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NICKEL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) A metallic element, nickel has the atomic number 28 and is a member of group VIII of the periodic table. The element has 5 stable isotopes and oxidation states of 0, +1, +2, +3, and +4.

Specific Substances

    1) ALCAN 756
    2) ALNICO
    3) EL 12
    4) FIBREX
    5) FIBREX P
    6) N1
    7) NI 0901-S
    8) NI 0901-S (HARSHAW)
    9) NI 233
    10) NI 270
    11) NI-4303T
    12) NICHEL (Italian)
    13) NICKEL
    14) NICKEL 200
    15) NICKEL 201
    16) NICKEL 205
    17) NICKEL 207
    18) NICKEL 270
    19) NICKEL 279
    20) NICKEL COMPOUNDS
    21) NICKEL (DUST)
    22) NICKEL ELEMENT
    23) NICKEL, METAL
    24) NICKEL PARTICLES
    25) NICKEL SPONGE
    26) NP-2
    27) PULVERIZED NICKEL
    28) RANEY ALLOY
    29) RANEY NICKEL
    30) RCH 55/5
    31) NICKEL AND COMPOUNDS
    1.2.1) MOLECULAR FORMULA
    1) Ni

Available Forms Sources

    A) FORMS
    1) Nickel is available as pellets, squares, rondelles, powder, electrolytic, ingot, shot, sponge, high-purity strip, and single crystals (Ashford, 1994; (HSDB , 2002; Lewis, 1997).
    B) SOURCES
    1) Occurring naturally as the sulfide and silicate, nickel is typically present in soil at concentrations of 5.0-1000 ppm and, occasionally, at extremes of 0.8-6200 ppm; it occurs naturally in groundwater at less than 10 to 50 ppm (Dragun, 1988; Lewis, 1998).
    2) A metallic element, nickel has the atomic number 28 and is a member of group VIII of the periodic table. The element has five stable isotopes and oxidation states of 0, +1, +2, +3, and +4 (ACGIH, 1991) (Harbison, 1998) (Lewis, 1997).
    3) Nickel carbonyl is formed by a reaction with carbon monoxide (See NICKEL CARBONYL).
    4) Nickel can be prepared by the following processes: the pyrometallurgical reduction of nickel oxide with metallurgical coke; the electric furnace reduction/electrolysis of nickel oxide, green with metallurgical coke; the reduction/carbonyl gas refining process of nickel oxide, green with hydrogen; the pressure leaching/solvent extraction/electrolysis or lateritic ore (coproduced with cobalt); the pressure leaching/reduction of nickel-copper matte/nickel matte with hydrogen (coproduced with cobalt) (Ashford, 1994).
    5) SOURCES OF EXPOSURE
    a) Occupations that frequently involve exposure to nickel include: ink production, spark plug manufacturing, ceramics, jewelers, rubber formation, electroplating, storage batteries, coin manufacture, auto or airplane parts, manufacture of stainless steel cooking utensils, and electrical parts manufacturers.
    b) There are multiple uses for nickel that may increase the risk of exposure to the general population:
    1) AIRBORNE NICKEL: Nickel containing dust was reported to cause dermatitis in an individual in a textile industry and a metal research laboratory (Kanerva et al, 1999; Schubert, 2000).
    2) CELLULAR PHONES: Contact dermatitis has been reported following exposure to cellular phones that contain nickel sulfate 5% (Pazzaglia et al, 2000).
    3) ELECTRONIC CIGARETTES: Nickel contact allergy was reported with the use of an electronic cigarette in an adult with a history of contact allergy; a dimethylglyoxime spot test was positive. Of 11 electronic cigarette models, three were positive for lead (Maridet et al, 2015).
    4) MUSICAL INSTRUMENT(S): A positive nickel allergy occurred in an adult who played the trumpet (2.5% nickel) (Nakamura et al, 1999).
    5) EYE WEAR: Contact dermatitis has been reported following exposure to metal-framed eye glasses (Danese & Bertazzoni, 1995).
    6) GARMENT: An adult developed contact dermatitis following exposure to a neoprene wet suit that contained nickel (probably used in the dyeing process) (Corazza & Virgili, 1998).
    7) ORTHODONTIC/DENTAL APPLIANCES: Nickel-titanium wires have produced atopic dermatitis in a child wearing braces (De Silva & Doherty, 2000), and in adult following titanium dental implants (Fernandez-Redondo et al, 1998).
    8) SURGICAL APPLIANCES/SKIN CLIPS: Cell-mediated hypersensitivity has been reported following the use of titanium clips (internal and external) containing nickel; titanium and titanium alloy may be used in many restorative surgeries, in various dental implants and in heart valves (Ross et al, 1998; Ashford, 1951).
    C) USES
    1) It is used as a catalyst in the petroleum, plastic, and rubber industries. Nickel is also combined with other metals to form products that may be commonly worn or found in the home. Other products have included jewelry, surgical and dental appliances, eye wear, cellular phones, and musical instruments (Danese & Bertazzoni, 1995; Ross et al, 1998; Fernandez-Redondo et al, 1998; Ashford, 1951) (Corrazza & Virgili, 1998) (Barrazza & Ollivaud, 1999) (Kanerva et al, 1999; Pazzaglia et al, 2000; De Silva & Doherty, 2000; Schubert, 2000).
    2) Nickel is used in various corrosion-resistant alloys; alloys (most commonly with iron, copper, zinc, or chromium); electroplated and electroformed coatings; alkaline storage batteries; nickel-cadium batteries; fuel cell electrodes; as a catalyst for some methanation and hydrogenation reactions; coins, machinery parts; magnets; surgical and dental prostheses; in cooling towers as anodic inhibitors (Ashford, 1951; ACGIH, 1991; Hathaway et al, 1996; HSDB , 2002; Lewis, 1997).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nickel is used as a catalyst in the petroleum, plastic and rubber industries. Nickel is also combined with other metals to form products that may be commonly worn or found in the home. Nickel is used in various corrosion-resistant alloys; alloys (most commonly with iron, copper, zinc, or chromium). It occurs naturally in soil and fresh and saltwater. Nickel carbonyl is a highly toxic nickel compound commonly used as a chemical reagent and is covered in another management (See NICKEL CARBONYL).
    B) TOXICOLOGY: Water-soluble nickel compounds do not readily enter cells; whereas, water-insoluble nickel compounds enter cells through phagocytosis and are carcinogenic. Carcinogenicity may be related to DNA protein binding, oxidation, and DNA-protein cross-linking by nickel.
    C) EPIDEMIOLOGY: Exposure to nickel is common. Severe toxicity to forms other than nickel carbonyl is uncommon. Contact dermatitis or hypersensitivity, possibly severe, occurs in sensitized individuals (2% to 5% of the general population). Nickel is the most common cause of allergic contact sensitization.
    D) WITH POISONING/EXPOSURE
    1) TOXIC EXPOSURE: Adverse effects can result from ingestion, skin contact, inhalation or parenteral routes of exposure; nickel may be absorbed from the gastrointestinal and respiratory tracts as well as percutaneously.
    2) INHALATION: Inhalation of nickel alloys or dust has been linked to pulmonary irritation, asthma, pneumoconiosis, pulmonary fibrosis and pulmonary edema. Early symptoms after inhalation are dizziness, sore throat, hoarseness, and weakness. Gingivitis, stomatitis, metallic taste, nasal irritation, nasal mucosal damage, nasal septum perforation, hyposmia/anosmia, cough and shortness of breath are sometimes reported. Exposure to nickel fumes may result in "metal fume fever."
    3) INGESTION: Oral toxicity of elemental nickel is low. Large doses taken orally may cause nausea, vomiting and diarrhea. Elemental nickel is present in some foods and water, but dietary exposures are generally not significant.
    4) DERMAL: "Nickel itch" may begin with a burning and itching sensation, followed by erythema and nodular eruptions. Once acquired, nickel sensitivity usually persists. Nickel and its inorganic compounds can be absorbed through the skin but not in amounts sufficient to cause intoxication.
    5) PARENTERAL: Parenteral exposures may occur from implanted metal prostheses, stainless steel needles or contaminated dialysate solutions. Inflammatory reactions have occurred around nickel-containing prostheses and medical implants. Nickel intoxication from dialysis exposure includes nausea, vomiting, headache, weakness and palpitations.
    6) CARCINOGENICITY: Some work environments (ie, nickel refinery work) and forms of nickel are associated with human malignancies, mainly nasal and respiratory cancers.
    0.2.4) HEENT
    A) Acute toxicity from nickel inhalation includes sore throat and hoarseness.
    B) There is speculation that conjunctivitis and epiphora have occurred in nickel plating work environments due to poor ventilation.
    C) Occasional exposure to nickel aerosol and other contaminants has caused nasal irritation, loss of sense of smell, damage to the nasal mucosa, and perforation of the nasal septum.
    D) In rare cases, nickel workers have complained of a bitter metallic taste.
    0.2.8) GASTROINTESTINAL
    A) Large doses taken orally or by inhalation may cause nausea, vomiting, and diarrhea.
    0.2.9) HEPATIC
    A) Hyperbilirubinemia and elevated SGPT have been reported.
    0.2.10) GENITOURINARY
    A) Changes found in the kidneys of one case included vacuolization of the proximal convoluted tubules, but no tubular necrosis.
    0.2.14) DERMATOLOGIC
    A) Contact dermatitis is the most common reaction to nickel. It is estimated that 5% of all eczemas are nickel reactions. "Nickel itch" may begin with a burning and itching sensation, followed by erythema and nodular eruptions. Once acquired, nickel sensitivity usually persists.
    B) Nickel and its inorganic compounds can be absorbed through the skin but not in amounts sufficient to cause intoxication.
    0.2.19) IMMUNOLOGIC
    A) Nickel is a sensitizer.
    0.2.20) REPRODUCTIVE
    A) Nickel salts are reported to be animal teratogens. Increased incidence of stillbirth and neonatal mortality of rat offspring were associated with maternal consumption of nickel chloride solutions prior to mating and during gestation. Nickel has been found in breast milk. Oral administration of nickel sulfate to rats caused decreased testicular, prostate, and seminal vesicle size as well as abnormalities of sperm and decreased sperm count.
    0.2.21) CARCINOGENICITY
    A) Nickel and many nickel compounds are considered human carcinogens or probable human carcinogens.
    B) ACGIH rates nickel as an A5, not suspected as a human carcinogen.
    C) Nickel-induced respiratory cancer has a latency period. Lung cancer may develop 13 to 14 years from the time of the first employment exposure. Nasal cancer may occur 15 or more years later.
    D) Roasting nickel subsulfide is associated with an increased risk for respiratory cancer.

Laboratory Monitoring

    A) Routine laboratory studies are not needed unless otherwise clinically indicated. Monitor serum electrolytes in a patient with severe vomiting. Obtain a chest radiograph in patients with cough, shortness of breath or hypoxia.
    B) Urine nickel concentrations can be useful for monitoring workplace exposures but not for guiding treatment.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) DERMATITIS: Topical steroids, oral antihistamines as needed as well as removal from the source of exposure are the mainstays of treatment. VOMITING/DIARRHEA: Fluid replacement with an IV in cases of significant vomiting and diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) HYPOXIA: Administer supplemental oxygen. Use bronchodilators and corticosteroids as needed for bronchospasm.
    C) DECONTAMINATION
    1) PREHOSPITAL: OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobias persist after 15 minutes of irrigation, an ophthalmologic examination should be performed at the hospital. INHALATION: Move the patient to fresh air. DERMAL: Decontamination is not likely to be helpful in cases of nickel dermatitis. INGESTION: GI decontamination is generally not necessary as the oral toxicity of elemental nickel is low.
    2) HOSPITAL: OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobias persist after 15 minutes of irrigation, an ophthalmologic examination should be performed. INGESTION: GI decontamination is generally not necessary as the oral toxicity of elemental nickel is low.
    D) ANTIDOTE
    1) None.
    E) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary. Endotracheal intubation should be performed in patients with severe hypoxia and inability to protect their own airway.
    F) ENHANCED ELIMINATION
    1) At the time of review, there are no effective methods of enhanced elimination for this agent.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent exposures, and those with mild dermatitis, can be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic patients and any patient with a self-harm attempt should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Admission is rarely necessary. All patients who have persistent significant symptoms should be admitted for observation until clinical symptoms have resolved.
    4) CONSULT CRITERIA: Consult a medical toxicologist for assistance with medical management. An industrial hygienists and occupational physician may be helpful in evaluating workplace exposures.
    H) TOXICOKINETICS
    1) Approximately 35% of inhaled nickel is absorbed into the blood from the respiratory tract in humans. After inhalation, high nickel concentrations are distribute to the lungs, kidney, skin and erratically into the blood. It is also found in brain, stomach and intestinal tissue. Parenterally administered nickel is 90% excreted in the urine. Elimination half-life through the urine is 17 to 39 hours. More than 90% of ingested nickel is excreted unabsorbed in the feces.
    I) DIFFERENTIAL DIAGNOSIS
    1) Exposure to other allergens, other causes of pulmonary edema, pulmonary irritation and GI distress.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Disulfiram (Antabuse(R)) is metabolized to 2 molecules of diethyldithiocarbamate (DDC). It has been shown effective in clearing cases of nickel dermatitis. 50 to 100 mg/day were used in the treatment. Many other topical and oral drugs are being investigated.

Range Of Toxicity

    A) TOXIC DOSE: Oral toxicity is low and unusual. A healthy individual has nickel concentrations in the plasma ranging from 1.4 to 3.4 mcg/L (average 2.1 mcg/L). Whole blood concentrations are usually twice the level of plasma or serum.
    B) NORMAL CONCENTRATION: A normal serum nickel concentration in humans is approximately 0.11 mcg/mL.
    C) MAXIMUM TOLERATED DOSE: It has been recommended that a plasma level of 10 mcg/L be set as a biomonitoring limit for nickel refinery workers.

Clinical Effects

Cardiovascular

    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CARDIOMYOPATHY
    a) Animal studies have reported coronary artery resistance, decreased myocardial contractility and ultrastructural myocardial damage at plasma levels of 60 mcg/L (Sunderman, 1983).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) TOXIC INHALATION INJURY
    1) WITH POISONING/EXPOSURE
    a) INGESTION may result in COUGH and DYSPNEA:
    1) Workers who accidentally drank water contaminated with 1.63 grams of nickel salts per liter developed cough and shortness of breath (Sunderman et al, 1988).
    b) DERMAL EXPOSURE may result in bronchospasm.
    1) ASTHMA has been reported from dermal exposure to nickel sulfide (Clayton & Clayton, 1994; McConnell et al, 1973).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-year-old welder developed a cough shortly after he inadvertently inhaled nickel fumes when he neglected to wear personal protective equipment at work. He presented to the hospital 4 days postexposure reporting fever, fatigue, a persistent dry cough, and shortness of breath. Symptoms had progressed to the point that he had difficulty standing up from a seated position. Upon examination his temperature was 38.3 degrees C, respiratory rate 32 breaths/minute, heart rate 102 beats/minute, blood pressure 143/82 mmHg, and O2 saturation of 92%. Chest X-ray showed reticular opacities to mid and lower lung fields and chest CT showed bilateral nonsegmental ground-glass opacities. Laboratory testing revealed leukocytosis and elevated C-reactive protein (16.47 mg/dL), LDH (315 international units/L), and surfactant protein A (SP-A) (89.9 ng/mL). Hypoxemia was confirmed by ABG analysis. Further testing based on cell counts from bronchoalveolar lavage and transbronchial lung biopsy led to a diagnosis of pneumonitis (acute lung injury) induced by inhalation of nickel fumes. He was admitted and treated with corticosteroids, which were tapered over 1 month. His symptoms and chest CT findings improved (Kunimasa et al, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) INGESTION may result in headache and lassitude (Clayton & Clayton, 1994).
    1) Workers who accidentally drank water contaminated with nickel sulfate and nickel chloride (1.63 g nickel/L) developed lassitude, headache, and giddiness (Sunderman et al, 1988).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 43-year-old man was admitted to the hospital after having a first generalized tonic-clonic seizure. There was no known family history of epilepsy. Physical and neurologic examinations were normal with the exception of mild drowsiness attributed to a postictal state. A diagnosis of first idiopathic generalized seizure was made until information concerning a coworker was obtained. He had been working in the same shop and had been admitted 1 week earlier for respiratory distress, coma, and de novo nonconvulsant focal status epilepticus.
    1) A toxicologic etiology was then suspected. On day 2, a urine analysis revealed a high nickel concentration (18.7 mcg/g) suggestive of acute nickel poisoning. The patient recovered uneventfully, was discharged on day 4, and was seizure-free without any treatment 6 months later (Denays et al, 2005).

Gastrointestinal

    3.8.1) SUMMARY
    A) Large doses taken orally or by inhalation may cause nausea, vomiting, and diarrhea.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) INGESTION: Large oral doses of nickel salts can cause nausea, vomiting, abdominal pain and diarrhea (Clayton & Clayton, 1994; Lewis, 1998; Sunderman et al, 1988).
    b) INHALATION: Inhalation may also cause nausea and vomiting that, in phase 2, may increase in severity to produce abdominal pain.

Hepatic

    3.9.1) SUMMARY
    A) Hyperbilirubinemia and elevated SGPT have been reported.
    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Transient hyperbilirubinemia occurred in 2 of 32 workers exposed to nickel contaminated drinking water (Sunderman et al, 1988).

Genitourinary

    3.10.1) SUMMARY
    A) Changes found in the kidneys of one case included vacuolization of the proximal convoluted tubules, but no tubular necrosis.
    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One report describes a patient with documented IgA nephropathy associated with placement of nickel alloy-based dental crowns. Microscopic hematuria, proteinuria, and hypertension worsened parallel to increased nickel placement over an 8 year period. Microscopic hematuria cleared shortly after removal of the nickel crown whereas proteinuria took 14 months to resolve (Strauss & Eggleston, 1985).
    B) RENAL TUBULAR DISORDER
    1) WITH POISONING/EXPOSURE
    a) Significantly elevated urinary lysozyme and N-acetyl-beta-D-glucosaminidase (NAG) activities in exposed males, and significantly elevated urinary total proteins, beta(2)microglobulin, retinol-binding protein, and NAG in exposed females have been reported (Vyskocil et al, 1994). The workers were exposed to airborne soluble nickel compounds at 4 to 26 times the threshold limit value. Females had greater exposure to the nickel compounds than males.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-year-old welder developed leukocytosis (12,000 cells /mcL) after he inadvertently inhaled nickel fumes when he neglected to wear personal protective equipment at work. He presented to the hospital 4 days postexposure reporting fever, fatigue, a persistent dry cough, and shortness of breath. He was admitted and treated with corticosteroids, which were tapered over 1 month. His symptoms improved (Kunimasa et al, 2011).
    B) ERYTHROCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) Reticulocytosis and erythrocytosis were reported in workers exposed to nickel contaminated water (Sunderman et al, 1988).

Summary Of Exposure

    A) USES: Nickel is used as a catalyst in the petroleum, plastic and rubber industries. Nickel is also combined with other metals to form products that may be commonly worn or found in the home. Nickel is used in various corrosion-resistant alloys; alloys (most commonly with iron, copper, zinc, or chromium). It occurs naturally in soil and fresh and saltwater. Nickel carbonyl is a highly toxic nickel compound commonly used as a chemical reagent and is covered in another management (See NICKEL CARBONYL).
    B) TOXICOLOGY: Water-soluble nickel compounds do not readily enter cells; whereas, water-insoluble nickel compounds enter cells through phagocytosis and are carcinogenic. Carcinogenicity may be related to DNA protein binding, oxidation, and DNA-protein cross-linking by nickel.
    C) EPIDEMIOLOGY: Exposure to nickel is common. Severe toxicity to forms other than nickel carbonyl is uncommon. Contact dermatitis or hypersensitivity, possibly severe, occurs in sensitized individuals (2% to 5% of the general population). Nickel is the most common cause of allergic contact sensitization.
    D) WITH POISONING/EXPOSURE
    1) TOXIC EXPOSURE: Adverse effects can result from ingestion, skin contact, inhalation or parenteral routes of exposure; nickel may be absorbed from the gastrointestinal and respiratory tracts as well as percutaneously.
    2) INHALATION: Inhalation of nickel alloys or dust has been linked to pulmonary irritation, asthma, pneumoconiosis, pulmonary fibrosis and pulmonary edema. Early symptoms after inhalation are dizziness, sore throat, hoarseness, and weakness. Gingivitis, stomatitis, metallic taste, nasal irritation, nasal mucosal damage, nasal septum perforation, hyposmia/anosmia, cough and shortness of breath are sometimes reported. Exposure to nickel fumes may result in "metal fume fever."
    3) INGESTION: Oral toxicity of elemental nickel is low. Large doses taken orally may cause nausea, vomiting and diarrhea. Elemental nickel is present in some foods and water, but dietary exposures are generally not significant.
    4) DERMAL: "Nickel itch" may begin with a burning and itching sensation, followed by erythema and nodular eruptions. Once acquired, nickel sensitivity usually persists. Nickel and its inorganic compounds can be absorbed through the skin but not in amounts sufficient to cause intoxication.
    5) PARENTERAL: Parenteral exposures may occur from implanted metal prostheses, stainless steel needles or contaminated dialysate solutions. Inflammatory reactions have occurred around nickel-containing prostheses and medical implants. Nickel intoxication from dialysis exposure includes nausea, vomiting, headache, weakness and palpitations.
    6) CARCINOGENICITY: Some work environments (ie, nickel refinery work) and forms of nickel are associated with human malignancies, mainly nasal and respiratory cancers.

Heent

    3.4.1) SUMMARY
    A) Acute toxicity from nickel inhalation includes sore throat and hoarseness.
    B) There is speculation that conjunctivitis and epiphora have occurred in nickel plating work environments due to poor ventilation.
    C) Occasional exposure to nickel aerosol and other contaminants has caused nasal irritation, loss of sense of smell, damage to the nasal mucosa, and perforation of the nasal septum.
    D) In rare cases, nickel workers have complained of a bitter metallic taste.
    3.4.3) EYES
    A) There is speculation conjunctivitis and epiphora have occurred in nickel plating work environments due to poor ventilation (Grant, 1993).
    3.4.5) NOSE
    A) Nickel workers may develop nasal carcinomas and nasal epithelial dysplasia (Hathaway et al, 1996; Torjussen et al, 1979).
    B) Occasional exposure to nickel aerosol and other contaminants has resulted in nasal irritation, loss of smell, damage to the nasal mucosa, and perforation of the nasal septum (Hathaway et al, 1996).
    3.4.6) THROAT
    A) HOARSENESS: Sore throat and hoarseness may develop following inhalation (Sunderman et al, 1988).
    B) In rare cases, nickel workers have complained of a bitter metallic taste (Raffle, 1994).

Dermatologic

    3.14.1) SUMMARY
    A) Contact dermatitis is the most common reaction to nickel. It is estimated that 5% of all eczemas are nickel reactions. "Nickel itch" may begin with a burning and itching sensation, followed by erythema and nodular eruptions. Once acquired, nickel sensitivity usually persists.
    B) Nickel and its inorganic compounds can be absorbed through the skin but not in amounts sufficient to cause intoxication.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: Nickel contact dermatitis is the most common reaction to nickel. It is estimated that 5% of all eczemas are nickel reactions (HSDB , 2000).
    b) CAUSES: These dermal reactions may occur to a number of nickel-containing objects encountered externally or internally (Lacroix et al, 1979; Trombelli et al, 1992). Nickel may be the most common sensitizer in women due to exposure to coins, watches, kitchen appliances, and jewelry containing nickel (Clayton & Clayton, 1994; Krushell & Burnett, 1990). Suspected sensitization to nickel- and chromium-containing cosmetics has also been reported (Zemba et al, 1992).
    1) Contact dermatitis has been reported in individuals following contact with the following: surgical (e.g., surgical clips internal and external) and dental prosthesis (including orthodontic hardware (wires) and titanium dental implants, bridges), household items (cellular phones), airborne exposure (textile industry), specialized clothing (neoprene wet suit), glasses with metal frames, and musical instruments (Danese & Bertazzoni, 1995) (Ross et al, 1998) (Fernandez-Redondo et al, 1998; Ashford, 1951; Corazza & Virgili, 1998; Kanerva et al, 1999; Pazzaglia et al, 2000; De Silva & Doherty, 2000; Schubert, 2000).
    2) Contact dermatitis attributable to nickel has been reported for people in the following occupations: hairdressers, bar staff, chefs and cooks, retail cash and checkout operators, and catering assistants (Shum et al, 2003).
    3) ORTHODONTIC APPLIANCES/PREVALENCE: Nickel hypersensitivity has been estimated to be as high as 30% in adolescents (particularly females) wearing orthodontic appliances (Lindsten & Kurol, 1997). The author concluded that nickel release from these appliances did NOT seem to alter blood levels of nickel.
    4) Some studies have reported that oral challenge with nickel preparations (Anon, 1989; Anon, 1989a; Antico & Soana, 1999), or swallowing of nickel coins (Ewing & Miller, 1991) has caused or exacerbated dermal reactions.
    5) The results of patch tests, leaching experiments, and the dimethylglyoxime (DMG) spot tests and electrochemical experiments to identify nickel and cation release from specific grades of stainless steel, nickel and nickel-plated materials were reported (Haudrechy et al, 1994).
    c) DIAGNOSIS: A wide variety of patch tests and immunologic assays have been utilized to diagnose nickel dermatitis. Leukocyte migration assay systems have been reviewed (Hallab et al, 2000).
    d) PRESENTATION: "Nickel itch" may begin with a burning sensation and localized itching on the hand, then erythema, papules, and nodular eruptions on the web of the fingers, wrists and forearm. The nodules may become pustules or may ulcerate (Hathaway et al, 1996) (Harbison, 1998).
    1) Nickel dermatitis probably consists of a simple dermatitis localized to the area of contact, and chronic eczema or neurodermatitis without apparent regard for contact (Clayton & Clayton, 1994). Recovery usually occurs after a week but may be delayed for several weeks. The chronic stage is characterized by a papular or papulovesicular dermatitis and possibly lichenification.
    2) Once acquired, nickel sensitivity usually persists (Hathaway et al, 1996; Wubs & Spruit, 1979) and may aggravate atopic dermatitis (Ho & Johnston, 1986).
    3) Nickel and its inorganic compounds can be absorbed through the skin but not in amounts sufficient enough to cause intoxication.

Endocrine

    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERGLYCEMIA
    a) RABBITS: Oral nickel chloride has produced prolonged hyperglycemia in rabbits given a galactose load.

Immunologic

    3.19.1) SUMMARY
    A) Nickel is a sensitizer.
    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH POISONING/EXPOSURE
    a) Nickel is a sensitizer (Haudrechy et al, 1994), which generally produces dermal responses but can also occasionally cause asthma (Ashford, 1951; Clayton & Clayton, 1994; McConnell et al, 1973).
    B) CELLULAR IMMUNE DEFECT
    1) WITH POISONING/EXPOSURE
    a) Nickel salts suppressed natural killer cell cytotoxicity of cultured human peripheral blood mononuclear cells and nickel sulfate decreased the natural killer cell (CD56) population of cultured lymphocytes (Zeromski et al, 1995). Similar results have been noted in rat broncho-alveolar lavage cells following in-vivo instillation of nickel sulfate into the lung (Goutet et al, 2000).
    C) IMMUNOSUPPRESSION
    1) WITH POISONING/EXPOSURE
    a) A study in rats demonstrated that nickel chloride suppresses T-cell function and promotes an immunosuppressive macrophage phenotype. Results of this study also suggest that a large quantity of nickel needs to reach the systemic circulation before adverse effects on immune function are observed (Harkin et al, 2003).
    D) LACK OF EFFECT
    1) WITH POISONING/EXPOSURE
    a) CELL VIABILITY: Nickel salts did not significantly affect the viability of human peripheral blood mononuclear cells exposed in vitro (Zeromski et al, 1995).

Reproductive

    3.20.1) SUMMARY
    A) Nickel salts are reported to be animal teratogens. Increased incidence of stillbirth and neonatal mortality of rat offspring were associated with maternal consumption of nickel chloride solutions prior to mating and during gestation. Nickel has been found in breast milk. Oral administration of nickel sulfate to rats caused decreased testicular, prostate, and seminal vesicle size as well as abnormalities of sperm and decreased sperm count.
    3.20.2) TERATOGENICITY
    A) HUMANS
    1) In a Russian study of female workers at a nickel hydrometallurgy refining plant, there was a statistically significant increased risk of 2.9, 6.1 and 1.9 for total birth defects, cardiovascular defects and musculoskeletal defects, respectively when compared to local construction workers. There was also an increase in spontaneous abortions with 16% in nickel workers compared to 9% in the general construction worker population (Chashchin, 1994).
    B) ANIMAL STUDIES
    1) Nickel salts are reported to be animal teratogens (Schardein, 1993).
    2) Nickel carbonyl, the most toxic nickel salt (See NICKEL CARBONYL), and nickel acetate each were shown to induce multiple malformations and death in a small sample of hamster embryos. Nickel chloride produced skeletal defects in mice and fetal death in rats (Schardein, 1993).
    3) Nickel chloride was not teratogenic in chickens (Ridgway & Karnofsky, 1952) or rats (Sunderman, 1977), but did cause birth defects when injected in mice (Lu, 1979). Nickel in the drinking water at 5 ppm produced runts in rats (Schroeder & Mitchener, 1971). It was embryotoxic in another study (Nadeenko, 1979).
    4) Nickel salts are reported to be animal teratogens (Schardein, 2000). Nickel acetate caused multiple malformations and death in hamster embryos and birth defects in sheep (Ferm, 1972). Nickel chloride produced skeletal defects in mice and fetal death in rats (Schardein, 2000). Nickel subsulfide was not teratogenic in rats (Sunderman, 1978). Nickel sulfate caused degeneration of sperm when injected into experimental animals (Hoey, 1966) and affected fertility in rats (Friberg et al, 1986). Ni(+2), in the form of nickel chloride, induced eye abnormalities in the frog, Xenopus laevis (Hauptman et al, 1993).
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) PLACENTAL BARRIER
    a) Nickel can cross the placental barrier. Nickel has been present in the lung, liver, kidney and intestine of most stillborn infants examined (HSDB , 2001; Clayton & Clayton, 1994).
    B) ANIMAL STUDIES
    1) Consumption of nickel chloride solutions prior to mating and during gestation did not affect the litter size of female rats (Smith et al, 1993).
    2) Increased incidence of stillbirth and neonatal mortality of rat offspring were associated with maternal consumption of nickel chloride solutions prior to mating and during gestation (Smith et al, 1993). Maternal weight gain during pregnancy was suppressed.
    3) Animal studies have shown nickel exposures could adversely affect the fetal maturation, reproduction, and development process (Clayton & Clayton, 1994; Hathaway et al, 1996); however, WHO 1991 and ATSDR 1993 do not report any findings to support these observations (Clayton & Clayton, 1994).
    4) In experimental animals, exposure during pregnancy has been associated with delayed embryonic development, increased resorptions, and increases in structural malformations (Hathaway et al, 1996).
    5) In a study using nickel chloride, pregnant rats fed 3 mg/kg by gavage for 8 days, revealed during days 7 through 14 of organogenesis that the direct cytotoxic effect of nickel (embryo-damaging effect of nickel crossing the placenta) may be possible for the teratogenicity of nickel rather than assumed effects of nickel on maternal and placental circulation (Szakmary, 1995).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) HUMANS
    1) BREAST MILK
    a) Nickel has been found in breast milk.
    B) ANIMAL STUDIES
    1) Nickel has been measured in the milk of lactating rats and in the nursing offspring following subcutaneous injection of nickel chloride into the dams (Dostal et al, 1989). The composition of the milk from nickel treated dams was altered, with principal effects being increased milk solids and lipids, but decreased protein and lactose.
    2) Increased incidence of rat offspring mortality was associated with maternal consumption of nickel chloride solutions during lactation (Smith et al, 1993).
    3) Nickel has been found in breast milk. Nickel has been measured in the milk of lactating rats and in the nursing offspring following subcutaneous injection of nickel chloride into the dams (Dostal et al, 1989). The composition of the milk from nickel treated dams was altered, with principal effects being increased milk solids and lipids, but decreased protein and lactose. Increased incidence of rat offspring mortality was associated with maternal consumption of nickel chloride solutions during lactation (Smith et al, 1993).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Mating behavior of female rats was not affected by consumption of nickel chloride solutions for 11 weeks prior to breeding (Smith et al, 1993).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS7440-02-0 (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) IARC Classification
    a) Listed as: Nickel, metallic and alloys
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    3.21.2) SUMMARY/HUMAN
    A) Nickel and many nickel compounds are considered human carcinogens or probable human carcinogens.
    B) ACGIH rates nickel as an A5, not suspected as a human carcinogen.
    C) Nickel-induced respiratory cancer has a latency period. Lung cancer may develop 13 to 14 years from the time of the first employment exposure. Nasal cancer may occur 15 or more years later.
    D) Roasting nickel subsulfide is associated with an increased risk for respiratory cancer.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) Nickel and certain nickel compounds are labeled as carcinogens or as substances which may reasonably be anticipated to be carcinogens (ACGIH, 1994; (Clayton & Clayton, 1994; HSDB , 2000; US DHHS, 1994).
    2) ACGIH rates elemental nickel (CAS#:7440-02-0)as an A5, not suspected as a human carcinogen (ACGIH, 2001). ACGIH carcinogenicity ratings (ACGIH, 2001) for other nickel compounds vary by type: Soluble compounds (NOS) - A4: not classifiable as carcinogenic to humans; Insoluble compounds (NOS) - A1: confirmed human carcinogen; Nickel subsulfide (CAS#:12035-72-2) - A1: confirmed human carcinogen.
    3) One human study reported by Grandjean et al, concluded that nickel subsulfide and nickel refining operations are stronger carcinogens than other nickel compounds (ACGIH, 1991).
    B) CARCINOGENICITY
    1) According to the International Agency for Research on Cancer (IARC & 2001, 2001), there is inadequate evidence for the carcinogenicity of metallic nickel and nickel alloys in humans.
    2) SUBSTANCES include:
    a) METALLIC NICKEL AND NICKEL DUST, CAS 7440-02-0 (Howard & Neal, 1992): Two studies of workers with exposures exclusively to metallic nickel and nickel concentrate dust did not report excess respiratory cancer and demonstrated there was no apparent association between the exposure and respiratory cancer (Clayton & Clayton, 1994; IARC, 1987). Metallic nickel is classified in 2B, possibly carcinogenic to humans, based on inadequate evidence in humans and sufficient evidence in animals (IARC, 2000). Metallic nickel, nickel monoxides, nickel hydroxides, and crystalline nickel sulfides show sufficient evidence of carcinogenicity in experimental animals (IARC & 2001, 2001).
    b) NICKEL ALLOYS: There is inadequate evidence of carcinogenic effects of nickel alloys in humans (IARC, 2000). A large cohort study of more than 5000 workers found no association with nickel alloy production (Moulin et al, 2000). Nickel alloys, nickel antimonide, nickel arsenides, nickel carbonyl, nickelocene, nickel salts, nickel selenides, and nickel telluride show limited evidence of carcinogenicity in experimental animals (IARC & 2001, 2001).
    c) NICKEL REFINERY DUST: Sufficient evidence; human lung and nasal cancer; nickel refinery dust is a complex mixture of many nickel moieties (IRIS, 2001).
    d) NICKEL SUBSULFIDE (CAS 12035-72-2) Sufficient evidence; human lung and nasal cancer in workers exposed to refinery dust containing high nickel subsulfide concentrations (IRIS, 2001).
    e) NICKEL SULFATE AND NICKEL SALTS: Human evidence of carcinogenicity is sufficient ((IARC, 1997)).
    f) NICKEL TITANATE: nickel trioxide, amorphous nickel sulfide show inadequate evidence of carcinogenicity in experimental animals (IARC & 2001, 2001).
    C) PULMONARY CARCINOMA
    1) WORK PROCESSES: As reviewed by the National Toxicology Program, numerous studies of nickel refinery workers have reported excess rates of nasal and lung cancer, and possible excessive cancer of the larynx. The most likely causative agents were nickel subsulfide, nickel sulfide and nickel oxide, with cancer linked principally to the early stages of nickel refining (ACGIH, 1991; US DHHS, 1994).
    a) Nickel roasting, smelting, electrolysis, plating and grinding have been associated with increased risk of respiratory cancer (IARC, 2000). The interaction between cigarette smoking and nickel exposure has found to be additive to cancer risk (rather than multiplicative) (Ashford, 1951).
    b) Nickel sinter plant work has been associated with increased mortality due to lung or nasal cancer (Muir et al, 1994; Roberts et al, 1989).
    c) There appears to be an inverse relationship between the solubility of the various nickel compounds and carcinogenicity (Hathaway et al, 1996). Cancers of the nasal sinuses and lungs have been known to occur in nickel refiners for more than 50 years (Bingham et al, 2001). The actual causative agent(s) of these cancers remains a matter of debate.
    2) The National Toxicology Program (NTP) classifies nickel and nickel compounds under its RAHC category (Reasonably Anticipated to be Human Carcinogens) (Bingham et al, 2001).
    3) Experimental neoplastigenic, tumorigenic, teratogenic, and carcinogenic data have been reported for nickel (Lewis, 2000).
    4) In a follow-up study from 1953 to 1993 of a group of nickel refinery workers with exposure going back to 1916, a 3-fold increased incidence of lung cancer was found in relation to exposure to soluble nickel. Smoking had a multiplicative effect with nickel exposure for producing lung cancer. There was also an 18-fold increased incidence of nasal cancer (Andersen et al, 1996).
    5) The original carcinogenicity studies were done in nickel refiners. A study of aircraft workers exposed to metallic nickel powder found no increased incidence of cancer (ACGIH, 1992). In Welsh nickel refiners who have been continuously studied, the incidence of respiratory cancers has diminished, but nasal sinus cancers have continued to be found with the same incidence (Peto, 1986).
    6) As reviewed by the National Toxicology Program, numerous studies of nickel refinery workers have reported excess rates of nasal and lung cancer, and possible excessive cancer of the larynx. The most likely causative agents were nickel subsulfide, nickel sulfide and nickel oxide, with cancer linked principally to the early stages of nickel refining (ACGIH, 1991; US DHHS, 1994).
    7) Nickel roasting, smelting, electrolysis, plating and grinding have been associated with excess incidence of respiratory cancer ((IARC, 1997)). The interaction between cigarette smoking and nickel exposure has found to be additive to cancer risk (rather than multiplicative) (Ashford, 1951).
    8) In a study of nickel sinter plant workers, the risk of dying from cancer of the nose or lung continued to be high for many years after cessation of exposure (Muir et al, 1994). The lung cancer risk with occupational exposure to nickel has been reviewed (Shen & Zhang, 1994).
    9) METALLIC NICKEL AND NICKEL DUST, CAS 7440-02-0 (Howard & Neal, 1992): Two studies of workers with exposures exclusively to metallic nickel and nickel concentrate dust did not report excess respiratory cancer and demonstrated there was no apparent association between the exposure and respiratory cancer (Bingham et al, 2001; (IARC, 1997)).
    10) Standard mortality ratios (SMR) for lung and nasal cancer were calculated for nickel refinery workers who were employed for a minimum of 5 years between 1930 and 1992. The SMR for lung cancer was 133 (95% CI 103 to 172) and for nasal cancer was 870 (95% CI 105 to 3141) (Grimsrud & Peto, 2006).
    D) PANCREATIC DISORDER
    1) A meta-analysis of multiple occupational exposures suggested that pancreatic cancer may be associated with exposure to nickel and nickel compounds (Ojajarvi et al, 2000).
    2) Increased mortality from stomach cancer was seen in a cohort of nickel platers who were exposed as long ago as 1945. No increased risk of lung cancer was found in this cohort, where exposure to chromium did not occur (Pang et al, 1996).
    E) IN VITRO STUDY
    1) This study found that insoluble nickel compounds, such as nickel chloride, produce Ni2+ ions in human hepatoma cell cultures. Ni2+ ions inhibit the acetylation histone H4. This hypoacetylation, through production of various reactive oxygen species, may be responsible for nickel's suppression of gene transcription (gene silencing) and carcinogenic effects. The authors hypothesize that use of antioxidants might be of benefit in humans occupationally exposed (Kang et al, 2003).
    3.21.4) ANIMAL STUDIES
    A) SARCOMA
    1) Powdered nickel injected intramuscularly in rats produced fibrosarcomas in 60 to 80% of the animals. When cadmium was injected in the opposite leg, 57% of the males and only 14% of the females developed tumors in the cadmium-exposed leg (Furst & Fan, 1993).
    B) NEOPLASM
    1) Of various nickel compounds tested in rats with chronic inhalation exposure, nickel subsulfide at airborne concentrations of 0.15 and 1 mg/m(3) and nickel oxide at 1.25 and 2.5 mg/m(3) were carcinogenic, producing alveolar/bronchiolar and adrenal medulla neoplasms. Nickel oxide was an equivocal carcinogenic agent in female mice. Nickel sulfate was not carcinogenic in either mice or rats, and nickel subsulfide was not carcinogenic in mice (Dunnick et al, 1995).
    2) Equimolar amounts of magnesium basic carbonate inhibited nickel-induced kidney tumor development in male rats, while metallic iron enhanced development of such tumors (Kasprzak et al, 1994).
    C) CARCINOMA
    1) Although magnesium has been shown to protect in vivo against nickel-induced carcinogenesis, the exact mechanism is unknown. In the divalent state, nickel and magnesium share many physicochemical properties (Conway et al, 1987). One possible explanation of the magnesium protective effect is simply competition between the cations for either the transport process or various intracellular target molecules (Hong et al, 1997).

Genotoxicity

    A) Some nickel compounds concentrate in the nuclei of animal cells. Nickel chloride did not cause DNA strand breaks or inhibit DNA repair in Chinese hamster ovarian cells by treatment with methyl methanesulfonate, but did inhibit DNA repair of cells exposed to UV light. DNA damage and evidence of DNA repair were observed in the leukocytes of Swiss albino mice after exposure to nickel chloride.
    B) Sister chromatid exchanges have been observed in human lymphocytes. Chromosomal aberrations in lymphocytes of some workers have also been reported. A larger number of chromosomal aberrations than expected have been identified in some study controls.
    C) Morphological transformation in animal cells have also been reported. Insoluble nickel compounds (nickel sulfide, nickel subsulfide, nickel oxides) produced mutations in G12 and G10 transgenic Chinese hamster cells. Some soluble nickel compounds were weakly mutagenic in AS52 cells.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Routine laboratory studies are not needed unless otherwise clinically indicated. Monitor serum electrolytes in a patient with severe vomiting. Obtain a chest radiograph in patients with cough, shortness of breath or hypoxia.
    B) Urine nickel concentrations can be useful for monitoring workplace exposures but not for guiding treatment.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Usual levels vary considerably in different populations but are in the range of 2.6 to 4.6 mcg/L (Committee on Medical and Biological Effects of Environmental Pollutants, 1975).
    2) A healthy individual has nickel concentrations in the plasma ranging from 1.4 to 3.4 mcg/L (averages 2.1 mcg/L) (Baselt, 2000).
    3) Whole blood concentrations are usually twice the level of plasma or serum (Baselt, 2000).
    4.1.3) URINE
    A) URINARY LEVELS
    1) A healthy individual has nickel concentrations in the urine ranging from 0.5 to 6.5 mcg/L (Harbison, 1998).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) In vitro lymphocyte transformation testing has been suggested for use in determining nickel sensitivity. Everness et al (1990) document an assay with a nickel sulfate concentration of 5 mcg/mL and a stimulation index (cells with stimulant cpm/cells alone cpm) of 3, indicating sensitivity.
    b) ATOPIC INDIVIDUALS may excrete larger amounts of urinary nickel from the same exposure than normal persons, perhaps because of increased absorption (Hindsen et al, 1994).
    c) Levels of nickel in lung tissue indicate inhalation exposure, but it is not clear if they predict increased cancer risk (Shen & Zhang, 1994).
    d) Patch testing has been used to diagnose nickel sensitivity, but even within a given individual, response over time appears to be variable (Hindsen et al, 1999).
    e) Sunderman (1993) summarizes considerations regarding biological monitoring of nickel exposures.

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Nickel can be detected in plasma using emission spectrophotometry or atomic absorption.
    2) Electrothermal atomic absorption spectrometry has been used effectively to monitor nickel concentrations in blood, fluids and tissue (Clayton & Clayton, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.5) DISPOSITION/DERMAL EXPOSURE
    6.3.5.1) ADMISSION CRITERIA/DERMAL
    A) Admission is rarely necessary. All patients who have persistent significant symptoms should be admitted for observation until clinical symptoms have resolved.
    6.3.5.2) HOME CRITERIA/DERMAL
    A) Asymptomatic patients with inadvertent exposures, and those with mild dermatitis, can be managed at home.
    6.3.5.3) CONSULT CRITERIA/DERMAL
    A) Consult a medical toxicologist for assistance with medical management. An industrial hygienists and occupational physician may be helpful in evaluating workplace exposures.
    6.3.5.5) OBSERVATION CRITERIA/DERMAL
    A) Symptomatic patients and any patient with a self-harm attempt should be referred to a healthcare facility.

Monitoring

    A) Routine laboratory studies are not needed unless otherwise clinically indicated. Monitor serum electrolytes in a patient with severe vomiting. Obtain a chest radiograph in patients with cough, shortness of breath or hypoxia.
    B) Urine nickel concentrations can be useful for monitoring workplace exposures but not for guiding treatment.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Oral toxicity of elemental nickel is low. Most toxicity is due to chronic environmental or occupational exposures. Treatment is usually limited to fluid replacement in cases of severe vomiting and diarrhea. Prehospital gastrointestinal decontamination is unlikely to be necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Oral toxicity of elemental nickel is low. Treatment of illness caused by ingestion of nickel salts is usually limited to fluid replacement in cases of severe vomiting and diarrhea. GI decontamination is generally not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) ORAL: Oral toxicity is low, necessitating treatment only for fluid replacement in cases of severe vomiting and diarrhea.
    2) OTHER: It is unusual for nickel to be injected, so blood levels are usually from chronic exposures, implanted devices or unusual circumstances like a dialysis tank. Reactions are either chronic manifestations, like various carcinomas, or involve nickel dermatitis. High plasma nickel levels may need chelation, as listed in the inhalation exposure section.
    3) Other treatment is symptomatic and supportive (oxygen, steroids and antibiotics have been used).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    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.
    D) Symptoms from inhalation are most often due to nickel carbonyl (See NICKEL CARBONYL as indicated). Nickel oxides and sulfides, and finely divided nickel may cause similar symptoms, but the inhalation toxicity of these other nickel compounds is poorly characterized.
    6.7.2) TREATMENT
    A) MONITORING OF PATIENT
    1) Routine laboratory studies are not needed unless otherwise clinically indicated. Monitor serum electrolytes in a patient with severe vomiting. Obtain a chest radiograph in patients with cough, shortness of breath or hypoxia.
    2) Urine nickel concentrations can be useful for monitoring workplace exposures but not for guiding treatment.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) 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) TREATMENT
    A) DERMATITIS
    1) 5-CHLORO-7-IODOQUINOLIN-8-OL (CLIOQUINOL)
    a) Creams containing 3% clioquinol and 1% hydrocortisone abolished the response to patch testing in 29 out of 29 nickel-sensitized cases (Memon et al, 1995). A combination of clioquinol and polyfloretin phosphate in polyethylene glycol had beneficial effects in another study (Gawkrodger et al, 1995). Toxicity in animal studies and concerns of toxicity in infants and children from topical use limit the utility of clioquinol.
    2) CYCLOSPORIN
    a) Thomson et al (1986) demonstrated an inhibition of skin patch test responses to nickel in the presence of topical cyclosporin (5% w/v) in 4 of 18 patients with proven nickel contact dermatitis.
    3) DIETHYLDITHIOCARBAMATE
    a) Spruit et al (1978) tried to treat contact dermatitis with diethyldithiocarbamate (DDC). Although the amount of nickel excreted increased greatly, it did not prevent hypersensitive eczematous skin reactions, even when an excess of the chelating agent was present.
    4) DIETHYLDITHIOCARBAMATE/TETRAETHYLTHIURAM DISULPHIDE
    a) Mixed results have been reported for the use of topical DDC or oral DDC alone or in combination with tetraethylthiuram disulphide (TETD) in the treatment of nickel dermatitis. Oral TETD at doses ranging from 50 to 400 mg/day for up to 10 weeks improved nickel-dermatitis in some individuals, but side effects (hepatotoxicity, lassitude) were present in many cases. Flares of dermatitis also resulted after the drug was discontinued (Gawkrodger et al, 1995).
    5) DIMETHYLGLYOXIME
    a) A dimethylglyoxime (DMG) concentration of 10% in polyethylene glycol has prevented nickel patch test reaction in 1 case. A cream of DMG (1%) in a petrolatum and lanolin base delayed penetration of nickel into damaged rabbit and human cadaver skin (Gawkrodger et al, 1995).
    6) DIPHENYLGLYOXIME
    a) Diphenylglyoxime has been effective in detoxifying nickel in vitro (Gawkrodger et al, 1995).
    7) DISULFIRAM
    a) Antabuse(R), which is metabolized to 2 molecules of diethyldithiocarbamate (DDC), has been shown effective in clearing cases of nickel dermatitis (Menne & Kaaber, 1978). 50 to 100 mg/day were used in the treatment (Christensen & Kristensen, 1982). Disulfiram does not facilitate the oral absorption of nickel as does DDC.
    8) ETHYLENEDIAMINETETRAACETIC ACID (EDTA)
    a) Various topical EDTA preparations, with or without hydrocortisone, have reduced or delayed allergic reactions to nickel patch testing (Gawkrodger et al, 1995).
    9) NICKEL SULFATE
    a) Sjovall et al (1987) reported good results with oral hyposensitization for patients with contact allergy to nickel using a 5 mg dose of nickel sulfate in a capsule, one capsule a week for six weeks.
    b) In a double blind, placebo controlled study, oral hyposensitization with nickel sulfate reduced the number of circulating nickel-responsive lymphocytes but did not result in clinical improvement (Ashford, 1951).
    10) TRICLOSAN POST TREATMENT
    a) Topical administration of triclosan (0.3% in 96% alcohol) significantly reduced the allergic response to nickel patch testing in 10 out of 10 nickel-sensitized cases (Ashford, 1951).
    11) TRIENTINE
    a) Burrows et al (1986) treated 23 nickel-sensitive patients with hand eczema with trientine (triethylenetetramine) 300 mg daily and a placebo in a double-blind, crossover trial. There was significant improvement in the hand eczema and no detectable increase in urinary nickel excretion.
    12) VITAMIN C, VITAMIN E, HYDROCORTISONE
    a) Creams containing these alone or in combination have not been effective in preventing allergic reactions to patch testing (Gawkrodger et al, 1995).
    13) BARRIER CREAMS AND GELS
    a) Some creams may delay or suppress allergic reactions to nickel. Coating of nickel-containing materials with polyurethane film may prevent symptoms in some individuals (Gawkrodger et al, 1995).
    b) One study reported that Carbopol barrier gels can increase the release of nickel from an alloy, but that this nickel remains bound on the surface of excised human skin and is not absorbed into the dermis. Careful washing after the use of barrier gels is recommended in order to prevent contact with the nickel bound to the gel on the skin surface (Fullerton & Menne, 1995).
    c) Carbopol gel plus 10% edetate calcium disodium eliminated the allergic response to a nickel disc in 21 out of 21 nickel-sensitized patients; 14 out of these patients had previously tested positive to the nickel disc alloy. Carbopol gel alone was less effective (Fullerton & Menne, 1995).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) DIURESIS
    1) Induction of diuresis reduced the mean elimination half-life of serum nickel to 27 hours, compared to 60 hours in a group not receiving intravenous fluids (Sunderman et al, 1988).

Abstracts

Case Reports

    A) ADULT
    1) ROUTE OF EXPOSURE
    a) LEACHING: There has been a set of case reports of nickel toxicity occurring from the leaching of a stainless steel water tank used in dialysis (Webster et al, 1980).

Range Of Toxicity

Summary

    A) TOXIC DOSE: Oral toxicity is low and unusual. A healthy individual has nickel concentrations in the plasma ranging from 1.4 to 3.4 mcg/L (average 2.1 mcg/L). Whole blood concentrations are usually twice the level of plasma or serum.
    B) NORMAL CONCENTRATION: A normal serum nickel concentration in humans is approximately 0.11 mcg/mL.
    C) MAXIMUM TOLERATED DOSE: It has been recommended that a plasma level of 10 mcg/L be set as a biomonitoring limit for nickel refinery workers.

Minimum Lethal Exposure

    A) SUMMARY
    1) Oral toxicity is low (10%), similar to zinc, chromium, and manganese (Errera, 1980). Toxicity via oral exposure is unusual. The usual adult oral intake of nickel is approximately 300 to 600 mcg/day.
    2) The USEPA suggests that an intake of 0.02 mg/kg/day for soluble nickel compounds as safe for humans (Ashford, 1951).
    3) INGESTION: 15 grams of nickel sulfate crystals proved to be fatal after a 2-1/2 year-old child ingested the substance (Harbison, 1998).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Metallic nickel is relatively nontoxic when ingested. Soluble nickel salts; however, are toxic when administered orally (Harbison, 1998).
    2) A normal serum nickel level in humans was determined to be 0.011 mg% or 0.11 mcg/mL (HSDB , 2000).
    3) Animal studies of both oral and inhalation exposure to nickel compounds have been extensively reviewed and compiled (Ashford, 1951).
    4) ANIMALS: Metallic nickel powder at 1 to 3 g/kg body weight, and insoluble inorganic nickel compounds at 500 mg/kg when fed to dogs and rodents, respectively, were well tolerated (Harbison, 1998) (HSDB , 2002).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) OCCUPATIONAL
    a) In 15 workers who accidentally drank water contaminated with 1.63 grams/liter of nickel and developed symptoms, serum nickel concentrations ranged from 13 to 1,340 micrograms/liter, and urine nickel concentrations ranged from 0.15 to 12 milligrams/gram creatinine on day 1 postexposure (Sunderman et al, 1988).
    b) Nineteen symptomatic electroplating workers accidentally drank nickel- contaminated water. After 24 hours their blood nickel level concentrations were 13 to 1340 mcg/L and urine concentrations were 0.23 to 27mcg/L (Harbison, 1998).

Workplace Standards

    A) ACGIH TLV Values for CAS7440-02-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Nickel, soluble inorganic compounds (NOS)
    a) TLV:
    1) TLV-TWA: 0.1 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: I
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    b) I: Inhalable fraction; see Appendix C, paragraph A (of TLV booklet).
    c) TLV Basis - Critical Effect(s): Lung dam; nasal cancer
    d) Molecular Weight: Varies
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:
    b) Adopted Value
    1) Nickel, insoluble inorganic compounds (NOS)
    a) TLV:
    1) TLV-TWA: 0.2 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A1
    2) Codes: I
    3) Definitions:
    a) A1: Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    b) I: Inhalable fraction; see Appendix C, paragraph A (of TLV booklet).
    c) TLV Basis - Critical Effect(s): Lung cancer
    d) Molecular Weight: Varies
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:
    c) Adopted Value
    1) Nickel, elemental
    a) TLV:
    1) TLV-TWA: 1.5 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A5
    2) Codes: I
    3) Definitions:
    a) A5: Not Suspected as a Human Carcinogen: The agent is not suspected to be a human carcinogen on the basis of properly conducted epidemiologic studies in humans. These studies have sufficiently long follow-up, reliable exposure histories, sufficiently high dose, and adequate statistical power to conclude that exposure to the agent does not convey a significant risk of cancer to humans; OR, the evidence suggesting a lack of carcinogenicity in experimental animals is supported by mechanistic data.
    b) I: Inhalable fraction; see Appendix C, paragraph A (of TLV booklet).
    c) TLV Basis - Critical Effect(s): Dermatitis; pneumoconiosis
    d) Molecular Weight: 58.71
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS7440-02-0 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Nickel metal and other compounds (as Ni)
    2) REL:
    a) TWA: 0.015 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A; [*Note: The REL does not apply to Nickel carbonyl.]
    3) IDLH:
    a) IDLH: 10 mg Ni/m3
    b) Note(s): Ca
    1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

    C) Carcinogenicity Ratings for CAS7440-02-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Nickel, soluble inorganic compounds (NOS)
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A1 ; Listed as: Nickel, insoluble inorganic compounds (NOS)
    a) A1 :Confirmed Human Carcinogen: The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies.
    3) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A5 ; Listed as: Nickel, elemental
    a) A5 :Not Suspected as a Human Carcinogen: The agent is not suspected to be a human carcinogen on the basis of properly conducted epidemiologic studies in humans. These studies have sufficiently long follow-up, reliable exposure histories, sufficiently high dose, and adequate statistical power to conclude that exposure to the agent does not convey a significant risk of cancer to humans; OR, the evidence suggesting a lack of carcinogenicity in experimental animals is supported by mechanistic data.
    4) EPA (U.S. Environmental Protection Agency, 2011): A ; Listed as: Nickel refinery dust
    a) A : Human Carcinogen.
    5) EPA (U.S. Environmental Protection Agency, 2011): Information reviewed but value not estimated. Refer to Full IRIS Summary. ; Listed as: Nickel, soluble salts
    6) 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): 2B ; Listed as: Nickel, metallic and alloys
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    7) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Nickel metal and other compounds (as Ni)
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    8) MAK (DFG, 2002): Category 1 ; Listed as: Nickel and nickel compounds (as inhalable dusts/aersosols)
    a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.
    9) MAK (DFG, 2002): Category 1 ; Listed as: Metallic nickel
    a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.
    10) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): K ; Listed as: Nickel Compounds (See Nickel Compounds and Metallic Nickel )
    a) K : KNOWN = Known to be a human carcinogen
    11) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Nickel (Metallic) (See Nickel Compounds and Metallic Nickel )
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS7440-02-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Nickel, metal and insoluble compounds (as Ni)
    2) Table Z-1 for Nickel, metal and insoluble compounds (as Ni):
    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: 1
    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): Not Listed
    3) Listed as: Nickel, soluble compounds (as Ni)
    4) Table Z-1 for Nickel, soluble compounds (as Ni):
    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: 1
    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): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Bingham et al, 2001 ITI, 1995 Lewis, 2000 RTECS, 2002
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 250 mg/kg
    2) LD50- (ORAL)RAT:
    a) 9 g/kg (Bingham et al, 2001)
    3) TCLo- (INHALATION)RAT:
    a) 100 mcg/m3 for 24H/17W-C -- liver impairment and changes in blood composition

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nickel is a micronutrient used in many enzymatic reactions.

Toxicologic Mechanism

    A) Water-soluble nickel compounds do not readily enter cells; whereas, water-insoluble nickel compounds enter cells through phagocytosis and are carcinogenic. Carcinogenicity may be related to DNA protein binding, oxidation, and DNA-protein cross-linking by nickel, as has been demonstrated in vitro (Costa, 1993; Zhuang et al, 1994).

Physicochemical

Physical Characteristics

    A) Nickel exists as a silvery-white, hard, malleable, magnetic metal which shows excellent resistance to corrosion. Crystalline nickel exists as metallic cubes. Raney nickel appears as either a grayish-black powder or as cubic crystals (Ashford, 1994; (Budavari, 2000; Lewis, 2000).

Molecular Weight

    A) 58.71

Other

    A) ODOR THRESHOLD
    1) Odorless (HSDB , 2002)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 49 CFR 172.101: Department of Transportation - Table of Hazardous Materials. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 11, 2005.
    5) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    6) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    9) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    10) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    11) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    12) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    13) ACGIH: Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed, Am Conference of Govt Ind Hyg, Inc, Cincinnati, OH, 1991.
    14) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    15) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    16) Andersen A, Berge SR, & Engeland A: Exposure to nickel compounds and smoking in relation to incidence of lung and nasal cancer among nickel refinery workers. Occup Environ Med 1996; 53:708-713.
    17) Anon: Diagnostic oral challenge with nickel, cobalt and chromium in patients with negative patch tests. ACTA Derm Venereol 1989; 147(Suppl):19-22.
    18) Anon: Nickel and/or cobalt as the cause of systemic contact dermatitis in patch test positive patients. ACTA Derm Venereol 1989a; 147(Suppl):12-16.
    19) Antico A & Soana R: Chronic allergic-like dermatopathies in nickel-sensitive patients. Results of dietary restrictions and challenge with nickel salts. Allergy Asthma Proc 1999; 20(4):235-242.
    20) Ashford R: Ashford's Dictionary of Industrial Chemicals. Wavelength Publications Ltd, London, England, 1994. .SK 1 Assier-Bonnet H, Lestang P & Revuz J: Contact sensitivity to surgical skin clips. Contact Derm 1998; 38:117. .SK 1 ATSDR: Toxicological Profile for Nickel. US Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA, Report TP-92/14, 1993. .SK 1 Bagot M, Terki N, Bacha S et al: Per os desensitization in nickel contact eczema: a double-blind placebo-controlled clinico-biological study. Ann Dermatol Venereoll 1999; Jun-Jul; 126(6-7):502-4. .SK 1 Barkvoll P & Rolla G: Triclosan reduces the clinical symptoms of the allergic patch test reaction (APR) elicited with 1% nickel sulphate in sensitized patients. J Clin Periodontol 1995; 22:483-487. .SK 1 Barnes JM & Denz FA: Effect of 2-3 dimercapto-propanol (BAL) on experimental nickel carbonyl poisoning. Br J Med 1951; 8:117-126.
    21) Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 5th ed, Chemical Toxicology Institute, Foster City, CA, 2000.
    22) Benson JM, Cheng YS, & Eidson AF: Pulmonary toxicity of nickel subsulfide in F344/N rats exposed for 1-22 days. Toxicology 1995; 103:9-22.
    23) Bingham E, Cohrssen B, & Powell CH: Patty's Toxicology, Vol 1 & 3. 5th ed, John Wiley & Sons, New York, NY, 2001.
    24) Budavari S: The Merck Index, 12th ed. on CD-ROM. Version 12:3a. Chapman & Hall/CRCnetBASE. Whitehouse Station, NJ. 2000.
    25) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    26) Christensen OB & Kristensen M: Treatment with disulfiram in chronic nickel hand dermatitis. Contact Dermatitis 1982; 8:59-63.
    27) Clayton GD & Clayton FE: Patty's Industrial Hygiene and Toxicology, Volume 2C, Toxicology, 4th ed, John Wiley & Sons, New York, NY, 1994, pp 2157-2173.
    28) Conway K, Wang XW, & Xu LS: Effect of magnesium on nickel-induced genotoxixity and cell transformation. Carcinogenesis 1987; 8:1115-1121.
    29) Corazza M & Virgili A: Allergic contact dermatitis due to nickel in a neoprene wetsuit (letter). Contact Derm 1998; 39:257-273.
    30) Costa M: Molecular targets of nickel and chromium in human and experimental systems. Scand J Work Environ Health 1993; 19(Suppl 1):71-74.
    31) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    32) Danadevi K, Rozati R, & Banu BS: In vivo genotoxic effect of nickel chloride in mice leukocytes using comet assay. Food Chem Toxicol 2004; 42:751-757.
    33) Danese P & Bertazzoni MG: Lymphomatoid contact dermatitis due to nickel. Contact Derm 1995; 33:268.
    34) De Silva BD & Doherty VR: Nickel allergy from orthodontic appliances. Contact Derm 2000; 42:102-103.
    35) Denays R, Kumba C, Lison D, et al: First epileptic seizure induced by occupational nickel poisoning. Epilepsia 2005; 46:961-962.
    36) Dostal LA, Hopfer SM, & Lin S: Effects of nickel chloride on lactating rats and their suckling pups and the transfer of nickel through rat milk. Toxicol Appl Pharmacol 1989; 101:220-231.
    37) Dragun J: The Soil Chemistry of Hazardous Materials, Hazardous Materials Control Research Institute, Silver Spring, MD, 1988.
    38) Dunnick JK, Elwell MR, & Radovsky AE: Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate hexahydrate chronic exposures in the lung. Cancer Res 1995; 55:5251-5256.
    39) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    40) ERG: Emergency Response Guidebook. A Guidebook for First Responders During the Initial Phase of a Dangerous Goods/Hazardous Materials Incident, U.S. Department of Transportation, Research and Special Programs Administration, Washington, DC, 2004.
    41) Elsner P & Burg G: Irritant reactivity is a better risk marker for nickel sensitization than atopy. ACTA Derm Venereol (Stockh) 1993; 73:214-216.
    42) Errera JJ: Nickel. J Am Med Technol 1980; 138.
    43) Ewing S & Miller R: Generalized nickel dermatitis in a 6-year-old boy as a result of swallowing a Canadian nickel. J Am Acad Dermatol 1991; 25:855-856.
    44) Ferm VH: Adv Teratol 1972; 5:51-75.
    45) Fernandez-Redondo V, Gomez-Centeno P, & Toribio J: Chronic urticaria from a dental bridge (letter). Contact Derm 1998; 38:178-179.
    46) Fletcher GG, Rossetto FE, & Turnbull JD: Toxicity, uptake, and mutagenicity of particulate and soluble nickel compounds. Environ Health Perspect 1994; 102(Suppl 3):69-79.
    47) Freeman HM: Standard Handbook of Hazardous Waste Treatment and Disposal, 2nd ed, McGraw-Hill Book Company, New York, NY, 1998.
    48) Friberg L, Norberg GF, & Vouk V: Handbook on the Toxicology of Metals, 2nd ed, Elsevier Science Publishers, New York, NY, 1986.
    49) Fullerton A & Menne T: In vitro and in vivo evaluation of the effect of barrier gels in nickel contact allergy. Contact Dermatitis 1995; 32:100-106.
    50) Furst A & Fan AM: Carcinogenic action of nickel and cadmium powders in the same rat. Biol Tr Elem Res 1993; 36:243-249.
    51) Galbreath KC, Crocker CR, Nyberg CM, et al: Nickel speciation measurements of urban particulate matter: method evaluation and relevance to risk assessment. J Environ Monit 2003; 5:56N-61N.
    52) Gawkrodger DJ, Healy J, & Howe AM: The prevention of nickel contact dermatitis. Contact Dermatitis 1995; 32:257-265.
    53) Gennart JP, Baleux C, & Verellendumoulin C: Increased sister chromatid exchanges and tumor markers in workers exposed to elemental chromium-containing, cobalt-containing and nickel-containing dusts. Mutat Res 1993; 299:55-61.
    54) Gollhausen R & Ring J: Allergy to coined money: nickel contact dermatitis in cashiers. J Am Acad Dermatol 1991; 25:365-369.
    55) Goutet M, Ban M, & Binet S: Effects of nickel sulfate on pulmonary natural immunity in Wistar rats. Toxicology 2000; 145:15-26.
    56) Grimsrud TK & Peto J: Persisting risk of nickel related lung cancer and nasal cancer among Clydach refiners. Occup Environ Med 2006; 63(5):365-366.
    57) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 1999; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    58) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    59) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    60) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    61) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2004; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    62) Hallab N, Jacobs JJ, & Black J: Hypersensitivity to metallic biomaterials: a review of leukocyte migration inhibition assays. Biomaterials 2000; 21:1301-14.
    63) Harkin A, Hynes MJ, Masterson E, et al: A toxicokinetic study of nickel-induced immunosuppression in rats. Immunopharmacol Immunotoxicol 2003; 25:655-670.
    64) Hartwig A, Schlepegrell R, & Dally H: Interaction of carcinogenic metal compounds with deoxyribonucleic acid repair processes. Ann Clin Lab Sci 1996; 26:31-38.
    65) Hathaway GJ, Proctor NH, & Hughes JP: Chemical Hazards of the Workplace, 4th ed, Van Nostrand Reinhold Company, New York, NY, 1996.
    66) Haudrechy P, Foussereau J, & Mantout B: Nickel release from nickel-plated metals and stainless steels. Contact Dermatitis 1994; 31:249-255.
    67) Hauptman O, Albert DM, & Plowman MC: Ocular malformations of xenopus-laevis exposed to nickel during embryogenesis. Ann Clin Lab Sci 1993; 23:397-406.
    68) Hindsen M, Bruze M, & Christensen OB: Individual variation in nickel patch test reactivity. Am J Contact Dermat 1999; 10(2):62-67.
    69) Hindsen M, Christensen OB, & Moller H: Nickel levels in serum and urine in five different groups of eczema patients following oral ingestion of nickel. ACTA Derm Venereol (Stockh) 1994; 74:176-178.
    70) Hoang TC, Tomasso JR, & Klaine SJ: Influence of water quality and age on nickel toxicity to fathead minnows (Pimephales promelas). Environ Toxicol Chem 2004; 23(1):86-92.
    71) Hoey MJ: J Reprod Fertil 1966; 12:461-471.
    72) Hong YC, Paik SR, & Lee HJ: Magnesium inhibits nickel-induced genotoxicity and formation of reactive oxygen. Environ Health Perspect 1997; 105:744-748.
    73) IARC & 2001: IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. Nickel and Nickel Compounds. <http://193.51.164.11/htdocs/Monographs/Vol49/Nickel, International Agency for Research on Cancer, World Health Organization, Geneva, Switzerland, 2001.
    74) IARC : Monographs on the Evaluation of Carcinogenic Risks to Humans -- Nickel. International Agency for Research on Cancer, World Health Organization. Geneva, Switzerland. 1997. Available from URL: http://193.51.164.11/default.html.
    75) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    76) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    77) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    78) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    79) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    80) IARC: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans -- Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, Supplement 7, International Agency for Research on Cancer, World Health Organization, Geneva, Switzerland, 1987.
    81) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    82) ICAO: Technical Instructions for the Safe Transport of Dangerous Goods by Air, 2003-2004. International Civil Aviation Organization, Montreal, Quebec, Canada, 2002.
    83) ILO: Encyclopaedia of Occupational Health and Safety, 4th ed. JM Stellman (Ed), Vol 1-4, 1-4, International Labour Organization, Geneva, Switzerland, 1998.
    84) ILO: Encyclopedia of Occupational Health and Safety, 3rd ed., Vols 1 & 2, International Labour Organization, Geneva, Switzerland, 1983.
    85) ITI: Toxic and Hazardous Industrial Chemicals Safety Manual, The International Technical Information Institute, Tokyo, Japan, 1995.
    86) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    87) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    88) Kanerva L, Alanko K, & Jolanki R: Laboratory assistant's occupational allergic airborne contact dermatitis from nickel presenting as rosacea. Eur J Dermatol 1999; 9:397-398.
    89) Kang J, Zhang Y, & Chen J: Nickel-induced histone hypoacetylation: the role of reactive oxygen species. Toxicol Sci 2003; 74:279-286.
    90) Kargacin B, Klein CB, & Costa M: Mutagenic responses of nickel oxides and nickel sulfides in Chinese hamster V79 cell lines at the xanthine-guanine phosphoribosyl transferase locus. Mutat Res 1993; 300:63-72.
    91) Kasprzak KS, Diwan BA, & Rice JM: Iron accelerates while magnesium inhibits nickel-induced carcinogenesis in the rat kidney. Toxicology 1994; 90:129-140.
    92) Katsifis SP, Kinney PL, & Hosselet S: Interaction of nickel with mutagens in the induction of sister chromatid exchanges in human lymphocytes. Mutat Research 1996; 359:7-15.
    93) Klein CB, Kargacin B, & Su L: Metal mutagenesis in transgenic Chinese hamster cell lines. Environ Health Perspect 1994; 102(Suppl 3):63-67.
    94) Krushell JS & Burnett JW: Nickel dermatitis. Cutis 1990; 45:87-88.
    95) Kunimasa K, Arita M, Tachibana H, et al: Chemical pneumonitis and acute lung injury caused by inhalation of nickel fumes. Internal Med 2011; 50(18):2035-2038.
    96) Lacroix J, Morin CL, & Collins PP: Nickel dermatitis from a foreign body in the stomach. J Pediatr 1979; 95:428-429.
    97) Lee YW, Pons C, & Tummolo DM: Mutagenicity of soluble and insoluble nickel compounds at the gpt locus in G12 chinese hamster cells. Environ Mol Mutagen 1993; 21:365-371.
    98) Lee-Chen SF, Wang MC, & Yu CT: Nickel chloride inhibits the DNA repair of UV-treated but not methyl methanesulfonate-treated Chinese hamster ovary cells. Biol Trace Elem Res 1993; 37:39-50.
    99) Lewis CG & Sunderman FW: Metal carcinogenesis in total joint arthroplasty. Clin Orthopaedics Related Res 1996; 329:S264-S268.
    100) Lewis RA: Lewis' Dictionary of Toxicology, Lewis Publishers, Boca Raton, FL, 1998.
    101) Lewis RJ: Hawley's Condensed Chemical Dictionary, 13th ed, John Wiley & Sons, Inc, New York, NY, 1997.
    102) Lewis RJ: Sax's Dangerous Properties of Industrial Materials, 10th ed, John Wiley & Sons, New York, NY, 2000.
    103) Lindsten R & Kurol J: Orthodontic appliances in relation to nickel hypersensitivity. J Orofac Orthoped 1997; 58:100-108.
    104) Lu CC: Teratology 1979; 19:137-142.
    105) Lyell A & Bain NH: Nickel allergy and valve replacement. Lancet 1974; 1:408-409.
    106) Maridet C, Atge B, Amici JM, et al: The electronic cigarette: the new source of nickel contact allergy of the 21st century?. Contact Dermatitis 2015; 73(1):49-50.
    107) McConnell LH, Fink JN, & Schlueter DP: Asthma caused by nickel sensitivity. Ann Intern Med 1973; 78:888.
    108) McLelland J & Lawrence CM: Premenstrual exacerbation of nickel allergy. Br J Dermatol 1991; 125:83.
    109) Menne T & Kaaber K: Treatment of pompholyx due to nickel allergy with chelating agents. Contact Dermatitis 1978; 4:289-290.
    110) Menne T: Prevention of nickel allergy by regulation of specific exposures. Ann Clin Lab Sci 1996; 26:133-138.
    111) Morgan LG & Usher V: Health problems associated with nickel refining and use. Ann Occup Hyg 1994; 38:189-198.
    112) Moulin JJ, Clavel T, & Roy D: Risk of lung cancer in workers producing stainless steel and metallic alloys. International Archives of Occupational and Environmental Health 2000; 73:171-180.
    113) Muir DCF, Jadon N, & Julian JA: Cancer of the respiratory tract in nickel sinter plant workers -- effect of removal from sinter plant exposure. Occup Environ Med 1994; 51:19-22.
    114) NFPA: Fire Protection Guide to Hazardous Materials, 12th ed, National Fire Protection Association, Quincy, MA, 1997.
    115) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    116) NIOSH : Pocket Guide to Chemical Hazards. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires January/31/2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    117) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    118) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    119) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    120) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    121) Nadeenko VG: Gig Sanit 1979; 6:86-88.
    122) Nakamura M, Arima Y, & Nobuhara S: Nickel allergy in a trumpet player (letter). Contact Derm 1999; 40:219-220.
    123) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    124) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    125) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    126) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    127) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    128) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    129) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    130) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    131) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    132) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    133) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    134) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    135) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    136) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    137) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    138) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    139) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    140) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    141) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    142) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    143) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    144) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    145) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    146) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    147) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    148) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    149) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    150) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    151) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    152) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    153) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    154) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    155) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    156) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    157) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    158) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    159) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    160) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    161) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    162) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    163) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    164) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    165) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    166) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    167) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    168) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    169) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    170) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    171) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    172) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    173) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    174) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    175) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    176) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    177) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    178) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    179) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    180) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    181) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    182) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    183) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    184) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    185) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    186) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    187) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    188) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    189) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    190) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    191) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    192) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    193) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    194) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    195) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    196) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    197) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    198) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    199) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    200) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    201) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    202) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    203) O'Brien P & Salacinski HJ: Evidence for a relationship between the generation of reactive intermediates and the physicochemical characteristics of nickel oxides. Arch Toxicol 1996; 70:787-800.
    204) OHM/TADS: Oil and Hazardous Materials/Technical Assistance Data System. US Environmental Protection Agency. Washington, DC (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    205) Ojajarvi IA, Partanen TJ, & Ahlbom A: Occupational exposure and pancreatic cancer: a meta-analysis. Occupational and Environmental Medicine 2000; 57:316-24.
    206) Pandey R, Kumar R, & Singh SP: Male reproductive effect of nickel sulphate in mice. Biometals 1999; 12:339-346.
    207) Pang D, Burges DCL, & Sorahan T: Mortality study of nickel platers with special reference to cancers of the stomach and lung, 1945-93. Occup Environ Med 1996; 53:714-717.
    208) Patierno SR, Dirscherl LA, & Xu J: Transformation of rat tracheal epithelial cells to immortal growth variants by particulate and soluble nickel compounds. Mutat Res 1993; 300:179-193.
    209) Pazzaglia M, Lucente P, & Vincenzi C: Contact dermatitis from nickel in mobile phones (letter). Contact Derm 2000; 42:362-363.
    210) Peters K, Gammelgaard B, & Menne T: Contact Dermatitis 1991; 25:237-241.
    211) Peto B: J Natl Cancer Inst 1986; 77:841.
    212) Pohanish RP & Greene SA: Rapid Guide to Chemical Incompatibilities, Van Nostrand Reinhold, New York, NY, 1997.
    213) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires January/31/2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    214) Ridgway LP & Karnofsky DA: Ann Acad Sci 1952; 55:203-215.
    215) Roberts RS, Julian JA, & Sweezey D: A study of mortality in workers engaged in the mining, smelting, and refining of nickel. Toxicol Ind Health 1989; 5:957-974.
    216) Rodriguez RE, Misra M, & Diwan BA: Relative susceptibilities of C57BL/6, (C57BL/6 x C3H/He)F1, and C3H/He mice to acute toxicity and carcinogenicity of nickel subsulfide. Toxicology 1996; 107:131-140.
    217) Ross IB, Warrington RJ, & Halliday WC: Cell-mediated allergy to a cerebral aneurysm clip: case report. Neurosurg 1998; 43:1209-1211.
    218) Sahu RK, Katsifis SP, & Kinney PL: Ni(II) induced changes in cell cycle duration and sister-chromatid exchanges in cultured human lymphocytes. Mutat Res 1995; 327:217-225.
    219) Santucci B, Cannistraci C, & Cristaudo A: Multiple sensitivities to transition metals -- the nickel palladium reactions. Contact Dermatitis 1996; 35:283-286.
    220) Schardein JL: Chemically Induced Birth Defects, 3rd ed, Marcel Dekker, Inc, New York, NY, 2000.
    221) Schroeder HA & Mitchener M: Arch Environ Health 1971; 23:102-106.
    222) Schubert HJ: Airborne nickel dermatitis (letter). Contact Derm 2000; 42:118-119.
    223) Seidenari S, Motolese A, & Belletti B: Pre-treatment of nickel test areas with sodium lauryl sulfate detects nickel sensitivity in subjects reacting negatively to routinely performed patch tests. Contact Dermatitis 1996; 34:88-92.
    224) Senft V, Losan F, & Tucek M: Cytogenetic analysis of chromosomal aberrations of peripheral lymphocytes in workers occupationally exposed to nickel. Mutat Res 1992; 279:171-179.
    225) Shen HM & Zhang QF: Risk assessment of nickel carcinogenicity and occupational lung cancer. Environ Health Perspect 1994; 102:275-282.
    226) Shum KW, Meyer JD, Chen Y, et al: Occupational contact dermatitis to nickel: experience of the British dermatologists (EPIDERM) and occupational physicians (OPRA) surveillance schemes. Occup Environ Med 2003; 60:954-957.
    227) Sittig M: Handbook of Toxic and Hazardous Chemicals and Carcinogens, 3rd ed, Noyes Publications, Park Ridge, NJ, 1991.
    228) Smith MK, George EL, & Stober JA: Perinatal toxicity associated with nickel chloride exposure. Environ Res 1993; 61:200-211.
    229) Snow ET, Xu LS, & Kinney PL: Effects of nickel ions on polymerase activity and fidelity during DNA replication in vitro. Chem Biol Interact 1993; 88:155-173.
    230) Sorokin VA, Valeev VA, & Gladchenko GO: Interaction of bivalent copper, nickel, manganese ions with native DNA and its monomers. J Inorg Biochem 1996; 63:79-98.
    231) Strauss FG & Eggleston DW: IgA nephropathy associated with dental nickel alloy sensitization. Am J Nephrol 1985; 5:395-397.
    232) Stridsklev IC, Hemmingsen B, & Karlsen JT: Biologic monitoring of chromium and nickel among stainless steel welders using the manual metal arc method. Internat Arch Occup Environ Health 1993; 65:209-219.
    233) Sunderman FW Jr, Dingle B, & Hopfer SM: Acute nickel toxicity in electroplating workers who accidentally ingested a solution of nickel sulfate and nickel chloride. Am J Ind Med 1988; 14:257-266.
    234) Sunderman FW Jr: Potential toxicity from nickel contamination of intravenous fluids. Ann Clin Lab Sci 1983; 13:1-4.
    235) Sunderman FW: Toxicol Appl Pharmacol 1977; 41:205.
    236) Sunderman FW: Toxicol Appl Pharmacol 1978; 43:381-390.
    237) Tkeshelashvili LK, Reid TM, & McBride TJ: Nickel induces a signature mutation for oxygen free radical damage. Cancer Res 1993; 53:4172-4174.
    238) Torjussen W, Solberg LA, & Hogetveit AC: Histopathologic changes of nasal mucosa in nickel workers. Cancer 1979; 44:963-974.
    239) Trombelli L, Virgili A, & Corazza M: Systemic contact dermatitis from an orthodontic appliance. Contact Dermatitis 1992; 27:259-260.
    240) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    241) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    242) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    243) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    244) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    245) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    246) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    247) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    248) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    249) US DHHS: US DHHS, Seventh Annual Report on Carcinogens -- 1994, National Toxicology Program, Washington, DC, 1994.
    250) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    251) Urben PG: Bretherick's Handbook of Reactive Chemical Hazards, Vol 1-2, 6th ed, (CD-ROM version), Butterworth-Heinemann Ltd, Oxford, England, 1999.
    252) Uter W, Fuchs T, & Hausser M: Patch test results with serial dilutions of nickel sulfate (with and without detergent), palladium chloride, and nickel and palladium metal plates. Contact Dermatitis 1995; 32:135-142.
    253) Vanhoogstraten IMW, Boos C, & Boden D: Oral induction of tolerance to nickel sensitization in mice. J Invest Dermatol 1993; 101:26-31.
    254) Veien NK, Hattel T, & Laurberg G: Low nickel diet -- an open, prospective trial. J Am Acad Dermatol 1993; 29:1002-1007.
    255) Vyskocil A, Senft V, & Viau C: Biochemical renal changes in workers exposed to soluble nickel compounds. Human Exp Toxicol 1994a; 13:257-261.
    256) Vyskocil A, Viau C, & Cizkova M: Chronic nephrotoxicity of soluble nickel in rats. Human Exp Toxicol 1994b; 13:689-693.
    257) Webster JD, Parker TF, & Alfrey AC: Acute nickel intoxication by dialysis. Ann Intern Med 1980; 92:631-633.
    258) Wubs PL & Spruit D: Course of nickel contact dermatitis. Contact Dermatitis 1979; 5:57-58.
    259) Xie JM, Funakoshi T, & Shimada H: Effects of chelating agents on testicular toxicity in mice caused by acute exposure to nickel. Toxicology 1995; 103:147-155.
    260) Zemba C, Romaguera C, & Vilaplana J: Allergic contact dermatitis from nickel in an eye pencil. Contact Dermatitis 1992; 27:116.
    261) Zeromski J, Jezewska E, & Sikora J: The effect of nickel compounds on immunophenotype and natural killer cell function of normal human lymphocytes. Toxicology 1995; 97:39-48.
    262) Zhuang Z, Huang X, & Costa M: Protein oxidation and amino acid-DNA crosslinking by nickel compounds in intact cultured cells. Toxicol Appl Pharmacol 1994; 126:319-325.
    263) Zhuang ZX, Shen Y, & Shen HM: DNA strand breaks and poly (ADP-ribose) polymerase activation induced by crystalline nickel subsulfide in MRC-5 lung fibroblast cells. Human Exp Toxicol 1996; 15:891-897.