Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

DICHLOROACETATE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dichloroacetate (DCA) is a chlorinated hydrocarbon acid. DCA is a principal by-product of chlorine disinfection of water containing humic and fulvic acids and is a product of the metabolism of various drugs and industrial chemicals.
    B) DCA is an investigational drug used for the management of metabolic and cardiovascular disorders. This monograph pertains mostly to sodium dichloroacetate.

Specific Substances

    1) DCA
    2) Dichloroacetate diisopropylammonium (vitamin B15)
    3) Dichloroacetate sodium salt
    4) Dichloroacetic acid sodium salt
    5) Dichloroctan sodny
    6) Molecular formula: C2-H-Cl2-O2.Na
    7) (Sodium dichloroacetate)
    8) CAS 2156-56-1 (Sodium dichloroacetate)
    9) DICHLOROACETATE SODIUM
    10) VITAMIN B15

Available Forms Sources

    A) FORMS
    1) DCA is a colorless solution prepared for intravenous medicinal use (Fox et al, 1996). Sterile, colorless solutions of 10 percent DCA are available for clinical investigations.
    2) When sodium dichloroacetate is heated to decomposition, it emits toxic fumes of chloride and disodium oxide (Lewis, 1996).
    B) SOURCES
    1) Environmental sources of DCA include chlorinated drinking water and groundwater contamination by certain industrial solvents and other chlorinated hydrocarbons (Stacpoole et al, 1998; Yan et al, 1997). Exposure to DCA as a contaminant in drinking water has become a safety concern for the non-clinical population.
    C) USES
    1) DCA is an investigational drug used to stimulate the activity of the mitochondrial pyruvate dehydrogenase enzyme complex to increase oxidation of glucose and lactate. It is used for the treatment of hyperglycemia, hypercholesteremia, and acquired and congenital lactic acidosis (Stacpoole et al, 1978; Yan et al, 1997; Sweetman, 2002). It is an investigational drug for treatment of stroke (Sweetman, 2002).
    a) DCA has also been shown to have a protective effect against myocardial ischemic damage (Wahr et al, 1994). In the 1970's, this compound was investigated as a vasodilator and hypotensive agent (Grant & Schuman, 1993).
    2) Dichloroacetic acid is produced in small quantities for use as an intermediate in the production of glyoxylic acid, dialkyloxy, and diaryloxy acids and sulfonamides (IARC, 1995). Human exposures may occur during commercial production and use of DCA and from drinking chlorinated water.
    3) Vitamin B15 is a mixture of sodium gluconate, glycine, and diisopropylammonium dichloroacetate. It is presumed that the active moiety of this vitamin is the complex diisopropylammonium salt of DCA (Stacpoole, 1989).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Reports of dichloroacetate (DCA) acute toxicity are limited. Clinical effects following ingestion include CNS depression and peripheral neuropathy. Most reported effects have involved chronic DCA use.
    0.2.6) RESPIRATORY
    A) Respiratory depression may occur due to the DCA metabolite, monochloroacetate, in massive overdoses.
    0.2.7) NEUROLOGIC
    A) CNS depression, including sedation and dizziness, may occur following overdoses.
    0.2.9) HEPATIC
    A) Elevations in serum hepatic enzymes and increases in urinary oxalate excretion have been reported.
    0.2.10) GENITOURINARY
    A) Dose-related increases in urinary oxalate excretion have been reported.
    0.2.11) ACID-BASE
    A) DCA is known to decrease serum lactate concentrations.
    0.2.16) ENDOCRINE
    A) Although not yet reported, overdoses may cause hypoglycemic effects.
    0.2.20) REPRODUCTIVE
    A) Human data concerning reproductive effects of DCA are currently unavailable.

Laboratory Monitoring

    A) Monitor vital signs in all symptomatic patients.
    B) Serum DCA levels are not clinically useful or readily available.
    C) Monitor CBC, serum electrolyte levels, and renal and hepatic function tests in all symptomatic patients.
    D) Arterial blood gases and/or pulse oximetry and pulmonary function tests may be advisable in patients with respiratory symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    D) MONITOR VITAL SIGNS REGULARLY, especially respiration. Provide assisted ventilation if needed.
    E) Treatment is SYMPTOMATIC and SUPPORTIVE.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    0.4.6) PARENTERAL EXPOSURE
    A) Monitor vital signs and respiratory status in all overdoses.
    B) Treatment is SYMPTOMATIC and SUPPORTIVE.

Range Of Toxicity

    A) No acute poisonings have been reported in humans at the time of this review. Doses of 150 milligrams/kilogram intravenously and 150 milligrams/kilogram orally have been well tolerated.

Clinical Effects

Summary Of Exposure

    A) Reports of dichloroacetate (DCA) acute toxicity are limited. Clinical effects following ingestion include CNS depression and peripheral neuropathy. Most reported effects have involved chronic DCA use.

Heent

    3.4.3) EYES
    A) DCA administered chronically to dogs has produced irreversible lens opacities and superficial corneal vascularization in some animals, at doses as low as 75 mg/kg (Stacpoole, 1989; Katz et al, 1981). Bilateral conjunctivitis with a clear discharge was a common finding in one toxicity study in dogs (Cicmanec et al, 1991).
    B) When administered to patients with retinal vascular disease, DCA increased the amplitude of the b-wave of the electoretinogram (Grant & Schuman, 1993).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) No reports of hypotension have been found in the literature, but due to possible inotropic and vasodilatory effects of DCA, massive overdoses may result in hypotensive effects (Grant & Schuman, 1993; Wahr et al, 1994).
    B) HYPERTENSIVE EPISODE
    1) DCA has been reported to transiently elevate systolic blood pressure in patients with lactic acidosis in clinical studies (Stacpoole et al, 1983). The authors considered this to be a salutary effect since most of the patients were initially hypotensive.

Respiratory

    3.6.1) SUMMARY
    A) Respiratory depression may occur due to the DCA metabolite, monochloroacetate, in massive overdoses.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) Although not yet reported following acute toxicity, respiratory depression may occur due to a DCA metabolite, monochloroacetate, which is a potent respiratory inhibitor and many times more toxic than DCA (Stacpoole, 1989).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) The most significant clinical effect noted in dogs, in a 90 day DCA toxicity study, was dyspnea, which was noted approximately at day 45, in the mid- and high-dose animals (39.5 mg/kg/day and 72 mg/kg/day, respectively). The primary characteristic of the dyspnea was increased forced expiratory effort. By the end of the study, all dogs in the high-dose group showed severe dyspnea, with coughing accompanying the difficult breathing (Cicmanec et al, 1991).
    1) Death in 3 dogs was attributed to pneumonia and dehydration. Hemosiderosis was prevalent in all affected animals. On necropsy at the end of the study, it was found that nearly all the treated dogs had pneumonia and bronchopneumonia.

Neurologic

    3.7.1) SUMMARY
    A) CNS depression, including sedation and dizziness, may occur following overdoses.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) CNS depressive effects of sedation, dizziness and anxiolytic effects occur unpredictably and without relation to gender, race, age group, or route of drug administration (Stacpoole et al, 1998; Stacpoole et al, 1978; Stacpoole et al, 1983) and appear to be minimal effects in clinical trials with healthy volunteers (Fox et al, 1996). Anxiolytic or sedative effects appear to be common adverse effects of therapy (Sweetman, 2002).
    B) SECONDARY PERIPHERAL NEUROPATHY
    1) Following ingestions, reversible polyneuropathy or peripheral neuropathy may occur. This has been reported most often following chronic ingestions (Sweetman, 2002).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEUROPATHY
    a) Animals given chronic, oral DCA doses (exceeding clinically effective doses) developed reversible polyneuropathy as well as lenticular opacities (Stacpoole et al, 1990).
    b) Stacpoole et al (1979) reported DCA doses of 125, 500, and 2000 mg/kg/day for 90 days in rats were associated with dose-related hind leg paralysis. On discontinuation of the drug, paralytic effects resolved in all animals, but persistent histologic changes in the central nervous system were noted in some animals.
    2) CEREBELLAR SYNDROME
    a) Cicmanec et al (1991) reported significant pathological changes in the cerebrum and cerebellum in DCA treated dogs in a 90 day DCA toxicity study. Doses ranged from 12.5 mg/kg/day to 72 mg/kg/day. Vacuolization of white myelinated tracts was observed in all dogs, with changes present in both the cerebrum and cerebellum in some dogs. Clinical findings included bilateral posterior paresis in some of the dogs during the study.
    b) DCA administered chronically to dogs (up to 100 mg/kg/day for 3 months) produced dose-dependent effects of hind limb weakness and/or paralysis (Katz et al, 1981).

Gastrointestinal

    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DIARRHEA
    a) Dogs receiving mid- to high-doses of DCA (39.5 mg/kg/day and 72 mg/kg/day, respectively) in a 90 day toxicity study, sporadically developed diarrhea. The diarrhea progressively worsened in these animals, ultimately involving the loss of about 750 mL of fluid per day in the most severe cases. Fluid therapy was required to avoid severe dehydration (Cicmanec et al, 1991). In another dog study, oral doses up to 100 mg/kg/day for 3 months resulted in limited cases of emesis and bloody stools (Katz et al, 1981).
    2) PANCREATITIS
    a) In a 90 day DCA toxicity study in dogs, pancreatic acinar degeneration associated with chronic inflammation was noted at necropsy in many of the dogs in the high dose (72 mg/kg/day) and in the mid dose (39.5 mg/kg/day) groups (Cicmanec et al, 1991).

Hepatic

    3.9.1) SUMMARY
    A) Elevations in serum hepatic enzymes and increases in urinary oxalate excretion have been reported.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) One healthy volunteer of 9 in a high dose (100 mg/kg DCA, with repeat dose 8 hours later of 50 mg/kg) pharmacokinetic trial had SGOT (AST) of 58 IU/L (normal 15 to 37 IU/L) and elevated SGPT (ALT) of 84 IU/L (normal 5 to 55 IU/L) (Fox et al, 1996).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATITIS
    a) In a 90-day toxicity study of DCA in dogs, hepatic vacuolar changes and chronic hepatitis were present in 4 high-dose animals (72 mg/kg/day) and one mid-dose (39.5 mg/kg/day) animal as seen on microscopy at necropsy. Hepatic lesions were considered primary lesions. Significant elevations in serum liver enzymes (ALT, AST, LDH) were apparent by trend analyses (Cicmanec et al, 1991).

Genitourinary

    3.10.1) SUMMARY
    A) Dose-related increases in urinary oxalate excretion have been reported.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) Dose-related increases in urinary oxalate excretion have been reported in clinical trials, and may be expected, since oxalate is a known metabolite of DCA (Fox et al, 1996; Curry et al, 1991). As much as a 7-fold increase in urinary oxalate excretion may occur (Shangraw & Fisher, 1996).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) TESTIS DISORDER
    a) In a 90 day DCA toxicity study in dogs, testicular changes with syncytial giant cell formation and degeneration of germinal epithelium were present in most of the DCA treated males (Cicmanec et al, 1991).
    b) Stacpoole et al (1979) reported germinal epithelial degeneration of the testes in rats given 125 to 2000 mg/kg/day of DCA for 90 days.
    c) Male rats with subchronic exposures to sodium DCA demonstrated adverse effects of the reproductive system. The lower doses (31.25 and 62.5 mg/kg) affected the accessory organs and sperm. Higher doses (125 mg/kg) affected the testis (retention of step 19 spermatids into stage 10 seminiferous tubules) (Toth et al, 1992).

Acid-Base

    3.11.1) SUMMARY
    A) DCA is known to decrease serum lactate concentrations.
    3.11.2) CLINICAL EFFECTS
    A) ALKALOSIS
    1) Serum lactate concentrations are expected to decrease following DCA administration due to its effect of oxidizing lactate through activation of pyruvate dehydrogenase (Wahr et al, 1994; Stacpoole, 1989; Stacpoole et al, 1992). Following therapy with a single infusion of 46 mg/kg in malaria patients, lactate concentrations decreased by 23 percent at 15 minutes post-infusion, and a significant increase in arterial blood pH was noted (Krishna et al, 1994).

Hematologic

    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA
    a) In a 90 day DCA toxicity study in dogs, reduced total erythrocyte counts and hemoglobin levels were noted by day 30 of the study in both high-dose (72 mg/kg/day) males and females. Hemoglobin levels dropped in mid-dose (39.5 mg/kg/day) dogs at days 45, 60, 75 and 90, and were found to be significant by trend analyses (Cicmanec et al, 1991).

Endocrine

    3.16.1) SUMMARY
    A) Although not yet reported, overdoses may cause hypoglycemic effects.
    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) Hypoglycemic effects may be expected following massive poisoning with DCA due to inhibition of gluconeogenesis (Stacpoole, 1989; Krishna et al, 1994).
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOGLYCEMIA
    a) In high oral dose rat studies (doses up to 2000 mg/kg/day for 3 months), significant dose-related depressions of serum glucose occurred in all treated animals (Katz et al, 1981).

Reproductive

    3.20.1) SUMMARY
    A) Human data concerning reproductive effects of DCA are currently unavailable.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) No data is currently available concerning human teratogenic effects (IARC, 1995).
    B) ANIMAL STUDIES
    1) Altered development of the heart and major vessels, and less frequently, the kidneys and the orbits of the eyes was reported in fetuses of female rats following DCA doses of 140 to 2400 mg/kg/day on days 6 to 15 of gestation (Smith et al, 1992; IARC, 1995). Within the cardiovascular system, defects between the ascending aorta and the right ventricle were predominant. Skeletal malformations were not reported.
    2) The no observed adverse effect level (NOAEL) for developmental DCA toxicity in the rat is 14 mg/kg/day (Smith et al, 1992).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS79-43-6 (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: Dichloroacetic acid
    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.
    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) Carcinogenicity has not been proven in humans. Available data is limited (IARC, 1995).
    2) IARC has classified DCA as group 3 (not classifiable as to its carcinogenicity to humans) (IARC, 1995).
    3.21.4) ANIMAL STUDIES
    A) HEPATIC CARCINOMA
    1) Oral administration of DCA to male mice produced an increased incidence of hepatocellular adenomas and carcinomas in 4 separate studies (IARC, 1995).
    2) Stauber & Bull (1997) reported that DCA-induced hepatic lesions in male mice displayed immunoreactivity to anti-c-Jun and anti-c-Fos antibodies, and were predominantly basophilic, and contained only small amounts of glycogen relative to surrounding hepatocytes.

Genotoxicity

    A) Studies have concluded that DCA is weakly mutagenic but should not be mutagenic at levels commonly found in drinking water.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs in all symptomatic patients.
    B) Serum DCA levels are not clinically useful or readily available.
    C) Monitor CBC, serum electrolyte levels, and renal and hepatic function tests in all symptomatic patients.
    D) Arterial blood gases and/or pulse oximetry and pulmonary function tests may be advisable in patients with respiratory symptoms.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Measure hemoglobin and hematocrit in symptomatic patients. Animal studies have shown decreased hemoglobin levels in poisonings (Cicmanec et al, 1991).
    B) BLOOD/SERUM CHEMISTRY
    1) Measure serum electrolytes in symptomatic patients, especially in the presence of fluid losses.
    2) Monitor renal and hepatic function tests in all symptomatic patients.
    4.1.3) URINE
    A) URINALYSIS
    1) Microscopic examination of the urine for oxalate crystals may be beneficial in symptomatic patients, since oxalate is a potentially toxic metabolite of dichloroacetate, and may predict renal toxicity (Stacpoole, 1989).
    4.1.4) OTHER
    A) OTHER
    1) ELECTROPHYSIOLOGICAL TESTING
    a) Patients with clinical symptoms of neuropathy may require nerve conduction velocity testing to monitor progression or regression of peripheral neuropathies. In most cases, peripheral neuropathy has been reversible (Stacpoole et al, 1998).
    2) MONITORING
    a) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
    3) PULMONARY FUNCTION TESTS
    a) If respiratory tract irritation is present, it may be useful to monitor pulmonary function tests.

Methods

    A) CHROMATOGRAPHY
    1) Stacpoole et al (1998) developed and validated a gas chromatography/mass spectrometry (GC-MS) technique to simultaneously measure DCA and its metabolites in plasma and urine. Shangraw & Fisher (1996) used a GC-MS assay which is sensitive to a DCA concentration of 0.4 mcg/mL with a coefficient of variation of 2.4 percent at that concentration.
    2) Krishna et al (1994) describe a gas chromatography with an electron capture detector (GC-ECD) method for analysis of DCA in serum.
    3) Yan et al (1997) developed a gas chromatography-mass spectrometry (GC-MS) method for the simultaneous quantitative measurement of lactate, DCA and its metabolites, monochloroacetate, glyoxylate, glycolate, and oxalate in human plasma. Quantitation limits of DCA and its metabolites range between 0.3 and 1.5 mcmol.
    4) A rapid microassay for serum DCA concentrations by gel-permeation high performance liquid chromatography has been developed. This method requires a very minimal amount of serum (10 microliters) and has a short analysis time (20 minutes) (Sakakihara et al, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Carefully observe patients with parenteral exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Monitoring

    A) Monitor vital signs in all symptomatic patients.
    B) Serum DCA levels are not clinically useful or readily available.
    C) Monitor CBC, serum electrolyte levels, and renal and hepatic function tests in all symptomatic patients.
    D) Arterial blood gases and/or pulse oximetry and pulmonary function tests may be advisable in patients with respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/ NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific treatment for dichloroacetate overdose other than supportive care.
    B) MONITORING OF PATIENT
    1) Monitor vital signs in all symptomatic exposures. Monitor fluid status as indicated in patients with symptoms of severe diarrhea or vomiting.
    C) AIRWAY MANAGEMENT
    1) Treat respiratory depression with assisted ventilation.
    D) THIAMINE
    1) Animal studies suggest that the neuropathy seen with dichloroacetate administration may be secondary to thiamine deficiency (Stackpoole et al, 1990). Human studies are not available and an optimal dose has not been established.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.

Eye Exposure

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

Dermal Exposure

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

Enhanced Elimination

    A) HEMODIALYSIS
    1) DCA is a small molecule that is totally ionized at biological pH and is dialyzable. Curry et al (1991) demonstrated an increased DCA clearance of approximately 60% during dialysis in 7 patients undergoing routine thrice weekly hemodialysis for endstage renal failure, who participated in a pharmacokinetic and pharmacodynamic study of DCA. The hemodialysis had no effect on the apparent volume of distribution of DCA. Dialysis increased plasma clearance of DCA, but had minimal influence on the metabolic effects of the drug.

Abstracts

Case Reports

    A) CHRONIC EFFECTS
    1) ADULT
    a) Moore et al (1979) reported polyneuropathy in a 21-year-old male 16 weeks after starting therapy with DCA (3 grams orally once daily) for hypercholesteremia. The patient's distal muscle groups were most severely affected. Tingling in the fingers and toes were primary complaints. Decreased strength in facial and finger muscles was noted on physical examination, as well as decreased to absent deep tendon reflexes and decreased strength in lower extremity muscle groups.
    1) EMG recordings revealed denervation changes in the intrinsic foot and distal leg muscles. Conduction velocity was slowed in both posterior tibial nerves. Eight weeks after discontinuation of DCA, symptoms had improved. Six months after stopping DCA, normal motor strength, increased deep tendon reflexes and significant improvement on electromyographic and nerve conduction examination was reported.

Range Of Toxicity

Summary

    A) No acute poisonings have been reported in humans at the time of this review. Doses of 150 milligrams/kilogram intravenously and 150 milligrams/kilogram orally have been well tolerated.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) ORAL -
    a) Healthy male and female subjects have received oral doses of 25 milligrams/kilogram, and 250, 25, and 2.5 micrograms/kilogram/day sequentially in pharmacokinetic studies (Stacpoole et al, 1998).
    b) A young adult received oral daily doses of 50 milligrams/kilogram for 4 months for treatment of familial hypercholesterolemia (Stacpoole, 1989).
    c) Adults with diabetes mellitus and/or hyperlipoproteinemia have been treated with 3 to 4 grams per day of sodium dichloroacetate for 6 to 7 days (Stacpoole et al, 1978).
    2) INTRAVENOUS -
    a) Healthy male and female subjects have received intravenous doses of 25 milligrams/kilogram and 250 micrograms/kilogram in single doses for pharmacokinetic studies (Stacpoole et al, 1998) or 30 to 100 milligrams/kilogram and a repeated dose (15 to 30 milligrams/kilogram) 8 hours later (Fox et al, 1996).
    b) Patients with metabolic or cardiovascular disorders are generally given 50 milligrams/kilogram as an intravenous infusion over 20 to 30 minutes (Stacpoole et al, 1988; (Stacpoole et al, 1992; Stacpoole et al, 1983; Blackshear et al, 1982) which may be repeated 12 hours later (Krishna et al, 1996).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) CONGENITAL LACTIC ACIDOSIS (CLA) - Children with CLA due to pyruvate dehydrogenase enzyme complex (PDC) deficiency have been treated investigationally with several months of DCA therapy at 50 to 100 milligrams/kilograms/day orally (Stacpoole et al, 1998). One child was effectively treated with a DCA dose of 150 milligrams/kilogram/day orally (Coude et al, 1978)

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) A minimum therapeutic serum level of 130 milligrams/liter of dichloroacetate for treating lactic acidosis should be maintained (Sakakihara et al, 1994).

Workplace Standards

    A) ACGIH TLV Values for CAS79-43-6 (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) Dichloroacetic acid
    a) TLV:
    1) TLV-TWA: 0.5 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Skin
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): URT and eye irr; testicular dam
    d) Molecular Weight: 128.95
    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 CAS79-43-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS79-43-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Dichloroacetic acid
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not applicable. This substance was not assessed using the EPA's 1986 cancer guidelines. ; Listed as: Dichloroacetic acid
    3) 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: Dichloroacetic acid
    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.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS79-43-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 2820 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) DCA acts by stimulating peripheral glucose use and inhibiting gluconeogenesis, thus lowering blood sugar levels in animals and humans with diabetes mellitus (Stacpoole, 1989).
    B) Oxidation of lactate is facilitated by DCA through activation of pyruvate dehydrogenase in patients with acquired and congenital forms of lactic acidosis (IARC, 1995; Kodama et al, 1986). DCA activates the regulatory enzyme pyruvate, thus decreasing formation of lactic acid from pyruvate (Gore et al, 1996). Additionally, DCA inhibits the specific tubular reabsorption of lactate and pyruvate, with increased urinary excretion of these substances; but these urinary increments are small (Kodama et al, 1986). The main factor lowering plasma lactate and pyruvate is the activation of PDH.
    C) DCA is used in the treatment of myocardial ischemia due to its effect of activating pyruvate dehydrogenase and increasing oxidative phosphorylation (Wahr et al, 1994; Stacpoole, 1989). When oxygen delivery to heart muscle is limited in ischemic events, a shift from fatty acid to carbohydrate oxidation may increase the ratio of ATP production:oxygen consumption. DCA improves cardiac output and left ventricular mechanical efficiency under ischemic conditions, and may also have some inotropic properties.
    D) Dimlich et al (1989) demonstrated in rats with induced cerebral ischemia, a lactic acidosis that was more severe in tissue where there were increased stores of glucose and glycogen. DCA reduced the dangerously elevated brain lactate, with a dose-related effect, and without a direct effect on glucose and glycogen.
    E) Ferrando et al (1998) have shown that DCA stimulates pyruvate oxidation which subsequently increases the level of intramuscular glutamine in severely burned patients. The acute elevation of glutamine did not affect skeletal muscle protein synthesis. The author suggests that a particular level of restoration or maintenance of intracellular glutamine concentration may be necessary to affect muscle protein synthesis.
    1) Due to the ability of DCA to stimulate de novo synthesis of glutamine in skeletal muscle, a potential therapy exists to counteract injury-induced muscle catabolism.
    F) Long-term dosing with DCA reduces plasma triglyceride and cholesterol levels (IARC, 1995). In hypercholesterolemic animals and humans, DCA has been shown to inhibit HMG CoA reductase activity in rat liver and human leukocytes. This may occur by decreasing both the catalytic activity of the enzyme and the total mass of enzyme protein (Stacpoole, 1989). DCA analogs that are not metabolized to glyoxylate fail to inhibit HMG CoA reductase.

Toxicologic Mechanism

    A) Reversible peripheral neuropathy induced by DCA may result from a thiamine deficiency due to an increased demand for this vitamin during DCA therapy (Stacpoole, 1989; Stacpoole et al, 1990) and may be preventable with co-administration of thiamine. Another possible mechanism for neuropathy during DCA therapy is an increase in oxalate excretion, which is known to cause both peripheral neuropathy and cataracts (Stacpoole, 1989).
    B) The sodium salt of dichloroacetate has direct effects on central nervous system function; however, the sites and mechanisms for these effects are unknown (Stacpoole, 1989).

Physicochemical

Physical Characteristics

    A) Dichloroacetic acid is a colorless to slightly yellowish liquid with a pungent acid-like odor (Budavari, 1996). In aqueous solution, dichloroacetic acid and dichloroacetate exist as an equilibrium mixture, the proportions of each depending mostly on the pH of the solution.
    B) Sodium dichloroacetate is a bitter-tasting, odorless, white compound (Stacpoole, 1989). It is hydroscopic, but stable in both solid and aqueous states. When sodium DCA is heated to decomposition, it emits toxic fumes of Cl and Na2O (Lewis, 1996).

Molecular Weight

    A) 150.92 (sodium dichloroacetate)

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) 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.
    5) 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.
    6) 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.
    7) 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.
    8) 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.
    9) 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.
    10) 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.
    11) 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.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    14) 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.
    15) Blackshear PJ, Fang LT, & Axelrod L: Treatment of severe lactic acidosis with dichloroacetate. Diabetes Care 1982; 5:391-394.
    16) Budavari S: The Merck Index, 12th ed, Merck & Co, Inc, Rahway, NJ, 1996.
    17) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    18) Caravati EM, Knight HH, & Linscott MS: Esophageal laceration and charcoal mediastinum complicating gastric lavage. J Emerg Med 2001; 20:273-276.
    19) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    20) Cicmanec JL, Condie LW, & Olson GR: 90-day toxicity study of dichloroacetate in dogs. Fund Appl Toxicol 1991; 17:376-389.
    21) Coude FX, Saudubray JM, & DeMaugre F: Dichloroacetate as treatment for congenital lactic acidosis (letter). New Engl J Med 1978; 299:1365-1366.
    22) Curry SH, Lorenz A, & Chu PI: Disposition and pharmacodynamics of dichloroacetate (DCA) and oxalate following oral DCA doses. Biopharm Drug Dis 1991a; 12:375-390.
    23) Curry SH, Lorenz A, & Henderson GN: Haemodialysis studies with dichloroacetate. Eur J Clin Pharmacol 1991; 40:613-617.
    24) 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.
    25) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    26) 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/.
    27) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    28) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    29) Fox AW, Yang X, & Murli H: Absence of mutagenic effects of sodium dichloroacetate. Fund Appl Toxicol 1996; 32:87-95.
    30) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    31) Gonzalez-Leon A, Schultz IR, & Xu G: Pharmacokinetics and metabolism of dichloroacetate in the F344 rat after prior administration of drinking water. Toxicol Appl Pharmacol 1997; 146:189-195.
    32) Gore DC, Jahoor F, & Hibbert JM: Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability. Ann Surgery 1996; 224:97-102.
    33) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    34) Grant WM & Schuman JS: Toxicology of the Eye, 4th ed, Charles C Thomas, Springfield, IL, 1993.
    35) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    36) Harrington-Brock K, Doerr CL, & Moore MM: Mutagenicity of three disinfection by-products: di-and trichloroacetic acid and chloral hydrate in L5178Y/TK +/- -3.7.2C mouse lymphoma cells. Mutation Res 1998; 413:265-276.
    37) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    38) 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.
    39) 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.
    40) 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.
    41) 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.
    42) 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.
    43) IARC: Dichloroacetic acid, 63, International Agency for Research on Cancer, World Health Organization, Geneva, Switzerland, 1995, pp 271-290.
    44) 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.
    45) 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.
    46) 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.
    47) Katz R, Tai CN, & Diener RM: Dichloroacetate, sodium: 3-month oral toxicity studies in rats and dogs. Toxicol Appl Pharmacol 1981; 57:273-287.
    48) Kodama H, Yamaguchi S, & Okabe I: Renal effects of dichloroacetate in vivo. Clinica Chimica Acta 1986; 160:265-271.
    49) Krishna S, Agbenyega T, & Angus BJ: Pharmacokinetics and pharmacodynamics of dichloroacetate in children with lactic acidosis due to severe malaria. Q J Med 1995; 88:341-349.
    50) Krishna S, Supanaranond W, & Pukrittayakamee S: Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. Metabolism 1994; 43:974-981.
    51) Krishna S, Supanaranond W, & Pukrittayakamee S: The disposition and effects of two doses of dichloroacetate in adults with severe falciparum malaria. Br J Clin Pharmacol 1996; 41:29-34.
    52) Kurlemann G, Paetzke I, & Moller H: Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy. Eur J Pediatr 1995; 154:928-932.
    53) Lewis RJ: Sax's Dangerous Properties of Industrial Materials, 9th ed, Van Nostrand Reinhold, New York, NY, 1996.
    54) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    55) 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.
    56) 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.
    57) 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.
    58) 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.
    59) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    60) 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.
    61) 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.
    62) 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.
    63) 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.
    64) 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.
    65) 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.
    66) 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.
    67) 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.
    68) 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.
    69) 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.
    70) 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.
    71) 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.
    72) 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.
    73) 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.
    74) 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.
    75) 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.
    76) 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.
    77) 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.
    78) 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.
    79) 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.
    80) 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.
    81) 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.
    82) 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.
    83) 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.
    84) 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.
    85) 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.
    86) 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.
    87) 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.
    88) 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.
    89) 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.
    90) 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.
    91) 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.
    92) 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.
    93) 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.
    94) 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.
    95) 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.
    96) 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.
    97) 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.
    98) 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.
    99) 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.
    100) 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.
    101) 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.
    102) 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.
    103) 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.
    104) 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.
    105) 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.
    106) 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.
    107) 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.
    108) 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.
    109) 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.
    110) 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.
    111) 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.
    112) 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.
    113) 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.
    114) 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.
    115) 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.
    116) 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.
    117) 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.
    118) 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.
    119) 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.
    120) 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.
    121) 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.
    122) 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.
    123) 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.
    124) 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.
    125) 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.
    126) 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.
    127) 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.
    128) 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.
    129) 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.
    130) 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.
    131) 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.
    132) 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.
    133) 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.
    134) 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.
    135) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    136) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    137) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    138) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    139) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    140) Okabe I, Kodama H, & Shimoizumi H: Treatment of lactic acidosis: effects of dichloroacetate on lactate and pyruvate levels in the cerebrospinal fluid (letter). Eur J Pediatr 1986; 145:159.
    141) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    142) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    143) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    144) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    145) S Sweetman : Martindale: The Complete Drug Reference. Pharmaceutical Press. London, UK (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    146) Sakakihara Y, Nakamura G, & Tokoeda Y: A rapid microassay for dichloroacetate in serum by gel-permeation chromatography. Eur J Clin Chem Clin Biochem 1994; 32:79-83.
    147) Shangraw RE & Fisher DM: Pharmacokinetics of dichloroacetate in patients undergoing liver transplantation. Anethesiology 1996; 84:851-858.
    148) Smith MK, Randall JL, & Read EJ: Developmental toxicity of dichloroacetate in the rat. Teratology 1992; 46:217-223.
    149) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    150) Stacpoole PW, Harman EM, & Curry SH: Treatment of lactic acidosis with dichloroacetate. New Engl J Med 1983; 309:390-396.
    151) Stacpoole PW, Harwood HJ, & Cameron DF: Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats. Fund Appl Toxicol 1990; 14:327-337.
    152) Stacpoole PW, Henderson GN, & Yan Z: Clinical pharmacology and toxicology of dichloroacetate. Environ Health Perspect 1998; 106:989-994.
    153) Stacpoole PW, Moore GW, & Kornhauser DM: Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. New Engl J Med 1978; 298:526-530.
    154) Stacpoole PW, Moore GW, & Kornhauser DM: Toxicity of chronic dichloroacetate (letter). New Engl J Med 1979; 300:372.
    155) Stacpoole PW, Wright EC, & Baumgartner TG: A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. N Engl J Med 1992; 327:1564-1569.
    156) Stacpoole PW: The pharmacology of dichloroacetate. Metabolism 1989; 38:1124-1144.
    157) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    158) Toth GP, Kelty KC, & George EL: Adverse male reproductive effects following subchronic exposure of rats to sodium dichloroacetate. Fund Appl Toxicol 1992; 19:57-63.
    159) 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.
    160) 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.
    161) 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-.
    162) 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.
    163) 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.
    164) 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.
    165) 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.
    166) 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-.
    167) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    168) 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.
    169) Vale JA, Kulig K, American Academy of Clinical Toxicology, et al: Position paper: Gastric lavage. J Toxicol Clin Toxicol 2004; 42:933-943.
    170) Vale JA: Position Statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:711-719.
    171) Wahr JA, Childs KF, & Bolling SF: Dichloroacetate enhances myocardial functional and metabolic recovery following global ischemia. J Cardiothor Vasc Anesth 1994; 8:192-197.
    172) Yan Z, Henderson GN, & James MO: Determination of dichloroacetate and its metabolites in human plasma by gas chromatography-mass spectrometry. J Chromatography B 1997; 703:75-84.