, Mellin G, et al. Delta-aminolevulinic acid dehydrase as a measure of lead exposure. Arch Envir Health 1970; 21: 140–5.

25. Kammholz LP, Thatcher LG, Blodgett FM, et al. Rapid protoporphyrin quantitation for detection of lead poisoning. Pediatrics 1972; 50: 625–31.

26. Paglia DE, Valentine WN, Dahlgren JG. Effects of low level lead exposure on pyrimidine 5’-nucleotidase and other erythrocyte enzymes. Possible role of pyrimidine 5’-nucleotidase in the pathogenesis of lead-induced anemia. J Clin Invest 1975; 56: 1164–9.

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28. Tort B, Choi YH, Kim EK, Jung YS, Ha M, Song KB, Lee YE. Lead exposure may effect gingival health in children. BMC Oral Health 2018; 18. doi: 10.1186/s12903-018-0547-x.

11.5 Cadmium (Cd)

Lothar Thomas

Cd belongs to subgroup II of the periodic table (the zinc group). It is an underground heavy metal that occurs naturally in the earth’s crust at 1 × 10–5 percent. The concentration of Cd in soil is around 0.1 ppm. In nature, Cd is mainly found as an accompanying element of zinc e.g., as zinc blende (sphalerite) or zinc spar (smithsonite). Pure Cd minerals such as Cd blende (greenockit, CdS), monteponite (CdO), and otavite (CdO3) are less common.

11.5.1 Indication

Suspected acute or chronic occupational Cd intoxication (usually due to inhalation) /1/.

11.5.2 Method of determination

Electrothermal atomic emission spectrometry /2/.

11.5.3 Specimen

Blood sampling with metal-free blood collection assembly.

  • Whole blood (lithium heparinate): 5 mL
  • 24 h urine: 10 mL
  • Random urine (calculation of the Cd/creatinine ratio): 10 mL

11.5.4 Reference interval

Refer to Lit. /3/ and Tab. 11.5-1 – References interval for cadmium.

11.5.5 Clinical significance

Cd is hazardous both by inhalation and ingestion and can cause acute and chronic intoxications. Cd dispersed in the environment persists in soils and sediments for decades. The most toxicological property of Cd is its long half-life in the human body, in particularly in kidneys and other vital organs such as the lungs or the liver. In addition to its extra ordinary cumulative properties, Cd is also a highly toxic metal that can disrupt biological systems, usually at doses that are much lower than most toxic metals /4/.

When taken up by plants, Cd concentrates along the food chain and accumulates in the body of people eating contaminated foods. Cd is also present in tobacco smoke, further contributing to exposure.

The main routes of exposure to Cd are via inhalation or cigarette smoke, ingestion of food and employment in primary metal industries. Cd is used in the following industrial products: pigments (Cd yellow), nickel-Cd batteries, stabilization of polyvinyl chloride in the plastics industry, coating for machinery parts and alloys, and control rods for nuclear reactors. Cd oxide in cigarette smoke and polluted air has relatively high bio availability.

Chronic Cd intoxication is suspected in areas with Cd-contaminated soil, especially via inhalation of Cd smoke.

The European Union countries have already discontinued usage of Cd-including pigments /1/. Daily, non-occupational exposure results from the ingestion of Cd-containing food and water.

Exposure to Cd is commonly determined by measuring Cd concentration in blood and Cd excretion in urine. Blood Cd reflects the recent Cd exposure. Cd in urine indicates accumulation, or kidney burden of Cd. Acute intoxication of cadmium

Acute Cd intoxication usually results from inhalation and causes respiratory tract irritation with flu-like symptoms and/or pulmonary edema (Tab. 11.5-2 – Environmental contamination, risk of disease, and intoxication caused by cadmium). Chronic cadmium exposure

Chronic Cd exposure can cause renal disease, anemia, osteoporosis, and bone fractures. Cd is also a potent carcinogen /5/. Chronic Cd exposure is usually related to food intake, especially in combination with smoking. Animal offal, shellfish, mussels, and oysters have the highest Cd content. The normal daily Cd intake from food is 10–20 μg. Tobacco smoking is an additional source of exposure for smokers. Each cigarette contains 1–2 μg Cd, so the amount of Cd in a packet of cigarettes corresponds to the amount of Cd ingested daily in food.

The normal absorption rate of orally ingested Cd is 5% but this increases to 15% in patients who are deficient in iron. The absorption rate of Cd fumes or particles via the respiratory tract is 10–50%; the absorption rate from tobacco smoke is around 10%.

The body Cd burden is negligible at birth, increases continually until the age of 60–70 years, and then declines. At low levels of exposure, bone is the main target and is more severely affected than the kidneys. The correlation between low Cd concentrations and proteinuria is weak /5/.

Cd accumulates in the liver and kidneys since the binding protein metallothionein is synthesized in these organs. As most renal Cd is bound to metallothionein, the form of Cd responsible for renal damage is the highly toxic Cd2+ ion that avidly reacts with cellular components /4/. In individuals with low levels of environmental exposure to Cd, the kidneys can contain up to 50% of the total body Cd. The amount of Cd excreted daily in urine is very low, representing somewhat 0.005–0.01% of the total body burden /4/. There is a well-documented dose-response relationship for Cd. The amount of Cd stored in the kidneys can be estimated non-invasively by determining the urinary Cd excretion as a surrogate marker. A urinary Cd concentration of 5 μg/g creatinine is considered the upper tolerable limit for occupational exposure to Cd in many countries. The earliest manifestation of Cd-induced renal damage considered as critical consists in increased urinary excretion of micro proteins like α1-microglobulin, retinol-binding protein and β2-microglobulin.

Because Cd very rarely crosses the placental and cerebrospinal fluid barriers, neither the fetus nor the brain are exposed to injury. For chronic Cd exposure, see also Tab. 11.5-2 – Environmental contamination, risk of disease, and intoxication caused by cadmium.

11.5.6 Comments and problems


The Cd concentrations in whole blood and urine can be used to estimate the body Cd burden. Hair analysis allows only a rough estimate, since the correlation between the hair Cd concentration and levels in organs such as the liver and kidney is weak.

Reference interval

Different reference values for Cd are used for samples, depending on the geographic region from which the group of interest originates as well as the method of determination.

Hair mineral analysis

Chronic high Cd exposure is reflected in the hair. However, contamination during sample preparation cannot be distinguished from toxic Cd content in the hair. The content in the hair provides only a rough estimate of levels in the organs.

11.5.7 Pathophysiology

Cd does not have any physiological functions and the body has not developed any special mechanisms for its transport or homeostasis. It is transported to tissues using mechanisms that evolved for essential metal ions such as Zn2+, Fe2+, Mn2+ and Ca2+. Many of the effects of Cd in the body result from its interaction with these metals, in particular Zn. Cd and Zn bind to macromolecules in the body, mainly via sulfur (S), oxygen (O), and nitrogen (N) atoms. Although both metals have a high affinity for metallothionein, proteins, and enzymes with sulfhydryl groups, Cd has a higher affinity than Zn /6/.

Cd has an enteral absorption rate of 3–7%; however, this can increase by a factor of 3–4 if iron deficiency anemia is present. The respiratory absorption rate of Cd is around 40%.

In the blood, Cd is transported by erythrocytes or bound to albumin. It is then taken up by hepatocytes, where it induces the synthesis of metallothionein, a low molecular weight protein that is rich in cysteine and has a high affinity for divalent metals. The toxicity of Cd is reduced significantly by binding to metallothionein /6/. The metallothionein-Cd complex is released into the blood stream reaching the kidney where it is filtered through the glomeruli and taken up by the renal proximal tubule cells by pinocytosis.

Within renal tubular cells, the metallothionein-Cd complex is degraded but the metallothionein-Cd complex degrades and releases free Cd, which recombines with metallothionein newly synthesized by tubular cells. Once tubular metallothionein is saturated with Cd it is no longer able to remove all the free Cd in the tubular cells, which may result in damage of the kidney tubules. The damaged tubule is no longer able to sequester Cd, and therefore increased excretion of Cd is observed in the urine.

Most of the Cd in the body is found in the liver, although it remains there for a short time only. In the longer term, it is stored in the kidneys. There, it has a half life of 17–30 years. Only small quantities of Cd are excreted in the urine.

Cd might act like an estrogen, mimicking the action of 17β-estradiol by binding to estrogen receptors /1/.

Oxidative stress plays an important role in Cd toxicity /7/. It leads to glutathione (GSH) depletion and the reduction of protein-bound sulfhydryl groups, which results in increased production of reactive oxygen species (ROS) such as the super oxide anion (O2–.), hydrogen super oxide (H2O2), and hydroxyl radicals (OH.) (see also Section 19.2 – Oxidative stress). Because Cd is a redox-stable metal, radicals can only be formed indirectly.

One of the mechanisms of cellular damage is disruption of the antioxidant system, of the hepatocytes in particular. Hepatocytes contain large amounts of glutathione, which is reduced as the result of Cd binding. This leads to Cd-induced hepatotoxicity and reduced amounts of glutathione in other organs such as the kidneys.

Mitochondria are thought to be particularly vulnerable to the damaging effects of Cd. Mitochondrial damage is likely, given that dysfunctional mitochondria are central to the formation of excess reactive oxygen species (ROS), and are known key intracellular targets for Cd. When mitochondria become dysfunctional, for example, through long term exposure to environmental toxicants like Cd, they produce less energy and more ROS. The imbalance between these ROS and the natural anti-oxidants creates the condition of oxidative stress /8/. It has been speculated that Cd causes single-strand DNA damage and disrupts the synthesis of nucleic acids and proteins /25/.


1. Miura N. Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: with references to current status of occupational cadmium exposure. Industrial Health 2009; 47: 487–94.

2. Stoeppler M, Brandt K. Contributions to automated trace analysis. Part V. Determinations of cadmium in whole blood and urine by electrothermal atomic-absorption spectrophotometry. Fresenius Z Anal Chem 1980; 300: 372–80.

3. Stellungnahme der Kommission Human-Biomonitoring des Umweltbundesamtes. Aktualisierung der Referenzwerte für Blei, Cadmium und Quecksilber im Blut und Urin von Erwachsenen. Bundesgesundheitsbl, Gesundheitsforsch, Gesundheitsschutz 2003; 46: 1112–3.

4. Bernard A. Cadmium & its adverse effects on human health. Indian J Med Res 2008; 128: 557–64.

5. Akesson A, Barregard L, Bergdahl IA, Nordberg GF, Nordberg M, Skerfving S. Non-renal effects and the risk assessment of environmental cadmium exposure. Environmental Health Perspectives 2014. doi: 10.1289/ehp.1307110.

6. Usuda K, Kono K, Ohnishi K, Nakayama S, Sugiura Y, Kitamura Y, et al. Toxicological aspects of cadmium and occupational health activities to prevent workplace exposure in Japan: a narrative review. Toxicology and Industrial Health 2010. doi: 10.1177/0748233710386404.

7. Liu J, Qu W, Kadiiska MB. Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicology and Applied Pharmacology 2009; 238: 209–14.

8. Gobe G, Crane D. Mitochondria, reactive oxygen species and cadmium toxicity in the kidney. Toxicol Lett 2010; 198: 49–55.

9. Satarug S, Garrett SH, Sens MA, Sens DA. Cadmium, environmental exposure, and health outcome. Environ Health Perspect 2010; 118: 182–90.

10. Third meeting of the FAO/WHO Expert Committee of Food Additives 1989.

11. FAO/WHO Expert Committee of Food Additives 2010. Report TRS 960-JECFA 73. https://apps.who.int/food-additives-contaminants-jecfa-database/chemical.aspx?chemID=1376

12. Järup L, Akesson A. Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 2009; 238: 201–8.

13. European Food Safety Authority. Cadmium in food. Scientific Opinion of the Panel on Contaminants in the Food Chain. 2009. www.efsa.europa.eu

14. Copes R, Clark NA, Rideout K, Palaty J, Tscheke K. Uptake of cadmium from Pacific oysters in British Columbia oyster growers. Environ Res 2008; 107: 160–9.

15. Mc Kelvey W, Gwynn RC, Jeffery N, Kass D, Thorpe LE, Garg RE, et al. A biomonitoring study of lead, cadmium, and mercury in the blood of New York city adults. Environ Health Perspect 2007; 115: 1435–41.

16. Friis L, Petersson L, Edling C. Reduced cadmium levels in the human kidney cortex in Sweden. Environ Health Perspect 1998; 106: 175–8.

17. Nishijo M, Nakagawa H, Morikawa J, Katsuyuki M, Kito T, et al. Mortality in a cadmium polluted area in Japan. Biometals 2004; 17: 535–8.

18. Akesson A, Bjellerup P, Lundh H, Lidfeldt J, Nerbrand C, Samsioe G, et al. Cadmium-induced effects on bone in a population-based study of women. Environ Health Perspect 2006; 114: 830–4.

19. Haswell-Elkins M, Satarug S, O´Rourke P, Moore M, Ng J, McGrath V, et al. Striking association between urinary cadmium level and albuminuria among Torres Strait Islander people with diabetes. J Expo Sci Environ Epidemiol 2007b; 17: 298–306.

20. Nawrot TS, van Hecke E, Thijs L, Richart T, Kutznetsova T, Jin Y, et al. Cadmium-related mortality and long-term secular trends in the cadmium body burden of an environmentally exposed population. Environ Health Perspect 2008; 116: 1620–8.

21. Adams SV, Quraishi SM, Shafer MM, Passarelli MN, Freney EP, Chlebowski RT, et al. Environmental Health Perspectives 2014. doi: 10.1289/ehp.1307054.

22. Eum KD, Lee MS Peak D. Cadmium in blood and hypertension. Sci Total Environ 2008; 407: 147—53.

23. Navas-Acien A, Silbergeld EK, Sharrett R, Calderon-Aranda E, Selvin E, Guallar E, et al. Metals in urine and peripheral arterial disease. Environ Health Perspect 2005; 113: 164–9.

24. Thompson J, Bannigan J. Cadmium: toxic effects on the reproductive system and the embryo. Reprod Toxicol 2008; 25: 304–15.

25. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metals toxicity and the environment. EXS 2012; 101: 133–64.

26. Satarug S, Ruangyuttikarn W, Nishijo M, Ruiz P. Urinary cadmium threshold to prevent kidney disease development. Toxics 2018; 6. doi: 10.3390%2Ftoxics6020026.

11.6 Mercury (Hg)

Lothar Thomas

Hg is a heavy metal and the only metal that is liquid at room temperature. In the solid phase, Hg is soft and flexible; in the gas phase, it exists in atomic form. Hg binds easily to sulfur and halogens and, at temperatures above 300 °C, reacts with oxygen to produce Hg(II)oxide (HgO). Hg exists in monovalent and divalent compounds, and forms Hg alloys (amalgams) with many metals. Hg is an naturally occurring element and a common environmental contaminant, accounting for only 1 × 10–5 percent of the earth’s crust. The most important Hg ore is cinnabar (cinnabarite, HgS). For the medical assessment of Hg intoxication, the form in which the Hg was absorbed is important:

  • As elemental Hg, a highly poisonous vapor
  • As inorganic Hg in the form of a salt, e.g. as Hg2Cl2 (calomel)
  • In organic form, as a carbon compound such as methylmercury (MeHg), which is less toxic than mercury vapor.

11.6.1 Indication

Suspected chronic mercury intoxication:

  • Individuals with dental amalgams
  • Daily consumption of fish
  • Hg inhalation at high levels of occupational exposure
  • Neurological and neuropsychiatric symptoms.

Suspected acute Hg intoxication:

  • Symptoms such as dyspnea, chest pain, nausea, vomiting, and swollen joints, in the context of occupational exposure to Hg.

11.6.2 Method of determination

Principle: The mercury ions of the specimen are adsorbed quantitatively on SDS coated chromosorb due to its complexation with 2-mercaptobenzoxazole, while the retained Hg2+ ions are then stripped from the column with minimal amounts of 2 molar nitric acid in acetone. The eluting solution is sent to cold vapor atomic absorption spectrometry for evaluating Hg2+ ion content /1/.

11.6.3 Specimen

  • Heparin or EDTA whole blood: 3 mL
  • 24 h urine (specify volume): 5 mL
  • Random specimen of urine (excretion with reference to creatinine): 5 mL
  • Hair samples

11.6.4 Reference interval

Refer to Ref. /1/ and Tab. 11.6-1 – Mercury reference intervals.

11.6.5 Clinical significance

Exposure to Hg in any general, non occupational population occurs mainly through the diet, and in any cases, through the consumption of fish. The consumption of fish on the global scale is widespread, however the benefits of fish diet must be balanced against any negative neurodevelopmental effects that may be by mercury exposure. Hg bio accumulates up the food chain, therefore large predatory species such as tuna, shark, and swordfish may have high concentrations of Hg in their tissue. Elemental Hg does not degrade or breakdown in the environment, and it tends to cycle through ecological and biological systems.

A further source of Hg exposure in the population is dental amalgam.

Anthropogenic exposure to Hg is generally to Hg vapor and can occur in dentistry, mining, smelting, combustion of coal and industrial processes (manufacture of electrical equipment and medical instruments). Thiomersal, a Hg-containing preservative, is a component of some vaccines but has been phased out from most routine childhood vaccines /3/. Hg is also used in medicinal products, bleaches, and Ayurvedic medicines (Tab. 11.6-2 – Causes of mercury exposure).

The route of exposure and extent of absorption depends on the form of Hg /4/:

  • Absorption of elemental Hg (Hg0) is negligible through the oral route. The half life of Hg0 in the blood is 40–60 days.
  • Oral absorption of inorganic Hg compounds is poor to moderate depending on the precise form. Dental amalgam consists of Hg0 (50%), parts of silver, tin, copper and zinc. The half life of inorganic Hg in the blood is 40–60 days.
  • Hg vapor is well absorbed by the respiratory route (nasal and oral mucosa, lungs). In the blood, 50% of the Hg vapor dissolves in the plasma and the other 50% distribute to erythrocytes. For this reason, and because Hg is lipophilic, Hg vapor in the blood rapidly reaches the organs and crosses the blood-brain barrier to reach the brain. The half life of Hg vapor in the blood is 3–6 days.
  • Oral absorption of organic Hg is nearly complete. The half life of organic Hg in the blood is 70 days. The intestinal absorption rate of MeHg is almost 100% and 90% is bound to erythrocytes following absorption. MeHg has a half life of 60–90 days in the blood. MeHg is oxidized to the toxic Hg2+ ion in the organs. MeHg, which binds preferentially to the amino acid cysteine in fish and other seafood, is less toxic than Hg vapor.

Once absorbed, Hg is distributed throughout the entire body, but has a particular affinity for the central nervous system and the kidneys. Its elimination is limited and takes place via renal excretion and feces. Acute mercury intoxication

Acute Hg intoxication with elemental Hg or inorganic compounds is rare /5/. Symptoms of acute Hg vapor intoxication include shortness of breath, chest pain, dyspnea, paroxysmal cough, nausea, vomiting, diffuse joint swelling, and rash. Deaths are observed at doses above 3–5 mg/kg body weight. Clear toxicity results in urinary levels of 50 to 100 μg Hg/L. See also Tab. 11.6-3 – Environmental contamination, risk of disease, and intoxication caused by mercury. Chronic mercury exposure

Occupational inhalation of Hg vapor (Hg0) has declined sharply in recent years /6/. Natural emissions of the element are 6–7 times greater than industrial emissions /7/. The exposure amount in Western industrialized nations is around one-third of the quantity of Hg that can be safely absorbed (daily oral intake rate or reference dose of methylmercury 0.2 μg/kg of body weight according to the United States Environmental Protection Agency and the WHO). A good half of this can be attributed to fish consumption and the other half to dental amalgam. The Environmental Protection Agency Public has developed public health actions levels at 1.1 μg/g of hair. Because imported fish species marketed in the USA contain increasing amounts of methylmercury, the provisional tolerable weekly intake in children of methylmercury established by the Joint FAO/WHO Expert Committee of Food Additives is 1.6 μg/kg body weight.

The signs and symptoms of chronic intoxication vary with the form of Hg and route of exposure but include nausea, stomatitis, increased salivation, skin and nail discoloration, metallic taste, vomiting, and abdominal pain. Chronic inhalation leads to sensory peripheral neuropathy and impairment of the central nervous system with personality change, irritability, intention tremor, ataxia, and lack of concentration. Renal effects include both tubular and glomerular damage. Long-term, chronic exposure of pregnant women as the result of regular fish consumption or the release of Hg from dental amalgam can cause disruption of the developing brain of the fetus and is associated with neuropsychological changes after birth.

The consumption of fish containing high levels of MeHg or of contaminated seeds has led to epidemics of chronic intoxication and many deaths. MeHg mainly damages the central nervous system. See also Tab. 11.6-3 – Environmental contamination, risk of disease, and intoxication caused by mercury. Laboratory diagnostics

Whole blood, urine, and hair specimens can be used to determine Hg. Each of these specimens is particularly suited to determining exposure to elemental, inorganic, or organic (mostly MeHg) Hg.

Urinary Hg determination is used mainly to detect inorganic Hg e.g. from dental amalgam. Excretion rates of 50–100 μg/L provide clear evidence of toxic exposure to inorganic Hg; however, lower values do not rule this out.

Whole blood Hg determination is the preferred approach if exposure to organic Hg is suspected, since organic Hg is excreted preferentially in the feces rather than in the urine.

MeHg in particular accumulates in the hair and its determination in 1 cm segments of hair is used as a surrogate marker to determine monthly Hg exposure.

Individuals who were exposed less recently can be identified more effectively by determining Hg in the urine rather than in whole blood. In the blood, inorganic Hg is mainly found extracellularly and organic Hg is mainly found intracellularly. The chemical form of the exposure can therefore be determined from the distribution of Hg between erythrocytes and plasma. In inorganic Hg intoxication, the ratio of erythrocyte Hg to plasma Hg is less than 2; in organic Hg intoxication, the ratio is 10–20 /8/. In individuals who were exposed less recently, Hg concentrations can be pathological in the urine and normal in whole blood. Furthermore, the values in both specimens are often within the reference interval.

The reference interval for Hg depends on the population in question. More commonly, threshold values are specified. Some thresholds for Hg adopted from the literature are listed in Tab. 11.6-4 – Mercury thresholds.

11.6.6 Comments and problems

Specification analysis

The chemical form of the mercury form (organic/inorganic) can be determined from the distribution ratio of Hg between erythrocytes and plasma.


The commonly recommended method for estimating the level of Hg exposure associated with amalgam fillings by measuring Hg in the saliva following the use of chewing gum is unreliable /9/.

Hair analysis

Chronic high mercury exposure can be detected in the proximal segment of the hair /2/. This investigation provides a rough estimate of exposure.

Evaluation of treatment

In the early phase acute Hg intoxication is managed with 2,3-dimercaptopropanol (BAL) by intramuscular route. Less severe inorganic Hg or MeHg intoxication are treated with the less toxic chelators 2,3 dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS) /10/. Urinary Hg excretion should be determined at the start of treatment, upon each dose increase, and then every four weeks.

11.6.7 Pathophysiology

Hg is the only metal that is liquid at room temperature. Due to its high surface tension, metallic Hg forms small beads in fluid media. If Hg reaches the environment as a solid salt or a vapor, it is transformed into organic MeHg by microorganisms (in water, by plankton in particular) and enters the food chain in this way. Hg compounds are also used as medications for the eyes, ears, nose, and throat as well as bleaching agents, toothpaste, additives to vaccines, in-vivo allergy tests, antiseptics, herbicides, fungicides, and dental amalgam. The current Hg concentration in the biosphere is ten times higher than the concentration that was present during the pre-industrial era /11/.

Oxidative stress is involved in the molecular mechanisms of toxicity of Hg. Once in the cell both Hg2+ and MeHg form covalent bonds with cysteine residues of proteins and deplete cellular antioxidants.

The key marker of exposure for MeHg neurotoxicity is the concentration of organic or inorganic Hg in the central nervous system (CNS). Hg enters the brain in its methylated form, but as long as it remains in that form, it can also exit the brain. Demethylated Hg persists as inorganic Hg, and accumulates. Its half life elimination is in the order of years. If exposure is brief, the proportion of inorganic Hg is 5–10%, but this value increases continuously with prolonged exposure /12/. In Minamata disease, the Hg concentration in the brain was 0.3–75 μmol/L. In the adult brain, MeHg poisoning damages the so-called primary areas of the cerebral cortex, affecting the visual, auditory, somatic sensory, and motor cortex, as well as the hippocampus and the granule layer of the cerebellum, causing a remarkable loss of neurons in these brain regions /13/.

MeHg vulnerability of the brain reflects the ability of lipophilic MeHg to cross cell membranes and concentrate in the cells of the CNS. The main route for MeHg transmembrane transport is the amino acid transport system for large amino acids. MeHg is oxidized to form highly toxic Hg2+ within the cells, which binds strongly to cell structures and is removed very slowly. Hg is more toxic than any other element, even arsenic, lead, and cadmium.

The molecular mechanisms of MeHg toxicity are based on its high affinity for thiol groups (-SH), which are found in enzymes, cytoskeletal proteins, and cysteine-containing peptides. The interaction between MeHg and thiol groups inactivates enzymes at cellular and subcellular level.

One cause of Hg neurotoxicity is oxidative stress due to reduced glutathione formation, which results in an increase in reactive oxygen species (ROS). This leads to DNA strand breakage, lipid per oxidation, and protein modification. Fig. 11.6-1 – Mechanisms of cellular damage to neurons and astrocytes shows a model of the toxic mechanisms of Hg.


1. Ghaedi M, Fathi M R, Shokrollahi A. Highly selective preconcentration of mercury ion and dtermination by cold vapor atomic absorption spectromety. Analytical letters 2006; 39: 1171–85.

2. Stellungnahme der Kommission Human-Biomonitoring des Umweltbundesamtes. Aktualisierung der Referenzwerte für Blei, Cadmium und Quecksilber im Blut und Urin von Erwachsenen. Bundesgesundheitsbl, Gesundheitsforsch, Gesundheitsschutz 2003; 46: 1112–3.

3. Ouboter PE, Landburg G, Satnarain G, Starke SY, Nanden I, Simon-Friedt B, et al. Mercury levels in women and children from interior villages in Suriname, Sout America. Int J Environ Res Publ Health 2018; 15: 1007–19.

4. Homme KG, Kern JK, Haley BE, Geier DA, King PG, Skykes LK, et al. New science challenges old notion that mercury dental amalgam is safe. Biometals 2014; 27: 19–24.

5. Taber KH, Hurley RA. Mercury exposure: effects across the lifespan. J Neuropsychiatry Clin Neurosci 2008; 20: iv-389.

6. Grandjean P, Satoh H, Murata K, Komyo E. Adverse effects of methylmercury: environmental health research implications. Environ Health Perspect 2010; 118: 1137–45.

7. Brätter P, Heseker H, Kruse-Jarres JD, Liesen H, Negretti de Brätter V, Pietrzik K, Schümann K. Mineralstoffe, Spurenelemente und Vitamine: Leitfaden für die ärztliche Praxis. Gütersloh; Bertelsmann Stiftung 2002: 110–2.

8. WHO. Environmental health criteria. Mercury. Geneva: WHO 1976.

9. Schiele R, Erler M, Reich E. Speichelanalysen eignen sich nicht zur Bewertung der Quecksilberbelastung. Dt Ärztebl 1996; 93: B-1135–6.

10. Boscolo M, Antonucci S, Volpe AR, Carmignani M, Di Gioacchino M. Acute mercury intoxication and use of chelating agents. J Biol Regul Homeost Agents 2009; 23: 217–23.

11. Dietz R, Outridge PM, Hobson KA. Anthropogenic contributions to mercury levels in present-day arctic animals – a review. Sci Total Environ 2009; 407: 6120–31.

12. Newland C, Paletz EM, Reed MN. Methylmercury and nutrition: adult effects of fetal exposure in experimental models. Neurotoxicology 2008; 29: 783–801.

13. Nascimento JLM, Oliveira KRM, Crespo-Lopez ME, Macchi BM, Maues ALM, da Conceicao M, et al. Methylmercury neurotoxicity & antioxidant defences. Indian J Med Res 2008; 128: 373–82.

14. Mc Kelvey W, Gwynn RC, Jeffery N, Kass D, Thorpe LE, Garg RE, et al. A biomonitoring study of lead, cadmium, and mercury in the blood of New York city adults. Environ Health Perspect 2007; 115: 1435–41.

15. Ekino S, Susa M, Ninomiya T, Imamura K, Kitamura T. Minamata disease revisited: an update on the acute and chronic manifestations of methyl mercury poisoning. J Neurol Sci 2007; 262: 131–44.

16. Murata K, Grandjean P, Dakeishi M. Neurophysiological evidence of methylmercury neurotoxicity. Am J Industial Med 2007; 50: 765–71.

17. Oken E, Bellinger DC. Fish consumption, methylmercury and child neurodevelopment. Curr Opin Pediatr 2008; 20: 178–83.

18. Clarson TW, Magos L. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol 2006; 36: 609–62.

19. Bjorkman L, Lundekvam BF, Laegreid T, et al. Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study. Environ Health 2007; 6: 30.

20. Geier DA, King PG, Sykes LK, Geier MR. A comprehensive review of mercury provoked autism. Indian J Med Res 2008; 128: 383–411.

21. Aschner M, Ceccatelli S. Are neuropathological conditions relevant to methylmercury exposure? Neurotox Res 2010; 18: 59–68.

22. Kommission „Human Biomonitoring“ des Bundesumweltamtes. Stoffmonographie Quecksilber: Referenz- und Human-Biomonitoring-Werte (HBM). Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz 1999; 6: 522–32.

23. US Environmental Protection Agency (EPA). Fish tissue criterion for methylmercury to protect human health. Washington DC, EPA 2006. www.epa.gov/waterscience/criteria/methylmercury/document.html

24. US Centers for Disease Control and Prevention (CDC). Third national report on human exposure to environmental chemicals. Atlanta, CDC 2005. www.cdc.gov/exposurereport/

25. Kjellström T, Kennedy P, Wallis S, Mantell C. Stage 1: Preliminary tests at age 4. Solna: National Swedish Environmental Protection Board, 1986. Physical and mental development of children with prenatal exposure to mercury from fish. Report 3080.

26. European Commission. Commission Regulation (EC) No 466/2001 of 8 March 2001 Setting Maximum Levels for Certain Contaminants in Foodstuffs, 2001. Accessed 2010. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32001R0466

27. Centers for Disease Control and Prevention (CDC). Blood and hair mercury levels in young children and women of childbearing age – United States. MMWRMorb Mortal Wkly Rep 2001: 50: 140–3.

28. Schoeman K, Bernd JR, Hill J, Nash K, Koren G. Defining a lowest observable adverse effect of hair concentrations of mercury for neurodevelopmental effects of prenatal methylmercury exposure through maternal fish consumption: a systematic review. Ther Drug Monit 2009; 6: 670–82.

11.7 Thallium (Tl)

Lothar Thomas

Thallium is named after the green spectral line it produces on flame spectroscopy (Greek “thallos” means “green shoot or twig”). Tl is considered a heavy metal on account of its density. In its pure form Tl is bluish-white in color and very soft and malleable. Tl has 47 isotopes. Natural Tl is a mixture of two stable isotopes, 205Tl (70.5%) and 203Tl (29.5%) and has an atomic mass of 204. Tl appears as monovalent thallo- and trivalent thalli- compounds. The chemical properties of monovalent Tl are similar to alkali metals (potassium) while trivalent Tl behaves more like aluminum. When exposed to aluminum and moisture Tl oxidizes at the surface, forming a coating of Tl(I) oxide (TI2O) and, at higher temperatures it forms Tl(III) oxide (Tl2O3/1/.

Inorganic Tl(I) compounds are more stable than Tl(III) analogues in aqueous solution at neutral pH. Covalent organothallium compounds are stable in the trivalent form /2/. Tl is particularly toxic in its Tl(I) compounds, such as sulfate (Tl2SO4), carbonate (Tl2CO3) and acetate (CH3COOTl). The sulfide (Tl2S) and iodide (TlI) are both poorly soluble and therefore, much less toxic. Tl salts are odorless, tasteless, and colorless .

Tl is generally found in the earth’s crust as salts and minerals. Its concentration is 0.3–0.6 mg/kg in the earth’s crust and 65 pmol/kg in seawater.

As a non-essential element, only Tl intoxication is important in human, animal, or plant metabolism.

11.7.1 Indication

Evidence of:

  • Acute poisoning due to the ingestion of water-soluble Tl salts in rodenticides or pesticides (banned in Europe), either accidentally or with suicidal or criminal motives
  • Chronic occupational exposure associated with the mining and processing of iron, cadmium, and zinc-containing ores, cement production, and Tl processing
  • Clinical symptoms of Guillain-Barré syndrome with hair loss.

11.7.2 Method of determination

  • Direct electrothermal atomic emission spectrometry (ETAES) /3/.
  • Photometry of thallium-halogenide complexes in the urine /4/.

11.7.3 Specimen

Heparin or EDTA whole blood: 3 mL

24 h collection of urine (specify volume): 5 mL

Hair sample

11.7.4 Reference interval

Refer to Ref. /5/ and Tab. 11.7-1 – Thallium reference intervals.

11.7.5 Clinical significance

The ionic ratio of Tl+ is similar to that of potassium (K+), therefore accounting for the replacement of the latter during enzymatic reactions /6/. Distribution of thallium

In nature, Tl is found in trace amounts in many minerals, mainly in sulfides ores (Fe, Pb, Zn) which are commonly employed for the production of sulfuric acid. In the roasting process, Tl may arrive in the flue dust or in the lead chamber slime or it can remain in the pyrides cinder which is used in the cement industry /12/. The release of Tl into the environment by human activities is the result of gaseous emissions from cement factories, coal-fired power plants, and metal sewers. Although it is very toxic (MAC 0.1 mg/m3), Tl is not a potential environmental pollutant. The Office of Environmental Health Hazard Assessment (OEHHA) has developed a public health cut-off of 0.1 μg/l for Tl in drinking water and the maximum contaminant level (MCL) at which known adverse effects of human health are anticipated, is 2 μg/L /7/.

Tl is used as a catalyst in alloys, optical lens, jewelry, low temperature thermometers, semiconductors, and scintillation counters. It is applied in clinical diagnostics as a contrast agent for cardiovascular and tumor imaging. Most gamma radiation detection equipment such as scintillometer and infrared radiation detection and transmission equipment contains Tl as an activator. Tl-arsenic-selenium crystals are essential filters for light diffraction in acousto-optic measuring devices /1/. Tl salts are used as rodenticides and insecticides for depilation and as a rodenticide and insecticide in some developing countries, although the WHO recommended in 1973 that the latter use be discontinued.

The clinical picture associated with Tl intoxication is non-specific, variable, and depends on the dose and administration route. Acute thallium intoxication

Because Tl salts are usually odorless, tasteless, and colorless, they were a popular method of murder in the past. Tl acetate, Tl carbonate, and Tl sulfate are fatal. Average lethal dose for at orally administered Tl sulfate is 10–15 mg/kg body weight. Intoxication can also result from inhaling contaminated dust. Industrial and deliberate poisoning are now rare thanks to strict regulations. The maximum blood concentration is reached after around 2 hours, at which stage Tl can also be detected in the urine.

In the early stage acute Tl2SO4 poisoning caused by rodenticides and insecticides can present with symptoms similar to those of Guillain-Barré syndrome, acute porphyria, myocardial infarction, diabetic neuropathy, arsenic intoxication, acute systemic lupus erythematosus, carbon monoxide poisoning, or organophosphate poisoning /8/.

It is important to consider the possibility of acute Tl intoxication at an early stage and to be familiar with the sequence of symptoms /2/:

  • After oral ingestion of Tl, the poison causes an inflammatory reaction in the structures that were exposed first, resulting in glossitis, pharygooesophagitis, gastritis, enteritis and colitis.
  • Often treatment-resistant nausea and vomiting occur during the day 3–4 day period following intoxication.
  • Neurological symptoms appear between 2–5 days which are characterized by painful, rapidly progressing peripheral neuropathy that dominates clinically in the second and third week.
  • Cardiac signs such as sinus tachycardia, irregular pulse, hypertension and angina-like pain occur in the second week after ingestion of Tl.
  • During the first 2 weeks after exposure, there is albuminuria, erythrocyturia, leukocyturia and the presence of cylindrical casts. However, the renal function is not grossly impaired.
  • Alopecia is the best known effect of Tl poisoning. Epilation begins about 10 days after ingestion, complete hair loss is seen in about 1 month. After 2–3 months, the hair will be restored to its former condition.
  • The typical clinical picture unfolds by 2–3 weeks of acute poisoning. By then, precious time for therapeutic intervention is lost /9/.
  • About one month after poisoning, transverse white lines called Mee’s lines appear in the nail plate as results of complete erosion after of the proximal parts of the nails. Chronic thallium intoxication

Chronic occupational exposure can occur in workers employed in the smelting of sulfide ores, the manufacture of cement, semiconductors, and special glasses.

The cardinal symptoms of chronic Tl intoxication are alopecia and leg hypersensitivity that is reminiscent of that seen in Guillain-Barré syndrome. Distal symmetrical axonal degeneration with secondary demyelination occurs /6/. Other typical symptoms include nail dystrophy, skin changes, cardiovascular disorders, renal impairment, polyneuritis, muscle paralysis, tachycardia, and even cardiogenic shock.

Less severe intoxication with sublethal doses below 10mg/kg body weight develops insidiously, with initial symptoms such as constipation, upper abdominal pain, and back pain appearing after 1–2 weeks. Diffuse alopecia usually leads to a diagnosis. The blood Tl concentration is usually below 500 μg/L. Laboratory diagnostics of thallium poisoning

Tl+ ions are generally eliminated by urine, bile, saliva feces, milk and tears. The half-life is 1–3 days after low doses and between 1 and 1.7 days under clinical therapy after ingestion or exposure /2/. Whole blood, urine, feces, hair, and nails are used as specimens to diagnose acute and chronic Tl intoxication. Acute intoxikation

In the acute phase, Tl intoxication must be distinguished from the following diseases:

  • Acute porphyria, by determining porphobilinogen, δ-ALAD, and total coproporphyrin
  • Guillain-Barré syndrome, by determining ganglioside antibodies
  • Acute rheumatic disease, by determining antinuclear antibodies.

After ingestion of water soluble Tl salts clinical symptoms occur with a half-life time of 1 to 1.7 days (lethal dosage) or 8–30 days /2/.

Tl concentration over time:

  • Low concentrations of Tl can be normalized quickly in the blood due to the short half life of Tl in the body. In acute intoxication, the Tl concentration is usually above 500 μg/L to 2 mg/L and occasionally as high as 41 mg/L /9/. Four weeks after acute exposure, however, the concentration is still greater than 20% of the concentration measured in the first week.
  • In acute intoxication initial excretion of Tl in urine is high, but after 24–48 hours, fecal elimination may be important. Tl can generally be detected up to 2 months after acute intoxication /2/.
  • As of day 4, microscopic evidence of intoxication (melanin deposits) can be seen in the hair roots.
  • During the first 2 weeks, albuminuria, erythrocyturia, leukocyturia, and cylindruria occur as the result of nephrotoxicity, but serum creatinine is only slightly to moderately increased. The complete blood count is usually normal but there may be a mild leukocytosis. Hepatic enzymes are elevated to no more than 5 times the upper reference interval value. Chronic intoxication

Patients with clinical symptoms of Tl toxicity have blood concentrations of 3–25 μg/L and urinary concentrations of 4–80 μg/L. Patients with significant intoxication have blood concentrations of up to 200 μg/L and usually have increased urinary concentrations, generally up to 500 μg/L, and occasionally higher. The hair Tl concentration provides only a rough estimate of levels in the organs. Therapeutic measures in thallium intoxication

The measures used depend on the type of intoxication. To eliminate the metal and interrupt the enterohepatic circulation, gastric lavage, forced diuresis, intravenous administration of potassium chloride, hemodialysis, and oral administration of potassium hexacyanoferrate II (Prussian blue) are used (usually in combination). Renal excretion mirrors total body Tl.

11.7.6 Comments and problems


Blood collection tubes must not contain polystyrene beads.

11.7.7 Pathophysiology

The amount of Tl ingested daily in food is less than 2 μg. In acute intoxication, Tl is absorbed rapidly, and almost completely, through the gastrointestinal tract, oral mucosa, and skin. After absorption Tl is distributed from the blood to tissue, kidneys display the highest concentrations, followed by bones, stomach, intestines, spleen, liver, muscle, lung, central nervous system (CNS), as well as hair and nails. In the CNS Tl causes neurodegeneration, demyelation, and the end products of lipid peroxidation /12/. Tl crosses the placental barrier and also reaches breast milk. Tl is eliminated by the kidneys and intestine, whereby Tl is secreted directly from the blood into the intestinal lumen /10/.

Tl is stored intracellularly, mainly in the mitochondria. Due to the presence of empty δ orbitals in electronic configuration, Tl has a high affinity for sulphur ligands. It can form complexes with and thus inactivate sulphydryl groups of proteins (to cysteine residues in particular) which are usually involved in reactions catalyzed by enzymes . Inhibition of enzymes with active sites containing cysteine residues promotes oxidative stress as a result of decreased glutathione formation /10/.

Tl+ can mimic K+ because of the same ionic radius and inability of the cell membrane to differentiate between this two cations. Tl+ follows K+ distribution pathways and in this way alters K+ dependent processes. Tl+ can substitute K+ in the Na+-K+-ATPase because its affinity is ten times higher than of K+. This disrupts K+ transport into the cell and mitochondrial K+ transport. Due to its K+-like behavior, Tl+ interferes with many vital metabolic processes and is highly cardiotoxic and neurotoxic.

Tl+ interferes with riboflavin hemostasis forming an insoluble complex and intravascular sequestration of riboflavin. Riboflavin deficiency leads to structural and functional anomalies in proteins. As a result, skin keratinization is disrupted, which leads to hyperkeratotic lesions on palms and soles, acneform lesions on the face and icthyotic lesions on the legs.


1. Cvjetko P, Cvjetko I, Pavlica M. Thallium toxicity. Arh Hig Rada Toksikol 2010; 61: 111–9.

2. Galvan-Arzate S, Santamaria A. Thallium toxicity. Toxicology Letters 1998; 99: 1–13.

3. Schlemmer G, Welz B. Grundlagen atomspektrometrischer Analytik. Lab Med 1986; 10: 160–5.

4. Aderjan R, Daldrup T, Gibitz HJ, Schneider A. Thallium. In: Gibitz HJ, Schütz H (eds). Einfache toxikologische Laboratoriumsuntersuchungen bei akuten Vergiftungen. Mittlg DFG Senatskommission für klinisch-toxikologische Analytik 1995; XXIII: 422–35.

5. Meißner D. Thallium. In: Biesalski HK, Köhrle J, Schümann K (eds). Vitamine, Spurenelemente und Mineralstoffe. Stuttgart; Thieme 2002: 231–2.

6. Osorio-Rico L, Santamaria A, Galvan-Arzate S. Thallium toxicity: general issue, neurological symptom, and neurotoxic mechanisms. Adv Neurobiol 2017; 18: 345–353.

7. Office of Environmental Health Hazard Assessment (OEHHA). Responses to comments on the technical support document public health goal for thallium in drinking water (displayed 23 April 2009). https://oehha.ca.gov/media/downloads/pesticides/report/thalirs_1.pdf

8. Zhao G, Ding M, Zhang B, Lv W, Yin H, Zhang L, et al. Clinical manifestations and management of acute thallium poisoning. Eur Neurol 2008; 60: 292–7.

9. Misra UK, Kalita J, Yadav RK, Ranjan P. Thallium poisoning: emphasis on early diagnosis and response to haemodialysis. Postgrad Med J 2003; 79: 103–5.

10. Manzo L, Sabbioni E. Thallium. In: Seiler HG, Sigel H, Sigel A (eds). Toxicity of inorganic compounds. New York; Marcel Dekker 1988: 677–88.

11. Mulkay JP, Oehme FW. A review of thallium toxicity. Vet Hum Toxicol 1993; 35: 445–53.

Table 11.1-1 Pathophysiological effects of toxic metal doses /567/



Toxic dose

Clinical presentation


Aluminum oxide

Aluminum hydroxide

Aluminum acetate


> 5 g

> 20 mg/m3

Lethal dose: Unknown

Osteopathy in end-stage renal failure, encephalopathy, myopathy (dialysis), pneumoconiosis, pulmonary fibrosis, lye burns



Arsenic trichloride




> 5 mg

> 0.2 mg/m3

> 0.05 mg/L of drinking water

Lethal dose: > 50 mg

Acute: headache, nausea, dizziness, circulatory collapse, cyanosis, anuria

Chronic: hyperkeratosis, tracheitis, conjunctivitis, skin pigmentation, polyneuritis, hemolytic anemia


Cadmium oxide

Cadmium sulfate

Cadmium sulfide

Cadmium chloride

> 3 mg

> 0.1 mg/m3

> 0.005 mg/L of drinking water

Lethal dose: > 1.5 g

Acute: gastroenteritis, pulmonary edema, hepatic impairment

Chronic: rhinitis atrophicans, emphysema, renal tubular damage, osteomalacia


Mercury nitrate


Sublimate (HgCl2)

Mercury oxycyanide

Calomel (Hg2Cl2)

> 0.4 mg

> 0.1 mg/m3

> 0.001 mg/L of drinking water

Lethal dose: > 150 mg

Acute: gastroenteritis, anuria, stomatitis, ulcerative hemorrhagic colitis

Chronic: neurasthenia, tremor, erethismus mercurialis, anemia, Atkinson reflex of the lenticular capsule


Leaded gasoline (tetraethyl lead)

Leaded glass

Lead vapor

> 1 mg

> 0.1 mg/m3

> 0.05 mg/L of drinking water

Lethal dose: > 10 g

Acute (rare): intestinal colic, quadriplegia, hepatic and renal failure

Chronic: anemia, pallor, restlessness, gum discoloration (Burton line), colic, saturnine encephalopathy, motor polyneuritis


Thallium acetate

Lethal dose: > 0.1 mg/m3

Acute: nausea, constipation, thirst, lower limb neuralgias, insomnia, hysteria, alopecia

Chronic: polyneuritis, cachexia

Table 11.2-1 Aluminum concentrations in plasma and urine: reference values, cut off values /2/


μmol/L (μg/L)



< 0.19 (< 5)

Reference interval for general population

≥ 0.48 (≥ 13)

Early signs of neurotoxicity

≥ 1.9 (≥ 50)

Critical value for the prevention of dialysis encephalopathy

> 3.7 (> 100)

Dialysis encephalopathy


< 0.56 μmol/L
(< 15 μg/L)

Reference interval for general population

≥ 4.5 μmol/24 h
(≥ 120 μg/L

≥ 100 μg/g creatinine)

Early signs of neurotoxicity

Table 11.2-2 Diseases and conditions associated with toxic plasma Al concentrations

Clinical and laboratory findings


It has been suggested that there is a relationship between high plasma Al concentrations and neurodegenerative disorders such as dialysis encephalopathy, Alzheimer’s disease, and Parkinson’s disease. In Al intoxication, Al is distributed throughout various regions of the brain, in particular to the hippocampus. The main results of this are neurobehavioral changes, including the integration of sensory, motor, and cognitive functions /5/. In children, a 20–50 fold increase in plasma Al concentration (above 100 μg/L, 3.7 μmol/L) leads to reduced verbal and motor performance /12/. The neurotoxic symptoms associated with the use of dialysis fluids containing high concentrations of Al, usually above 200 μg/L are speech disturbances, dyspraxia, tremors, partial paralysis and marked decline in learning and memory /5/.

Bone disease

According to a Swedish study, there is no association between the Al content of trabecular bone, density of bone, and bone mass in older people and the Al content does not influence the extent of osteoporosis /13/.

In chronic hemodialysis patients, Al intoxication can lead to Al-induced bone disease (AIBD) in addition to neurotoxicity and anemia. Effects are seen at Al concentrations as low as 50–100 μg/L.


Al intoxication in iron deficiency results in a microcytic hypochromic anemia. Plasma iron transport is disrupted (functional iron deficiency) since a significant proportion of plasma apotransferrin is occupied by Al. Apotransferrin is the transport protein for iron and Al.

In French Guiana, the clays consumed by geophagous individuals contain large quantities of Al, a hematological toxin. Compared to a control group, geophagous anemic women had the following Al concentrations: plasma 13.9 ± 14 μg/L versus 4.9 ± 7.1 μg/L; urine 92.8 ± 251.2 μg/L versus 12.1 ± 23 μg/L /14/.

Pulmonary fibrosis

Inhalation of Al-containing dust with silicates in the Al processing industry can lead to pulmonary fibrosis (Shaver’s disease) with unspecific cough, expectoration, and dyspnea that can progress to bronchopneumonia, pneumothorax, or cardiac injury.

Al welders in the automobile industry

A longitudinal study assessed neurobehavioral performance and Al exposure in a group of welders aged 41–45 years in the automobile industry compared to a control group. The mean environmental dust load during welding was 0.5–0.8 mg/m3 with a mean internal load (pre-shift: 23–43 μg Al/g creatinine in urine; 5–9 μg Al/L plasma). Follow-up over a period of four years did not show any neurobehavioral impairment. The criteria investigated included verbal intelligence, logical thinking, psychomotor behavior, memory, and attention /15/.

Cancer mortality in bauxite mines

Bauxite is a reddish clay that is refined to produce alumina Al(OH)3 which is then reduced to make the metal Al. Mine workers are exposed to bauxite dust and silicon. Workers in Al smelts in which bauxite is processed into Al(OH)3 and then into metallic Al using soda and heat are exposed not only to Al dust but also to other air pollutants. In one study /16/, cancer mortality among Al and bauxite workers was not higher than that of the general population but was 65% higher than that of employees in the same company who worked in different environments, e.g. in an office environment.

Poisoning with aluminum phosphide (AlP) /1718/

Phosphines are phosphorous compounds that are formed by replacing the hydrogen atoms of phosphanes (PH3) with carbohydrate residues or Al. AlP is a rodenticide that releases gaseous PH3 when it comes into contact with moisture, in particular gastric acid. PH3 is colorless, flammable, has an odor of garlic or rotting fish, and is highly toxic. When ingested orally, it is absorbed rapidly by the gastrointestinal tract and lungs. PH3 is a strong reducing agent that irreversibly inhibits mitochondrial cytochrome c oxidase and other enzymes. Cellular damage is due to lipid peroxidation of cell membranes. The fatal dose for humans corresponds to an intake of 150–500 grams, whereby the critical blood PH3concentration is 10 mg/L.

AIP, a commonly used grain preservative and fumigant, is available in airtight containers so as to maintain its freshness and activity. Once the container is opened, tablets get exposed and on coming in contact with moisture, phosphine gas is liberated. AlP is the most frequent suicidal agent in Asian countries (India and Iran in particular) because it is cheap and freely available. Symptoms of intoxication appear soon after ingestion and death occurs within 12–24 hours. The mortality rate is 60–80%, depending on the dose. Clinical findings include restlessness, excessive thirst, cardiac arrhythmia, tachypnea, and severe metabolic acidosis. Death is due to myocarditis, shock, and multi-organ failure.

Table 11.3-1 Diseases and conditions associated with acute and chronic arsenic intoxication

Clinical and laboratory findings

Acute intoxication with arsenic hydride (AsH3) /18/

AsH3 does not exist naturally in the environment. It is produced intentionally or unintentionally by humans or synthesized by bacteria. AsH3 is a colorless, non-irritant gas with a garlic odor. It is produced commercially when aluminum arsenite is treated with water or hydrochloric acid or when arsenic compounds are reduced in an acid solution. AsH3 is the most toxic As compound. Inhalation of 800 mg/m3 results in immediate death, 80–160 mg/m3 causes death after 30 minutes, and a concentration of 32 mg/m3 causes death after a longer period of time. Initial symptoms appear after a latency period of 1–24 h and include headache, vertigo, chills, dyspnea, nausea, vomiting, diarrhea, chest pain, and pain in the upper abdomen and lumbar area.

Laboratory findings: Port-wine-colored urine a few hours after exposure. Urinary As concentration greater than 200 μg/L (normally below 10 μg/L) indicates a toxic dose. In acute intoxication, urinary concentration on the day of exposure was 720 μg/L, falling to 10 μg/L after 10 days. In acute intoxication, urinary concentrations of up to 3,940 μg/L have been measured. Additional findings: Increased free hemoglobin, rise in lactate dehydrogenase and bilirubin after 24–48 h. This is caused by erythrocyte hemolysis. As can be detected in the hair, skin, and bone tissue two weeks following exposure. The hemolysis is thought to be due to the inhibitory reaction of AsH3 with sulfhydryl groups of Na+-K+-ATPase. This results in erythrocyte swelling and hemolysis.

Chronic As intoxication

As is an important environmental contaminant found in soil, water, and air. It comes from geological sources or results from human activities. Millions of people in Bangladesh, India, China, and large areas of the American continent are exposed to increased concentrations of inorganic As in drinking water. Chronic oral ingestion of inorganic As can trigger a range of diseases. Skin manifestations include hyper pigmentation, hyperkeratotic lesions, and skin cancer. Other diseases associated with chronic As intoxication include peripheral vascular diseases (Blackfoot disease), hypertension, ischemic heart disease, non-cirrhotic portal hypertension, hepatomegaly, peripheral neuropathy, respiratory and renal impairment, hematological abnormalities, and diabetes mellitus. The effects are mediated by trivalent compounds of inorganic As (arsenite), which inactivate proteins and disrupt body functions by binding to sulfhydryl groups /19/.

Skin disease

Skin changes, in particular melanosis, are early indicators of chronic As intoxication. Intoxication caused by drinking water shows a dose-response relationship. In general, the prevalence of skin diseases increases when the As concentration in drinking water exceeds 100 μg/L. Compared with a water As concentration of less than 8.1 μg/L, the odds ratios for skin diseases associated with As concentrations of 8.1–40, 40.1–91, 91.1–175, and 175.1–864 μg/L were 1.26, 1.91, 3.03, and 5.39 respectively /20/. Another study showed a synergistic effect between As concentrations greater than 131 μg/L and smoking for increased risk of skin disease /9/.

Peripheral vascular disease

The prevalence of peripheral vascular diseases, especially those associated with foot gangrene (Blackfoot disease), in regions such as Taiwan with high concentrations of inorganic As in drinking water is as high as 6.5–18.9 per 1,000 inhabitants in some areas. In areas where the As concentration in water exceeds 0.6 mg/L, the prevalence is 1.4% in inhabitants aged between 40 and 59 years /21/.

Cardiovascular disease

Long-term exposure to inorganic As is an independent risk factor for cardiovascular disease. A review of a number of studies has demonstrated a dose-response relationship between cardiovascular mortality and the As content of drinking water /22/. In a Taiwanese study, for example, the relative risks of cardiac mortality for annual cumulative As absorptions of 0.1–9.9 mg, 10–19.9 mg, and greater than 20 mg were 2.5, 4.0, and 6.5 respectively /22/.

Cerebral infarction

In the Taiwanese population, a dose-response relationship exists between the amount of inorganic As absorbed and the frequency of cerebral infarction. The odds ratios for cerebral infarction in subjects with cumulative annual As intakes of less than 0.1 mg, 0.1–4.9 mg, and greater than 4.9 mg are 1.0, 2.7, and 3.4 respectively. The odds ratios for water As concentrations of less than 0.1, 0.1–50, 50.1–299.9, and greater than 300 μg/L are 1.0, 3.4, 4.5, and 6.9 respectively /21/.

Lungs and respiratory tract

In Bangladesh, the prevalence of lung or respiratory tract disease in persons whose drinking water contains 136–1,000 μg/L of As, is 2.1% and 53% of individuals with skin lesions caused by As also suffer from lung disease (usually obstructive) /23/.

Liver disease

In West Bengal, the prevalence of hepatomegaly in individuals who regularly drink water with inorganic As concentrations of more than 50 μg/L is 15 times higher than in those whose drinking water contains lower concentrations /23/.

Complications during pregnancy

Women who regularly drink water with As concentrations > 50 μg/L, but particularly above 100 μg/L, have a high frequency of miscarriage, stillbirth, and birth defects /23/. This is thought to be due to DNA damage, which is established by measuring N7-methyl guanosine /24/.


The most frequent manifestation of chronic inorganic As intoxication is peripheral neuropathy that can last for years or for life. Peripheral nerve conductivity is reduced. In children, intellectual ability is impaired, depending on the As content of drinking water. It occurs if the As concentration in drinking water > 50 μg/L and the cumulative As absorption > 100 mg /10/.

Diabetes mellitus

Increased inorganic As in drinking water is associated with diabetes mellitus. Regions with an increased prevalence of peripheral circulatory disorders also have an increased prevalence of diabetes. In some regions in Mexico, there is a relationship between the As concentration in drinking water (20–400 μg/L), urinary excretion of As, and the prevalence of type 2 diabetes /24/. One reason is thought to be the insulin-dependent inhibition of glucose uptake into adipocytes when As concentrations exceed μg/L. Expression of the GLUT4 receptor on the adipocyte membrane is thought to be impaired /17/.

Formation of reactive oxygen species

Arsenites can modify cysteine residues to form diotholes and alter the redox status in cells. This also modifies signaling pathways that regulate early response genes. This is thought to occur even at relatively low As concentrations /17/.

Malignant Disease /4/

Ingestion or inhalation of high levels of inorganic As can cause malignant tumors of the skin, lungs, urinary bladder, and other organs.

Bladder carcinoma: the risk is low if the inorganic As concentration of drinking water is below 100 μg/L. This is not the case at higher concentrations, or if smoking is present as an additive risk factor. Exposure to 10–80 μg/day for 40 years is associated with an odds ratio of 1.28 and exposure to more than 80 μg/day for 40 years is associated with an odds ratio of 1.7. For smokers in this group, however, the odds ratio increases to 3.87.

Bronchial carcinoma: the risk depends on the concentration of inorganic As in the water. Concentrations of 100–299 μg/L are associated with a relative risk of 2.28; for concentrations of 300–699 μg/L, the relative risk is 3.03, and for concentrations of 700 μg/L and above, the relative risk is 3.29.

Skin cancer: non-melanoma skin cancer has been associated with As exposure. Individuals with As-contaminated drinking water whose fingernail As content was greater than 0.345 μg/g had an odds ratio of 2.07 for squamous cell carcinoma and 1.44 for basal cell carcinoma /25/. In two regions of Mongolia and China where 96.2% and 69.3% of water samples have an As concentration that exceeds 50 μg/L, the corresponding skin cancer prevalences are 44.8% and 37.1% respectively /23/.

Table 11.4-1 Lead mobilization test for the determination of body lead stores /3/

Pb mobilization test to assess Pb burden

On the first day, each patient should empty his bladder and than receive an intravenous infusion of 1 g of calcium disodium EDTA (CaNa2EDTA) mixed with 200 mL 5% dextrose in water over two hours. Pb has a higher affinity to EDTA than calcium, and the Pb-EDTA complex is excreted and can be measured in the urine. The patients are requested to collect a 24-hour urine in 2 L lead-free bottles over three consecutive days. The total amount of urine Pb collected over three days is considered the total body Pb store. The patients should be hydrated orally with water in amounts sufficient to provide a steady rate of urine flow of at least 1 mL/min.

Clinical significance: In 1958 an abnormally Pb burden consisting of 80 to 600 μg Pb following calcium EDTA was defined /3/. In 2006 the definition was reduced to greater than 20 μg/72 h /4/. The toxic limit is ≥ 600 μg.

Table 11.4-2 Lead reference intervals

Whole blood /2/

Children 6–12 yrs

Up to 60 μg/L (0.29 μmol/L)

Women 18–69 yrs

Up to 70 μg/L (0.34 μmol/L)

Men 18–69 yrs

Up to 90 μg/L (0.43 μmol/L)

Urine /3/

< 150 μg/L (0.72 μmol/L)

The 95th percentiles are shown. Conversion: μg/L × 0.00483 = μmol/L

Table 11.4-3 Clinical disorders due to increased lead concentration in the blood and urine


μmol/L (μg/L)


Whole blood

< 0.5 (< 100)

Reference interval (dependent on the country)

< 0.24 (< 50)

> 0.5 (> 100)

Inhibition of δ-aminolevulinic acid dehydrogenase


Increased urinary δ-aminolevulinic acid and zinc protoporphyrin

> 1.93 (> 400)

Increased urinary coproporphyrin


Influence on learning capacity and IQ in children

> 1.45 (> 300)


> 1.93 (> 400)

Deficits on performance of cognitive tasks


Chronic encephalopathy in children

> 2.90 (> 600)

Impaired renal tubular functions


Peripheral neuropathy

> 3.9 (> 800)

Chronic encephalopathy in adults


Acute lead encephalopathy


< 0.72 μmol/24 h
(< 150 μg/24 h)

Reference interval

> 2.9 μmol/24 h
(> 600 μg/24 h)

Indication for toxic lead burden in mobilization test with CaNa2EDTA

Table 11.4-4 Diseases and conditions associated with lead intoxication

Clinical and laboratory findings

Acute lead intoxication

The acute and chronic symptoms caused by Pb intoxication mainly involve the hematopoietic system, gastrointestinal tract, central and peripheral nervous system, and kidneys. The most common symptoms of acute intoxication (now rare) are lead-induced colic with loss of appetite, constipation, and dyspepsia. Exposure to large amounts of Pb salts leads to gastroenterocolitis, colic, hemolysis, hepatic failure, respiratory disorders, and paralysis. Acute Pb nephropathy occurs as a result of renal tubular damage. Acute symptoms can also develop following chronic high exposure levels as a result of the mobilization of large quantities of Pb from the bones caused by immobility, febrile infection, or acidosis, for example.

Acute lead intoxication should be considered in patients presenting with symptoms and signs of acute intermittent porphyria (AIP). Acute lead poisoning mimics the signs of AIP with elevated aminolaevulinic acid (ALA) excretion in urine with the primary site of inhibition being ALA dehydratase.

Laboratory findings: blood Pb concentration above 800 μg/L (3.9 μmol/L), increased concentration of α1-microglobulin and N-acetyl-β-D-glucosaminidase in the urine as a result of tubular injury.

Chronic lead intoxication

Chronic Pb intoxication typically has an insidious onset, with non-specific symptoms such as headache, fatigue, apathy, irritability, and loss of appetite. Occupational lead exposure commonly causes mild microcytic to normocytic anemia. At blood Pb concentrations above 800 μg/L (3.8 μmol/L), manifestations of Pb encephalopathy such as disorientation, insomnia, sensory disturbances, seizures, parkinsonian symptoms, delirium, and coma appear.

The typical symptoms of chronic Pb intoxication with blood concentrations greater than 100–200 μg/L (0.48–0.96 μmol/L) are:

  • General: abdominal colic, anemia, basophilic stippling, Burton line, loss of appetite, hypertension
  • Neuropathy: hyperreflexia, tremor, muscle weakness (wrist drop), paresthesias
  • Encephalopathy: headaches, seizures, memory disturbance, irritability
  • Genitourinary/renal: infertility, disturbed renal function

LEAD (PB) exposure through drinking water /11/

In view of the toxic effect of Pb on vulnerable population groups, the European Union set a maximum level of Pb in drinking water as of 2013 of 10 μg/L (0.05 μmol/L). In one study of young women, the median blood Pb concentration was 24 μg/L (0.12 μmol/L) when the Pb content of drinking water was below 5 μg/L (0.02 μmol/L) and 31 μg/L (0.15 μmol/L) when levels were higher. In households with lead pipes, the Pb content of drinking water was 26 μg/L (0.13 μmol/L). When no tap water was drunk or used for cooking for 11 weeks, the blood Pb concentration decreased by 12.3 μg/L (0.06 μmol/L) /12/.

Because infants readily absorb Pb enterally if the Pb content of drinking water is in the range of μg/L, non-breast fed infants aged 3–6 months absorb 23 μg of Pb daily if infant formula is dissolved in tap water (900 mL/day). This exceeds the WHO’s provisional tolerable weekly intake of 18 μg/day.

Pb exposure in children

Increased blood Pb concentrations are associated with illnesses in children. Very high concentrations that exceed 700 μg/L (3.4 μmol/L) lead to encephalopathy, seizures, and death /13/. Concentrations that exceed 100 μg/L (0.48 μmol/L) are associated with lower intelligence quotient-IQ, delayed or impaired neurobehavioral development, decreased hearing acuity, speech and language handicaps, growth retardation, poor attention span, and anti-social and diligent behaviors. Children are especially sensitive to Pb exposure. In contrast to adults, they absorb 30–75% of orally ingested Pb and more Pb is stored in the brain during the prenatal and perinatal periods. The Center for Disease Control and Prevention in the United States has set a threshold value for Pb toxicity of 100 μg/L (0.48 μmol/L). An inverse relationship exists between blood Pb concentration and the intelligence quotient (IQ) in children. The IQ decreases by 1–3 points when the blood Pb concentration increases from 100 (0.48 μmol/L) to 200 μg/L (0.96 μmol/L) /14/. Chelation therapy is recommended for children with concentrations exceeding 450 μg/L (2.2 μmol/L). However, therapy is not associated with improvements in cognitive performance when concentrations are 200–440 μg/L (0.96–2.1 μmol/L) /15/. More recent studies /16/ have shown that the relationship between Pb concentration and IQ is not linear and that the loss of IQ points is relatively higher at lower Pb concentrations than at higher Pb concentrations. Most children show a decline in quotient-IQ while blood Pb concentrations are still below 100 μg/L (0.48 μmol/L). In addition to cognitive deficits, children also develop behavioral deficits that correspond to the attention deficit hyperactivity syndrome phenotype. These deficits are irreversible.


During pregnancy and the postpartum period, Pb is released into the blood from the skeletal system, leading to increased blood concentrations. High levels of maternal Pb exposure can lead to reduced birth weight, pre term delivery, or miscarriage. The breast milk also contains an increased concentration of Pb, which can pose a risk to the newborn /17/.

Occupational Pb exposure

Acute and chronic occupational intoxication mainly occurs as a result of inorganic Pb compounds that are inhaled or swallowed as dust, fumes, or vapor. Daily absorption of more than 0.6 mg creates a positive Pb balance; the toxic dose starts at a Pb exposure of more than 1 mg. Daily absorption of 3.5 mg causes intoxication after 4 months and the lethal dose corresponds to a Pb load of more than 10 g /18/. Chronic occupational Pb exposure is a particular problem in developing countries. Following an exposure duration of 9.8 ± 6 years, workers in a brick-making plant that produces glass bricks had blood Pb concentrations of 361.5 ± 176.9 μg/L (1.74 ± 0,85 μmol/L). The workers displayed the following symptoms: Burton’s line was present in 68%, almost all had signs of peripheral neuropathy, 57% had loss of memory, 48% were agitated, and 30% complained of constant headaches. There were significant correlations between blood Pb levels and urine Pb excretion /19/.


Early symptoms of Pb-related neuropathy appear after many years of exposure and blood Pb concentrations of > 200 μg/L (0.96 μmol/L). Neuropsychological disorders, increased irritability, headaches, reduced concentration, and functional disorders such as extensor weakness of the upper extremities occur /20/. These are due to presynaptic and postsynaptic effects produced by non-competitive inhibition of the N-methyl-D-aspartate receptor (NMDAR) by Pb. The presynaptic effects of Pb are thought to be caused by a disturbance in NMDAR-dependent signaling of brain-derived natriuretic factor /16/. Impairment of the NMDAR has been shown to produce learning deficits on both the behavioral and cellular level.

Cardiovascular disease

According to a meta analysis, there is no direct relationship between Pb exposure and cardiovascular disease. However, there is a relationship between Pb exposure and hypertension, which increases the prevalence of cardiovascular diseases /21/.


In Pb intoxication, the osmotic resistance and shortening of red blood cell survival are reduced. Pb causes a disruption in heme synthesis by the inhibition of ALA dehydratase (ALAD), coproporphyrin oxidase, and ferrochelatase. The hemoglobin (Hb) concentration starts to decline moderately when blood Pb concentrations reach 500 μg/L (2.4 μmol/L). According to one study /22/, the Hb concentrations of newly employed workers in the Pb processing industry decrease from 140 g/L to 134 g/L within 3 months if occupational safety measures are not taken. Differentiation of Pb intoxication and porphyria refer to Ref. /27/.

Renal disease /6/

The classical nephropathy develops when blood Pb levels exceed 600 μg/L (2.9 μmol/L). Pb accumulation in the proximal tubule leads to minimal proteinuria, a benign urinary sediment, hyperuricemia, and often hypertension. Increased urinary secretion of N-acetyl-β-D-glucosaminidase and α1-microglobulin can be observed early among Pb-exposed individuals. The glomerular filtration rate (GFR) is < 60 [mL × min–1 × (1.73 m2)–1] in 1.5% of individuals with occupational Pb exposure, which is the same as the prevalence in the normal population. In one study over 2.1 years, a mean Pb exposure of 313 μg/L (1.5 μmol/L) did not have an effect on the GFR. Renal biopsies of patients with prolonged low-level exposure show tubular atrophy and interstitial fibrosis without cellular infiltration. In the proximal tubules, acid-fast nuclear inclusion bodies, consisting of Pb-protein-binding complex can be seen.

Mortality /23/

In the Third National Health and Nutrition Examination Survey, baseline blood Pb concentrations were measured in 13,946 participants and related to all-cause mortality in the following 10 years. The mortality rate for individuals with Pb concentrations greater than 36.2 μg/L (0.16 μmol/L) was increased by a factor of 1.25 compared to those with concentrations below 19.4 μg/L (0.09 μmol/L) and the cardiac mortality rate increased by a factor of 1.55.

Drug-dependent individuals /7/

The following Pb blood concentrations were found in 597 marijuana users (439 men, 158 women) in Leipzig: 27.3% had concentrations above 150 μg/L (0.72 μmol/L), 12.2% had a concentration that required investigation, and 60.5% had a level of up to 150 μg/L (0.72 μmol/L) (men), or up to 100 μg/L (0.48 μmol/L) (women). The main cause was marijuana that had been adulterated with Pb.

Gingival health in children

Findings indicate a relationship between blood Pb level and oral health problems in children, especially gingivitis /28/.

Table 11.5-1 References interval for cadmium /3/

Whole blood

Children 6–12 yrs ≤ 0.5 μg/L (4.4 nmol/L)

Adults 18–69 yrs* ≤ 1.0 μg/L (8.9 nmol/L)


Children 6–12 yrs ≤ 0.5 μg/L (4.4 nmol/L)

Adults 18–69 yrs* ≤ 0.8 μg/L (7.0 nmol/L)

* Non-smokers. Conversion: μg/L × 8.90 = nmol/L

Table 11.5-2 Environmental contamination, risk of disease, and intoxication caused by cadmium

Clinical and laboratory findings

Exposure through food /1213/

Because of its high rates of soil-to-plant transfer, Cd is a contaminant found in most human foodstuffs, which renders diet a primary source of exposure among nonsmoking, non occupationally exposed populations /9/. According to the FAO/WHO Joint Expert Committee on Food Additives (JECFA) renal dysfunction is the most sensitive toxicological end-point and recommends the use of urinary biomarkers to estimate the risk. Years ago the povisional tolerable weekly intake (PTWI) for chemicals was defined. The PTWI for Cd was 7 μg/kg body weight /10/. In 2010 the Committee noted that a monthly basis is more appropriate, owing to the long Cd half-life of 15 years in human kidneys /11/. The PTWI for Cd of 7 μg/kg body weight was therefore withdrawn in favour of the PTMI. An analysis relating β2 microglobulin excretion to Cd excretion from individuals ≥ 50 years showed that the urinary excretion below 5.24 (5th to 95th percentiles 4.94 to 5.57) μg Cd/g creatinine was not associated with an increase in excretion of β2 microglobulin. The Committee decided that a lower bound of the 5th population percentile dietary Cd exposure of 0.8 μg/kg body weight/day or 25 μg/kg body weight/month would result in a urinary Cd concentration of 5.24 μg/g creatinine. The PTMI was calculated 25 μg/kg body weight. The estimates of exposure to Cd through the diet examined by the Committee at the 2010 meeting was:

  • Children 0.5–12 years: 3.9–20.6 μg/kg body weight/month
  • Adults: 2.2–12 μg/kg body weight/month (mean)
  • Adults: 6.9–12.1 μg/kg body weight/month (high level)
  • Adults: 2.2–12 μg/kg body weight/month (mean)
  • Adults: 25 μg/kg body weight/month (vegetarians).

Regular ingestion of oysters, oil seeds, and offal is a source of Cd exposure due to their relatively high Cd content. After 12 years, oyster farmers who consume 18 oysters per week (87 μg/week) have a blood Cd concentration of 0.83 (0.34–2.27) μg/L and a urinary Cd concentration of 0.76 (0.16–4.04) μg/L /14/. Sunflower seeds, peanuts, flaxseed, and linseed contain more Cd than other plant products. Sunflower seeds, for example, have a Cd content of 0.2–2.5 mg/kg. Liver and kidney contain more Cd than muscle meat; elk liver contains 2.1 mg/kg and elk kidney contains 20.2 mg/kg.

Bio monitoring carried out by the German Federal Environment Agency /3/ determined blood concentrations in adults with a geometric mean of 0.44 μg/L. Mean urinary concentrations were 0.22 μg/L and 0.55 μg/g creatinine. Ex-smokers had a mean blood concentration of 0.33 μg/L and non-smokers had a mean level of 0.25 μg/L. Smokers, however, had a significantly increased concentration of, on average, 1.06 μg/L. The mean Cd concentration for the population of New York City was 0.77 μg/L, ranging from 0.25–9.67 μg/L /15/.

Acute CADMIUM intoxication /6/

The prevalence of acute Cd intoxication has declined significantly as a result of improvements in occupational safety and decontamination of soil. Cases are rare nowadays and mainly accidental. The toxicity of Cd is directly related to the solubility of its salts, which make Cd2+ ions readily available. The highly soluble fluoride and nitrate are the most toxic compounds. Acute intoxication is mainly caused by inhaling Cd vapors or particles. These particles are colorless, odorless, and non-irritant at low concentrations. Acute Cd intoxication caused by fumes or particles presents with flu-like symptoms. Initial symptoms include dry nasal and pharyngeal mucosa, cough, headache, and possibly confusion and fever. Brief, intense exposure to cadmium oxide (CdO) fumes can result in severe, often fatal, pulmonary edema that can develop suddenly or 24 hours after exposure. Interstitial pneumonia and fibrosing bronchiolitis can also occur.

Chronic CADMIUM intoxication – Generally /1/

There has been a continuous fall in the number of cases of chronic Cd intoxication in recent years. Cd levels in the kidneys of the Swedish population declined by 60% between 1976 and 1998 /16/. Specific symptoms include inflammation of the nasopharyngeal mucosa (Cd rhinitis) and progressive degenerative changes to the olfactory organs. The toxic effects of Cd, following both inhalation and oral intake, target the kidney. In addition to renal impairment, which is a major consequence of long-term exposure to Cd, olfactory toxicity, male infertility, hypertension, and cardiovascular disease can also occur.

The major sources of occupational exposure to Cd are metalworking, producing, processing and handling of Cd powders. Thus, occupational Cd exposure occurs mainly by inhalation of particulate matters in fumes or dust present in contaminated air /6/.

– Itai-itai disease

Itai-itai disease develops following long-term exposure to high doses of Cd. The disease mainly affects women and is characterized by significantly reduced glomerular and tubular renal function as well as generalized osteoporosis and osteomalacia that can lead to fractures. Patients complain of pain in the back and extremities and have difficulty walking.

– Nephropathy

The most frequently reported Cd toxicity in non-occupationally exposed populations is related to the kidney, notably the injury to the proximal tubular epithelial cells that reabsorb and concentrate Cd form the glomerular filtrate. Renal tubular cells are highly susceptible to Cd-induced apoptosis because of high abundance of mitochondria and substantial reliance on autophagy to maintain homeostasis. One of the consequential results of the injury and death of renal tubular cells by Cd is a reduction in tubular reabsorption capacity, leading to loss of nutrients through urine, notably glucose, amino acids, calcium and zinc /26/.

The renal toxicity of Cd is dose-dependent, and impairment occurs only if the amount of Cd stored in the kidneys exceeds a critical threshold of 100–200 μg/g wet weight. Most of the Cd is bound to metallothionein; the free Cd2+ ion is toxic, with a critical concentration of 2 μg/g wet weight. Cd nephropathy leads to tubular proteinuria, disturbed calcium and phosphate metabolism, bone demineralization, formation of renal calculi, and fractures. Prospective studies have shown that Cd-induced proteinuria is highly predictive of cardiovascular events, stroke, nephritis, and nephrosis as well as overall mortality /17/.

Laboratory diagnostics /26/: Urinary concentration of β2-microglobulin and N-acetyl-β-D-glucosamidase (NAG) are often used to diagnose Cd-induced kidney tubular pathologies. Urinary Cd excretion is used as an indicator of cumulative long-term exposure or body load. Urinary Cd levels > 1 μg/L were associated with a 48% increase in the risk of CKD development in adult people in the U.S. NHANES 1999–2006 cycle. In one study, urinary Cd of 0.57–1.84 μg/g creatinine was identified as threshold levels for urinary β2-microglobulin 1065 μg/g creatinine. Elevated urinary β2-microglobulin excretion ≥ 283 μg/day were reported for individuals who excreted 3.05 μg of Cd per day. In Japanese studies, urinary Cd excretions of 1.6-4.6 μg/g creatinine were associated with β2-microglobulin excretion of 1,000 μg/g creatinine, an indicative of severe and irreversible tubular dysfunction. A new study /26/ recommends a urinary Cd threshold to prevent kidney disease development of 0.5 μg/g creatinine. This level is 10-fold lower than the current threshold for kidney toxicity established by the FAO/WHO of 5.24 μg/g creatinine.

– Bone disease

Cd nephropathy reduces the synthesis of 1,25 dihidroxycalciferol, which disrupts the calcium and phosphate balance and results in osteoporosis, osteomalacia, and pseudo fractures.

Chronic low-level Cd exposure is also thought to be associated with reduced tubular function, skeletal demineralization, and osteoporosis. In women aged 53–64 years, reduced tubular function and reduced bone mineral density occurred at mean Cd concentrations of 0.38 μg/L and urinary excretion of 0.8 μg/g creatinine. Diabetics and postmenopausal women were more vulnerable to Cd-induced bone disease than non-diabetics and non menopausal women /18/.

– Diabetes mellitus

A dose-response relationship exists between Cd excretion and albuminuria in type 2 diabetes. This was demonstrated in a study of Torres Strait islanders with type 2 diabetes /19/. Individuals with albuminuria had urinary Cd excretions that were 61% higher than in diabetics without albuminuria who displayed moderate Cd excretion of 0.74 μg/g creatinine. A possible interpretation of this result is that Cd excretion should not exceed 0.74 μg/g creatinine in type 2 diabetes.

– Malignancy

A number of studies have demonstrated a relationship between Cd and cancer. A 15-year study in Belgium /20/ showed that the frequency of lung carcinoma was increased by a factor of 1.7 in individuals who had a twofold increase in Cd burden, by a factor of 4.2 in those who lived in Cd contaminated environments, and by a factor of 1.57 in those who lived in areas in which the soil Cd was doubled.

The Women’s Health Initiative failed to show any relationship between dietary Cd ingestion and the occurrence of breast, endometrial, or ovarian cancer in postmenopausal women over a study period of 10.5 years /21/.

– Hypertension

In a Korean study, 26.7% of individuals in the study group had hypertension. The mean blood Cd concentration was 1.67 μg/L. When individuals were divided into four groups, those in the tertile with the highest blood Cd concentrations had a 1.51 times higher risk of hypertension than those in the tertile with the lowest concentrations /22/. A clear association between blood pressure and Cd concentration is evident in non-smokers only.

– Peripheral arterial disease /23/

Continued smoking, with its associated Cd exposure, increases the risk of peripheral arterial disease by a factor of 4.13. Urinary excretion of Cd is 36% higher in patients with peripheral arterial disease than in controls. The peripheral arterial disease group had a mean Cd excretion of 0.36 μg/L; the 25th percentile was 0.19 μg/L and the 90th percentile was 1.16 μg/L.

The risk of peripheral arterial disease was 3.05 times higher in individuals whose values were ≥ 75th percentile than those with values at the 25th percentile.

– Reproductive disorders /23/

Several studies have shown that Cd leads to reproductive disorders in men and women /24/. Cd accumulates in the ovary and is associated with decrements in oocyte development. Cd accumulates in the developing embryo from the four cell stage through later stages of embryonic development.

Table 11.6-1 Mercury reference intervals

Blood /2/

Children 6–12 yrs

Up to 1.5 μg/L (75 nmol/L)

Adults 18–69 yrs

Up to 2.0 μg/L (100 nmol/L)

Urine /2/

Children 6–12 yrs

Up to 0.4 μg/L (20 nmol/L)

Adults 18–69 yrs

Up to 1.0 μg/L (50 nmol/L)

Conversion: μg/L × 50 = nmol/L. Blood reference values applied to individuals who consume fish up to three times a month. Urinary reference values applied to individuals without dental amalgam.

Table 11.6-2 Causes of mercury exposure


Type of exposure


  • Waste from Hg-containing instruments such as thermometers and barometers
  • Occupational exposure to Hg vapor
  • Dental amalgam
  • Injection and ingestion


  • Calomel
  • Ingestion of battery materials


  • Consumption of fish and other seafood
  • Exposure to fungicides
  • Antiseptics and antifungals (thiomersal)

Table 11.6-3 Environmental contamination, risk of disease, and intoxication caused by mercury

Clinical and laboratory findings

Exposure through food /6/

Because Hg is not degraded in the environment, it accumulates continuously. The Hg content of the biosphere has increased by a factor of 10 above those present in preindustrial times as the result of human activities that involve its release and use. The main sources of Hg exposure for the population are elemental Hg (Hg0) released as Hg vapor from dental amalgam and organic Hg in the form of methylmercury (MeHg) from the food chain. The most important source of MeHg exposure is consumption of fish and other seafood. Hg reaches the oceans naturally as the result of volcanic eruptions or due to human activities (emissions from coal-fired power plants, heating systems, treatment of seeds using MeHg as a fungicide). Elemental Hg is converted into organic Hg by phytoplankton and sulfate-reducing bacteria using methylation and enters the food chain. Depending on the industrial Hg emissions in the respective region and the lifespan of the marine organism, its Hg content in food can vary from less than 0.5 μg/g to 3 μg/g.

Regulatory decisions /6/: the Swedish National Institute of Public Health has recommended a safe limit for dietary exposure of 0.4 μg/kg of body weight per day, corresponding to a hair Hg concentration of about 6 μg/g. At that level, an adult weighing 70 kg, can eat 200 g of fish per week at a Hg concentration of 1 μg/g wet weight. The Joint Food and Agriculture Organization/WHO Expert Committee on Food Additives has recommended a provisional tolerable weekly intake of 2 μg/kg of body weight. According to the US Environmental Protection Agency, a 70 kg adult should consume no more than 50 μg Hg per week (0.1 μg × 7 days × 70 kg of body weight). Therefore, Hg levels in saltwater fish should not exceed 0.1 μg/g. Within the European Union, a common limit of 0,5 μg/g fish has been applied, but a few species, such as tuna and swordfish, were allowed to contain up to 1 μg/g wet weight.

Bio monitoring carried out by the German Federal Environment Agency /2/ determined blood concentrations below 0.2 to 34.8 μg/L in adults with a geometric mean of 0.43 μg/L. Urinary excretion ranged from less than 0.1 to 16.0 μg/g creatinine with a mean value of 0.34 μg/g creatinine. Blood concentrations increased with consumption of fish and fish products, dental amalgam, and frequent consumption of wine, sparkling wine, and fruit wine. Urinary Hg concentration increased with the number of amalgam fillings.

The mean Hg blood level in the New York City population was 2.7 μg/L, ranging from 0.2–35.8 μg/L. Hg concentrations in adults who reported consuming fish or shellfish 20 times or more in the last 30 days were 3.7 times the levels in those who reported no consumption /14/.

Acute and chronic poisoning with methyl-Hg (MeHg), Minamata disease /15/

The term “Minamata disease” is used as a synonym for MeHg poisoning. The first well-documented outbreak of MeHg poisoning due to fish consumption occurred in 1953 in Minamata, Japan. MeHg from the waste water of a factory that produced acetaldehyde had bio accumulated in the fish. The disease was given the name “Minamata disease” since its victims lived on the Minamata coastline. The victims had eaten contaminated fish during the period from 1950 to 1968. At least 200,000 people were poisoned. The median hair Hg level of individuals in the coastal area in 1960 was 23.4 (0–920) μg/g. Following a ban on the consumption of fish, brain Hg levels fell from 10 μg/g to 0.08 μg/g between 1960 and 1988.

Clinical symptoms of acute intoxication: Visual and hearing impairment, olfactory and gustatory disturbances, cerebellar ataxia, somatosensory disturbances and psychiatric symptomatology in adults. Acute fetal intoxication resulted in serious disturbances in mental and motor developments. The level of MeHg in umbilical cord blood rose from 0.2 mg/kg in 1950 to 1.2 mg/kg in 1960 and fell again to less than 0.1 mg/kg in 1970.

Clinical symptoms of chronic intoxication: while it is easy to diagnose acute MeHg intoxication, chronic intoxication is more difficult to diagnose (borderline cases, in particular). Determination of Hg in the blood or urine is not helpful here; electrophysiologic methods such as the measurement of short-latency somatosensory evoked potentials were used /16/. The chronic poisoned patients principally complained of paresthesia at the distal parts of the extremeties and around the lip since the cessation of MeHg pollution even though their exposure appeared to be ceased more than 30 years ago and their brain Hg levels had reduced by a factor of around 100 since they stopped eating contaminated fish and their hair Hg levels had also decreased significantly.

Although neurotoxic injury was the norm in children as well as adults from Minimata Bay, other studies of children with increased MeHg levels did not demonstrate clinical symptoms of Minamata disease. In a study on the Faroe Islands /17/, in which mothers at childbirth had median hair Hg levels of 4.5 (0.2–39.1) μg/g and their children had median hair Hg values of 2.99 (1.69–6.20) μg/g at the age of 7 and 0.96 (0.45–2.29) μg/g at the age of 14, the children did not have neurotoxic disorders.

MeHg and child neurodevelopment

The fetal brain is very sensitive to MeHg. Mothers who have been exposed to MeHg but have minimal or no symptoms can give birth to children with severe neurological disorders, including blindness, deafness, and seizures. Studies have also shown that postnatal exposure to MeHg is associated with learning difficulties even though the amount of Hg in the brain is at micro molecular level. It is not possible to specify a Hg threshold for this effect /12/. It is hypothesized that altered reward processing, dopamine, and GABAergic neurotransmitter systems, and cortical regions associated with choice and perseveration are especially sensitive to developmental MeHg at low exposure levels. Reproducible effects of Hg exposure, anatomical changes and sensory evoked potentials, can be seen down to a neonatal Hg level of 0.3 μg/L /12/. For this reason, pregnant women are advised not to consume more than 0.1 μg Hg/kg/day (US Environmental Protection Agency) or 0.22 μg Hg/kg/day (WHO), which corresponds to 1–2 cans of tuna per week. In spite of this, 500,000 children with blood Hg concentrations that exceed 5.8 μg/L are born each year (a level that is associated with cognitive defects) /12/. According to various studies, every increase in a pregnant woman’s hair Hg level of 1 μg/g leads to a reduction of 0.18 points in the IQ of the child. According to another study, each increase in the hair Hg level of 1 μg/g during pregnancy reduces the IQ of the child by 0.7 points /17/.

Dental amalgam exposure /4/

Amalgam fillings consist of 50% metallic mercury (Hg0). Hg vapor is released continuously from amalgam, both by the dentist (filling, polishing, removal) and the patient with the filling (chewing, grinding, contact with hot and acidic drinks). Hg vapor enters the bloodstream easily and, together with the consumption of fish and other seafood, is the main cause of Hg exposure in humans. Individuals with dental amalgam have been shown to have a 2–5 fold increase in Hg concentration in the blood and urine and 2–12 fold increases in various organs. Amalgam fillings in the mother cause increased Hg concentrations in the blood and hair of the newborn and the Hg level in the breast milk also correlates to the amount of dental amalgam. In chronic, low-level exposure to Hg vapor, the Hg concentrations in the blood and urine do not reflect the amount of Hg stored in the body, so the body Hg burden can be significant despite low measured levels. It can therefore be assumed that deleterious health effects of dental amalgam occur at values well below the body, so the body Hg burden can be significant despite low measured levels. It can therefore be assumed that deleterious health effects of dental amalgam occur at values well below the Human Bio monitoring Value I (HBM I value) of 5 μg/L. In a review of dentists, the risk of damage was considered to be low at urinary Hg concentrations of up to 22 μg/L /18/. According to an autopsy study /19/ of adults, for every 10 amalgam fillings, there was an increase in the occipital cortex of 1.5 μg Hg/kg of tissue.

Autism spectrum disorders (ASDs) /4/

Approximately 10% of women of childbearing age in the USA have blood Hg levels that exceed the safe upper levels recommended by the US Environmental Protection Agency of 5.5 μg/L in the blood or more than 1  μg Hg/g hair. In healthy children, there is a relationship between the amount of dental amalgam and the hair Hg concentration. This relationship does not exist in children with ASDs; they have lower Hg concentrations despite being exposed to Hg. A theory exists that some fetuses that fall within the ASDs are more sensitive to Hg exposure for biochemical or genetic reasons and also have reduced Hg elimination /20/. Other authors have come to a similar conclusion i.e., that the stabilizing agent thiomersal (ethylmercury thiosalicylate) that was used in vaccines is a possible cause for ASDs. Thiomersal itself is not primarily responsible for ASDs /21/.

Table 11.6-4 Mercury thresholds

Threshold value


5 μg/L whole blood

Human biomonitoring threshold /22/.

4,6 μg/L (23 nmol/L) whole blood

4 nmol Hg/mmol creatinine

95% percentile for the USA population according to the US National Health and Nutrition Survey (NHNS)

10 μg/L (50 nmol/L) whole blood

19.8 nmol Hg/mmol creatinine

Significant increase; search for cause and ways to reduce exposure (NHNS recommendation)

40 μg/L (200 nmol/l) whole blood

Consult clinical toxicologist to discuss further management (NHNS recommendation)

40 μg/L (200 nmol/L) whole blood

Maternal Hg levels causing fetal development defects occur /23/

100 μg/L (500 nmol/L) whole blood

Clinical tremor, ataxia, paresthesias in adults /24/

Above 6 μg/g hair

According to the Swedish Environmental Protection Agency, delayed brain development in children is associated with higher maternal Hg concentrations /25/

0,6 μg/g hair

In 2001, the European Commission decided that fish should contain no more than 1 μg Hg/g. The consumption of around 200 g fish per week does not cause the hair Hg content to exceed the specified threshold /26/. The safe limit in the USA is 1.0 μg/g hair /27/.

0,3 μg/g hair; in longitudinal studies, 0.5 μg/g hair

Lowest observable adverse effect hair concentration (LOAEHC) of prenatal MeHg exposure through maternal fish that can cause fetal neurodevelopmental risk /28/.

Table 11.7-1 Thallium reference intervals

Whole blood /5/

< 2.0 μg/L (10 nmol/L)

Urine /5/

< 2.3 μg/24 h (11.5 nmol/24 h)*


< 20 ng/g hair

* Based on daily volume of 1.5 L; conversion: μg/L × 4.88 = nmol/L

Figure 11.6-1 Mechanisms of cellular damage to neurons and astrocytes by methylmercury (MeHg). MeHg inhibits uptake of glutamate and amino acids that are associated with the synthesis of astrocytic glutathione (GSH). Accumulation of glutamate in the extracelluler space and the resulting excessive activation of N-methyl-D-aspartate (NMDA) receptors can lead to cytotoxicity and cell death. Other proposed mechanisms include the MeHg caused dysfunction of mitochondria, impaired cytoplasmic Ca2+ homeostasis and the release of reactive oxygen species (ROS). Modified with kind permission from Ref. /13/.

Microtubules Glutamate receptor Ca 2+ Ca 2+ Neuron ROS GSH Astrocyte GSH ROS MeHg Neuron MeHg MeHg Nuclear damage Lipid peroxidation GS-Hg GSH Mitochondria Glutamate MeHg MeHg MeHg GSH
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