Toxicity of Hexavalent Chromium
Environmental Physical Agents

Author: Eugenio Sportoletti Baduel
Date: 18/03/2013


Introduction to chromium

Chromium (symbol Cr, atomic number 24) is a steely-gray, lustrous, hard metal that takes a high polish and has a high melting point. It is also odorless, tasteless, and malleable. It is the only elemental solid which shows antiferromagnetic ordering at room temperature (and below). Above 38 °C, it transforms into a paramagnetic state. Chromium is a member of the transition metals, in group 6. Chromium exhibits a wide range of possible oxidation states, where the +3 state is most stable energetically; the +3 and +6 states are most commonly observed in chromium compounds, whereas the +1, +4 and +5 states are rare. Chromium is mined as chromite (FeCr2O4) ore. The relation between Chromium (III) and Chromium(VI) strongly depends on pH and oxidative properties of the location, but in most cases, the Chromium (III) is the dominating species. In humans, trivalent chromium is an essential nutrient required for normal energy metabolism. Currently, the biological target for the essential effects of trivalent chromium is unknown. Chromodulin, also known as glucose tolerance factor (GTF), has been proposed as one possible candidate. The function of chromodulin, an oligopeptide complex containing four chromic ions, has not been established; however, a possible mechanism is that chromodulin facilitates the interaction of insulin with its cellular receptor sites and thus improves glucose tolerance, although this has not been proven. In general, hexavalent chromium compounds are more toxic than trivalent chromium compounds.

1) Hexavalents chromium

Hexavalent chromium refers to chemical compounds that contain the element chromium in the +6 oxidation state. All chromium ore is processed via hexavalent chromium, specifically the salt sodium dichromate.

COMPOUNDSFormulaMolec. wt.Density (g/mc3)Melting pt.
Calcium chromateCaCrO4156,12,89NR
Chromium trioxideCrO3100,02,70197°C
Lead chromatePbCrO4323,26,12844°C
Potassium chromateK2CrO4194,22,73975°C
Potassium dichromateK2Cr2O7294,22,68398°C
Sodium chromateNa2CrO4162,22,72792°C
Sodium dichromateNaCr2O7262,22,52357°C
Strontium chromateSrCrO4203,63,90NR
Zinc chromateZnCrO4181,43,40NR

Source: HSDB 2009. NR = not reported

1.1 Chromium applications
Workers in many different occupations are exposed to hexavalent chromium. The steel industry is the major consumer of chromium. Chromium(VI) compounds are widely used as corrosion inhibitors, in the manufacture of pigments, in metal finishing and chrome plating, in stainless steel production, in leather tanning, and in wood preservatives. Chromium(VI) compounds are also used in textile-dyeing processes, printing inks, drilling muds, pyrotechnics, water treatment, and chemical synthesis.

1.2 International guideline values
In the U.S., the OSHA PEL for airborne exposures to hexavalent chromium is 5 µg/m3. The National Institute for Occupational Safety and Health proposed a recommended exposur limit (REL) of 0.2 µg/m3 for airborne exposures to hexavalent chromium. For drinking water, no United States EPA Maximum Contaminant Level (MCL) exists, though the current MCL for total chromium is based on the assumption that all of it is Chromium (VI). California has finalized a Public Health Goal (PHG) of 0.02 µg/L and is now in the process of establishing an enforceable MCL. The USEPA setted the MCL of 0.1 mg/L and the World Health Organisation (WHO) recommended a maximum allowable concentration of 0.05mg/L for chromium (VI).

1.3 Clinic
Most of hexavalent chromium compounds are irritating to the eyes, skin and mucous membranes, and chronic exposure to them can cause permanent eye damage if not properly cared for. Ingestion of liquids containing chromium (VI) causes severe gastroenteritis with nausea, abdominal pain, vomiting and diarrhea. This phase follows the kidney and liver damage and acute tubular necrosis with development of acute renal failure is very serious and possible evolution towards exitus.

2) Toxicokinetics

(Toxicological profile for chromium, Agency for Toxic Substances & Desease Registry, 2012)

Chromium may cause adverse health effects following inhalation, ingestion or dermal exposure. The toxicokinetics of a given chromium compound depend on the valence state of the chromium atom and the nature of its ligands. In general, toxicity of chromium is mainly caused by hexavalent compounds as a result of a higher cellular uptake of chromium (VI) compounds than chromium (III). This is explained by the fact that the chromate anion (CrO4)2- can enter the cells via facilitated diffusion through non-specific anion channels (similarly to phosphate and sulfate anions). Absorption of chromium (III) compounds is via passive diffusion and phagocytosis. Hexavalent chromium is unstable in the body and is reduced intracellularly (by many substances including ascorbate and glutathione) providing very reactional pentavalent chromium and trivalent chromium. Both of these intermediates can alterate DNA.

2.1 Absorption

The primary route of absorption associated with occupational exposure is inhalation of chromium dust.

  • Inhalation exposure: Chromium can be absorbed from the lungs as indicated by the detection of high concentration of the element in urine, serum and tissues of humans occupationally exposed to soluble chromium (III) or chromium (VI) compounds in air. The absorption of inhaled chromium compounds depends on a number of factors, including physical and chemical properties of the particles (oxidation state, size, solubility) and the activity of alveolar macrophages. In most cases, chromium (VI) compounds are more readily absorbed from the lungs than chromium (III) compounds, due in part to differences in the capacity to penetrate biological membranes. On the other hand, part of the chromium deposited in the pulmonary tissue which is less rapidly absorbed because of lower solubility can cause local toxicity.
  • Oral exposure: Chromium (III) is an essential nutrient required for normal energy metabolism. A dietary intake of 50-200 µg/day is recommended. Absorption after oral exposure in humans varies from essentially none for the highly insoluble chromium (III) compounds (chromic oxide), to 0.5-2.0% of the dose for chromium (III) compounds in the diet, and approximately 2-10% for chromium (VI) such as potassium chromate. It has been shown that, in the stomach, chromium (VI) compounds are reduced to chromium (III) compounds explaining the relatively poor gastrointestinal absorption of orally administered chromium (VI) compounds.
  • Dermal exposure: Systemic toxicity has been observed in humans following dermal exposure to chromium compounds, indicating significant cutaneous absorption. Dermal absorption depends on the physical and chemical properties of the compound, the vehicle, and the integrity of the skin.

2.2 Distribution
In contrast to chromium (III), which is bound to plasma proteins such as transferrin, chromium (VI) entering the blood stream is taken up selectively by erythrocytes, reduced, and bound predominantly to heamoglobin.

  • Inhalation exposure: Examination of autopsy tissues from workers exposed to chromium revealed higher chromium levels in the hilar lymph nodes, lung, spleen, liver, kidney, heart compared to normal healthy males. Lung concentration of chromium increases with age.
  • Oral exposure: High levels of chromium were found in liver, kidney, and brain after an acute, lethal ingestion of a chromium (VI) compound (7.5 mg chromium (VI)/kg as potassium dichromate). Autopsy studies indicate that chromium concentrations are highest in the kidney, liver, lung, aorta, heart, pancreas, and spleen at birth and tend to decrease with age.
  • Dermal exposure: The finding of systemic toxic effects in humans who were dermally exposed to chromium compounds indicates the distribution of the element to these organs.
    In addition, chromium may be transferred to fetuses through the placenta and to infants via breast milk.

2.3 Metabolism
Once inside the cell, hexavalent chromium is metabolized to trivalent chromium, either enzymatically (via microsomal enzymes) or non-enzymatically (via ascorbate and GSH). This intracellular reduction yields reactive intermediates, chromium(V) and chromium(IV). These reactive intermediates are formed along with oxygen radicals generated via Fenton-like and other possible reactions that occur during intracellular reduction.

2.4 Elimination
Chromium is normally excreted through the kidneys in urine, with some excretion through the bile and feces; minor routes of excretion include breast milk, sweat, hair, and nails.

  • Inhalation exposure: Normal urinary levels of chromium in humans have been reported to a median level of 0.4 µg/L. In occupational settings, urinary concentrations of chromium are principally the reflection of the hexavalent soluble quantity recently absorbed. Workers exposed mainly to chromium (VI) compounds had higher urinary chromium concentrations than workers exposed primarily to chromium (III) compounds. The hexavalent form of chromium is not detected in urine, indicating that chromium (VI) is rapidly reduced before excretion.
  • Oral exposure: Given the low absorption of chromium compounds by the oral route, the major pathway of elimination after oral exposure is through the feces. Daily urinary excretion levels of chromium were nearly identical in men and women (averages of 0.17 and 0.20 µg/L, respectively; 0.18 µg/L combined) who ate normal dietary levels of chromium ( ± 60 µg chromium (III)/day). When chromium intake was supplemented fivefold with chromium chloride, urinary excretion also increased fivefold.
  • Dermal exposure: Information regarding the excretion of chromium in humans after dermal exposure to chromium compounds is limited.

3) Genotoxicity

(IRIS Toxicological Review of Hexavalent Chromium, 2010 External Review Draft)

Numerous studies have evaluated the genotoxicity of chromium(VI) compounds. Results of occupational exposure studies in humans, although somewhat compromised by concomitant exposures to other potential genotoxic compounds, provide evidence of chromium(VI)-induced DNA strand breaks, chromosome aberrations, increased sister chromatid exchange, unscheduled DNA synthesis, and DNA-protein crosslinks. Although most of the older occupational exposure studies gave negative or equivocal results, more recent studies have identified chromosomal effects in exposed workers. Findings from occupational exposure studies are supported by results of in vivo studies in animals, in vitro studies in human cell lines, mammalian cells, yeast and bacteria, and studies in cell-free systems.

4) Carcinogenicity

(U.S. EPA Guidelines for Carcinogen Risk Assessment, 2005a)

Under the Guidelines for Carcinogen Risk Assessment, chromium (VI) is “likely to be carcinogenic to humans” via mutagenesis.
Hexavalent chromium is readily taken up by cells through sulfate transporters, due to the structural similarity of hexavalent chromium to the tetrahedral sulfate and phosphate anions. Once inside the cell, chromium (VI) quickly undergoes a series of reduction reactions to yield pentavalent, tetravalent, and ultimately the thermodynamically stable chromium (III). Many potential enzymes as well as non-enzymatic cellular reductants capable of reducing hexavalent chromium exist within the cell. These reductants include glutathione, ascorbate, cysteine, lipoic acid, NADH, fructose, and ribose. Following this intracellular reduction, several possible mechanisms leading to mutagenicity can occur. Chromium (VI) itself does not interact directly with DNA. However, the products of its reduction within the cell (pentavalent, tetravalent, and trivalent chromium) have all been shown to be DNA reactive. Chromium (VI) is reduced by glutathione to yield pentavalent chromium and thiyl radicals, which can react with other thiol molecules to produce superoxide radicals. Both chromium (V) and chromium (III) can participate in Fenton reactions, generating hydroxyl radicals. All of these species can cause DNA single- and double-strand breaks, base modifications, and lipid peroxidation, which may lead to mutations if not adequately repaired.

Chromium (III) is the ultimate product of the intracellular reduction of chromium (VI). Trivalent chromium is capable of interacting directly with DNA, forming stable coordination complexes with nucleic acids and peptides. In particular, chromium (III) is capable of forming ternary complexes with DNA and an intracellular reducer, such as ascorbate, glutathione, or cysteine, as well as crosslinking DNA and proteins, and forming intrastrand DNA-DNA crosslinks. These chromium-DNA complexes, as well as DNA-protein and DNA-DNA crosslinks, all have the capability of causing DNA single- and double-strand breaks, which, if not adequately repaired, could lead to cell death, or if misrepaired, could result in mutation.Thus, once inside the cell, hexavalent chromium, through reduction to its pentavalent, tetravalent, and trivalent forms, is capable of inducing a wide range of mutagenic and genotoxic damage, including the formation of DNA adducts, DNA-protein and DNA-DNA crosslinks, mutations, DNA single and double-strand breaks, abasic sites, oxidized DNA bases, chromosomal aberrations, sister chromatid exchanges, and micronuclei.

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