Chromium Toxicity

Etiology

Chromium metal is prized for its luster and corrosion resistance; Cr(0) is used to make steel.[6][7] Trivalent and hexavalent chromium have other industrial applications, including coal and oil refining, metal and ore processing, leather tanning, dye and pigment production, welding, cement production, ammunition, agricultural fertilizers, and wood preservation.[2][3][4][8] Nonoccupational sources of chromium exposure occur primarily by consuming contaminated food and drinking water or exposure to tobacco-containing products that contain chromium released by pyrolysis.[1][9][10][11] 

Historically, there were concerns of potential chromium toxicity secondary to implanting metal-on-metal chromium-cobalt hip arthroplasty components. Symptoms did not correlate with serum chromium concentrations, and more recent findings suggest the observed toxicity is more likely due to cobalt exposure.[12] These components have been redeveloped recently, reducing concerns with modern medical devices.

Not all chromium exposure is hazardous. Trivalent chromium has been classified as an essential micronutrient since the 1950s, with a recommended intake of 120 mcg/d due to its role in glucose and lipid metabolism. However, numerous nutritional supplements containing Cr(III) are marketed for weight loss and glucose regulation.[4][9][6][7] Recent research disputes the essentiality of trivalent chromium; some studies suggest that compounds containing Cr(III) are potentially toxic and carcinogenic.[7][10][13][14] 

Nevertheless, chromium supplements, particularly chromium picolinate and chromium chloride, are popular with consumers, increasing from the fourth-highest–selling vitamin and mineral supplements in 2016 to the second-highest in 2021.[10][14]

Epidemiology

Chromium is naturally ubiquitous and can be found in volcanic emissions, rocks, animals, plants, soil, and water. Chromium concentrations in uncontaminated water range from 1 μg/L to 10 μg/L in rivers and lakes to 0.2 μg/L to 1 μg/L in rainwater, and approximately 0.3 μg/L in seawater.[1] Estimated chromium concentrations in the air in rural and residential areas range from 0.2 ng/m³ to 9 ng/m³ but can be 10 to 100 times higher in urban areas, equating to a lung intake of 1.8 μg/d.[11] Unsurprisingly, chromium is found in many foodstuffs, especially meat, fish, fruits, and vegetables, with estimated concentrations ranging from less than 10 μg/kg to 1,300 μg/kg.[1][3]

However, worldwide industrial processes produce more than 16.4 million tons of chromium annually. More than 170,000 tons are produced annually in the United States, of which 900 to 970 tons are released into the air, and almost 250 tons are discharged to surface water.[1][2][11] Additionally, environmental contaminants discharged from the 386 National Priority List hazardous waste sites known to contain high levels of Cr(VI) are estimated to be 45,000 tons annually, equated by one study to as much as 3,000 mg/kg in soil, 800 μg/L in seawater, and 5,200 μg/L in rivers and lakes.[11][3] Consequently, the United States Environmental Protection Agency (EPA) has set a water safety standard of 0.1 mg/L or 100 ppb for total chromium, and the State of California has set a public health goal of 20 ng/L or 0.02 ppb for hexavalent chromium.[1][6] The World Health Organization is more conservative than the EPA in its safety standard, recommending no more than 0.05 mg/L or 50 ppb of Cr(VI) in drinking water.[9]

Over 110 million workers worldwide are exposed annually to welding fumes that frequently contain Cr(VI). In the United States, more than 550,000 welders are exposed to Cr(VI)-containing metal fumes annually, and more than 1 million construction workers are exposed to cement and grout.[13] A recent meta-analysis demonstrated that 11,564 of 973,697 workers with occupational exposure to Cr(VI) across multiple occupations and countries had at least 1 kind of cancer, resulting in an overall prevalence of 1.17%.[15] 

Numerous government agencies have set acceptable standards for chromium exposure. The Occupational Safety and Health Administration (OSHA) permits daily levels of 0.5 mg/m³ in air for Cr(III) and 0.005 mg/m³ for Cr(VI). The National Institute for Occupational Safety and Health (NIOSH) recommends a more stringent standard of 0.001 mg/m³ for Cr(VI).[6] The European Union and nations like China and the United Kingdom have also set occupational exposure limits for chromium, with the most stringent recommendations for Cr(VI) exposure.[7]

Pathophysiology

Hexavalent chromium can enter cells as chromate through anion channels due to its resemblance to sulfate and phosphate.[2][3][8][9] Once inside the cell, antioxidant compounds such as ascorbate, glutathione, and cysteine, as well as enzymes such as superoxide dismutase and catalase, reduce Cr(VI) to Cr(III) via pentavalent and tetravalent intermediates.[1][3][9][11] Ascorbate mediates 80% to 90% of these reduction reactions, with another 5% to 15% mediated by glutathione or cysteine.[1][11] The toxic effects of Cr(VI) are exerted primarily through oxidative stress induced by the formation of intracellular reactive oxygen species such as superoxide, hydrogen peroxide, and hydroxyl radicals, as well as highly reactive intermediates.[2][3][7][13]

The unstable Cr(V) and Cr(IV), and the stable Cr(III) adduct with proteins and DNA, precipitate double- and single-stranded DNA breaks, and form DNA crosslinks via multiple mechanisms. These genetic mutations are dose-dependent and determined by the initial intracellular Cr(VI) concentration.[1][3][8][9] Chromium intermediates and metabolites can induce cellular apoptosis, alter gene methylation, disrupt histone and micro-RNA regulation, induce microsatellite instability, and decrease p16 and p53 tumor suppression activity.[8][11][14]

All forms of chromium exert their toxic effects primarily in the intracellular environment and are much less toxic when reduced to Cr(III) extracellularly.[1][9][13] Between 80% to 90% of ingested Cr(VI) is reduced to Cr(III) in saliva and gastric juice at a capacity of 8 mg/L to 31 mg/L or approximately 80 mg/d; this is a significant protective mechanism against oral exposures.[1] 

Extracellular Cr(III) is often considered a micronutrient. Some studies propose Cr(III) interacts with tyrosine kinase insulin receptors, causes translocation of glucose transporter 4 (GLUT4) to the cell membrane, and increases AMP protein kinase (AMPK), all of which account for a preliminarily suggestive role in diabetes, metabolic syndrome, and PCOS.[7] However, other studies suggest potential long-term toxicity from Cr(III) supplementation due to potential reoxidation to higher valence forms and recommend against excessive supplement use.[14]

Pulmonary System

Pulmonary exposure to Cr(VI) via inhalation has been associated with the development of lung cancer, particularly with poorly soluble compounds. It is hypothesized that these poorly soluble compounds may adhere to the respiratory epithelium, dissolve slowly, and result in chronic genotoxic insults due to oxidative stress.[5][11] Proposed mechanisms of tumorigenesis due to Cr(VI) include decreased cell-substrate adhesion, alveolar macrophage suppression, chronic inflammation due to increased cytokine release, direct DNA damage, and disrupted cell cycle progression leading to fibrosis, epithelial and alveolar hyperplasia, and cellular atypia.[4][11] Occupational asthma via an IgE antibody-mediated mechanism has been reported 36 months after inhalational exposure to Cr(VI).[7]

Integumentary System

Cr(VI) is a skin sensitizer of similar potency to phenylenediamine and hexamethyl-diisocyanate and has been known to cause dermal irritation and ulceration, particularly on damaged skin.[4][5][7] Dermal injury occurs via a type IV delayed hypersensitivity reaction; Cr(VI) conjugates with epidermal proteins and interacts with T lymphocytes. Repeat exposures release inflammatory mediators.[7] Other studies have demonstrated that dermal exposure to Cr(VI) results in the increased expression of messenger RNA for interleukins 4 and 6 and immune interferon (IFN-γ), type I IGE-mediated hypersensitivity reactions, elevated cholesterol synthesis, and inhibition of DNA damage repair.[4] 

Gastrointestinal System

Gastrointestinal chromium exposure seems to be associated with lower toxicity due to the protective mechanisms detailed. Nevertheless, oxidative stress due to Cr(VI) led to villous vacuolization and apoptosis, crypt hyperplasia, and villous nuclear aberrancy in one animal study.[1] Ingestion of chromate salts can cause mucosal burns and irritation similar to dermal toxicity.[5] Additionally, gastrointestinal exposure has been associated with abnormal liver function, cell cycle acceleration, brush border impairment, and disruption in cell polarity in molecular pathway analysis.[4]  

Central and Peripheral Nervous Systems

In the central nervous system, Cr(VI) accumulates over the lifespan; studies suggest children and older adults are particularly vulnerable.[2] Animal studies have demonstrated acetylcholinesterase dysfunction and neurodegeneration in addition to oxidative stress, and human studies have implicated chromium in social memory loss, depression, schizophrenia, autism, olfactory dysfunction, and polyneuropathy. Further study is needed to identify the extent and mechanisms of chromium neurotoxicity.[2]

Renal System

Massive exposures to hexavalent or trivalent chromium, defined in animal studies as ≥15 mg/kg, cause acute tubular injury via oxidative stress, primarily at the proximal convoluted tubule. Chronic long-term exposure to chromium may contribute to chronic renal failure in conjunction with other causes.[16][17]

Embryonic Adverse Effects

Studies have shown that Cr(VI) crosses the placenta and can negatively affect fetal tissue development. Hexavalent chromium may also upregulate apoptosis in the placenta.[9][18] In a murine study, high concentrations of Cr(III) blocked blastocyst formation. Low concentrations decreased blastocyst cell number and proliferation, induced oxidative stress and apoptosis, and disrupted post-implantation development.[19]

Toxicokinetics

Absorption of chromium compounds may occur via inhalation, ingestion, and dermal or mucosal contact.

Particle size plays an important role in inhalational absorption; larger, less soluble particles are associated with higher levels of chronic toxicity, and particles smaller than 5 μm are absorbed into the bloodstream or across the pharyngeal mucosa.[7][11] Inhalational exposure to Cr(VI) results in selective distribution within the lung. Absorption into the bloodstream increases the Cr(VI) concentration in erythrocytes. Chronic exposure distributes Cr(VI) to the liver, bone, kidneys, and spleen.[7] Cr(VI) may also cross the placenta into the fetal circulation and may be found in breast milk after inhalational exposure.[9][7][18][20] Cr(VI) is reduced to Cr(III) in the lungs by ascorbate, glutathione, and alveolar macrophages.[7][20] Trivalent chromium may be detectable in the lungs for decades after exposure.[7][20]

Dermal absorption of chromium compounds is facilitated by epidermal barrier compromise. Hexavalent chromium-containing compounds traverse the epidermal barrier more efficiently than those containing trivalent chromium; irritation and sensitization can occur with exposure to both.[4][5][7]

Gastric juices reduce Cr (VI) in the stomach, and 2% to 10% of the ingested dose is absorbed as Cr(VI) in the duodenum, facilitated by intestinal bacteria. Trivalent chromium demonstrates low oral absorption rates of less than 1%.[7][20] Gastric juices are responsible for most Cr(VI) metabolism in the gastrointestinal tract; absorption in the duodenum accounts for the remainder.[1][7][20]

Chromium excretion is primarily via urine and largely as Cr(III). As much as 80% of the chromium load is excreted by the kidneys after inhalational exposure, and the kidneys excrete 60% of a given dose within 6 hours of ingestion.[7][20]  Approximately 10% of ingested chromium is excreted via the biliary system; smaller amounts are excreted in breast milk, saliva, and sweat.[7] Elimination half-life varies, likely due to the extensive metabolism and distribution of Cr(VI) and a tendency of Cr(III) to become trapped intracellularly, extending its time to elimination.[20]

History and Physical

Patients who present with acute toxicity will likely have a history of occupational exposure, and therefore, an employment history is vital. Industries that either produce or use chromium are relevant. These industries include welding (especially stainless steel welding), petroleum refining, mining and ore processing, leather tanning, dye and pigment production (or their use, such as in textiles and art), construction, law enforcement, or military (weapons/ammunition), or agriculture.[2][3][4][8] 

It is important to document the area where the patient was exposed, the available room ventilation, the type of respiratory protection worn, the circumstances of the exposure, and any decontamination that occurred before medical evaluation. Acute toxicity by dermal contact will likely present with chemical burns, blistering, ulceration, necrosis, or sloughing, depending upon the level of contamination, concentration of the compound, duration of exposure, and amount of personal protective equipment used.

Cr (VI) should be suspected if the offending agent is a brightly colored solid or reddish liquid, as many Cr (VI) compounds are pigments.[2][3][10][20] A Safety Data Sheet (SDS) can help determine if chromic acid, sodium chromate, calcium chromate, potassium chromate, potassium dichromate, or ammonium dichromate are present in the chemical exposure and at what concentration.[5][20] Chronic dermal toxicity is more likely to present with hypersensitivity symptoms such as contact dermatitis, skin ulcerations, eczema, skin thickening, and keratoconjunctivitis with acute eye exposure.[20]

Acute or chronic inhalation toxicity may be less common as many workplaces will have engineering and personal protective equipment controls due to OSHA, NIOSH, and WHO standards and regulations meant to limit occupational exposures. [6] However, signs of lung inflammation and respiratory irritation in acute exposure, such as cough, dyspnea, rhinorrhea, wheezing, choking, bronchospasm, and asthma exacerbation are expected.[5][7][11][20] 

Subacute or chronic inhalation exposures are well-known to cause nasal ulceration, nasal septal perforation, and epistaxis, in addition to occupational asthma and rhinitis. They may ultimately predispose the patient to squamous cell carcinoma of the lung due to ongoing oxidative damage.[20] Non-respiratory symptoms associated with inhalation exposure to Cr (VI) include gastric ulcers, gastritis, colitis, dizziness, headache, weakness, abnormal sperm count, and motility.[20] Vitamin B12 and folate deficiencies have also been reported, although the mechanism of this toxicity is unclear.[20]

Ingestions of Cr (VI) may present with caustic mucosal burns, pulmonary edema, GI bleeding, ulcers, gastritis, indigestion, anemia, leukocytosis, and bronchitis in larger doses due to accidental or intentional ingestion but are likely to be asymptomatic or exhibit mild symptoms at the smaller doses seen in occupational exposures due to detoxification via gastric juice.[1][5][20] 

Due to its low bioavailability, acute Cr (III) toxicity by ingestion is unlikely. Still, it may reduce iron absorption and cause symptoms of anemia and rhabdomyolysis at large doses.[14][20] Patients may report a history of chromium supplement use for weight loss or glucose regulation; these preparations contain chromium picolinate or chromium chloride, forms of trivalent chromium.[7][10][14] 

Hepatotoxicity from ingestion may present as jaundice, hyperbilirubinemia, elevated lactate dehydrogenase, and transaminitis, and nephrotoxicity may demonstrate acute renal failure, proteinuria, hematuria, and anuria with both Cr (III) and Cr (VI) toxicity as the kidneys are the primary organs of excretion for chromium compounds.[16][17][20] Chronic ingestion toxicity has been associated with liver and stomach cancers.[20] Other malignancies associated with chromium toxicity include laryngeal, bladder, kidney, lymphoma, leukemia, pancreatic, thyroid, bone, and testicular cancers.[2][11][12][14][15]

Evaluation

Whole blood, plasma, and urinary chromium levels are all available but likely to be a send-out analysis and less helpful in managing acute toxicity. However, they may be beneficial in detecting or managing chronic occupational exposures. Blood and plasma chromium have a normal range of 0.10 mcg/L to 0.16 mcg/L, while urinary chromium excretion is approximately 0.22 mcg/L.[20]

Regarding detection of acute and chronic toxicity, absorbed Cr (III) has an elimination half-life of 40 hours and reaches 95% steady state in 7 days, while Cr (VI) has a half-time of 30 days with a 95% steady state of 130 days due to RBC sequestration and slow release as erythrocytes die and are replaced.[20]

Treatment / Management

Overall, treatment of acute toxicity is supportive. Immediate treatment of chromium toxicity involves environmental removal to provide fresh air. Also, consider humidified supplemental oxygen, ventilatory support, bronchodilators, and expectorants as needed.

Recommendations for oral toxicity include avoidance of bicarbonate, antacids, and induction of vomiting. Clinicians can consider oral ascorbate or gastric lavage. Treatment of dermal toxicity involves mechanical decontamination, washing, and eye irrigation as needed, and calcium disodium edetate (EDTA) can be considered a binding agent. Finally, several treatments can be considered to increase the elimination of chromium from the body, including hemodialysis, ascorbic acid, N-acetylcysteine, and calcium EDTA.[20] Hemodialysis can be helpful in the case of massive exposures to chromium to ensure rapid and effective elimination.

Other agents have preliminarily demonstrated some efficacy in animal studies, primarily due to proposed and demonstrated antioxidant effects. These include selenium, vitamin E, zinc, and melatonin. However, no studies have yet demonstrated that higher doses of antioxidants reduce adverse effects of chromium compounds in humans.[2][8][13] Regardless, occupationally exposed individuals are encouraged to consume foods rich in vitamin C (ascorbate), vitamin E, vitamin B6, folate, selenium, and zinc to reduce overall oxidative stress and ameliorate the effects of Cr (III) and Cr (VI) exposure.[13](B3)

Differential Diagnosis

Occupational exposure is a key historical component in diagnosing chromium toxicity due to its relatively nonspecific and wide-ranging effects on the body—moreover, many other chemicals in the industrial setting cause similar symptoms. For example, other acids or vesicants will cause similar chemical burns with dermal exposure. Ultraviolet exposure may cause similar keratitis in welders. Eczema and asthma may be exacerbated by a myriad of other factors or be idiopathic. Increased respiratory secretions, vomiting, diarrhea, wheezing, and bronchospasm may be seen with cholinergic toxicity. Epistaxis and septal perforation can be seen with many nasal irritants. Hydrocarbons and volatile compounds will cause constitutional symptoms such as dizziness, weakness, and malaise. Other heavy metals such as mercury, lead, cadmium, and arsenic are also known to cause damage by oxidative stress and increase the risk of mutagenicity and cancer development.[15] 

Clinical suspicion should be high when a history is given of fluctuating symptoms throughout the day or week, especially on workdays. Also, recreational exposure to chromium-containing compounds through hobbies can be a source of clinically significant exposure.

Chronic toxicity is more subtle, but any new diagnosis of cancer should include a detailed occupational history, including chromium, especially squamous cell carcinoma of the lungs, and gastric and liver malignancies. Excessive chromium supplementation should be considered an etiology of gastric ulcers, hepatotoxicity, and anemia.

Prognosis

The prognosis for acute chromium toxicity is generally excellent, with deaths noted primarily from massive ingestions.[20] Cancerous lesions due to chronic toxicity, however, may go undetected until the advanced disease burden causes systemic symptoms. One study estimated an overall mortality of 6 in 1,000 workers due to lung cancer at an exposure level of 1 mcg/m³.[13] High clinical suspicion and careful occupational history may aid in early detection and improved prognosis.

Complications

Long-term complications include scarring from skin and mucosal burns, dermal sensitization and asthma due to dermal or inhalation toxicity, and decreased nutrient and vitamin absorption due to gastrointestinal toxicity. There is also an increased risk of anemia, chronic liver disease, chronic kidney disease, and a lifetime increased risk of cancer.[2][4][5][7]