90 CHROMIUM

Steven B. Bird

Chromium (Cr) in forming brick molds because of its high melting point and moderate ther-
Atomic number = 24 mal expansion.
Atomic weight = 51.99 Da The carcinogenic potential of hexavalent chromium was first recognized
Normal concentrations as a cause of nasal tumors in Scottish chrome pigment workers in the late
  Whole blood = 20–30 mcg/L (385–577 nmol/L) 1800s. In the 1930s, the pulmonary carcinogenicity of hexavalent chromium
was first described in German chromate workers.10
  Serum = 0.05–2.86 mcg/L (1–54 nmol/L)
  Urine = <1 mcg/g creatinine (<0.22 nmol/mmol creatinine)
PHARMACOLOGY
Chromium is an essential element involved in glucose metabolism. The
INTRODUCTION mechanism appears to be either facilitation of insulin binding to insulin
Chromium toxicity results from occupational exposure, environmental expo-
receptors or by amplification of the effects of insulin on carbohydrate and
sure, or a combination of both routes. Like many metals, the clinical manifes-
lipid metabolism.19
tations of chromium toxicity depend upon whether the exposure is acute or
The chemical properties and health risks of chromium depend mostly on its
chronic and on the chemical form of chromium. Acute toxicity is more likely
oxidative state, and on the solubility of the chromium compound. Chromium
to involve multiple-organ failure, whereas chronic exposure is more likely to
is found naturally in the hexavalent (Cr6+) or in the trivalent (Cr3+) valence
lead to cancer.
states, the species most relevant to human exposures. However, chromium has
HISTORY AND EPIDEMIOLOGY very different properties in the Cr6+ and Cr3+ oxidation states. The relationship
Chromium (from the Greek word for color, chroma) is a naturally occurring between these oxidative states is described by the following equation12:
element that is found in oxidation states of –2 to +6, but it primarily exists in Cr2O72- + 14 H+ + 6 electrons → 2Cr3+ + 7H2O + 1.33 eV
the trivalent (Cr3+) and hexavalent (Cr6+) forms. It was first discovered in 1797
in the form of Siberian red lead (crocoite: PbCrO4), and occurs only in combina- This difference of 1.33 eV in electric potential between the Cr6+ (in Cr2O72-)
tion with other elements, primarily as halides, oxides, or sulfides (Table 90–1). and Cr3+ states reflects both the significant oxidizing potential of Cr6+ and
Elemental chromium (Cr0) does not occur naturally but is extracted commer- the high energy required for the oxidation of Cr3+ to Cr6+. Reduction of Cr6+
cially from ore. Chromium is found most abundantly in chromite ore (FeCr2O4).7 to Cr3+ occurs in vivo by abstraction of electrons from cellular constituents
Elemental chromium is a blue-white metal that is hard and brittle. It such as proteins, lipids, DNA, RNA, and plasma transferrin and accounts for
is typically polished to a fine, shiny surface, affords significant protection the toxicity of Cr6+.37
against corrosion, and added to steel to form stainless steel (an alloy of chro- The rapidity and completeness of the reduction of Cr6+ is the subject of
mium, nickel, and iron). One of the most important uses of chrome plating is considerable scientific debate. Hexavalent chromium is reduced to Cr3+ in
to apply a hard, smooth, surface to machine parts such as crankshafts, print- saliva, the gastrointestinal tract, respiratory tract epithelium and pulmonary
ing rollers, ball bearings, and cutting tools. This is known as “hard” chrome macrophages, and in blood.2,32 During this reduction, several other oxidative
plating. Elemental chromium is also used in armor plating safes, and is used states transiently occur (namely Cr4+ and Cr5+) and contribute to the cytotox-
icity, genotoxicity, and carcinogenicity of Cr6+ chromium compounds.46
Although most Cr6+ is rapidly reduced on entering the gastrointestinal tract,
  TABLE 90–1    Common Forms of Chromium ingestion of Cr6+ in drinking water leads to measurable chromium concentra-
Chemical Oxidation
tions in plasma, red blood cells, and urine. Hexavalent chromium accumulates
Name Formula State Uses in most body tissues, raising concerns that chromium-induced toxicity and
carcinogenesis are more widespread than was previously appreciated.10
Barium chromate BaCrO4 6 +
Safety matches, anticorrosive,
paint pigment Environmental Exposure
Calcium chromate CaCrO4 6 +
Batteries, metallurgy The processing of chromium ores primarily releases Cr3+ into the environ-
ment. However, some hexavalent chromium is released from chromate man-
Chromic acid H2CrO4 6+ Electroplating, oxidizer ufacturing and coal-based power plants. The most significant environmental
Chromic chloride CrCl3 3 +
Supplement in total parenteral sources of Cr6+ are chromate production, ferrochrome pigment manufactur-
nutrition ing, chrome plating, and certain types of welding.
The general population is exposed to chromium via drinking water,
Chromic fluoride CrF3 3+ Mordant in dye industry, food and food supplements (eg, chromium picolinate), joint arthroplasty,
mothproofing for wool
coronary artery stents, and cigarettes. Chromium is used extensively to
Chromic oxide Cr2O3 3+ Metal plating, wood treatment prevent equipment and piping corrosion in industrial cooling towers and
Chromite ore FeCr2O4 3 +
Water tower treatment air conditioning (trivalent chromium). Dermal exposure occurs from use
of tanned leather products or wood treated with CCA (copper, chromate,
Chromium picolinate C18H12CrN3O6 3 +
Nutritional supplement and arsenate), which contains hexavalent chromium that is reduced to
Lead chromate PbCrO4 6 +
Yellow pigment for paints and dye trivalent chromium by organic compounds once incorporated in wood.
Lumber treated with CCA was voluntarily removed from the US consumer
Potassium dichromate K2Cr2O7 6 +
Oxidizer of organic compounds, market in 2003, because of possible health concerns resulting from exposure
leather tanning, porcelain painting
to the arsenic and chromium. No specific adverse health effects related to
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CCA-treated lumber were reported by the Environmental Protection Agency nor are there data to specify the concentration of chromium necessary to
before the voluntary withdrawal. A reanalysis of cancer mortality and produce adverse systemic effects. Further discussion of orthoprosthetic
hexavalent chromium–contaminated drinking water from Liaoning cobaltism is found in the chapter on cobalt effects in MoM Hip implants.
Province, China, demonstrated an increase in stomach cancer rate in (Chap. 91).16
communities with chromium-contaminated drinking water.5 Significant
exposure from more than 160 chromate production waste sites within PHARMACOKINETICS AND TOXICOKINETICS
Hudson County, New Jersey, was discovered in the late 1980s.17 A final report Because they possess significantly different properties, Cr3+ and Cr6+ must be
published by the Agency for Toxic Substances and Disease Registry in 2008 evaluated separately.
found an increased risk of lung cancer in populations living in proximity
to historic chromium ore–processing residue sites, although the increases Absorption
were not statistically significant.33 Trivalent Chromium Compounds
Oral absorption of Cr3+ salts is limited. Approximately 98% is recovered in
Occupational Exposure the feces, just 0.1% is excreted in the bile, and 0.5% to 2.0% is excreted in the
Workers in industries that use chromium are exposed to 100 times greater urine.14,16 Human case reports and animal studies also corroborate the gener-
concentrations of chromium than the general population. Chromium pig- ally poor absorption of Cr3+ salts by the oral, inhalational, and dermal routes,
mentation production and leather tanning use significantly more Cr6+ com- except through burns and other disrupted mucosal or epithelial surfaces.27
pounds, whereas metal finishing, wood preservation, and cooling towers use
Cr3+ compounds (Table 90–2). Hexavalent Chromium Compounds
Several studies focus on the risk of chromium exposure in welders.41,42 Cr6+ is modestly absorbed after ingestion partly as a result of the structural
Stainless steel welding liberates significantly more hexavalent chromium similarity between hexavalent chromium compounds and phosphate and
than do other types of welding. Although the lung cancer rate of stainless sulfate.11 These 3 chemicals undergo facilitated diffusion through non-
steel (containing chromium) welders was not found to be different from specific anion channels as well as active transport. In human volunteers,
that in regular steel welders, in 2006 the Occupational Safety and Health approximately 10% of an ingested dose of sodium chromate was absorbed;
Administration (OSHA) lowered the permissive exposure limit of hexavalent duodenal administration increased this to roughly 50%.14 This difference
chromium by 10-fold for welders. More recently, a meta-analysis of occupa- likely relates to the reduction of the hexavalent chromium to trivalent chro-
tional exposures demonstrated a statistically significant increase in both lung mium in the acidic environment of the stomach. Similarly, 3 hours after the
and stomach cancer in workers with exposure to hexavalent chromium.50 ingestion of a lethal amount of potassium dichromate (hexavalent), greater
than 80% of the chromium was reduced to the trivalent state in the blood.20
Medical Device Exposure Hexavalent chromium compounds are generally not well absorbed after der-
Recent concerns and media attention are directed to the use of metal on metal mal exposure. Whatever the route of exposure, Cr6+ is absorbed much more
(MoM) implants for total hip arthroplasty and surface refinishing. Unlike non- readily than Cr3+, but the Cr6+ is then rapidly reduced to Cr3+ after absorption.
MoM implants in which the articular surfaces are made of ceramic or polyeth- Epidemiologically, inhalation of Cr6+ is the most consequential route of
ylene, these metal implants have metal rubbing on metal. For more than 20 exposure. Furthermore, the greatest health consequences from Cr6+ expo-
years, it has been known that blood concentrations of metal ions increase in sure are due to inhalation. The exact rate of absorption is unknown, but is
patients with MoM hip arthroplasty. One-year postoperative blood chromium dependent on the solubility of the specific Cr6+ compound, the size of the
concentrations increased by 21 times over the preoperative concentrations.21 particles, the phagocytic activity of the pulmonary macrophages, and the
Metal release will cause some tiny metal particles to wear off of the device general health of the lungs. In animal studies roughly 50% to 85% of small
around the implant, which causes damage to bone and/or soft tissue sur- (<5 µm) inhaled Cr6+ potassium dichromate particles are absorbed.34
rounding the implant and joint. Although some patients with failed MoM hip
implants report memory difficulties, chronic pain, and pain in the implanted Distribution
hip, the true incidence and nature of adverse health outcomes due to release Because most of the Cr6+ is rapidly reduced on absorption by the gastrointes-
of chromium ions and particles from these implants is not yet established. tinal tract and by red blood cells (RBCs), Cr3+ accounts for virtually the entire
Currently, there is insufficient evidence to conclusively demonstrate that body burden of chromium. Trivalent chromium accumulates to the greatest
with regard to chromium, MoM hip implants produce side effects beyond extent in the kidneys, bone marrow, lungs, lymph nodes, liver, spleen, and
those that may occur at the site of implantation. There is no consensus on testes. The kidneys and liver alone account for approximately 50% of the
what might be the significance of elevated blood chromium concentrations, total body burden.11

Elimination
  TABLE 90–2    Occupations at Risk for Chromium Exposure Urinary excretion of trivalent chromium occurs rapidly. Roughly 80% of par-
enterally administered Cr6+ is excreted as Cr3+ in the urine and 2% to 20% in
Cement workers the feces.31 The urinary excretion half-life of Cr6+ ranges from 15 to 41 hours.22
Chromite ore workers Because Cr6+ undergoes reduction to Cr3+ following uptake by RBCs, an appar-
Electroplaters ent slow compartment is created, with the elimination half-life dependent
Foundry workers on the life span of erythrocytes. Small amounts of chromium are detectable
Galvanized steel workers in sweat, breast milk, nails, and hair.
Glass polishers and glazers
Lithographers PATHOPHYSIOLOGY
Machinists Trivalent Chromium
Painters Trivalent chromium is an essential trace metal required for the metabo-
Photograph developers lism of glucose and fats. The complex nutritional interactions of trivalent
Tanners chromium with numerous metabolic pathways are not understood, and
Textile dyers remain the subject of much debate among researchers. However, it is clear
that dietary chromium deficiency leads to insulin resistance with elevated
Welders
insulin concentrations, hypercholesterolemia, hyperglycemia, increased
Wood preservers
body fat, and the attendant risks of these metabolic derangements. Trivalent

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chromium enhances insulin sensitivity and glucose disappearance concomi- specimens.51 Unlike acute exposures, low-dose chronic chromium exposure
tantly with lower insulin concentrations in an obese rat model, with no dif- occasionally causes transiently elevated urinary β2-microglobulin concen-
ference in lean controls.9 trations, with no obvious lasting effects.49
Chromium picolinate is a popular Cr3+ dietary supplement. There is a Type IV (delayed-type) hypersensitivity reactions occur after acute expo-
dearth of rigorous science concerning the efficacy or safety of chromium sure to hexavalent chromium compounds. Chronic hexavalent chromium
picolinate. However, organ deposition of Cr3+ occurs.40 There is no strong evi- exposures also occur via dermal contact. Up to 24% of cement workers
dence of any significant end-organ toxicity due to exposure to Cr3+, perhaps who have frequent contact with wet cement (which contains Cr6+), auto-
because Cr3+ is so poorly absorbed. There is little or no rigorous evidence that mobile part handlers, and locksmiths develop skin sensitivity to chromium
exposure to Cr3+ compounds increases cancer risk. Animal work and epide- compounds.26,28
miologic studies of workers exposed to Cr3+ compounds fail to demonstrate a Occupational chromium exposure leads to contact dermatitis in as many
statistically significant increased incidence of cancer.3 as 10% to 20% of chromium workers.44 There remains considerable debate
over the relative sensitization abilities of Cr3+ and Cr6+. Furthermore, what
Hexavalent Chromium was initially thought to be sensitization to Cr3+ exposure was more likely
Hexavalent chromium is a powerful oxidizing agent that has corrosive exposure to Cr6+ with subsequent in vivo reduction to Cr3+. It is likely, how-
and irritant effects. The greatest toxicity from Cr6+ lies in its ability to ever, the Cr6+ is a more potent sensitizer than Cr3+, and that there is limited
produce oxidative DNA damage. Strand breaks with DNA, DNA–DNA cross-reactivity between the 2 forms of chromium.15 Similarly, exposure to
and DNA–protein crosslinks, and nucleotide modifications all occur.12 chromium-containing gaming table felt has led to hand dermatitis referred
Although the exact mechanisms of how Cr6+ is genotoxic are unknown, to as “blackjack disease,” and virtually all occupations that involve exposure
transient toxic chromium intermediates such as Cr4+ and Cr5+ are prob- to inhaled chromium can lead to painless, scarring skin and nasal septum
ably responsible.39 ulcerations, referred to as “chrome holes”.25
Inconsistent data suggest that either immunostimulation or immunosup-
pression result from chronic chromium exposure. At least one study suggests DIAGNOSTIC TESTING
that chromium induced immunosuppression is responsible for implant asso- Chromium is detected in blood, urine, and hair of exposed individuals.
ciated infections in patients after hip or knee arthroplasty.39 Although human Because of the great difficulty in speciation, differentiation between Cr3+
data are incomplete, adverse developmental effects, including cleft palate, and Cr6+ is generally not performed; instead, the total chromium concentra-
hydrocephalus, and neural tube defects, are demonstrated in animals.13 tion is usually reported. Needles used for phlebotomy and plastic containers
used for sample storage generally contain significant amounts of chromium.
CLINICAL MANIFESTATIONS Unfortunately, there are no commercially available chromium-free needles.
The clinical manifestations of chromium poisoning depend on the valence Modern, highly sensitive assay equipment, such as graphite furnace atomic
of chromium, the source and route of exposure, and the duration of expo- absorption spectrometry, neutron activation analysis, and graphite spark
sure. The clinical manifestations of chromium exposure are best divided into atomic emission spectrometry, require diligence in sample handling to
acute and chronic (low-level exposure) effects. ensure that biological samples are not contaminated.
Acute Because of the inherent difficulties in quantifying trace elements such
Manifestations of acute, massive Cr6+ ingestions are similar to other caustic as chromium, and the lack of standard chromium reference materials, the
metal ingestions. Gastrointestinal hemorrhage, with or without bowel per- reported normal serum and urine chromium concentrations in unexposed
foration, occurs acutely.51 Because of the strong oxidative properties of Cr6+, people have varied by more than 5,000-fold over the last 50 years.34 Conse-
intravascular hemolysis with disseminated intravascular coagulation is also quently, older reference ranges should be interpreted with caution. Lastly,
observed. Renal effects include acute tubular necrosis leading to acute kid- although cigarette smoke contains chromium, no studies have quantified the
ney injury.49 Metabolic abnormalities after acute, massive, exposure include effect of smoking on serum, blood, or urinary chromium concentrations.
metabolic acidosis with elevated lactate concentration, hyperkalemia, and Blood or Serum
uremia. Acute respiratory distress syndrome (ARDS) develops up to 3 days Chromium is distributed evenly between the serum and erythrocytes. Serum
after exposure. Although Cr6+ is generally not well absorbed after dermal expo- chromium concentrations are reflective of recent exposure to both Cr3+ and
sure, it is a caustic that causes skin inflammation and ulceration, which ulti- Cr6+. Serum concentrations in people without occupational exposure to
mately increases dermal absorption. Dermal chromic acid (H2CrO4) burns lead chromium are reported to be from 0.05 mcg/L (1 nmol/L)8 up to more than
to severe systemic toxicity with as little as 10% body surface area involvement. 2.8 mcg/L (54 nmol/L).34 It is not certain whether concentrations above these
Chronic values should be considered potentially toxic, as no clear correlation has
Because most chronic exposures are inhalational, the respiratory tract is the been found between serum or blood concentrations and physiologic effects.
organ most affected after chronic chromium exposure. When inhaled, Cr6+ Urine
is a respiratory tract irritant that causes inflammation and, with continued Although urine chromium concentrations reflect the acute absorption of
exposure, ulceration including nasal septum perforation.23 Furthermore, chromium over the previous 1 to 2 days, wide individual variation in metabo-
the sensitizing effects of Cr6+ leads to chronic cough, shortness of breath, lism and total body burden limit the value of urinary chromium monitoring.
occupational asthma, bronchospasm, and anaphylactoid reactions. Chronic Urine should be collected over a 24-hour period because of diurnal variation
deposition of chromium dust is also associated with pneumoconiosis.38 in excretion. Data from the third National Health and Nutrition Examination
Epidemiologic studies of chromate workers in the 1980s indicated a sig- Survey (NHANES III) demonstrated mean and median urinary chromium
nificantly increased risk of lung cancer in those individuals exposed to Cr6+ concentrations in approximately 500 individuals without known exposure to
compounds.24,35 Small cell and poorly differentiated carcinomas are the most chromium of 0.22 mcg/L (4.2 nmol/L) and 0.13 mcg/L (2.5 nmol/L). When
common types, although nearly all pathologic types of lung cancer are asso- corrected for creatinine, the values were 0.21 and 0.12 mcg/g creatinine,
ciated with inhalational Cr6+ exposure.1 The latency between exposure and respectively.30
development of lung cancer ranges from 13 to 30 years, although cases are
reported after as few as 2 years.6 Hair and Nails
Although conclusive evidence is lacking, it appears that chronic expo- Hair and nail samples are not reliable indicators of exposure to chromium
sure to Cr6+ via all routes causes mild to moderate elevation in hepatic because of the difficulty distinguishing between chromium contamination
aminotransferases and abnormal liver architecture, visible on histologic of the hair sample from chromium incorporated into the hair during normal

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hair protein synthesis. Chromium found in hair is not due to contamination kidney injury or chronic kidney disease, peritoneal dialysis or hemodialy-
or exposure to shampoo or tap water.18 Chromium concentrations in hair are sis is a reasonable therapeutic choice to attempt to reduce serum chro-
up to 1,000 times higher than those found in serum. mium concentrations, although there are no data that clinical outcomes
are affected.
Ancillary Tests
After confirmed or suspected acute chromium exposure, complete blood SUMMARY
count, serum electrolytes, blood urea nitrogen, creatinine, urinalysis, and ■■ Hexavalent chromium remains an uncommon, but serious, cause of
liver enzymes testing should be performed. If signs of systemic toxicity are acute metal poisoning, whereas trivalent chromium is minimally toxic.
evident, serial determination of coagulation function and disseminated ■■ Acute ingestion of Cr6+ chromium salts causes gastrointestinal hemor-
intravascular coagulation may be useful to guide therapy. rhage, hepatic necrosis, and acute kidney injury.
■■ Toxicity after chronic Cr6+ chromium exposure includes ulcerations
MANAGEMENT of the skin and nasopharynx (“chrome holes”), and more significantly,
Acute chromium ingestions are infrequent, but often severe, with signifi- lung and stomach cancer. Definitive data regarding other types of
cant morbidity and mortality. Consequently, after adequate airway, breath- cancer resulting from chronic Cr6+ exposure are unavailable.
ing, and circulatory support are addressed, attention should be given to ■■ Regardless of the time course of the poisoning, treatment for chromium
decontamination. exposure includes removal of the patient from the source of exposure,
gastrointestinal decontamination, and supportive care.
Decontamination ■■ There is insufficient evidence to support the use of chelators in either
Because of its serious but very limited toxicity, Cr3+ compounds require lim- acute or chronic chromium poisoning.
ited decontamination measures. Decontamination with soap and water is
recommended after skin contact. No specific pulmonary decontamination
is required.
Hexavalent chromium is caustic and profuse vomiting and hemateme-
sis usually follow acute ingestions. Nasogastric lavage is reasonable after
Cr6+ ingestions if the patient presents to the emergency department within
several hours of exposure and no vomiting has occurred. There are no data
regarding the use of activated charcoal in acute chromium ingestions and
endoscopic visualization will be more difficult after administration of acti-
vated charcoal. Therefore, we recommend using activated charcoal in order
to obtain adequate endoscopic visualization.
Oral N-acetylcysteine increases the renal excretion of chromium in rats,4
but there are no human data to support this therapy. Years of clinical experi-
ence using N-acetylcysteine for other indications and the very low incidence
of adverse effects, however, makes the administration of oral N-acetylcysteine
in the setting of acute chromium toxicity reasonable.
Although ascorbic acid facilitates reduction of Cr6+ to Cr3+ in vitro, there
are no data to substantiate decreased absorption.44 There is some evidence
that topical ascorbic acid reduces dermal Cr6+ exposure, but this was not
demonstrated in controlled trials.39 Therefore, the routine use of ascorbic
acid cannot be recommended at this time.

Chelation Therapy
Currently available chelators do not appear efficacious at either lowering
serum or blood chromium concentrations or ameliorating chromium toxic-
ity in experimental models. Specifically, calcium ethylenediaminetetraacetic
acid (CaEDTA) had no effect on urinary chromium excretion in experimental
animals48 and dimercaprol (British anti-Lewsite {BAL}) was not beneficial in
an animal model of chromium poisoning.29
In a single study, dimercaptopropane sulfonate (DMPS) had no effect
on urinary chromium excretion in humans.45 d-Penicillamine also failed to
increase urinary excretion of chromium.29 There are no studies of chromium
chelation with 2,3-dimercaptosuccinic acid (succimer). Therefore, at this
time, there is no evidence to support the use of any chelation therapy after
acute Cr6+ or Cr3+ poisoning.

Extracorporeal Elimination
Hemodialysis, hemofiltration, and peritoneal dialysis do not efficiently
remove chromium. Studies in animals and human case reports indicate
that as little as 1% of chromium is removed by hemodialysis or hemofiltra-
tion after acute dichromate (a hexavalent compound) exposure.20,43 Limited
data in dialysis patients demonstrate some ability of peritoneal dialysis
and hemodialysis to remove intravenously administered chromium.36
Therefore, in the setting of normal renal function, extracorporeal means of
eliminated chromium are not likely to be of benefit. In the setting of acute

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