Chromium is a trace mineral. It exists in two forms: trivalent and hexavalent states. Trivalent chromium (Cr III), the form found in foods and supplements, is biologically active and safe (42626). The other form of chromium, hexavalent chromium (Cr VI), is a known toxin that can cause skin problems and lung cancer following long-term occupational exposure (9141,42572,42648). Unless otherwise noted, the information in this monograph pertains only to trivalent chromium.

LIKELY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Chromium has been safely used in doses up to 1000 mcg daily for up to 6 months (1934,5039,5040,6858,6859,6860,6861,6862,6867,6868)(7135,7137,10309,13053,14325,14440,17224,90057,90061)(90063,94234,95095,95096,95097,98687); however, most of these studies have used chromium doses in a range of 150-600 mcg. The Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, long-term. Chromium has been safely used in a small number of studies at doses of 200-1000 mcg daily for up to 2 years (7060,7135,42618,42628,42666,110605,110607,110609). However, the Food and Drug Administration (FDA) and Institute of Medicine (IOM) evaluations of the safety of chromium suggest that it is safe when used in doses of 200 mcg daily for up to 6 months (13241,13242).

CHILDREN: LIKELY SAFE ...when used orally and appropriately in amounts not exceeding the daily adequate intake (AI) levels by age: 0-6 months, 0.2 mcg; 7-12 months, 5.5 mcg; 1-3 years, 11 mcg; 4-8 years, 15 mcg; males 9-13 years, 25 mcg; males 14-18 years, 35 mcg; females 9-13 years, 21 mcg; females 14-18 years, 24 mcg (7135). POSSIBLY SAFE...when used orally and appropriately in amounts exceeding AI levels. Chromium 400 mcg daily has been used safely for up to 6 weeks (42680).

PREGNANCY: LIKELY SAFE ...when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for pregnancy is 28 mcg daily for those 14-18 years of age and 30 mcg daily for those 19-50 years of age (7135). POSSIBLY SAFE ...when used orally in amounts exceeding the adequate intake (AI) levels. There is some evidence that patients with gestational diabetes can safely use chromium in doses of 4-8 mcg/kg (1953); however, patients should not take chromium supplements during pregnancy without medical supervision.

LACTATION: LIKELY SAFE ...when used orally and appropriately in amounts not exceeding adequate intake (AI) levels. The AI for lactation is 44 mcg daily for those 14-18 years of age and 45 mcg daily for those 19-50 years of age (7135). Chromium supplements do not seem to increase normal chromium concentration in human breast milk (1937). There is insufficient reliable information available about the safety of chromium when used in higher amounts while breast-feeding.

•  Dermatologic

  Orally, chromium-containing supplements may cause acute generalized exanthematous pustulosis (42561), skin rashes (42679), and urticaria (17224). Also, chromium picolinate or chromium chloride may cause systemic contact dermatitis when taken orally, especially in patients with contact allergy to chromium (6624,90058). In one clinical study, a patient taking chromium nicotinate 50 mcg daily reported itchy palms that improved after the intervention was discontinued. It is unclear of this effect was due to the chromium or another factor (95096).
  
  Topically, hexavalent chromium, which can be present in some cement, leather products, or contaminated soil, may cause allergic contact dermatitis (42645,42789,90060,90064,110606).
  
  A case of lichen planus has been reported for a patient following long-term occupational exposure to chromium (42688).

•  Endocrine

  Orally, cases of hypoglycemia have been reported for patients taking chromium picolinate 200-1000 mcg daily alone or 200-300 mcg two or three times weekly in combination with insulin (42672,42783). Chromium picolinate has also been associated with weight gain in young females who do not exercise and in those following a weight-lifting program (1938).

•  Gastrointestinal

  Orally, chromium in the form of chromium picolinate, chromium polynicotinate, chromium-containing brewer's yeast, or chromium-containing milk powder may cause nausea, vomiting, diarrhea, decreased appetite, constipation, flatulence, or gastrointestinal upset (14325,42594,42607,42622,42643,42679).
  
  Long-term exposure to heavy metals, including chromium, has been associated with increased risk of gallbladder disease and cancer (42682,42704).

•  Genitourinary

  Orally, chromium polynicotinate has been associated with disrupted menstrual cycles in patients taking the supplement to prevent weight gain during smoking cessation (42643).

•  Hematologic

  Anemia, hemolysis, and thrombocytopenia were reported in a 33 year-old female taking chromium picolinate 1200-2400 mcg daily for 4-5 months (554). The patient received supportive care, blood product transfusions, and hemodialysis and was stabilized and discharged a few days later. Lab values were normal at a one-year follow-up.

•  Hepatic

  Liver damage has been reported for a 33-year-old female taking chromium picolinate 1200 mcg daily for 4-5 months (554). Also, acute hepatitis has been reported in a patient taking chromium polynicotinate 200 mcg daily for 5 months (9141). Symptoms resolved when the product was discontinued. Two cases of hepatotoxicity have been reported in patients who took a specific combination product (Hydroxycut), which also contained chromium polynicotinate in addition to several herbs (13037).

•  Musculoskeletal

  Acute rhabdomyolysis has been reported for a previously healthy 24-year-old female who ingested chromium picolinate 1200 mcg over a 48-hour time period (42786). Also, chromium polynicotinate has been associated with leg pain and paresthesia in patients taking the supplement to prevent weight gain during smoking cessation (42643).

•  Neurologic/CNS

  Orally, chromium picolinate may cause headache, paresthesia, insomnia, dizziness, and vertigo (6860,10309,14325,42594). Vague cognitive symptoms, slowed thought processes, and difficulty driving occurred on three separate occasions in a healthy 35-year-old male after oral intake of chromium picolinate 200-400 mcg (42751). Transient increases in dreaming have been reported in three patients with dysthymia treated with chromium picolinate in combination with sertraline (2659). A specific combination product (Hydroxycut) containing chromium, caffeine, and ephedra has been associated with seizures (10307). But the most likely causative agent in this case is ephedra.

•  Psychiatric

  Orally, chromium picolinate has been associated with irritability and mood changes in patients taking the supplement to lose weight, while chromium polynicotinate has been associated with agitation and mood changes in patients taking the supplement to prevent weight gain during smoking cessation (6860,42643).

•  Renal

  Orally, chromium picolinate has been associated with at least one report of chronic interstitial nephritis and two reports of acute tubular necrosis (554,1951,14312). Laboratory evidence suggests that chromium does not cause kidney tissue damage even after long-term, high-dose exposure (7135); however, patient- or product-specific factors could potentially increase the risk of chromium-related kidney damage. More evidence is needed to determine what role, if any, chromium has in potentially causing kidney damage.
  
  Intravenously, chromium is associated with decreased glomerular filtration rate (GFR) in children who receive long-term chromium-containing total parenteral nutrition - TPN (11787). Topically, burns caused by chromic acid, a hexavalent form of chromium, have been associated with acute chromium poisoning with acute renal failure (42699). Early excision of affected skin and dialysis are performed to prevent systemic toxicity.

•  Other

  Another form of chromium, called hexavalent chromium, is unsafe. This type of chromium is a by-product of some manufacturing processes. Chronic exposure can cause liver, kidney, or cardiac failure, pulmonary complications, anemia, and hemolysis (9141,11786,42572,42573,42699). Occupational inhalation of hexavalent chromium can cause ulceration of the nasal mucosa and perforation of the nasal septum, and has been associated with pneumoconiosis, allergic asthma, cough, shortness of breath, wheezing, and increased susceptibility to respiratory tract cancer and even stomach and germ cell cancers (42572,42573,42601,42610,42636,42667,42648,42601,42788,90056,90066). Although rare, cases of interstitial pneumonia associated with chromium inhalation have been reported. Symptoms resolved with corticosteroid treatment (42614).

• Adult

  Oral:

  General: There is insufficient information to establish safe and tolerable upper intake levels for chromium (7135). However, daily adequate intake (AI) levels for chromium have been established: males 19-50 years, 35 mcg; males 51 and older, 30 mcg; females 19-50 years, 25 mcg; females 51 and older, 20 mcg. During pregnancy: 14-18 years, 29 mcg; 19-50 years, 30 mcg. When lactating: 14-18 years, 44 mcg; 19-50 years, 45 mcg.
  
  Sometimes chromium amounts are listed in micromols. The conversion factor to mcg is: 1.92 micromol = 100 mcg (6867).
  
  Chromium has been used in various salt forms and at various doses. See Effectiveness section for condition-specific information.

• Children

  Oral:

  General: There is insufficient information to establish safe and tolerable upper intake levels for chromium (7135). However, daily adequate intake (AI) levels for chromium have been established by age: 0-6 months, 0.2 mcg; 7-12 months, 5.5 mcg; 1-3 years, 11 mcg; 4-8 years, 15 mcg; males 9-13 years, 25 mcg; females 9-13 years, 21 mcg; males 14-18 years, 35 mcg; females 14-18 years, 24 mcg (6867,42580). See Effectiveness section for condition-specific information.

• Standardization & Formulation

  Chromium chloride is the natural form of trivalent chromium (95098). The most common chromium salt used in supplements is the synthetic chromium picolinate. Other chromium salts used include chromium chloride and chromium polynicotinate (2659,95098). Chromium may also come in the form of brewer's yeast or chromium yeast (95098). Chromium picolinate is a complex of chromium and picolinic acid, which is a naturally occurring metabolic derivative of tryptophan. It contains 12.4% elemental trivalent chromium (2659,95094). Chromium polynicotinate is often referred to as niacin-bound chromium because it includes chromium bound to molecules of niacin (2659).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, chromium may have additive effects with antidiabetic agents and increase the risk of hypoglycemia.  Details Some research shows that taking chromium might lower blood glucose levels, especially in patients with poorly controlled type 2 diabetes (7137,14440,15169,94234,95097,95098,98687).

ASPIRIN Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, aspirin might increase chromium absorption.  Details Animal research suggests that aspirin may increase chromium absorption and chromium levels in the blood (21055).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of chromium and insulin might increase the risk of hypoglycemia.  Details In clinical research, chromium has been shown to increase insulin sensitivity (1952,14440,95095),

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Chromium might bind levothyroxine in the intestinal tract and decrease levothyroxine absorption.  Details Clinical research in healthy volunteers shows that taking chromium picolinate 1000 mcg with levothyroxine 1 mg decreases serum levels of levothyroxine by 17% when compared to taking levothyroxine alone (16012). Advise patients to take levothyroxine at least 30 minutes before or 3-4 hours after taking chromium.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D NSAIDs might increase chromium levels in the body.  Details Drugs that are prostaglandin inhibitors, such as NSAIDs, seem to increase chromium absorption and retention (7135).

 Details  Details  Details  Details  Details

 BEHAVIORAL AND PSYCHIATRIC DISORDERS

 CHROMATE/LEATHER CONTACT ALLERGY

 KIDNEY DISEASE

 LIVER DISEASE

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Presentation

Acute chromium toxicity can cause vomiting, diarrhea, hemorrhage, and blood loss into the gastrointestinal tract resulting in cardiogenic shock (11786).

Another form of chromium, called hexavalent chromium (CR VI), is 100 times more toxic than trivalent chromium. Industrial hexavalent chromium is considered cytotoxic and genotoxic (6863,42658,42663,42686,42693). It penetrates the cells easily (unlike trivalent chromium) and appears to induce oxidative damage to DNA (7326,42565,42749,42778).

Treatment

There is insufficient reliable information available about the treatment of overdose with chromium.

Absorption: When ingested, most chromium is excreted unabsorbed in the feces. The small percentage that is absorbed, typically 0.4% to 2.5%, is rapidly excreted in the urine (7135). Approximately 0.5% to 2% of chromium is absorbed (42740,42725).

Adding the picolinate or nicotinate salt increases absorption, retention, and accumulation of chromium compared to inorganic salts such as chromium chloride (6861,6864,9141,95096,95098). Nicotinate may also have increased bioavailability over picolinate (95096). Some manufacturers suggest that chromium polynicotinate is better absorbed than chromium picolinate, but there is no scientific support for this claim.

Distribution: After absorption, chromium is bound to transferrin (6869). The distribution may occur across fast, medium, and slow compartments, with serum chromium not in equilibrium with tissue-organ stores (42811). Once absorbed, chromium concentrates in the kidney, heart, liver, brain, muscle, spleen, testes, epididymis, and lungs (6863).

Chromium retention decreases with aging, as found in a very large collection of hair, sweat, and serum samples (7058). It is unclear whether this is due to inadequate nutrition or normal physiology (42779).

Excretion: The small percentage of chromium that is absorbed is rapidly excreted in the urine (7135,42579). Stressors, such as elevated blood sugar, strenuous physical activity or work, infection, and emotional and physical trauma, may increase the excretion of chromium (37163,42721,42744,42748).

General: Chromium (Cr) is a white, hard, brittle metal that is an essential trace element. The activity of chromium depends on its valance state. Metallic chromium, or chromium 0, has no activity. The other two common forms, chromium III (Cr III) and chromium VI (Cr VI), have different activities. Cr VI is typically used in chemical and welding industries and is carcinogenic to humans. Cr III is the form found in foods and supplements (13721).

Chromium is sometimes referred to as glucose tolerance factor (GTF), but GTF is actually a complex of molecules found in the body that includes chromium bound to single molecules of glycine, cysteine, glutamic acid, and two molecules of nicotinic acid. Chromium is thought to be the active component of the complex. Some dietary sources of chromium include canned foods (due to chromium leaching from the can), meats and animal fats, fish, brown sugar, coffee, tea, some spices, calf liver, whole wheat bread, rye bread, and brewer's yeast (7061).

Symptomatic chromium deficiency is rare. When it does occur, it is most often due to malnutrition, pregnancy, stress, or long-term use of chromium deficient total parenteral nutrition (TPN). Symptoms include severe glucose intolerance, weight loss, and metabolic encephalopathy (6863,13730). Although not yet confirmed, some researchers suspect that tissue levels of chromium might decline with age (6863).

Antidiabetes effects: People with diabetes may have lower chromium levels (7058,11908,13725). Low chromium levels are associated with impaired glucose, insulin, and lipid metabolism, and resultant increased cardiovascular risk (95097). Some athletes might also be at risk for low chromium levels since strenuous aerobic exercise seems to increase urinary excretion of chromium (6860,6861). However, exercise-induced losses seem to be less in those who regularly exercise (6862). People who strength train seem to have increased absorption of chromium (7136). It is difficult to measure chromium status to determine who might require supplementation. Blood chromium levels are not in equilibrium with chromium stores and, therefore, do not provide a good indicator of chromium status (6859). However, elevated blood chromium levels may indicate excessive chromium exposure (11786). Levels in the urine and hair do not reflect overall chromium status (6867). There is no reliable method available to diagnose chromium deficiency, other than observing the outcome following supplementation in patients suspected of being deficient (3859,6869). Symptoms of chromium deficiency can include impaired insulin function and glucose tolerance, leading to elevations in insulin and fasting hyperglycemia, impairments in growth, increased serum cholesterol and triglycerides, neuropathy, weight loss, decreased respiratory function, and nitrogen metabolism abnormalities (6863,6869,11786,95098).

Discovery of the role of chromium in insulin function occurred when patients on long-term TPN developed symptoms of diabetes that did not respond to insulin, but were reversed by chromium (6869,42641,42787). Because of the symptoms associated with chromium deficiency, researchers have speculated that chromium supplementation might be an effective treatment for diabetes. There is some evidence that patients with diabetes might have lower than normal levels of chromium due to increased chromium excretion (6858). However, patients with diabetes also seem to have increased gastrointestinal absorption of chromium. It's also theorized that patients with diabetes may not be able to adequately convert chromium from the diet to a usable form in the body (6867). Chromium seems to be transported to insulin-sensitive cells by transferrin, in response to increases in plasma insulin levels (6869). It is suspected to potentiate insulin by increasing receptor numbers and affinity, and increasing insulin binding to cells (6859,6867). Chromium increases insulin sensitivity through activation of signaling pathways involved with glucose transporter 4 (GLUT4), leading to translocation (95097). Chromium may also enhance the synthesis of insulin receptor mRNA as well as insulin-like growth factor receptors (95097). A single oral dose of chromium before a high carbohydrate meal seems to lessen postprandial hyperglycemia in healthy, young volunteers. This suggests chromium potentiates the effect of insulin (13726). Additionally, chromium picolinate has been shown to increase insulin sensitivity and stimulate insulin receptor sites in patients with type 2 diabetes (42554).

Other clinical research shows that chromium dinicocysteinate can reduce insulin resistance by reducing oxidative stress and blood levels of tumor necrosis factor (TNF)-alpha and insulin in patients with type 2 diabetes (42707). However, chromium picolinate does not appear to have these effects. In animal models, a chromium-containing peptide called chromodulin has been identified, which potentiates the actions of insulin at its receptors, including activation of receptor tyrosine kinase activity (6869). Additionally, in laboratory study, chromium activated trafficking of glucose transporter-4 and increased insulin-stimulated glucose transport through a cholesterol-dependent mechanism (42602). In patients with diabetes, these actions seem to translate into decreased insulin resistance, improved glucose tolerance, and lower blood glucose levels (6862). Researchers are interested in chromium for treatment of obesity and metabolic syndrome (syndrome X) due to its potential effects on lipids and body composition.

Some clinical research shows that chromium might reduce oxidative stress and inflammation, and thereby some of the adverse effects and complications of diabetes (13724). A meta-analysis of clinical studies in adults, most of whom have diabetes, shows that chromium supplementation is associated with modest reductions in high-sensitivity C-reactive protein and TNF-alpha when compared with control (105030). But the clinical significance of this is not known.

Clinical research suggests that adding 100 mg of nicotinic acid 200 mcg of chromium chloride significantly improves glucose metabolism (11687); the effects of chromium may be augmented by nicotinic acid.

Antioxidant effects: Chromium is considered to have antioxidant effects (13724,42785). In human research, chromium dinicocysteinate supplementation significantly lowered protein carbonyl levels, a marker of protein oxidation, from baseline in diabetic patients (42707). Another study in diabetic patients reported an improvement in plasma thiobarbituric acid reactive substances (TBARS) (30863). In patients with polycystic ovary syndrome, chromium lowered levels of malondialdehyde (98687). A meta-analysis of patients with diabetes and other chronic disorders shows that taking chromium 400-1000 mcg orally daily for 8-24 weeks improves some markers of oxidative stress, such as malondialdehyde levels, when compared with control; however other markers, such as glutathione and superoxide dismutase levels, were not improved (110608). Some clinical research also shows that chromium might reduce oxidative stress in patients with diabetes; however, in patients without diabetes, chromium might act as a pro-oxidant (13724).

Bone-resorption effects: In vitro evidence suggests that chromium extract may increase the release of bone-resorbing cytokines by peripheral blood mononuclear cells. Thus, when used as an alloying element in metallic implants, chromium may increase tissue damage and bone resorption surrounding a metallic implant (42784).

Immunomodulating effects: In vitro evidence suggests that chromium extract reduces cell proliferation and inhibits interleukin (IL)-2-dependent response of peripheral blood mononuclear cells exposed to phytohemagglutinin. Thus, when used as an alloying element in metallic implants, chromium may reduce lymphocyte-mediated immune response to an infection that develops in tissue surrounding a metallic implant (42784).

Genetic effects: Although laboratory studies have shown that trivalent chromium compounds can produce chromosome or DNA oxidative damage, human studies have not demonstrated these findings (42790). On the other hand, hexavalent chromium penetrates the cells easily (unlike trivalent chromium) and appears to induce oxidative damage to DNA (7326,42565,42749,42778).

Growth effects: There is interest in using chromium to enhance muscle protein synthesis. In the presence of sufficient essential amino acids or protein, insulin stimulates muscle protein synthesis. With low amounts of essential amino acids, insulin inhibits protein breakdown and has minimal effects on the rate of muscle protein synthesis. Therefore, it has been speculated that an improvement in insulin signaling combined with adequate doses of essential amino acids, could affect muscle protein synthesis (95099). Chromium is hypothesized to increase muscle mass by increasing amino acid uptake into muscle cells via potentiation of insulin activity (6862,42813). Laboratory research suggests that chromium picolinate increases internalization of insulin and increases leucine uptake in muscle cells. Because of its effects on glucose transporter 4 (GLUT-4) translocation, and its ability to increase insulin response through the AMPK pathway, chromium has been used in clinical research to improve muscle protein synthesis. In one small clinical study in healthy young adults, taking a suboptimal dose of whey protein isolate (BiPro USA) 6 grams and a combination product containing chromium picolinate/histidinate and amylopectin (Velositol, Nutrition 21, LLC) 2 grams, followed by acute resistance exercise, significantly increased the muscle fractional synthesis rate compared to whey protein alone (95099).

Also, evidence from animal research suggests that chromium supplementation can increase growth rate in mice and rats (42733).

Lipid effects: Chromium inhibits the hepatic enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase leading to interference of cholesterol metabolism (95097).

Neurologic effects: It is theorized that chromium might enhance glucose utilization in the brain and stimulate norepinephrine release (2659). There is also interest in using chromium as an adjunct to antidepressant medications in people with depression. Preliminary clinical research suggests that chromium decreases endocrine responses to serotonin receptor stimulation, which could produce antidepressant activity (8929). A case series of adults with persistent depressive disorder shows that chromium supplementation might improve response to antidepressants, such as sertraline and amitriptyline, in patients with inadequate response (2659). However, clinical research in patients with atypical depression has yielded conflicting results (10309,42600).

Weight loss effects: Clinical research shows that ingestion of chromium picolinate reduces fat cravings, food intake, and hunger, which may lead to weight loss (42634). Chromium may induce these effects by affecting the brain's hunger receptors. Some research suggests that chromium might sensitize insulin-sensitive glucoreceptors in the brain, resulting in appetite suppression, activation of the sympathetic nervous system, stimulation of thermogenesis, and down-regulation of insulin secretion (6170,6860).