Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1.2.1) MOLECULAR FORMULA
1) Cr

Available Forms Sources

A)

1) Chromium compounds occur in valence forms +1, +2, +3, +4, +5, and +6, but the +3 (trivalent) and +6 (hexavalent) forms are the most important (Clayton & Clayton, 1994).
2) Hexavalent chromium compounds, incorrectly called chromates (unless they exist as CrO3(-2) ions), usually have a yellow pigment. Compounds included are chromium trioxide (CrO3; chromium VI oxide), the anhydride of chromic acid, chromates, dichromates, and polychromates. These are generally the most toxic chromium compounds, particularly the water-insoluble forms. Certain compounds are considered human carcinogens (Clayton & Clayton, 1994; ACGIH, 1991).

a) Water-soluble hexavalent chromium compounds include chromic acid, its anhydride, and monochromates and dichromates of sodium, potassium, ammonium, lithium, cesium, and rubidium (ACGIH, 1991).
b) Water-insoluble hexavalent chromium compounds include zinc chromate, calcium chromate, lead chromate, barium chromate, strontium chromate, and sintered chromium trioxide (ACGIH, 1991).

B)

1) Direct sources of hexavalent chromium include chemical and refractory plants. Indirect sources include fossil fuel combustion, waste incineration, and cement plant emissions (HSDB , 2000).

a) Steel plants, refractory facilities, chemical manufacturing, sewage sludge, and municipal incineration are likely to emit mixtures of trivalent and hexavalent chromium (HSDB , 2000).

1) Hexavalent chromium may be emitted from cooling towers and chrome plating facilities. Trivalent chromium may be emitted from ore refining, ferro-chromium production, cement production, coal combustion, and old combustion (HSDB , 2000).
2) Waste generated from the industry is another source of hexavalent chromium.
3) After hexavalent chromium waste is put in landfills, slow leaching may occur and could enter surrounding waters (HSDB , 2000).
4) After its release into waterways, hexavalent chromium frequently remains mobile and unchanged (particularly under oxygenated conditions, such as near the ocean surfaces) due to a low concentration of reducing matter (HSDB , 2000).
5) After its release into atmosphere, hexavalent chromium may be reduced to the trivalent form at a significant rate by vanadium ion, ferrous ion, bisulfate ion, and arsenic ion (HSDB , 2000).

C)

1) Hexavalent chromium salts are used in metal finishing process, in tanning leather, in catalytic manufacture, in fungicides, in preservatives for woods, in cooling waters (as corrosion inhibitor), in glassware-cleaning solutions, in the manufacture of safety matches, and in the textile and dye industry (as mordants) (Hayes & Laws, 1991; Barceloux, 1999; HSDB , 2000).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Hexavalent chromium salts are used in a variety of industries, including metal finishing, leather tanning, glassware cleaning, wood preserving, textiles, and dyeing.
B) TOXICOLOGY: Hexavalent chromium is a powerful oxidizing agent that has corrosive and irritant effects to the airway, skin, mucous membranes, and gastrointestinal (GI) tract. It produces oxidative DNA damage. Examples of the hexavalent chromium are chromium trioxide, chromic anhydride, chromic acid, dichromate salts.
C) EPIDEMIOLOGY: Acute overdose is rare. Workers in industries that use chromium are generally exposed to about 100 times as much chromium as the general population. Stainless steel welding liberates significantly more hexavalent chromium that do other types of welding.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE EXPOSURE ACUTE: Effects are primarily due to irritant effects. Inhalation can cause cough, wheezing, rhinorrhea, eye and upper respiratory irritation. Dermal irritation can occur from skin contact. Ingestion can cause nausea and vomiting. CHRONIC: Inhalation can cause bronchitis and pneumoconiosis and also increases the risk of lung cancer. Contact dermatitis is common. Eye exposure can cause keratitis, conjunctival inflammation, and brown bands of corneal discoloration.
2) SEVERE EXPOSURE: ACUTE: Effects are due to corrosive effects. Inhalation can cause severe bronchospasm, perforation of the nasal septum, and acute lung injury which can lead to delayed systemic toxicity. Eye exposure can cause severe corneal damage. Ingestion can cause abdominal pain, vomiting, diarrhea, GI bleeding, burns to the GI mucosa, delayed acute lung injury, shock, coma, metabolic acidosis, acute hepatic failure, acute renal failure, and coagulopathy. Methemoglobinemia is not common but has occurred.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Fever has been reported following chromate poisoning.

0.2.20)

A) A review of the literature found no reports of reproductive or developmental effects of chromium in humans (Eizaguirre-Garcia et al, 2000; Clarkson et al, 1985).
B) Both trivalent and hexavalent chromium have been found to cross the placental barrier in hamsters and mice. Both were shown to enter the fetus during mid to late gestation. Developmental effects caused by both differed between hamster and mice. Fetal uptake of hexavalent chromium was much greater than that of the trivalent form. Effects on placental tissue could have also affected the fetus.

0.2.21)

A) Air concentration of 1 microgram per cubic meter of hexavalent salts causes an estimated lifetime cancer risk of 1.2 X 10 (-2).

1) Dose-response relationships have been established for pulmonary cancer and occupational exposure to mixture of hexavalent and trivalent chromium. Such occupational exposure can occur in chromate production plants or in industries using chrome pigment.

a) Lung cancers, in particular small cell carcinomas, occur at a higher incidence in individuals exposed to chromates. Latent period can be about 10 to 15 years. The relative risk for workers is about 20 times greater than that of the general population.

2) Increased risk of nasal, pharyngeal, and gastrointestinal carcinomas and cancer of the sinuses has been reported. Latent period can be about 20 years.
3) Hexavalent chromium is listed by USEPA as a Group A compound by inhalation and as a Group D compound by oral route. It is rapidly reduced intracellularly to generate reactive oxygen species and intermediates.

Laboratory Monitoring

A)

B)

C)

1) Observe carefully for esophageal or gastric perforation and late complications such as pyloric stenosis and strictures.

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) For patients with a history of ingestion, consider early (within 12 hours) endoscopy.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treat hemorrhagic gastroenteritis with aggressive fluid and blood replacement. Perform early endoscopy to assess the extent of esophageal or gastric injury. Early surgical consultation for patients with severe grade II or grade III burns, large deliberate ingestions, or signs, symptoms, or laboratory findings concerning for tissue necrosis or perforation. Consider treatment with ascorbic acid and N-acetylcysteine. Treat patients with symptomatic methemoglobinemia with methylene blue.

C) DECONTAMINATION

1) PREHOSPITAL: Dilute with small amounts of water after ingestion.
2) HOSPITAL: Dilute with small amounts of water after ingestion. Consider insertion of a small, flexible nasogastric tube to aspirate gastric contents, if it can be performed very shortly after a large ingestion. The risk of perforation must be weighed against any potential benefit.

D) AIRWAY MANAGEMENT

1) Early airway protection for patients with indication of upper airway injury and stridor or signs of respiratory distress or severe pulmonary edema.

E) ANTIDOTE

1) There is no specific antidote for hexavalent chromium poisoning. Chelation therapy (eg, with BAL) is not effective. Treat symptomatic methemoglobinemia with methylene blue.

F) METHEMOGLOBINEMIA

1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

G) ASCORBIC ACID

1) Ascorbic acid has been suggested to assist the conversion of hexavalent to less toxic trivalent compounds. Although no definitive studies exist, the treatment is benign and may be helpful. In animal studies, the effective dose was 2 to 4 g of ascorbic acid orally per gram of hexavalent chromium compound ingested. Patients with severe toxicity after ingestion have been treated with intravenous ascorbic acid, but the optimum dose is not known.

H) ACETYLCYSTEINE

1) Intravenous acetylcysteine (NAC) has been used in several animal studies and one human case of dichromate poisoning, although efficacy is not established. Infuse NAC at 150 mg/kg infusion over 60 minutes, followed by 50 mg/kg infusion over 4 hours, followed by 6.25 mg/kg/hour infusion.

I) ENHANCED ELIMINATION

1) There is no evidence for the efficacy of enhanced removal procedures such as dialysis and hemoperfusion. Exchange transfusions may rapidly reduce blood chromium concentrations, but there are no data suggesting that clinical outcomes are positively affected.

J) PATIENT DISPOSITION

1) HOME CRITERIA: Patients who are asymptomatic after low concentrations, following dermal, inhalation, or ocular exposure, may be observed at home.
2) OBSERVATION CRITERIA: Any patient with any ingestion or symptomatic dermal or inhalation exposure should be sent to a healthcare facility. Consider prolonged (12 hours) observation for late-onset airway compromise following ingestion or inhalation.
3) ADMISSION CRITERIA: Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.
4) CONSULT CRITERIA: For ingestion cases, consult a gastroenterologist for early endoscopy and a surgeon if perforation is suspected. A toxicologist or poison center should be consulted for all patients with severe toxicity or patients that require hospital admission.

K) PITFALLS

1) The absence of oral burn DOES NOT rule out the possibility of necrosis or perforation of the esophagus or stomach. Early airway protection is paramount following caustic ingestions; delays in securing a definitive airway can result in increased difficulty due to progressive airway edema.

L) TOXICOKINETICS

1) The lung and the gastrointestinal tract absorb chromium compounds. Hexavalent compounds are more easily absorbed than trivalent compounds. Oral absorption average 0.5% to 2%. In the stomach and after absorption, most hexavalent chromium is reduced to trivalent forms. Chromium is rapidly excreted mainly by the kidney. The elimination half-life of hexavalent chromium is 15 to 41 hours.

M) DIFFERENTIAL DIAGNOSIS

1) Chemical burns, epiglottis in adults, croup or laryngotracheobronchitis in children, pneumonia, congestive heart failure, esophageal perforation, bronchiolitis, other occupational-related illness resulting from inhalation of volatile metal oxides (especially zinc), other causes of pneumoconiosis (eg, coal workers' pneumoconiosis, silicosis, asbestosis).

0.4.3)

A) Oxygen and early airway management in patients with respiratory distress. Administer inhaled beta adrenergic agonists in patients with bronchospasm.

0.4.4)

A) Extensive saline irrigation, pre- and post-irrigation pH testing, slit-lamp evaluation for corneal injury, and ophthalmological consultation in serious cases.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing, copious irritation. Topical 10% EDTA ointment can be used to treat chromate scabs and skin ulcers. Early aggressive excision has been suggested as the best method to prevent systemic toxicity after large chromium acid burns. However, the efficacy of this intervention is not known.
2) ASCORBIC ACID has been suggested to assist the conversion of hexavalent to less toxic trivalent compounds. Although no definitive studies exist, the treatment is benign and may be helpful. Topical 10% ascorbic acid has been used to treat contact dermatitis.

Range Of Toxicity

A)

B)

C)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) MILD TO MODERATE EXPOSURE ACUTE: Effects are primarily due to irritant effects. Inhalation can cause cough, wheezing, rhinorrhea, eye and upper respiratory irritation. Dermal irritation can occur from skin contact. Ingestion can cause nausea and vomiting. CHRONIC: Inhalation can cause bronchitis and pneumoconiosis and also increases the risk of lung cancer. Contact dermatitis is common. Eye exposure can cause keratitis, conjunctival inflammation, and brown bands of corneal discoloration.
2) SEVERE EXPOSURE: ACUTE: Effects are due to corrosive effects. Inhalation can cause severe bronchospasm, perforation of the nasal septum, and acute lung injury which can lead to delayed systemic toxicity. Eye exposure can cause severe corneal damage. Ingestion can cause abdominal pain, vomiting, diarrhea, GI bleeding, burns to the GI mucosa, delayed acute lung injury, shock, coma, metabolic acidosis, acute hepatic failure, acute renal failure, and coagulopathy. Methemoglobinemia is not common but has occurred.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Fever has been reported following chromate poisoning.

3.3.3)

A) WITH POISONING/EXPOSURE

1) FEVER has been reported following chromate poisoning (Sander & Camp, 1939; Goldman & Karotkin, 1935; Philipson, 1892).

Heent

3.4.2)

A) WITH POISONING/EXPOSURE

1) CHRONIC

a) Erosion and discoloration of the teeth may occur with hexavalent chromium compounds. In addition, papillomas of oral cavity and larynx have been reported in workers exposed to high air concentration of hexavalent chromium (with chromium level of 0.4 mg/m(3)) (Hathaway et al, 1996).

3.4.3)

A) WITH POISONING/EXPOSURE

1) CORNEAL INJURY: Severe corneal injury may result from ocular contact with solid or concentrated solutions of chromic acid and other hexavalent salts (Grant, 1993).
2) ANESTHESIA: Astigmatism and anesthesia of affected surfaces may persist after acute exposure.
3) KERATITIS: Chronic keratitis, conjunctival inflammation and brown bands of discoloration in the corneal surface may occur with chronic exposure (Grant, 1993).
4) MYDRIASIS has been reported after acute chromium ingestion (Sander & Camp, 1939).
5) CONJUNCTIVITIS: Severe conjunctivitis of the right eye occurred following accidental ocular exposure to tannalysing fluid (wood preservative) that contained chromium trioxide, arsenic pentoxide, and copper oxide (Routledge et al, 1998). In addition, exposure to mist in the air can cause conjunctivitis in some workers (Hathaway, et al, 1996).

3.4.5)

A) WITH POISONING/EXPOSURE

1) NASAL SEPTUM: Ulceration and perforation of the nasal septum and larynx may occur in workers exposed to chronic inhalation of fumes (Dixon, 1929). A purulent discharge with crust formation and breathing difficulty were the primary symptoms.

a) Poor, personal hygiene with hand to nose transfer of chromate salts may also result in nasal ulceration (Dingle, 1992).

2) RHINORRHEA and nasal hyperemia may result from acute exposure (Fregert, 1982).

3.4.6)

A) WITH POISONING/EXPOSURE

1) BURNS: Oral burns may be noted.

Cardiovascular

3.5.2)

A) SHOCK

1) WITH POISONING/EXPOSURE

a) Circulatory collapse and shock may occur within a few hours of acute oral ingestion (Loubieres et al, 1999).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE REPORT/PEDIATRIC: Hypotension has been reported in the case of a 22-month-old child following ingestion of 1 g ammonium dichromate which responded poorly to inotropic agents and fluid expansion. ECG revealed normal cardiac function with left ventricular shortening fraction of 30% (Meert et al, 1994).
b) CASE REPORT: A 35-year-old woman ingested 50 mL of chromic acid and subsequently developed persistent hypotension that was unresponsive to fluid expansion. The patient died approximately 12 hours after ingestion due to multiorgan failure (Loubieres et al, 1999).

C) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 42-year-old man developed hypertension (BP 180/110 mmHg) after exposure, on a skin abrasion, to a liquid wood preservative, containing chromium trioxide, arsenic pentoxide, and copper oxide (Routledge et al, 1998).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Acute exposure to massive concentrations of chromic acid mist can severely damage deep lung structure (Meyers, 1950). Pulmonary edema may be delayed following acute exposure. The case of a 22-month-old child with pulmonary edema and normal heart size presenting 24 hours following ingestion of 1 g ammonium dichromate was reported (Meert et al, 1994).
b) CASE REPORT: Acute pulmonary edema with subsequent respiratory failure was reported in a 22-year-old man approximately 3 days following occupational dermal exposure to electroplating solution that contained chromic acid. This exposure resulted in first-degree chemical burns that covered approximately 15% of his total body surface area (Lin et al, 2009).

B) BRONCHITIS

1) WITH POISONING/EXPOSURE

a) Chronic industrial exposure may result in bronchitis or pulmonary carcinoma (Ballal, 1986; Burrows, 1983).
b) CASE SERIES: The prevalence of respiratory symptoms was high in glass workers with elevated nickel and chromium blood levels (21 of 53 subjects with elevated levels had symptoms).

1) Workers with isolated elevations in either nickel or chromium did not have increased risk, suggesting an interaction (Srivastava et al, 1992).

C) FIBROSIS OF LUNG

1) WITH POISONING/EXPOSURE

a) PNEUMOCONIOSIS: Spotty, moderately severe non-nodular pneumoconiosis has been described (Taylor & Davies, 1977).
b) Inhalation has an irritant effect in the lower respiratory tract and may result in pulmonary fibrosis and emphysema (Dingle, 1992).

D) BRONCHOSPASM

1) WITH POISONING/EXPOSURE

a) Bronchial asthma generally occurs within 4 to 8 hours after exposure (Committee on Biologic Effect of Atmospheric Pollutants, 1974).

E) BRONCHOPNEUMONIA

1) WITH POISONING/EXPOSURE

a) Bronchopneumonia was reported in a 32-year-old man 4 days after ingesting potassium dichromate powder. The patient died on day 6 from progressive hepatic and renal failure (Sharma et al, 2003).

F) ADULT RESPIRATORY DISTRESS SYNDROME

1) WITH POISONING/EXPOSURE

a) Respiratory distress syndrome (ARDS) may be noted with significant oral ingestion (Iserson et al, 1983).

G) METAL FEVER

1) WITH POISONING/EXPOSURE

a) Metal fume fever has been reported after exposure to chromium oxide in a ferro-chrome alloy plant (Stoke, 1977).

Neurologic

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Toxic or hepatic encephalopathy has been reported; usually occurring as a late manifestation of hepatic failure (Breuer et al, 2015; Kaufman et al, 1970), but has occurred within 15 minutes of oral ingestion (Ellis et al, 1982).

B) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) Cerebral edema and meningoencephalitis can occur. The death of a child following a 1 g ingestion of ammonium dichromate was reported. At autopsy, the brain appeared edematous with scattered areas of neuronal shrinkage and pyknosis (Meert et al, 1994).

C) COMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT/PEDIATRIC: Circulatory insufficiency and coma (GCS of 5) developed in an 11-year-old boy following ingestion of 10 ml of a hexavalent chromium compound. The coma resolved in 3 days after beginning treatment with n-acetylcysteine, antibiotics, corticosteroids, and hemodialysis (Ulmeanu et al, 1997).
b) CASE REPORT: A 35-year-old woman ingested 50 mL of pure chromic acid (25 g hexavalent chromium) and developed encephalopathy followed by coma requiring the need for mechanical ventilation and hemodynamic support. Twelve hours after ingestion, the patient died due to multiorgan system failure (Loubieres et al, 1999).
c) CASE REPORT/PEDIATRIC: A 16-year-old boy developed hepatic and renal failure after ingesting an unknown quantity of potassium dichromate. He became comatose 5 days after ingestion and a CT scan of the brain showed mild cerebral edema. Following liver transplantation and hemodialysis, the coma resolved and the patient completely recovered with normal liver and kidney function (Stift et al, 2000).

D) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache and agitation occurred in a 42-year-old man following dermal exposure to a liquid wood preservative containing chromium trioxide, arsenic pentoxide, and copper oxide. The headache disappeared within 24 hours after exposure (Routledge et al, 1998).

Gastrointestinal

3.8.2)

A) GASTROENTERITIS

1) WITH POISONING/EXPOSURE

a) Violent gastroenteritis with rice-water stools, yellow-green or coffee-ground emesis, ulceration, corrosive burns of the mouth, esophagus, and gastrointestinal tract, and hemorrhage have occurred shortly after oral ingestion of chromates (Hantson et al, 2005; Stift et al, 2000; Kolacinski et al, 1999; Stift et al, 1998; Michie et al, 1991; Iserson et al, 1983; Reichelderfer, 1968).
b) CASE REPORT/PEDIATRIC: Ulceration and hemorrhage of the esophagus, stomach, duodenum, and jejunum mucosal areas was reported in the autopsy of a 22-month-old child who had ingested 1 g of ammonium dichromate (Meert et al, 1994).
c) Rectal administration of potassium dichromate as a folk remedy has resulted in perianal necrosis and gastrointestinal hemorrhage (Wood et al, 1990).

B) NAUSEA, VOMITING AND DIARRHEA

1) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) CHILD: An 11-year-old child ingested 10 mL of a hexavalent chromium compound and developed abdominal pain, hematemesis, and diarrhea shortly after ingestion (Ulmeanu et al, 1997).
2) ADULT: A 35-year-old woman intentionally ingested 50 mL of pure chromic acid (25 g hexavalent chromium) and one hour later presented to the emergency department with severe abdominal pain, vomiting, and ulcerations of the mouth. Bloody diarrhea and melena subsequently developed requiring massive blood transfusions. The patient, however, died of multiorgan failure 12 hours after ingestion (Loubieres et al, 1999). An autopsy revealed a mediastinal hematoma anterior to the upper esophagus and extensive necrosis of the digestive mucous membranes.
3) ADULT: A 48-year-old man intentionally ingested 150 mL of solution containing 22.5 g of potassium dichromate after consuming approximately 200 mL of 40% ethanol, and experienced hematemesis, diarrhea, and abdominal pain approximately 3 hours later. Seven hours post-ingestion, the patient continued vomiting, had bloody stools, and complained of diffuse abdominal and chest pain. With hemodialysis and supportive treatment, the patient gradually recovered (Kolacinski et al, 1999).
4) ADULT: A 55-year-old man experienced nausea, vomiting, bloody diarrhea, and abdominal pain after unintentionally ingesting a small amount of 20% chromic acid (estimated chromium ingested: 2.3 g). Over the next several days, the patient also developed acute renal and liver failure. With supportive treatment, including hemodialysis, the patient gradually recovered and was discharged 45 days postexposure (Baresic et al, 2009).
5) ADOLESCENT: A 17-year-old girl developed nausea, vomiting, epigastric pain, diarrhea and renal tubular toxicity after ingesting 2 to 3 g of potassium dichromate (40 to 60 mg/kg body weight) in a suicide attempt. Esophagogastric endoscopy revealed a small ulceration in the gastric fundus. Following supportive care, she recovered and was transferred to a psychiatric ward after 48 hours (Hantson et al, 2005).

C) BURN

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 16-year-old boy developed abdominal pain, vomiting and melena after ingesting an unknown quantity of potassium dichromate. Endoscopy revealed bleeding necrotic lesions of the esophagus and stomach without evidence of perforation (Stift et al, 2000).

3.8.3)

A) ANIMAL STUDIES

1) LACK OF EFFECT

a) In dogs, a dose of 11.2 ppm hexavalent chromium (calculated doses: 0.012 to 0.3 mg/kg) in drinking water for 4 years caused no pathological effects but the tissue concentration of chromium was increase to 6 ppm (IRIS , 2000; HSDB , 2000).

Hepatic

3.9.2)

A) ABNORMAL LIVER FUNCTION

1) WITH POISONING/EXPOSURE

a) Elevated liver enzyme levels were reported following ingestion of 150 mL solution containing 22.5 g potassium dichromate. The liver enzyme levels normalized following supportive treatment (Kolacinski et al, 1999).
b) CASE REPORT: Elevated liver enzyme concentrations (ALT and AST peak of 235 units/L and 780 units/L, respectively) were noted approximately 3 days after a 22-year-old man presented to the emergency department following occupational dermal exposure to electroplating solution that contained chromic acid. The exposure resulted in first-degree chemical burns that covered approximately 15% of his total body surface area (Lin et al, 2009).
c) CASE REPORT: Four days after a 55-year-old man unintentionally ingested a small amount of 20% chromic acid (estimated chromium ingested: 2.3 g), his AST and ALT concentrations peaked at 1510 units/L and 1470 units/L, respectively. His gamma glutamic transpeptidase and bilirubin concentrations were also elevated at 105 units/L and 90 mcmol/L, respectively (Baresic et al, 2009).

B) LARGE LIVER

1) WITH POISONING/EXPOSURE

a) Acute hepatitis may occur as a late manifestation, but is less common than renal injury (Fristedt et al, 1965; Michie et al, 1991). Liver enlargement and centrilobular necrosis and Kupffer cell proliferation have been noted at autopsy (Pascale et al, 1952; Meert et al, 1994).

C) HEPATIC FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) PEDIATRIC

a) Acute hepatic failure occurred in an 11-year-old boy following ingestion of 10 mL of a hexavalent chromium compound. The hepatic failure resolved one month after ingestion following hemodialysis and aggressive supportive care (Ulmeanu et al, 1997).
b) A 16-year-old boy developed liver failure following ingestion of an unknown quantity of potassium dichromate. The patient's initial serum chromium concentration was approximately 2500 mcg/L and neither plasmaphereses nor hemodialysis was successful in removing chromium from the circulation. The patient underwent liver transplantation six days after ingestion and his serum chromium level decreased to approximately 20% of the original level, suggesting chromium may have accumulated in the liver (Stift et al, 2000; Stift et al, 1998).
c) A 4-year-old child presented with abdominal pain and vomiting after ingesting an unknown amount of a chromated copper arsenate (CCA) wood preservative containing 13.3% chromium, 7.8% copper, and 11.3% arsenic. Severe chemical burns were observed with an upper esophagogastroduodenal endoscopy. Fulminant liver and kidney failure were reported the next day. Due to hepatic encephalopathy, intubation and mechanical ventilation were necessary. The patient's initial blood chromium concentration, obtained 3 days post-ingestion, was 2180 mcg/L. Sodium 2,3-dimercaptopropane-1-sulfonate was administered intravenously in order to increase the urinary excretion of chromium; however, because of the inability to remove significant amounts of intracellular chromium, liver transplantation was considered the only viable option. In order to extract as much as possible the amount of protein and erythrocyte-bound chromium and minimize the risk of toxicity to the transplanted liver, plasmapheresis and erythrocyte apheresis were performed, decreasing blood chromium concentrations by 22% and 77%, respectively. Liver transplantation was successful and the patient recovered uneventfully (Breuer et al, 2015).

2) ADULT

a) CHROMIC ACID: An autopsy of a 35-year-old woman who ingested 50 mL of pure chromic acid revealed liver failure. Microscopic examination of the liver showed fatty degeneration of approximately 80% of the cells and extensive necrosis (Loubieres et al, 1999).
b) POTASSIUM DICHROMATE: A 32-year-old man died 6 days after ingesting 73.46 mg/kg of potassium dichromate powder, despite aggressive intensive care. Initially, the patient developed metabolic acidosis and hypotension followed by hepatorenal syndrome (BUN 124 mg/dL, Cr 7.4 mg/dL, hyperbilirubinemia, hypoalbuminemia and elevated hepatic enzymes) (Sharma et al, 2003).

3.9.3)

A) ANIMAL STUDIES

1) CHRONIC TOXICITY

a) In rats, a dose of 134 ppm hexavalent chromium in drinking water for 2 to 3 months caused liver lesions (HSDB , 2000).

Genitourinary

3.10.2)

A) RENAL TUBULAR DISORDER

1) WITH POISONING/EXPOSURE

a) PROXIMAL TUBULE: Renal proximal convoluted tubular damage with marked interstitial edema is frequently observed as a late manifestation during the first or second day. Hematuria and oliguria may be noted (Iserson et al, 1983).
b) CASE REPORT: A 17-year-old girl developed renal tubular toxicity with normal glomerular filtration and creatinine clearance after ingesting 2 to 3 g of potassium dichromate (40 to 60 mg/kg body weight) in a suicide attempt. Beta2-microglobulin and retinol-binding protein were evaluated as biomarkers of proximal tubular renal injury. Following supportive care, she recovered and was transferred to a psychiatric ward after 48 hours (Hantson et al, 2005).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure occurred after ingestions and dermal exposure of chromic acid (Chapman et al, 2013; Xiang et al, 2011; Lin et al, 2009; Loubieres et al, 1999; Saryan & Reedy, 1988; Bader, 1986) , dichromates (Meert et al, 1994; Michie et al, 1991; Picaud et al, 1991; Kaufman et al, 1970), potassium dichromate (Sharma et al, 2003; Stift et al, 2000), an unknown hexavalent chromium compound (Ulmeanu et al, 1997), and following ingestion of a chromated copper arsenate (CCA) wood preservative containing 13.3% chromium, 7.8% copper, and 11.3% arsenic (Breuer et al, 2015).
b) CASE REPORT: A 55-year-old man unintentionally ingested a small amount of 20% chromic acid (estimated chromium ingested: 2.3 g), and developed nausea, vomiting, bloody diarrhea, abdominal pain, and a decrease in urine output to approximately 100 mL that progressed to anuria over the next 4 days. An abdominal ultrasound revealed enlarged kidneys. Laboratory data demonstrated serum creatinine and urea concentrations of 748 mcmol/L and 31.1 mmol/L, respectively, 9 days postingestion. Following supportive treatment, including hemodialysis, the patient's condition gradually improved and he was discharged approximately 45 days postingestion (Baresic et al, 2009).

C) CYSTITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Eosinophilic cystitis surrounding chromated catgut suture material has been reported in a patient who had a positive patch test to chromate and to intradermal chromic catgut (Engler et al, 1986).

D) ACUTE TUBULAR NECROSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT/PEDIATRIC: Extensive necrosis of almost all cortical tubular cells was observed at autopsy in a 22-month-old child after ingestion of 1 g of ammonium dichromate. The glomeruli were not involved, but the adrenal cortex was hemorrhagic and necrotic (Meert et al, 1994).

E) ABNORMAL RENAL FUNCTION

1) WITH POISONING/EXPOSURE

a) CHRONIC TOXICITY

1) Urinary biochemical indicators were evaluated in 84 man and 38 woman ferrochromium-producing workers, with an average employment time of 12 years exposed to water soluble hexavalent chromium compounds. The control group consisted of 42 men and 20 women. The biochemical indicators included urinary chromium, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), N-acetyl-beta-D-glucosaminidase (NAG), total protein, and beta2-microglobulin.
2) Urinary chromium levels were 1.8 times higher in the exposed group as compared to the controls. Activities of GGT, AST, NAG, ALP, and LDH were significantly increased (p less than 0.05) when urinary chromium concentration exceeded 45 mcg/g creatinine. Activities of GGT, AST, and NAG were elevated (p less than 0.05) in workers employed for more than 10 years. No clear chromium dose response relationship was observed. The injury site appeared to be the proximal tubule. The authors proposed urinary chromium concentrations over 15 mcg/g creatinine as a threshold for nephrotoxicity. The most sensitive early indicators of renal injury were thought to be GGT, NAG, and ALP (Wang et al, 1994).

b) Early renal effects to low-level hexavalent chromium exposure in 166 chrome platers and 106 controls were studied. Urinary total proteins (U-TP), urinary albumin (U-Alb), urinary retinol binding protein (U-RBP), and urinary chromium were measured. Average employment time was 12.6 years. Urinary chromium ranged from "non-detected" to 19.91 mcg/g creatinine in the platers. Age-adjusted U-TP, U-Alb, and U-RBP did not show a significant difference between platers and controls. A significant positive correlation was found between age-adjusted U-TP and urinary chromium. Urinary chromium was not correlated to age-adjusted U-Alb or U-RBP (Nagaya et al, 1994).

1) The authors concluded that U-TP had the greatest positive correlation to age in platers and controls. Increases in U-TP secondary to chromium exposure suggest that chromium exposure accelerates renal aging. Early effects of low-level chromium may not be specific to renal function.

3.10.3)

A) ANIMAL STUDIES

1) CHRONIC TOXICITY

a) In rats, a dose of 134 ppm hexavalent chromium in drinking water for 2 to 3 months caused kidney lesions (HSDB , 2000).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Metabolic acidosis (pH 7.43; PaO2 93 mmHg; PaCO2 12 mmHg) was reported in a 35-year-old woman following ingestion of 50 mL chromic acid (25 g hexavalent chromium). The patient died 12 hours after ingestion due to multiorgan failure. Laboratory analysis showed a final pH of 7.02 (Loubieres et al, 1999).

Hematologic

3.13.2)

A) ANEMIA

1) WITH POISONING/EXPOSURE

a) Hemorrhagic diathesis, thrombocytopenia, and anemia have been observed, usually occurring after 3 to 7 days. Intravascular hemolysis occurs rarely (Lin et al, 2009; Sharma et al, 1978).

1) CASE REPORT/PEDIATRIC: Coagulopathy resulting in increased prothrombin and partial thromboplastin times and a decreased platelet count occurred within 48 hours following the ingestion of 1 g ammonium dichromate in a 22-month-old child (Meert et al, 1994).

b) CASE REPORT: Laboratory analysis of a 35-year-old woman, who died 12 hours after ingesting 50 mL of pure chromic acid (25 g hexavalent chromium), revealed anemia (hemoglobin 56 g/L, hematocrit 1%) and thrombocytopenia (Loubieres et al, 1999).

B) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Chromates are capable of oxidizing free hemoglobin in vitro to methemoglobin, and clinically significant methemoglobinemia has been seen in overdose (Iserson et al, 1983)
b) CASE REPORT: A methemoglobin level of 9% was reported in a 35-year-old woman following ingestion of 50 mL pure chromic acid (concentration 99.7%; 25 g of hexavalent chromium) (Loubieres et al, 1999).

Dermatologic

3.14.2)

A) SKIN ULCER

1) WITH POISONING/EXPOSURE

a) CHROME HOLES: Highly corrosive to skin and mucous membranes. Deep perforating ulcers (chrome holes) may be noted (Burrows, 1983; Deng et al, 1990).
b) CASE REPORT: Multiple dermal chrome ulcers were reported in a 22-year-old man following occupational dermal exposure to electroplating solution that contained chromic acid (Lin et al, 2009).

B) HYPERSENSITIVITY REACTION

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) The trivalent form of chromium is the active allergen; however, it does not significantly penetrate the stratum corneum; thus, patch tests are negative and intradermal tests positive.
2) The majority of occupational dermatitis occurs secondary to exposure to hexavalent chromium. It is believed that the hexavalent salt penetrates the skin, where it is reduced to trivalent chromium and reacts with skin proteins to form antigens (Milner, 1980).
3) Currently, there is no dermal occupational exposure limit for hexavalent chromium. Stern et al (1993) reviewed nine chromium patch test studies and performed statistical analyses on the aggregate dose-response relationship from 72 separate observations from these studies. Based on this analysis and review of studies of allergic responses to bleaches and detergents, the effective threshold for elicitation of allergic contact dermatitis in sensitized populations was postulated to be approximately 10 ppm (mg/L)Cr(VI) (as chromium) in solution (Stern et al, 1993).

C) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) Occupational allergic contact dermatitis has been reported secondary to chromate in cement, with the greatest risk being from the wet and dry premixed concrete product as opposed to the powdered mixture (Turk & Rietschel, 1993; Olumide, 1987a; Farm, 1986; Goh, 1986); in yellow chromated components of automobile engine parts (Hjerpe, 1986); in metal sprays (Handfield-Jones et al, 1987); in chrome plating processes (Lee & Goh, 1988), in leather tanning (Das M et al, 1989); and in milk testers using dichromate preservatives (Herzog et al, 1988).
b) The threshold concentration of extractable Cr(VI) in solid material such as cement or earth may be as low as 10 ppm (mcg/g) (Stern et al, 1993).
c) The minimum elicitation threshold (MET) for Cr(VI) to produce an allergic response in 54 Cr(VI) sensitive individuals on a mg Cr(VI)/cm(2) skin basis was investigated. The Cr(VI) 10% MET in the group studied was 0.089 mcg/cm(2). One subject responded to a Cr(III) patch test of 33 mcg/cm(2), but failed to respond on retest. Based on this study, soil concentrations of a minimum 450 ppm Cr(VI) and 165,000 Cr(III) would be necessary to produce an allergic contact dermatitis hazard for at least 99.9% of individuals in a community population (Nethercott et al, 1994).
d) Oral ingestion of chromium in amounts within the range of normal daily intake or inhalation of chromium fumes may result in exacerbation of chronic dermatitis (Kaaber & Veien, 1978; Kaaber & Veien, 1977).

1) The lowest observed effect level (LOEL) oral dose of Cr(VI) for contact dermatitis elicitation was 0.26 mcg/kg (Stern et al, 1993). For soil concentrations, extractability must be considered.

e) CASE REPORT: Contact dermatitis in a chromate-sensitive patient occurred after exposure to chromium-containing acupuncture needles (Castelain et al, 1987).
f) Contact dermatitis of the neck due to chromates in military uniforms has also been reported; whereas, contact dermatitis of the feet may occur due to dichromates used in leather tanning (Das M et al, 1989; Olumide, 1987b; Olumide, 1987c).
g) Leather products may cause chromium dermatitis. Although only chromium III is used for tanning, small amounts of chromium hexavalent may be found in the final leather product due to oxidation of chromium III during the tanning process. Therefore, both chromium hexavalent and chromium III can cause dermatitis at low levels in the leather user (Hansen et al, 2003).
h) Non-healing dermatitis and cutaneous granuloma have occurred in patients treated with orthopedic internal fixation devices, containing chromium and other metals. These lesions resolved only after removal of the prostheses (Rostoker et al, 1987; Thomas et al, 1987; Macias & Palacios, 1986).
i) A high incidence of chromium allergy (contact dermatitis) has been reported in Israeli women following exposure to detergents and bleaches. Testing showed that the chromium concentration was greater than 5 ppm in 56% of the consumer products tested and between 1 and 5 ppm in 32% of the consumer products tested (Ingber et al, 1998).

D) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) Systemic symptoms and death have occurred after external burns, with a delay of onset of GI symptoms of hours or days. Burns initially resemble first and second degree burns, but extend to subcutaneous tissue within a couple of days (Kelly et al, 1982; Schiffl et al, 1982).
b) CASE REPORT: A 22-year-old man presented to the emergency department with first-degree chemical burns over both legs (estimated to be approximately 15% of total body surface area) following occupational dermal exposure to electroplating solution that contained chromic acid. Initial laboratory evaluation revealed leukocytosis (white blood cell count 22,000/mm(3)) and elevated creatine phosphokinase concentrations (450 units/L [normal, 0 to 140 units/L]). Over the next several days, systemic symptoms developed, including acute pulmonary edema, anemia, thrombocytopenia, and acute renal failure. Following treatment with DMPS, acetylcysteine, ascorbic acid, continuous venovenous hemofiltration, and plasmapheresis, the patient's condition gradually improved, and he was discharged approximately 33 days postexposure. There was no evidence of sequelae at the 3-month follow-up (Lin et al, 2009).
c) CASE REPORT: A 19-year-old industrial worker unintentionally fell into a vat of heated chromic acid and developed chemical burns over 60% of his body. In addition, the patient also developed acute renal failure approximately 48 hours later. The patient gradually recovered, with initiation of hemodialysis the next day and continued for 25 days until his renal function normalized, and excision of burn eschars with application of a series of allografting and autografting treatments (Xiang et al, 2011).
d) CASE REPORT: A 52-year-old man presented with severe burns on his legs bilaterally, affecting 14% of his total body surface area, with 20% as full thickness burns and 80% as deep partial thickness burns, after falling into a heated (150 degrees F) container of 59% hexavalent chromic acid and 14% sulfuric acid at an electroplating factory. His initial serum chromium concentration was 622 ng/mL. Surgical debridement and allografting, and IV infusions of normal saline, sodium bicarbonate, calcium edetate, and N-acetylcysteine were initiated. Acute renal failure developed, with a peak serum creatinine concentration of 3.3 mg/dL on hospital day 3. Hemodialysis was considered, but not initiated, and his renal function normalized after 18 days. Following several surgical debridement and autograft procedures, the patient was discharged to a rehabilitation facility. Prior to discharge, his serum chromium concentration had decreased to 65 ng/mL (Chapman et al, 2013).
e) CASE REPORT: Severe chemical burns were reported, following an upper esophagogastroduodenal endoscopy, in a 4-year-old boy who ingested an unknown amount of a chromated copper arsenate (CCA) wood preservative, containing 13.3% chromium, 7.8% copper, and 11.3% arsenic (Breuer et al, 2015).

E) ERUPTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute ingestion of one teaspoonful of potassium dichromate crystals resulted in an erythematous macular rash on the arms and legs, which rapidly spread and became confluent. The onset was one week postingestion, with resolution beginning 4 days later (Goldman & Karotkin, 1935).

Musculoskeletal

3.15.2)

A) INCREASED MUSCLE TONE

1) WITH POISONING/EXPOSURE

a) Muscle cramps may be noted (Wang et al, 1985).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH POISONING/EXPOSURE

a) An anaphylactoid reaction, with urticaria, dyspnea, and chest tightness, occurred in a welder after occupational exposure to chromium vapors. A challenge with sodium chromate aerosol produced delayed urticaria, angioedema and decreased FEV1 and an increase in plasma histamine (Moller et al, 1976).

B) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) Leather products may cause chromium dermatitis. Although only chromium III is used for tanning, small amounts of chromium hexavalent may be found in the final leather product due to oxidation of chromium III during the tanning process. Therefore, both chromium hexavalent and chromium III can cause dermatitis at low levels in the leather user (Hansen et al, 2003).

C) LACK OF EFFECT

1) DENTAL MATERIALS: No evidence for an association between the use of chromium in dental materials and chromate allergy has been found (Yontchev et al, 1986; Burrows, 1986).

3.19.3)

A) ANIMAL STUDIES

1) DELAYED HYPERSENSITIVITY

a) Genetic control of delayed-type hypersensitivity was studied in mice. Mice with I-A(b,d,f,k,r) were high magnitude responders and mice with I-A(q,s) were low magnitude responders.

1) Response to chromium chloride does not cross-react with response to cobalt or nickel chloride (Ishii et al, 1993).

Reproductive

3.20.1)

A) A review of the literature found no reports of reproductive or developmental effects of chromium in humans (Eizaguirre-Garcia et al, 2000; Clarkson et al, 1985).
B) Both trivalent and hexavalent chromium have been found to cross the placental barrier in hamsters and mice. Both were shown to enter the fetus during mid to late gestation. Developmental effects caused by both differed between hamster and mice. Fetal uptake of hexavalent chromium was much greater than that of the trivalent form. Effects on placental tissue could have also affected the fetus.

3.20.2)

A) LACK OF INFORMATION

1) A review of the literature found no reports of reproductive or developmental effects of chromium in humans (Eizaguirre-Garcia et al, 2000; Clarkson et al, 1985). However, chloride salts of chromium, chromium trioxide, and potassium dichromate have been shown to be teratogenic in animal studies (Schardein, 1993).
2) In a study of congenital anomalies in Glasgow, no increase in relative risk was found in and about a heavily polluted chromium waste site (Eizaguirre-Garcia et al, 2000).
3) ANIMAL STUDIES

a) Injected chromium trioxide caused birth defects and resorptions in hamsters (Gale, 1974; Gale & Bunch, 1979). Chromium chloride and trioxide were teratogenic in mice (Iijima, 1975; Iijima, 1979). Sodium dichromate was mildly teratogenic in chickens (Ridgway & Karnofsky, 1952).
b) Chromium(VI), as potassium dichromate, was embryotoxic and fetotoxic, but not teratogenic, in mice at levels in the drinking water of 250 to 750 ppm given on days 6 to 14 of gestation (Junaid et al, 1996).

3.20.3)

A) PLACENTAL TRANSFER

1) ANIMAL STUDIES

a) Transplacental transfer of chromium chloride has been shown in mice (Friberg et al, 1986), and chromium levels in the human fetus are ten times those found in adults (HSDB , 2000). The embryonic and fetal uptake of chromate was ten times greater than that of trivalent chromium in rats (Friberg et al, 1986).

B) ANIMAL STUDIES

1) Increased endocrine tumors were seen in offspring of male mice injected intraperitoneally with 1 mmol/kg chromium(III) chloride 2 weeks before mating (Yu et al, 1999).

3.20.5)

A) LACK OF EFFECT

1) Bonde & Ernst (1992) studied semen quality in 30 tungsten inert gas (TIG) welders and 47 non-welding workers. Chromium concentrations in post shift spot urine samples ranged from 0.17 to 4.74 nmol/mmol creatinine (median 1.08). Chromium blood concentrations ranged from 6.0 to 46.4 nmol in blood. Serum testosterone, follicle-stimulating hormone (FSH) and lutenizing hormone (LH) were also measured. Sperm quality was assessed by volume, concentration, total sperm count, proportion of normal sperm forms, proportion of motile sperm, and sperm penetration rate. Serum testosterone concentrations showed a slight decrease as urinary chromium increased but was not statistically significant in this sample population.

a) No association was found between the level of chromium in biological fluids and the quality of semen or male sexual male hormones in this TIG welder population. Care must be used in extrapolating this study to other TIG welder populations or other types of welders or chrome platers with potentially higher exposures to chromium(VI).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS18540-29-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) Air concentration of 1 microgram per cubic meter of hexavalent salts causes an estimated lifetime cancer risk of 1.2 X 10 (-2).

1) Dose-response relationships have been established for pulmonary cancer and occupational exposure to mixture of hexavalent and trivalent chromium. Such occupational exposure can occur in chromate production plants or in industries using chrome pigment.

a) Lung cancers, in particular small cell carcinomas, occur at a higher incidence in individuals exposed to chromates. Latent period can be about 10 to 15 years. The relative risk for workers is about 20 times greater than that of the general population.

2) Increased risk of nasal, pharyngeal, and gastrointestinal carcinomas and cancer of the sinuses has been reported. Latent period can be about 20 years.
3) Hexavalent chromium is listed by USEPA as a Group A compound by inhalation and as a Group D compound by oral route. It is rapidly reduced intracellularly to generate reactive oxygen species and intermediates.

3.21.3)

A) STOMACH CANCER

1) In a metaanalysis of 56 studies, the risk of stomach cancer was increased by a significant 27% in people with high exposure to chromium VI or with an occupation associated with exposure, including chromium production, chromium plating, leather work, and work with Portland cement. In an analysis of studies identifying increased risk of lung cancer, the risk of stomach cancer was increased by a significant 41% (Welling et al, 2015).

B) PULMONARY CARCINOMA

1) Occupational exposure to hexavalent chromium has been associated with an increased incidence of lung cancer in many groups (Norseth, 1986): welders (Sjogren et al, 1987; Becker et al, 1985); chromeplaters (Franchini et al, 1983; Sorahan et al, 1987); chromium chemical producers (Braver et al, 1985); chromite ore refiners (Enterline, 1974); chromium pigment producers (Sheffet et al, 1982; Langard & Vigander, 1983; Hayes et al, 1989).

a) A retrospective mortality study of workers in chrome leather tanneries revealed no occupationally related increased risk of cancer (Stern et al, 1987). However, another study found no excess lung cancer but a statistically significant increase in bladder cancer (Montanaro et al, 1997).

2) Increased incidence of LUNG CANCER among workers in the manufacture of chrome pigments has been reported in Germany, Norway, Canada, and the United States (ACGIH, 1996; HSDB , 2000). Exposures were generally mixed, involving both trivalent and hexavalent chromium compounds. Relative risk for lung cancer has been in the range of 3- to 50-fold, with a latent period of as much as 36 years (Clayton & Clayton, 1994).
3) In a retrospective mortality study of employees at the largest chromate manufacturing site in the USA, a subgroup with previous high-level exposure at another older site had an increased risk of cancer (odds ratio = 1.22 for each 3 years of high-level exposure). Employees who had worked exclusively at the newer facility did not have an increased incidence of cancer deaths (Pastides et al, 1994).
4) Lung cancer deaths increased progressively over time in several successive cohorts of chromate workers studied since 1984. Cancer risk was increased with exposure to all forms of chromium: total, insoluble (trivalent) and soluble (hexavalent) (Mancuso, 1997a). In a related study, chromium deposits were still present in lung tissue up to 18 years after last exposure (Mancuso, 1997b).

a) A retrospective study examined the estimated risk of lung cancer in a cohort of 2357 chromate industry workers exposed to hexavalent chromium. There were 122 lung cancer deaths in the cohort. Several models were developed to estimate risk. The preferred model showed that workers exposed at the current OSHA PEL of 0.1 mg/m(3) for 45 years will have a 25% excess risk of lung cancer death or 255 per 1000. This calculation was in agreement with other published risk estimates (Park et al, 2004).

5) Trivalent chromium was not a risk for lung cancer in a retrospective mortality study of 2,357 workers exposed between 1950 and 1985. This study was based on the cohort originally followed by Hayes and colleagues (Hayes et al, 1989).
6) Exposure to trivalent chromium was based on the ratio of trivalent to hexavalent chromium in dust samples collected after closure of the plant. A strong dose-response effect was seen for cumulative exposure to hexavalent chromium; signs of irritation and trivalent chromium were not risk factors. This is the first study of chromium workers to take smoking status into account (Gibb et al, 2000a).
7) The risk of lung cancer mortality for former chromate production workers was increased, and increased with increasing duration of employment and latency since first employment. The risk was still increased more than 20 years after last exposure. Cancer deaths of the nasal cavity/sinus were also increased. This study did not have information on smoking habits, but absence of other smoking-related diseases indicates a lack of smoking effect (Rosenman & Stanbury, 1996).
8) Overall cancer mortality and respiratory cancer deaths have remained increased in a third follow-up study of German arc welders who have been studied since 1980, but this increase has been indirectly attributed to asbestos (Becker, 1999).
9) In a retrospective mortality study involving approximately 100,000 residents in an area of China with increased levels of hexavalent chromium in the drinking water, neither total cancer deaths nor deaths from stomach or lung cancer were increased over the range of average rates for China (Zhang & Li, 1997).
10) It has been reported that conversion to a low-lime, or a no lime process, and enhanced industrial hygiene practices has improved the work environment among US chromate production employees. One study examined the possible cancer mortality risks among these employees (n=617) in the postchange environment. Overall, lower than expected mortality patterns (based on national and state-specific referent populations) among chromium chemical workers were observed. Three lung cancer deaths (3.59 expected) were noted and lung cancer mortality was 16% less than expected (Luippold et al, 2005).
11) A cohort study of men who worked in 2 German chromate production facilities (more than 12,000 urine chromium sample results, collected as part of routine medical monitoring, were analyzed) reported a significant 2-fold increase in lung cancer mortality among employees with a cumulative concentration of chromium in urine of 200 mcg/L-years or more (standard mortality ratio (SMR) 2.09; 95% CI 1.08 to 3.65). A moderate excess in mortality was reported for cancer of the trachea, bronchus and lung (SMR 1.48; 95% CI 0.93 to 2.25). Results of logistic regression analysis showed that cumulative chromium urinary concentrations of 200 mcg/L-years or more were associated with increased risk of lung cancer death (odds ratio 6.9; 95% CI 2.6 to 18.2); the risk did not change after controlling for smoking (Birk et al, 2006).

C) CARCINOMA

1) Langard (1993) reviewed epidemiologic studies on chromium-exposed cohorts and available evidence for human carcinogenicity. The study concluded that it is assumed that all hexavalent chromium compounds are carcinogenic after inhalation exposure. Review analysis suggested that zinc chromate is a highly potent carcinogen and that calcium chromate may also be carcinogenic. Chromates of low water solubility may be less carcinogenic than more water soluble chromates (Langard, 1993; Langard, 1990).
2) CHEMICAL FORMS: Chromium-induced carcinogenicity appears to be related to exposure to hexavalent compounds and not to trivalent compounds because only chromium (VI) is readily transported into cells.

a) Furthermore, the solubility of chromium compounds has some influence on carcinogenicity (Lee & Goh, 1988; Levy et al, 1987) Petrille & de Flora, 1987; US Dept of Health Education & Welfare, 1975).

3) Risk of mortality from cancer was not increased in a group of chromate employees who had worked exclusively under modern, controlled conditions (Pastides et al, 1994). However, a subgroup of employees who transferred from older facilities had a higher risk of mortality (odds ratio = 1.27 for each 3 years of previous exposure; 90% confidence interval (CI) = 1.07 to 1.51) and cancer (odds ratio = 1.22 for each 3 years of previous exposure; 90% CI = 1.03 to 1.45). This group accounted for only 11% of the workers in this study but had 60% (3/5) of the lung cancers and 46% (6/13) of all observed cancers (excluding skin cancers).
4) Soluble hexavalent chromates are considered human carcinogens, and insoluble chromates such as stainless steel welding fumes have been linked with increased risk for human lung cancer (ACGIH, 1996).
5) Exposure to hexavalent chromium compounds may be a risk factor for squamous cell cancer of the tongue (Tisch & Maier, 1996).

D) LYMPHOMA

1) Two cases of Hodgkin disease were found in a small population with high environmental exposure to chromium, making an observed risk of 65 to 92 times that for non-exposed populations. This may be a chance occurrence and is not conclusive (Bick et al, 1996).

3.21.4)

A) NEOPLASM

1) Offspring of male mice exposed to trivalent chromium developed endocrine tumors. Chromium was administered as chromium(III) chloride given intraperitoneally at a dose of 1 mmol/kg 2 weeks before mating (Yu et al, 1999).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor CBC, INR, PTT, urine output, urinalysis, liver enzymes, and kidney function tests for patients with significant exposure.
B) If respiratory irritation is evident, obtain a baseline chest x-ray with frequent monitoring of arterial blood gases and/or pulse oximetry for delayed-onset acute lung injury.
C) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm.

1) Observe carefully for esophageal or gastric perforation and late complications such as pyloric stenosis and strictures.

D) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (eg, dyspnea, headache, fatigue, CNS depression, tachycardia, acidosis).

4.1.2)

A) Monitor CBC, INR, PTT, liver enzymes, and kidney function tests for patients with significant exposure.

4.1.3)

A) Monitor urine output and urinalysis for patients with significant exposure.
B) B(2)-microglobulins were significantly higher in chromeplaters exposed to hexavalent chromium than in unexposed controls (Lindberg & Vesterberg, 1983a).
C) Potassium dichromate-induced renal tubular damage in rats results in a bimodal increase in excretion of Tamm-Horsfall mucoprotein, which is located in the epithelial cells of the ascending limb and distal convoluted tubule.

1) The first peak at 12 hours occurs prior to structural changes in the tubular epithelia. The second peak at 24 to 72 hours coincides with tubular necrosis and cast formation. Excretion of this mucoprotein may be useful in evaluating early renal damage (Schwartz et al, 1972).

4.1.4)

A) OTHER

1) CHEST X-RAY

a) If respiratory irritation is evident, obtain a baseline chest x-ray with frequent monitoring of arterial blood gases and/or pulse oximetry for delayed-onset acute lung injury.
b) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm.

1) Observe carefully for esophageal or gastric perforation and late complications such as pyloric stenosis and strictures.

2) MEDICAL SURVEILLANCE

a) Initial examination should be followed up by periodic medical examinations for worker exposed to hexavalent chromium (HSDB , 2000).

1) Initial examination should include a complete history, a complete blood count, chest roentgenogram, FVC and FEV, urinalysis/kidney function tests, liver function tests, and dermatological examination.
2) Periodic medical examination should include evaluation of skin and respiratory complaints and tests included as part of the initial examination.

Methods

A)

1) Chromium (VI) and complexes of chromium (III) can be rapidly determined in plasma and other biological specimens via a high performance anion-exchange liquid chromatograph coupled to visible range (370 nm) and UV (280 nm) detectors and an atomic-absorption spectrometer. The detection limits for chromium (III) for each method were 2 and 5 ng, respectively (Suzuki, 1987).
2) Use of a heated graphite atomizer with an atomic absorption spectrophotometer provided for a nonflame technique for determining chromium in urine with better sensitivity than conventional flame techniques. The detection limit was 2.5 ppb for 20 ul samples (Ross & Shafik, 1973).
3) A gas chromatography technique using a flame photometric detector with a 425.4 nm filter, which is specific for chromium, has been described for monitoring urine chromium levels (Ross & Shafik, 1973).
4) Chromium may be detected in the urine using a colorimetric method employing the violet complex of 1,5-diphenylcarbazide, with a detection limit of 3.5 ng (Langard & Norseth, 1979).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Symptomatic patients, and those with endoscopically demonstrated grade II or higher burns should be admitted. Patients with respiratory distress, grade III burns, acidosis, hemodynamic instability, gastrointestinal bleeding, or large ingestions should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients who are asymptomatic after low concentrations, following dermal, inhalation, or ocular exposure, may be observed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) For ingestion cases, consult a gastroenterologist for early endoscopy and a surgeon if perforation is suspected. A toxicologist or poison center should be consulted for all patients with severe toxicity or patients that require hospital admission.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient with any ingestion or symptomatic dermal or inhalation exposure should be sent to a healthcare facility. Consider prolonged (12 hours) observation for late-onset airway compromise following ingestion or inhalation.

Monitoring

A)

B)

C)

1) Observe carefully for esophageal or gastric perforation and late complications such as pyloric stenosis and strictures.

D)

Oral Exposure

6.5.1)

A) Remove contaminated clothing. Irrigate exposed eyes and skin with copious amounts of water. Administer oxygen. Dilute with small amounts of water after ingestion.

6.5.2)

A) DILUTION

1) Dilute with small amounts of water after ingestion.
2) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
3) The patient should take nothing by mouth following initial dilution and until after endoscopic evaluation.

B) NASOGASTRIC SUCTION

1) INDICATIONS: Consider insertion of a small, flexible nasogastric tube to aspirate gastric contents after large, recent ingestion of caustics. The risk of worsening mucosal injury (including perforation) must be weighed against the potential benefit.
2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric emptying.
b) AIRWAY PROTECTION: Alert patients - place in Trendelenburg and left lateral decubitus position, with suction available. Obtunded or unconscious patients - cuffed endotracheal intubation. COMPLICATIONS:

1) Complications of gastric aspiration may include: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach (Vale, 1997). Combative patients may be at greater risk for complications.

6.5.3)

A) EXCHANGE TRANSFUSION

1) Exchange transfusion may be useful. Exchange transfusion of 10.9 liters of blood over a 5 hour period produced a reduction of 67 percent in blood chromium concentrations from 5.9 to 1.9 micrograms/milliliter in one case (Kelly et al, 1982).
2) Double-volume exchange transfusion with 1.6 L whole blood resulted in plasma lowering of chromium concentration from 4,163 mcg/L to 1,043 mcg/L and RBC chromium concentration from 7,795 mcg/L to 1,474 mcg/L in the first 20 hours following ingestion of 1 gram ammonium dichromate by a 22-month-old child (Meert et al, 1994).
3) MONITOR VOLUME STATUS HEMATOCRIT AND PLATELET COUNT: Gastrointestinal hemorrhage may result following ingestion of chromium salts and transfusions may be necessary.

B) MONITORING OF PATIENT

1) Monitor CBC, INR, PTT, urine output, urinalysis, liver enzymes, and kidney function tests for patients with significant exposure.
2) If respiratory irritation is evident, obtain a baseline chest x-ray with frequent monitoring of arterial blood gases and/or pulse oximetry for delayed-onset acute lung injury.
3) Obtain an upright chest x-ray in patients with signs and symptoms suggesting severe burns, perforation, or bleeding (or adults with deliberate, high volume or high concentration ingestions) to evaluate for pneumomediastinum or free air under the diaphragm.

a) Observe carefully for esophageal or gastric perforation and late complications such as pyloric stenosis and strictures.

4) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (eg, dyspnea, headache, fatigue, CNS depression, tachycardia, acidosis).

C) ENDOSCOPIC PROCEDURE

1) The following recommendations are extrapolated from experience with ingestions of acids and/or alkaline corrosives.
2) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
3) INDICATIONS: Endoscopy should be performed in adults with a history of deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after unintentional ingestion (Crain et al, 1984). Endoscopy should also be performed in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion (Gaudreault et al, 1983; Nuutinen et al, 1994). Children and adults who are asymptomatic after accidental ingestion do not require endoscopy (Gupta et al, 2001; Lamireau et al, 2001; Gorman et al, 1992).
4) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.

a) REFERENCES: (Dogan et al, 2006; Symbas et al, 1983; Crain et al, 1984a; Gaudreault et al, 1983a; Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992)

5) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):

a) Advancing across the cricopharynx under direct vision
b) Gently advancing with minimal air insufflation
c) Never retroverting or retroflexing the endoscope
d) Using a pediatric flexible endoscope
e) Using extreme caution in advancing beyond burn lesion areas
f) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).

6) GRADING

a) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding, and perforation is related to the severity of the initial burn (Zargar et al, 1991):
b) Grade 0 - Normal examination
c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation or gastrointestinal bleeding may occur.
g) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.

7) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
8) SCINTIGRAPHY - Scans utilizing radioisotope labelled sucralfate (technetium 99m) were performed in 22 patients with caustic ingestion and compared with endoscopy for the detection of esophageal burns. Two patients had minimal residual isotope activity on scanning but normal endoscopy and two patients had normal activity on scan but very mild erythema on endoscopy. Overall the radiolabeled sucralfate scan had a sensitivity of 100%, specificity of 81%, positive predictive value of 84% and negative predictive value of 100% for detecting clinically significant burns in this population (Millar et al, 2001). This may represent an alternative to endoscopy, particularly in young children, as no sedation is required for this procedure. Further study is required.
9) MINIPROBE ULTRASONOGRAPHY - was performed in 11 patients with corrosive ingestion . Findings were categorized as grade 0 (distinct muscular layers without thickening, grade I (distinct muscular layers with thickening), grade II (obscured muscular layers with indistinct margins) and grade III (muscular layers that could not be differentiated). Findings were further categorized as to whether the worst appearing image involved part of the circumference (type a) or the whole circumference (type b). Strictures did not develop in patients with grade 0 (5 patients) or grade I (4 patients) lesions. Transient stricture formation developed in the only patient with grade IIa lesions, and stricture requiring repeated dilatation developed in the only patient with grade IIIb lesions (Kamijo et al, 2004).

D) CORTICOSTEROID

1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
8) STUDIES

a) ANIMAL

1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).

b) HUMAN

1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
2) META ANALYSIS

a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).

3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).

a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).

6) ADVERSE EFFECTS

a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).

E) DIURESIS

1) After initial hydration, forced diuresis may be accomplished with furosemide 1 mg/kg up to 40 mg/dose.

F) ACIDOSIS

1) Correct hypotension with intravenous fluids, blood and pressors as needed.
2) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
3) HEMOLYSIS

a) INDICATIONS: Alkaline diuresis should be performed if there is any evidence of hemolysis to prevent renal deposition of red blood cell breakdown product.
b) SODIUM BICARBONATE/INITIAL DOSE

1) Administer 1 to 2 milliequivalents/kilogram of sodium bicarbonate as an intravenous bolus. Add 132 milliequivalents (3 ampules) sodium bicarbonate and 20 to 40 milliequivalents potassium chloride (as needed) to one liter of dextrose 5 percent in water and infuse at approximately 1.5 times the maintenance fluid rate. In patients with underlying dehydration additional administration of 0.9% saline may be needed to maintain adequate urine output (1 to 2 milliliters/kilogram/hour). Manipulate bicarbonate infusion to maintain a urine pH of at least 7.5.

c) SODIUM BICARBONATE/REPEAT DOSES

1) Additional sodium bicarbonate (1 to 2 milliequivalents per kilogram) and potassium chloride (20 to 40 milliequivalents per liter) may be needed to achieve an alkaline urine.

d) CAUTION

1) Obtain hourly intake/output and urine pH. Assure adequate hydration and renal function prior to alkalinization. Do not administer potassium to an oliguric or anuric patient. Monitor fluid and electrolyte balance carefully. Monitor blood pH, especially in intubated patients, to avoid severe alkalemia.

G) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

H) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

I) CHELATION THERAPY

1) May be used but has not been shown to be of definite benefit.
2) BAL did not change renal or dialyzer clearance of hexavalent chromium in dogs (Ellis et al, 1982).

a) Administer BAL (Dimercaprol) 3 to 5 milligrams/kilogram/dose every 4 hours intramuscularly for the first 48 hours, then 2.5 to 3 milligrams/kilogram every 6 hours for the second 48 hours, then every 12 hours for 7 additional days.
b) Side effects of BAL therapy include urticaria, generalized aches, salivation, and hypertension.

3) EDTA does not chelate hexavalent chromium salts.
4) NAC: In a study of potassium dichromate poisoning in rats, N-acetylcysteine (500 milligrams/kilogram intraperitoneally) resulted in a statistically significant increase in the total amount of chromium excreted for the 3 day study period compared to controls and reversed the oliguria associated with this toxin (Banner et al, 1986).

a) A 17-year-old girl developed nausea, vomiting, epigastric pain, diarrhea, and renal tubular toxicity with normal glomerular filtration and creatinine clearance after ingesting 2 to 3 grams of potassium dichromate (40-60 mg/kg body weight) in a suicide attempt. To enhance the extracellular reduction of hexavalent chromium to the less bioavailable trivalent chromium (based on experimental studies), she was administered 3 grams of ascorbic acid intravenously. To increase the amount of chromium excreted in the urine, she was also given a loading dose of N-acetylcysteine (150 mg/kg over 30 minutes) intravenously. She recovered (Hantson et al, 2005).

5) In animal models of acute chromate toxicity, various polyamino carboxylic acids were shown to be effective in chelating chromium from vital organs, subcellular fractions and blood cells (Behari & Tandon, 1980).

a) Two polyaminocarboxylic acids, nitrilotriacetic acid (NTA) and 1,2 cyclohexylenediamine tetraacetic acid (CDTA), produced a survival rate of 60 percent or greater in mice receiving a lethal dose of potassium chromate (Tandon & Srivastava, 1985).

J) EXPERIMENTAL THERAPY

1) ASCORBIC ACID

a) HUMAN DATA

1) In one case of ingestion of 5 grams of sodium dichromate in a 2-year-old, ascorbic acid was given 1 gram daily; the child survived (Walpole et al, 1985). Meert et al (1994) report the case of a one gram ingestion of ammonium dichromate by a 22-month-old child treated with a continuous IV infusion of ascorbic acid at 100 mg/hr in addition to gastric lavage using an ascorbic acid solution (100 g/L); the child died. These authors speculate that larger ascorbic acid doses and the administration of N-acetylcysteine may have allowed more effective reduction of chromium VI in this case (Meert et al, 1994).
2) A 17-year-old girl developed nausea, vomiting, epigastric pain, diarrhea, and renal tubular toxicity with normal glomerular filtration and creatinine clearance after ingesting 2 to 3 grams of potassium dichromate (40-60 mg/kg body weight) in a suicide attempt. To enhance the extracellular reduction of hexavalent chromium to the less bioavailable trivalent chromium (based on experimental studies), she was administered 3 grams of ascorbic acid intravenously. To increase the amount of chromium excreted in the urine, she was also given a loading dose of N-acetylcysteine (150 mg/kg over 30 minutes) intravenously. She recovered (Hantson et al, 2005).
3) TOPICALLY: Topical administration of 10% ascorbic acid has resulted in 60% to 100% resolution of chromium dermatitis in 7 workers following chronic occupational hexavalent chromium exposure. The ascorbic acid was administered, at least three times daily, as a solution or as an ointment (Bradberry & Vale, 1999). However, these results have not been confirmed in controlled clinical trials, and the authors speculate that the resolution of the dermatitis may have been due to a decrease in hexavalent chromium re-exposure instead of the specific ascorbic acid treatment.

b) ANIMAL DATA

1) Administration of 1 gram per 0.135 gram of elemental chromium was effective in preventing toxicity in a small study in rats if given before stomach emptying occurred (within 2 hours) (Samitz et al, 1962).
2) DOSE: The dose of ascorbic acid per gram of hexavalent chromium salt used in the animal model was: chromic acid (trioxide) 3.85 grams; sodium dichromate 2.9 grams; potassium dichromate 2.62 grams; ammonium dichromate 3 grams (Samitz et al, 1962).

c) MECHANISM: Ascorbic acid reacts with hexavalent chromium to form a less toxic trivalent complex (Korallus et al, 1984; Bradberry & Vale, 1999).
d) CONCLUSION: These animal data and human anecdotal reports are promising but not definitive. If readily available, ascorbic acid can be considered, with the realization that no proven benefit exists.

K) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) OBSERVATION REGIMES

1) If concentrated solutions of chromic acid are inhaled, hospitalize and observe for delayed onset of severe pulmonary edema.

B) MONITORING OF PATIENT

1) Obtain baseline chest x-ray and vital signs.

C) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

D) BURN

1) Evaluate for nasopharyngeal burns.

E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) BURN

1) Treat burns prophylactically for infection.

B) SKIN ABSORPTION

1) CHROMATE SCABS: EDTA ointment 10% may facilitate removal of chromate scabs (Finkel, 1982).
2) ULCERS: Chronic chrome ulcers generally heal in several weeks with no specific treatment.
3) CONTACT DERMATITIS: Contact dermatitis reportedly has been prevented by repeated application of a 10% ascorbic acid solution during exposure to reduce the active hexavalent chromium to an inactive trivalent form (Milner, 1980).

a) Favorable results have also been obtained in 64% of patients who used a barrier cream containing 2% glycine and 1% tartaric acid. Tartaric acid reportedly reduces hexavalent to trivalent chromium which is then chelated by glycine and tartaric acid (Romaguera et al, 1985).

4) ULCERS: A 10% disodium edetate ointment was effective in treating skin ulcers (Hayes & Laws, 1991).
5) CASE REPORT: A 22-year-old man presented to the emergency department with first-degree chemical burns over both legs (estimated to be approximately 15% of total body surface area) following occupational dermal exposure to electroplating solution containing chromic acid. Initial laboratory evaluation revealed leukocytosis (white blood cell count 22,000/mm(3)) and elevated creatine phosphokinase concentrations (450 units/L [normal, 0 to 140 units/L]). Over the next several days, systemic symptoms developed, including acute pulmonary edema, anemia, thrombocytopenia, and acute renal failure. Chelation therapy with DMPS 125 mg every 12 hours was initiated on day 1 post-exposure, as well as IV acetylcysteine, 50 mg/kg every 4 hours, and IV ascorbic acid, 100 mg every 12 hours, and continued for the next 10 days. In addition, continuous venovenous hemofiltration and plasmapheresis were initiated on day 3 post-exposure and continued for the next seven days. The patient's condition gradually improved, and he was discharged approximately 33 days post-exposure. There was no evidence of sequelae at the 3-month follow-up (Lin et al, 2009).

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) SUMMARY: Exchange transfusion was useful in one case, but no data are available to compare this with other methods.
2) CASE REPORT: Exchange transfusion of 10.9 liters of blood over a 5 hour period produced a reduction of 67 percent in blood chromium concentrations from 5.9 to 1.9 micrograms/milliliter in this case (Kelly et al, 1982).
3) MONITOR VOLUME STATUS HEMATOCRIT AND PLATELET COUNT: GI hemorrhage may result following ingestion of chromium salts and transfusions may be necessary.

B)

1) SUMMARY: Chromium clearances of 4 to 16 mg/8 hours of hemodialysis have been reported (Kaufman et al, 1970). However, hemodialysis clearance rates have not been shown to be greater than inherent renal clearance (Behari & Tandon, 1980).
2) CASE REPORT: In a fatal oral ingestion of 5 grams of potassium dichromate, neither hemodialysis nor charcoal hemoperfusion were effective. Only approximately 265 milligrams of chromium was removed by 4 hours of hemodialysis (Iserson et al, 1983).
3) CASE REPORT: In a fatal case of sodium dichromate ingestion, hemodialysis resulted in an average clearance of 12.4 +/- 2.4 milliliters/minute. During 8 hours of dialysis, approximately 62 milligrams of chromate were removed (Ellis et al, 1982).
4) CASE REPORT: A 9-hour hemodialysis session, initiated 8 hours after an intentional ingestion of a 150 milliliter solution containing 22.5 grams potassium dichromate, eliminated 3300 micrograms of chromium. The total amount of chromium eliminated by dialysis and spontaneous urinary excretion during the first 400 hours of hospitalization was 36.7 milligrams, or 0.16% of the ingested dose (Kolacinski et al, 1999).
5) CASE REPORT: A 55-year-old man unintentionally ingested a small amount of 20% chromic acid (estimated chromium ingested: 2.3 g), and developed nausea, vomiting, blood-watery diarrhea, abdominal pain, and a decrease in urine output to approximately 100 mL that progressed to anuria over the next 4 days. An abdominal ultrasound revealed enlarged kidneys. Laboratory data demonstrated a serum creatinine and urea concentrations of 748 mcmol/L and 31.1 mmol/L, respectively, 9 days post-ingestion. Hemodialysis was performed for 3 days, resulting in a decrease in the urea and creatinine concentrations, and an increase in the urine output. Following cessation of hemodialysis treatment, the patient's daily urine output continued to increase to 3,400 mL on hospital day 22; however, the urea and serum creatinine concentrations also increased to 42.2 mmol/L and 1,540 mcmol/L, respectively. Hemodialysis was restarted and continued until the patient's urea and creatinine concentrations decreased and remained stable at 8.6 mmol/L and 249 mcmol/L, respectively (hospital day 41). The patient's condition continued to improve and he was discharged 45 days post-ingestion with reduced renal function. At the 8 month follow-up, serum creatinine and urea concentrations had continued to decline to 186 mcmol/L and 8.2 mmol/L, respectively, with a creatinine clearance of 30 mL/min (Baresic et al, 2009).

C)

1) Peritoneal dialysis is similar in efficacy to hemodialysis. A clearance rate of 22.4 mg/24 hours was reported (Kaufman et al, 1970).
2) A study of the efficacy of peritoneal dialysis (5 patients) versus hemodialysis (6 patients) in 11 patients with renal failure was done following intravenous injection of 500 microcuries Ci(51)CrCl(3). Hemodialysis clearance of chromium was about three times that of peritoneal dialysis (2.5 +/- 0.8 ml/min vs 0.8 +/- 0.3 ml/min) (Schiffl et al, 1982).

D)

1) Hemoperfusion removed less than 1 percent of the total dose administered (potassium chromate 50 milligrams/kilogram) in a study performed with 5 anesthetized dogs (Ross et al, 1991).
2) Administration of 140 mg/kg/dose of N-acetylcysteine at 30 minute intervals for 3 doses after initiation of hemoperfusion removed less than 1 percent of the total dose administered (potassium chromate 50 mg/kg) in a study of 5 anesthetized dogs (Ross et al, 1991).

E)

1) A 4-year-old child presented with abdominal pain and vomiting after ingesting an unknown amount of a chromated copper arsenate (CCA) wood preservative containing 13.3% chromium, 7.8% copper, and 11.3% arsenic. Fulminant liver and kidney failure were reported the next day. The patient's initial blood chromium concentration, obtained 3 days post-ingestion, was 2180 mcg/L. Sodium 2,3-dimercaptopropane-1-sulfonate was administered intravenously in order to increase the urinary excretion of chromium; however, because of the inability to remove significant amounts of intracellular chromium, liver transplantation was considered the only viable option. In order to extract as much as possible the amount of protein and erythrocyte-bound chromium and minimize the risk of toxicity to the transplanted liver, plasmapheresis and erythrocyte apheresis were performed, decreasing blood chromium concentrations by 22% and 77%, respectively. The calculated absolute chromium removal by plasmapheresis and by erythrocyte apheresis was approximately 0.6 mg and 1.4 mg, respectively. The explanted liver contained 11,700 mcg chromium/kg (equivalent to 9.5 mg chromium). Liver transplantation was successful and the patient recovered uneventfully (Breuer et al, 2015).

Abstracts

Case Reports

A)

1) ROUTE OF EXPOSURE

a) DERMAL: A 49-year-old man was sprayed with hot chromic acid involving approximately 40% body surface area. He was irrigated at the scene and admitted to the hospital 1 hour after injury. The first urine sample contained hemoglobin. Treatment included IV crystalloids, mannitol, glucose, glucuronic acid, and whole blood.

1) Nine hours after injury approximately half of the burned skin was excised, and grafts were placed. During the postoperative period, he became confused and began vomiting bile-stained fluid. Thrombocytopenia developed on the second day after injury, and he became unconscious.
2) Treatment included antibiotics, chelating agents, and diuretics. By the 4th day, the patient had developed hallucinations, muscle spasms, guaiac positive stools, and emesis. Respiratory arrest occurred, and the patient died on the 6th day (Wang et al, 1985).

b) INJECTION: A 31-year-old man injected IV an unknown amount of a cleaning compound, Alodina 1000, composed of 60% chromic acid and 40% potassium fluozirconate. For the next 3 days, he had nausea, vomiting, dark red urine, and loose reddish stools.

1) When he sought medical care 7 days after injection, his creatinine was 19.1 mg/dL and BUN was 190 mg/dL, but he had normal LFTs. Urine chromium 8 days after injection was 3640 mcg/L (normal 0 to 10). The patient required hemodialysis until the 19th day of his illness. On the 48th day post-injection, the serum creatinine was 1.5 mg/dL, and the patient was well at a 3 month follow-up visit (Bader, 1986).

c) ORAL: A 17-year-old man ingested approximately 5 g of potassium dichromate 2 hours prior to admission in a suicide attempt. Vital signs were BP-130/58, P-120, R-48. Initial treatment included IV saline oxygen by mask, and morphine sulfate for pain.

1) After 15 minutes, vital signs were BP-80 mmHg/palpation, P-130, R-24/minute, CVP-0. Treatment included IV saline and dimercaprol (5 mg/kg IM). The initial chromium level was >6000 mcg/dL.
2) Because the patient had bloody stools, endoscopy was done which revealed caustic burns in the stomach and duodenum. Hemodialysis decreased the hyperkalemia but did not decrease the chromium level significantly.
3) Despite transfusions and dopamine to support the blood pressure, the patient died of hypovolemic shock 14 hours post-ingestion (Clochesy, 1984; Iserson et al, 1983).

B)

1) A 3-year-old ingested 40 match heads and developed acute renal failure a few days after the ingestion (Picaud et al, 1991). In France, match head materials contain potassium chlorate and potassium bichromate. The estimated amount of potassium bichromate ingested was 5 mg.

Range Of Toxicity

Summary

A)

B)

C)

Therapeutic Dose

7.2.1)

A) GENERAL/SUMMARY

1) Although the role of chromium as an essential nutrient in humans is not fully delineated, the estimated requirement for chromium in humans is about 1 microgram/day (Clinical Nutrition Cases, 1988).
2) Chromium is important in glucose and lipid metabolism, and chromium deficiency may be one factor associated with the development of atherosclerosis (Schroeder et al, 1970).

Minimum Lethal Exposure

A)

1) ADULT: The oral dose that will cause death in humans has been estimated to be 1 to 3 g of hexavalent chromium (Barceloux, 1999; HSDB , 2000).
2) PEDIATRIC: A single dose of 10 mg/kg body weight has been estimated to be the lethal oral dose for a 14 year-old boy (HSDB , 2000).

B)

1) POTASSIUM DICHROMATE

a) ORAL: A 32-year-old man died 6 days after ingesting 73.46 mg/kg of potassium dichromate powder. Initially, the patient developed metabolic acidosis and hypotension followed by fatal hepatorenal syndrome (Sharma et al, 2003).
b) ORAL: Death was reported in a 14-year-old boy after ingestion of 1.5 g of potassium dichromate, despite gastric lavage and administration of dimercaprol, ascorbic acid, peritoneal dialysis, and exchange transfusion (Kaufman et al, 1970).

2) CHROMIUM TRIOXIDE (CHROMIUM VI OXIDE)

a) DERMAL: Dermal corrosion of an area less than 10% of the body surface area has resulted in death. Fatal nephritis has occurred due to use of CHROMIUM TRIOXIDE (CHROMIUM VI OXIDE) to cauterize a wound (Major, 1922).

3) CHROMIC ACID

a) ORAL: Death due to multiorgan system failure occurred in a 35-year-old woman 12 hours after ingesting 50 mL of pure chromic acid (25 g hexavalent chromium) (Loubieres et al, 1999).

Maximum Tolerated Exposure

A)

1) Metallic chromium and the trivalent and divalent forms appear to have low toxicity, although dermatitis has been reported in workers exposed to trivalent chromium compounds. A nodular type of pulmonary disease occurred in workers exposed to an airborne concentration of 0.26 mg/m(3) of chromium from ferrochrome alloys, but the effects could not be attributed directly to exposure to chromium fumes alone (Hathaway et al, 1996).
2) Levels of 12 different chromium aerosols from 1.5 to 40 mcg/m(3) were tested in 250 volunteers. Shock and irritation of the upper respiratory tract resulted from even brief exposure to airborne levels from 10 to 24 mcg/m(3) (HSDB , 2000).
3) Ingestion of 10 mL of a hexavalent chromium compound by a child resulted in gastroenteritis, circulatory insufficiency, acute renal and hepatic failure, and coma. The patient survived following n-acetylcysteine treatment, aggressive supportive care, and hemodialysis (Ulmeanu et al, 1997).

B)

1) Nasal irritation has occurred in facilities where the mean water-soluble airborne hexavalent chromium concentrations were 0.068 mg/m(3). Airborne levels as low as 0.06 mg/m(3) of CHROMIUM TRIOXIDE (CrO3; CHROMIUM VI OXIDE) have also been shown to cause nasal irritation (ACGIH, 1991).
2) A concentration of 350 to 500 ppm of hexavalent chromium in soil should be sufficiently low to protect exposed persons from chromium-induced allergic contact dermatitis in chromate-sensitive individuals (Paustenbach et al, 1992).
3) Cancer risk attributed to hexavalent chromium in soil is estimated at no more that 1 in 1,000,000 at a concentration of 100 ppm (Paustenbach et al, 1992).

C)

1) CHROMIUM PIGMENTS: Ingestion of a paint containing insoluble chromite ore resulted in seizures in a 14-month-old child, with onset one week postingestion; no gastrointestinal or renal dysfunction was noted (Sander & Camp, 1939).
2) CHROMIC ACID: Ingestion of 5 and 15 g of chromic acid by adults has been survived (Pederson & Morch, 1978; (Fristedt et al, 1965).
3) POTASSIUM DICHROMATE

a) Signs and symptoms have occurred after ingestion of as little as 0.5 g of potassium dichromate (Partington, 1950).
b) Ingestion of about 16 g of potassium dichromate was survived by a 48-year-old man (Philipson, 1892).
c) An 18-year-old girl recovered after developing intravascular hemolysis and renal failure following ingestion of a few grams of potassium dichromate (Sharma et al, 1978).
d) ORAL: A 17-year-old girl developed nausea, vomiting, epigastric pain, diarrhea and renal tubular toxicity with normal glomerular filtration and creatinine clearance after ingesting 2 to 3 g of potassium dichromate (40 to 60 mg/kg body weight) in a suicide attempt. Esophagogastric endoscopy revealed a small ulceration in the gastric fundus. Following supportive care, she recovered and was transferred to a psychiatric ward after 48 hours (Hantson et al, 2005).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) In a nonfatal ingestion of approximately 50 mL of 10 percent sodium dichromate solution by a 24-month-old child, the following chromium levels were reported (Walpole et al, 1985).

DAY	SERUM mcg/L	URINE mcg/L	PERITONEAL DIALYSATE mcg/L
1	210	-	2
2	9	300	1
3	13	60	-
4	12	-	-
5	-	80	-
6	-	150	-
22	5	-	-
Ref Values	5	5-10	-

b) The following whole blood, plasma/serum, and urine chromium levels were reported after a 44-year-old male ingested an unknown amount of chromic acid. On presentation he was tachypneic, tachycardic, and had abdominal tenderness. His course was complicated by metabolic acidosis, hypotension, acute tubular necrosis, and renal failure treated with hemodialysis, anemia, and ulcerations of the esophagus, stomach, and duodenum. Although the patient was discharged 24 days after admission, he was found dead at home one month after ingestion (Saryan & Reedy, 1988).

DAYS POST-INGESTION	WHOLE BLOOD (mcg/dL)	PLASMA/SERUM (mcg/dL)	URINE (mcg/L)
1	-	96	-
3	-	-	5130
4	24	33	-
9	14	21	142

c) The erythrocyte chromium concentrations of a 35-year-old female, who ingested 50 mL of pure chromic acid (25 g hexavalent chromium), peaked at 1903 mcmol/L 3 hours after ingestion and declined to 865 mcmol/L 11 hours after ingestion (Loubieres et al, 1999).
d) The initial serum chromium concentration in a 16-year-old male, who ingested an unknown quantity of potassium dichromate, was approximately 2400 mcg/L (Stift et al, 2000).

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): A ; Listed as: Chromium(VI)

a) A : Human Carcinogen.

3) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Chromium(VI)

a) D : Not classifiable as to human carcinogenicity.

4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
5) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
6) MAK (DFG, 2002): Category 2 ; Listed as: Chromium(VI) compounds (as dusts/aerosols), with the exception of those practically insoluble in water such as lead chromate, barium chromate (but zinc chromate Section III Category 1)

a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.

7) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Listed as: Chromium (VI) compounds; see 1910.1026
2) Table Z-1 for Chromium (VI) compounds; see 1910.1026:

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3:

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s):

a) \5\: See Table Z-2 for the exposure limits for any operations or sectors where the exposure limits in section 1910.1026 are stayed or otherwise not in effect.

Pharmacology Toxicology

Pharmacologic Mechanism

A)

B)

1) Soluble hexavalent chromium compounds are taken up into the cells by simple diffusion through the plasma membrane and the sulfate transport system. Rapid eduction to the trivalent form then occurs with the action of enzymatically mobilized electrons (from reduced glutathione and reduced nicotinamide adenine dinucleotide) (HSDB , 2000; IRIS , 2000). The action of diaphorase in the cytoplasm also reduces hexavalent chromium (Clayton & Clayton, 1994).

a) In vitro studies showed that the reduction of 1 hexavalent chromium molecule requires 3 glutathione molecules. The reduction rate is faster at pH values of 5 or less or when glutathione was present in excess of 100 to 1000 fold (similar to conditions in the liver and red blood cells) (HSDB , 2000).
b) Experimental data showed that reduction of hexavalent chromium within liver microsomes was found to be via reduced nicotinamide adenine dinucleotide. Glutathione played a minor role (HSDB , 2000).
c) The intracellular reduction of hexavalent chromium generates reactive intermediates such as chromium (5+), chromium (4+), hydroxyl free radicals, and singlet oxygen (IRIS , 2000).

2) If the amount of hexavalent chromium exceeds the reduction capacity of the cell, excess hexavalent chromium is then diffused out of the cells and into the bloodstream (HSDB , 2000).
3) The detoxification of hexavalent chromium compounds occurs in the saliva, red blood cells, epithelial lining fluid, liver cells, and pulmonary alveolar macrophages (Clayton & Clayton, 1994). However, in the red blood cells, hexavalent chromium can also form a stable complex with hemoglobin (HSDB , 2000).
4) At 1.56 ppm, hexavalent chromium completely inhibited (within 2 to 3 minutes) the respiration of glutamate and alpha-oxoglutarate in vitro. At 21 ppm, hexavalent chromium completely inhibited respiration of beta-hydroxybutyrate, malate, and pyruvate in vitro (HSDB , 2000).

Toxicologic Mechanism

A)

1) Hexavalent chromium is reduced to trivalent form within the skin by methionine, cystine, and cysteine. Within the skin, trivalent chromium is cleared at a slow rate and can combine with proteins or other skin components to form whole skin allergens (HSDB , 2000).

B)

1) Hexavalent chromium poisoning of the kidneys can lead to a decrease of ascorbic acid content. Such decrease may reduce the oxidative protection to the tissue and increase the susceptibility to toxicity (HSDB , 2000).

Physicochemical

Ph

A)

Molecular Weight

A)

Animal Toxicology

Clinical Effects

11.1.2)

A) Toxicosis consistent with arsenic and chromium poisoning occurred in a herd of cows that were observed licking wood ashes after CCA (copper, chromium, and arsenic) treated wood was burned. Signs of the toxicosis were depression, ataxia, weakness, recumbency, green, watery diarrhea, and death in 4 cows (Thatcher et al, 1985).

References

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CHROMIUM HEXAVALENT SALTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Pharmacologic Mechanism

Toxicologic Mechanism

Ph

Molecular Weight

Clinical Effects

General Bibliography