Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

CHLORAMBUCIL

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Chlorambucil is an aromatic nitrogen mustard derivative and alkylating agent that interferes with DNA replication. It is used to treat patients with chronic lymphatic (lymphocytic) leukemia, malignant lymphomas, including lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease.

Specific Substances

    1) 4-(bis(2-chloroethyl)amino)benzenebutanoic acid
    2) CB 1348
    3) Chloraminophene
    4) Chloroambucil
    5) N,N-di-2-chloroethyl-gamma-para-aminophenylbutyric acid
    6) CAS 305-03-3
    1.2.1) MOLECULAR FORMULA
    1) C14-H19-Cl2-N-O2

Available Forms Sources

    A) FORMS
    1) Chlorambucil is available as 2 mg oral tablets (Prod Info LEUKERAN(R) oral tablets, 2011).
    B) USES
    1) Chlorambucil is used to treat patients with chronic lymphatic (lymphocytic) leukemia, malignant lymphomas, including lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease (Prod Info LEUKERAN(R) oral tablets, 2011).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Chlorambucil is used to treat patients with chronic lymphatic (lymphocytic) leukemia, malignant lymphomas, including lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease.
    B) PHARMACOLOGY: Chlorambucil is an aromatic nitrogen mustard derivative and alkylating agent that interferes with DNA replication and induces cellular apoptosis by accumulation of cytosolic p53 and activation of the apoptosis promoter, BAX.
    C) TOXICOLOGY: After an overdose, the effects of decreased DNA synthesis and cell death are noticed primarily in organ systems with rapidly dividing cells (bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: Overdose is rare, but can be life-threatening.
    E) WITH THERAPEUTIC USE
    1) Myelosuppression is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Leukopenia, thrombocytopenia, neutropenia, anemia, and pancytopenia have been reported. Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks. Bone marrow effects are most often reversible; however, irreversible bone marrow failure has been reported. INFREQUENT: Nausea, vomiting, diarrhea, and oral ulceration. RARE: Tremors, muscular twitching, myoclonus, confusion, agitation, ataxia, flaccid paresis, hallucinations, seizures, skin hypersensitivity reactions (eg, rashes, urticaria, angioedema, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), pulmonary fibrosis, hepatotoxicity, jaundice, drug fever, peripheral neuropathy, and interstitial pneumonia.
    F) WITH POISONING/EXPOSURE
    1) Excessive dosage or prolonged administration can induce severe myelosuppression. Patients who receive a total of 6.5 mg/kg or more in one course of therapy with continuous dosing are most likely to develop severe neutropenia. Nausea, vomiting, acute renal failure, agitation, irritability, ataxia, muscle twitching, seizures, lethargy, myoclonus, and coma have also been reported.
    0.2.20) REPRODUCTIVE
    A) Chlorambucil is classified as FDA pregnancy category D. Chlorambucil use during pregnancy resulted in congenital anomalies, particularly unilateral renal agenesis, in humans and animals. Chlorambucil was shown to induce prolonged or permanent azoospermia in adult males and amenorrhea in females. Permanent and reversible sterility was also noted in both sexes with a high incidence found in prepubertal and pubertal males. It is not known whether chlorambucil is present in breast milk.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor renal function and liver enzymes.
    D) Monitor serum electrolytes.
    E) Monitor serial CBC with differential with platelet count. Myelosuppression (eg, leukopenia, neutropenia, thrombocytopenia, anemia, and pancytopenia) is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks.
    F) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) after large overdose as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe CNS or respiratory symptoms or acute allergic reactions.
    E) ANTIDOTE
    1) None.
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    G) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    H) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    I) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    J) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of benefit due to high protein binding and large volume of distribution.
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients with a chlorambucil overdose need to be admitted, as toxicity develops over several days. Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an chlorambucil overdose. In addition, consultation with an infectious disease physician with expertise in the management of neutropenic patients with infections is strongly recommended.
    4) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    L) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking chlorambucil may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity).
    M) PHARMACOKINETICS
    1) Tmax: Oral: 0.83 +/- 0.53 hour (chlorambucil); 1.9 +/- 0.7 hours (major metabolite phenylacetic acid mustard (PAAM)). Bioavailability: Oral: 70% to 80%. Protein binding: Albumin: 99% (in-vitro). Vd: 0.31 L/kg. Metabolism: Chlorambucil is primarily metabolized in the liver to phenylacetic acid mustard (PAAM), the major active metabolite. Renal excretion: 20% to 60% of radioactivity is observed in the urine; however, less than 1% is in the form chlorambucil or its major metabolite, phenylacetic acid mustard (PAAM). Elimination half-life: 1.5 hours; phenylacetic acid mustard: 1.8 +/- 0.4 hours.
    N) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or neurotoxicity.

Range Of Toxicity

    A) TOXICITY: Dosages ranging from 0.125 to 6.8 mg/kg in children and 5 to 250 mg/day in adults have resulted in seizures. Irreversible bone marrow damage and neutropenia may occur at doses greater than 6.5 mg/kg total dose. THERAPEUTIC DOSE: ADULTS; varies by course; initial or short course, 0.1 to 0.2 mg/kg/day (about 4 to 10 mg/day for the average patient) orally for 3 to 6 weeks. Intermittent, biweekly, or once-monthly pulse course, initially with a single dose of 0.4 mg/kg orally, increased by 0.1 mg/kg to produce mild hematologic toxicity, until control of lymphocytosis, or toxicity. CHILDREN: Safety and effectiveness in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Chlorambucil is used to treat patients with chronic lymphatic (lymphocytic) leukemia, malignant lymphomas, including lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease.
    B) PHARMACOLOGY: Chlorambucil is an aromatic nitrogen mustard derivative and alkylating agent that interferes with DNA replication and induces cellular apoptosis by accumulation of cytosolic p53 and activation of the apoptosis promoter, BAX.
    C) TOXICOLOGY: After an overdose, the effects of decreased DNA synthesis and cell death are noticed primarily in organ systems with rapidly dividing cells (bone marrow, gastrointestinal tract).
    D) EPIDEMIOLOGY: Overdose is rare, but can be life-threatening.
    E) WITH THERAPEUTIC USE
    1) Myelosuppression is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Leukopenia, thrombocytopenia, neutropenia, anemia, and pancytopenia have been reported. Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks. Bone marrow effects are most often reversible; however, irreversible bone marrow failure has been reported. INFREQUENT: Nausea, vomiting, diarrhea, and oral ulceration. RARE: Tremors, muscular twitching, myoclonus, confusion, agitation, ataxia, flaccid paresis, hallucinations, seizures, skin hypersensitivity reactions (eg, rashes, urticaria, angioedema, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), pulmonary fibrosis, hepatotoxicity, jaundice, drug fever, peripheral neuropathy, and interstitial pneumonia.
    F) WITH POISONING/EXPOSURE
    1) Excessive dosage or prolonged administration can induce severe myelosuppression. Patients who receive a total of 6.5 mg/kg or more in one course of therapy with continuous dosing are most likely to develop severe neutropenia. Nausea, vomiting, acute renal failure, agitation, irritability, ataxia, muscle twitching, seizures, lethargy, myoclonus, and coma have also been reported.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Drug fever has been associated with chlorambucil therapy presenting as fever, rigors, and malaise within hours to days of chlorambucil therapy initiation, often following a drug-free interval. Other symptoms include skin rash, lymphadenopathy, vomiting, diarrhea and hypotension, which resolve upon discontinuation of chlorambucil and reoccurs within the same time period when chlorambucil is reinitiated (Weber et al, 2007).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: Transient blindness was reported in one child who had received 1.5 mg/kg per day (32 mg total). This has not been a common finding (Ammenti et al, 1980). Another case involving blindness with optic atrophy has been reported (Yiannakis & Larner, 1993).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Chlorambucil administration has been associated with the occurrence of acute pneumonitis, interstitial pneumonia, and pulmonary infiltrates. In addition, one case of noncardiogenic pulmonary edema has been reported (Prod Info LEUKERAN(R) oral tablets, 2011; Crestani et al, 1994; Braunwald et al, 1990; Cannon, 1990).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Tremors, muscular twitching, myoclonia, confusion, ataxia, and flaccid paresis have occurred following chlorambucil administration; however, resolution occurs following discontinuation of the drug. Peripheral neuropathy and, rarely, seizures have also been reported (Prod Info LEUKERAN(R) oral tablets, 2011).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) ADULTS: Seizures in adult patients receiving chlorambucil are rare; the majority of cases have occurred in patients who received high-dose chlorambucil. However, patients with an underlying seizure focus may have seizures precipitated by lower doses of pulse chlorambucil (Salloum et al, 1997).
    b) PEDIATRICS: There is a relatively high incidence of chlorambucil-induced seizures in children treated for nephrotic syndrome (Salloum et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Seizures have been reported in both adults and children (Wolfson & Olney, 1957; Byrne et al, 1981; Blank et al, 1983; Salloum et al, 1997).
    b) Onset is within 1.5 to 5 hours after chlorambucil overdose via ingestion. This is a rare side effect during therapeutic or slightly higher doses. Onset of seizures have been reported up to 90 days after initiation of therapy (LaDelfa et al, 1985; Williams et al, 1978; Naysmith & Robson, 1979; Salloum et al, 1997).
    c) During the seizures, generalized slowing of EEG activity in the theta and/or delta range occurs. Additionally, frequent abnormal spike-wave activity without focus is observed (Alberts et al, 1979; McLean et al, 1979; Pradhan & Marsan, 1963).
    C) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Coma developed 5 hours after a 2.5-year-old child ingested a single dose of chlorambucil 5 mg/kg (Wolfson & Olney, 1957).
    D) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Agitation and irritability developed after a 2-year-old ingested a single dose of chlorambucil 20 mg (Green & Naiman, 1968).
    E) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Ataxia has occurred in several cases (Green & Naiman, 1968; Wolfson & Olney, 1957).
    b) CASE REPORT: Ataxia and muscle twitching were reported in a 3.5-year-old who ingested 1.5 to 6.8 mg/kg (exact dose unknown) of chlorambucil (Byrne et al, 1981).
    F) DROWSY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Lethargy, staring spells, intermittent episodes of irritability, myoclonic-like muscle jerks, vomiting, and an exaggerated startle reflex occurred in a 22-month-old within 6 hours following an ingestion of 3.2 mg/kg of chlorambucil (Vandenberg et al, 1988).
    G) MYOCLONUS
    1) WITH THERAPEUTIC USE
    a) Chlorambucil-induced myoclonus in two elderly adults receiving low doses for treatment of lymphoma. This is the first report of myoclonus at low doses in persons with no previous history (Wyllie et al, 1997).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Chlorambucil, given to experimental animals in doses ranging from 3 to 40 mg/kg has created EEG patterns similar to "petit mal" seizures. The results have been reproducible (Ehrsson et al, 1981). The threshold of neurotoxicity appears to be higher in older animals (Williams et al, 1978).
    b) As much as 50 mg/kg have been given to rats orally in a single dose. These animals recovered after symptoms of bradycardia, salivation, hematuria, dyspnea and seizures (Prod Info LEUKERAN(R) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Although reported infrequently, nausea and vomiting have occurred following chlorambucil administration. Single oral doses of 20 mg or more may also cause nausea and vomiting (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have been reported with single oral doses of 20 mg or more; gastrointestinal upset and anorexia may persist for several days (Byrne et al, 1981; Green & Naiman, 1968).
    b) CASE REPORT: A 2-year-old who ingested 1.5 mg/kg developed gastrointestinal upset 1.4 hours post ingestion. Anorexia and intermittent vomiting continued for the next 48 hours (Green & Naiman, 1968).
    c) CASE REPORT: Persistent vomiting was also seen 4 hours after a 3.5-year-old ingested between 1.5 to 6.8 mg/kg of chlorambucil (Byrne et al, 1981).
    B) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) Oral ulceration has rarely been reported with chlorambucil therapy (Prod Info LEUKERAN(R) oral tablets, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicity and jaundice have been reported following chlorambucil administration (Prod Info LEUKERAN(R) oral tablets, 2011; Braunwald et al, 1990).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Acute renal failure NOT associated with rhabdomyolysis was reported in a 38-year-old man who ingested 250 mg in a single dose (Blank et al, 1983).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Myelosuppression is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Leukopenia, thrombocytopenia, neutropenia, and anemia have been reported (Ezlindi & Stutzman, 1965; Galton, 1961; Masturon, 1960). Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks (Prod Info LEUKERAN(R) oral tablets, 2011; Knoben & Anderson, 1988b).
    b) Bone marrow effects are most often reversible; however, irreversible bone marrow failure has been reported. Excessive dosage or prolonged administration can induce severe bone marrow depression (Prod Info LEUKERAN(R) oral tablets, 2011; Krakoff, 1971). Patients who receive a total of 6.5 mg/kg or more in one course of therapy with continuous dosing are most likely to develop severe neutropenia (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Excessive dosage or prolonged administration can induce severe bone marrow depression (Prod Info LEUKERAN(R) oral tablets, 2011; Krakoff, 1971). As the total dose approaches 6.5 mg/kg, there is a risk of causing irreversible bone marrow damage (Prod Info LEUKERAN(R) oral tablets, 2011).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia is a common side effect of chlorambucil therapy (Prod Info LEUKERAN(R) oral tablets, 2011).
    C) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia is a common side effect of chlorambucil therapy (Prod Info LEUKERAN(R) oral tablets, 2011).
    D) ACUTE LEUKEMIA
    1) WITH THERAPEUTIC USE
    a) Acute leukemia has been reported. The risk increases with both chronicity and the size of the cumulative dose (Prod Info LEUKERAN(R) oral tablets, 2011; Cameron, 1977; Kauppi et al, 1996).
    E) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Many patients develop a slowly progressive lymphopenia while on treatment; levels will rapidly return to normal soon after the completion of drug therapy (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: The lymphocyte nadir (900/mm(3)) occurred 19 days following an ingestion of 3.2 mg/kg in a 22-month-old child, with resolution by 23 days postingestion (Vandenberg et al, 1988).
    F) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia is usually present after 3 weeks of therapy and is dose-related. The neutrophil count may continue to decline for up to 10 days after the last dose, but it usually rapidly returns to normal. Patients who receive a total of 6.5 mg/kg or more in one course of therapy with continuous dosing are most likely to develop severe neutropenia (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: The white blood cell nadir (4300/mm(3)) occurred 7 days following an ingestion of 3.2 mg/kg in a 22-month-old child with resolution by 23 days postingestion (Vandenberg et al, 1988).
    G) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Pancytopenia is a common side effect of chlorambucil therapy (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Pancytopenia was the primary finding reported after overdose with chlorambucil (Green & Naiman, 1968; Enck & Bennett, 1977).
    H) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia is a common side effect of chlorambucil therapy (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: The thrombocyte nadir (166000/mm(3)) occurred 19 days following an ingestion of 3.2 mg/kg of chlorambucil in a 22-month-old child, with resolution by 23 days postingestion (Vandenberg et al, 1988).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 61-year-old previously healthy woman with Stage IV, poorly differentiated, nodular, histiocytic lymphoma developed erythematous urticarial-like plaques over nose and cheeks and periorbital edema following eight days of treatment with chlorambucil 4 mg daily. This reaction recurred upon rechallenge (Peterman & Braunstein, 1986).
    B) GENERALIZED EXFOLIATIVE DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Three cases of chlorambucil-related skin eruption were confirmed by exclusion of other drugs, rechallenge and skin testing. In one case, a 72-year-old man developed exfoliative dermatitis after 6 weeks on chlorambucil 8 mg daily (Hitchins et al, 1987).
    C) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Skin hypersensitivity reactions including rare reports of skin rash progressing to erythema multiforme, and Stevens-Johnson syndrome have been reported. Allergic reactions such as urticaria and angioedema have also been reported following initial or subsequent dosing (Prod Info LEUKERAN(R) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Chlorambucil is classified as FDA pregnancy category D. Chlorambucil use during pregnancy resulted in congenital anomalies, particularly unilateral renal agenesis, in humans and animals. Chlorambucil was shown to induce prolonged or permanent azoospermia in adult males and amenorrhea in females. Permanent and reversible sterility was also noted in both sexes with a high incidence found in prepubertal and pubertal males. It is not known whether chlorambucil is present in breast milk.
    3.20.2) TERATOGENICITY
    A) RENAL ABNORMALITIES
    1) Unilateral renal agenesis has been reported in two offspring after the mothers received chlorambucil during the first trimester of pregnancy (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) Unilateral renal agenesis (failure of the kidney to develop on one side) was reported in aborted fetuses of two women, one with Hodgkins disease and the other with systemic lupus erythematosus treated with chlorambucil (Steege & Caldwell, 1980). The left kidney and ureter were absent in a fetus exposed to 6 mg/day for the first 3.5 months of gestation, but 2 other fetuses exposed to maternal doses of 10 mg/day for 2 weeks at 4.5 months followed by 10 mg/day for 4 weeks at 5 to 6 months, and 378 mg/22 days in the 7th month, were apparently normal at delivery (IARC, 1975).
    B) ANIMAL STUDIES
    1) CONGENITAL ANOMALIES
    a) Reduced brain size and microcephaly were seen in animal fetuses exposed to chlorambucil on day 9, 10, 11, or 12 (Tanaka et al, 1991). Tail, cranial, and limb defects occurred in animal fetuses exposed to chlorambucil on day 10, 11, 12 or 13 of gestation (Salder & Kochhar, 1975).
    b) Defects of the retina, lenses, and optic nerves have been produced in animals with prenatal maternal administration (Grant, 1986).
    2) RENAL ABNORMALITIES
    a) Urogenital malformations, including absence of a kidney, were reported in fetuses after pregnant animals were treated with chlorambucil (Prod Info LEUKERAN(R) oral tablets, 2011).
    b) Up to 40% of ICR animal embryos exposed to chlorambucil by maternal administration on day 13 of gestation have shown neural tube defects (Ando et al, 1990). Stunted growth and limb defects were seen in fetal animals maternally exposed IP to 9.5 mg/kg on day 14 of gestation (Brummett & Johnson, 1979).
    c) Dose-related alterations in renal growth and function were seen in rats prenatally exposed to chlorambucil on day 11 of gestation, even when gross urogenital abnormalities were not evident. The critical period for inducing renal malformations by prenatal chlorambucil exposure in rats is from days 11 and 15 of gestation (Kavlock et al, 1987).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified chlorambucil as FDA pregnancy category D (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) Inform pregnant patients or patients who become pregnant of the risks to the fetus. Women of childbearing potential should avoid becoming pregnant (Prod Info LEUKERAN(R) oral tablets, 2011).
    B) PLACENTAL BARRIER
    1) Chlorambucil is thought to cross the placenta and to be teratogenic producing unilateral renal agenesis and ureteral hypoplasia (Bermas & Hill, 1995; Steege & Caldwell, 1980).
    C) ANIMAL STUDIES
    1) Fetotoxicity (reduced viable offspring and fewer pups born) was observed in animals given a single chlorambucil intraperitoneal (IP) injection on day 11 of gestation (Kavlock et al, 1986).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether chlorambucil is present in breast milk (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) Nursing mothers should either discontinue nursing or discontinue therapy, taking into account the importance of the drug to the mother (Prod Info LEUKERAN(R) oral tablets, 2011).
    3.20.5) FERTILITY
    A) FERTILITY DECREASED MALE
    1) Both reversible and permanent sterility have been reported in males receiving chlorambucil therapy with a high incidence of sterility in prepubertal and pubertal males. Prolonged or permanent azoospermia (absence of sperm) has been reported in adult males (Prod Info LEUKERAN(R) oral tablets, 2011).
    B) AMENORRHEA
    1) Induction of amenorrhea has been observed in females taking alkylating agents, including chlorambucil. Autopsy results of ovaries of women who had been receiving combination chemotherapy, including chlorambucil for malignant lymphoma showed varying degrees of fibrosis, vasculitis, and depletion of primordial follicles (Prod Info LEUKERAN(R) oral tablets, 2006).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS305-03-3 (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: Chlorambucil
    b) Carcinogen Rating: 1
    1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Chlorambucil is a human carcinogen. Increased risk for cancer, especially acute myeloblastic leukemia, has been reported in patients receiving chlorambucil for the treatment of cancer and other diseases (Budavari, 1989; (IARC, 1975; Menkes et al, 1975; Sotrel et al, 1976; Stachowiak et al, 1976; Westberg & Swolin, 1976; Lerner, 1978; Witz et al, 1978; Buriot et al, 1979) Zimonyi et al, 1979; (Dumont et al, 1980; Aymard et al, 1980; Berk et al, 1981; Blanc et al, 1981; Mueller & Brandis, 1981; Aymard et al, 1983; Kaldor et al, 1990; Boivin et al, 1995).
    2) Two cases of leukemia developed in a group of 77 patients receiving chlorambucil for juvenile chronic arthritis (Kauppi et al, 1996). Increased relative risk for leukemia 7 years after treatment of Hodgkin's disease with chlorambucil was 2.0 (Boivin et al, 1995).
    3) The risk for cancer increases with both duration of therapy and cumulative dose (Prod Info, 1984; (Cameron, 1977; Prod Info Leukeran(R), chlorambucil, 1990; Braunwald et al, 1990a).
    4) CASE SERIES: In a review of all types of malignancy occurring in patients with rheumatoid arthritis treated with chlorambucil (mean daily dose 4.25 mg, mean duration 25 months), 8 of 39 patients developed multiple and recurrent cutaneous malignancy and 3 of 39 patients developed myeloid leukemia or a preleukemic state. In the control group, 30 patients with rheumatoid arthritis who received the purine analogs azathioprine or 6-mercaptopurine (mean dose 100 mg, mean duration 24 months), only one of 30 developed cutaneous malignancy and no patient developed hematological malignancy (Patapanian et al, 1988).
    5) Chronic myeloid leukemia, erythroleukemia, and bronchial adenocarcinoma have also been linked with chlorambucil therapy in case reports (Goldhirsch et al, 1980; Schreiber et al, 1984; Sacanella et al, 1992; Polenakovic & Grcevska, 1995).
    6) These associations with human cancers are generally based on limited case reports or small retrospective studies. They are complicated by frequent use of multidrug therapy; nevertheless the risk for cancer, especially acute myeloid leukemia, is associated with chlorambucil, and appears to be independent of the disease for which the patient was receiving the drug.
    7) TDLo (PO) MAN: 84 mg/kg/2.5 years (continuous) (leukemia) (RTECS, 1989).
    8) TD (PO) WOMAN: 200 mg/kg/6 years (continuous) (leukemia) (RTECS, 1989).
    9) TD (PO) CHILD: 108 mg/kg/77 weeks (continuous) (leukemia) (RTECS, 1989).
    3.21.4) ANIMAL STUDIES
    A) ANIMAL STUDIES
    1) Chlorambucil has also been carcinogenic in animal studies. It acted as an initiator of papillomas in Swiss mice when applied at a dose of 0.05% in methanol in 10 weekly skin applications, followed by 18 weekly applications of croton oil (IARC, 1975).
    2) It induced lung adenomas in male and female A/J mice by the IP route at total doses of 9.6 to 420 mg/kg (IARC, 1975). Lung tumors, lymphosarcomas, and ovarian tumors occurred in Swiss mice given IP injections of 1.5 or 3 mg/kg, 3 times/week for 6 months (IARC, 1975). Lung tumors, lymphoreticular system tumors, and mammary gland carcinomas were seen in BALB/c mice given 1 mg/kg by gavage, 5 times/week for 12 weeks (Cavaliere et al, 1990).
    3) Lymphomas were increased in male Charles River CD rats given chlorambucil by the IP route at doses of 2.2 or 4.5 mg/kg, 3 times/week for 6 months (IARC, 1975). Tumors of the mammary gland, central and peripheral nervous tissue, hematopoietic and lymphatic tissue, and external auditory canal were seen in Sprague-Dawley rats receiving 3 mg/kg on various dosing schedules for 18 months (Berger et al, 1986).

Genotoxicity

    A) Chlorambucil causes chromatid or chromosomal damage in man (Lawler & Lele, 1972; Stevenson & Patel, 1973).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor renal function and liver enzymes.
    D) Monitor serum electrolytes.
    E) Monitor serial CBC with differential with platelet count. Myelosuppression (eg, leukopenia, neutropenia, thrombocytopenia, anemia, and pancytopenia) is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks.
    F) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) CHLORAMBUCIL LEVELS: Have not been consistently reported in overdose cases. No direct relationship is yet available. In one case reported by Blank et al (1983), serum chlorambucil levels were taken but the time relationship is unclear. This patient had an initial level, at an unknown time since ingestion, of 638 nanograms/mL which dropped to 310 nanograms/mL in 7 hours, and to nondetectable over the next 5.5 hours (Blank et al, 1983).
    B) HEMATOLOGIC
    1) Myelosuppression (eg, leukopenia, neutropenia, thrombocytopenia, anemia, and pancytopenia) is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days (Ezlindi & Stutzman, 1965; Galton, 1961; Masturon, 1960). Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks (Prod Info LEUKERAN(R) oral tablets, 2011; Knoben & Anderson, 1988b).
    a) CASE REPORT: In one case report of a child, the WBC nadir (4300/mm(3)) and thrombocyte (166000/mm(3)) nadirs occurred 7 days and 19 days after the ingestion of 3.2 mg/kg of chlorambucil, with resolution by 23 days postingestion (Vandenberg et al, 1988).

Methods

    A) CHROMATOGRAPHY
    1) Serum chlorambucil levels may be measured by high performance liquid chromatography (Chang, 1978; Oppitz et al, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with a chlorambucil overdose need to be admitted, as toxicity develops over several days. Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.1.2) HOME CRITERIA/ORAL
    A) There is no data to support home management.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with a chlorambucil overdose. In addition, consultation with an infectious disease physician with expertise in the management of neutropenic patients with infections is strongly recommended.
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor renal function and liver enzymes.
    D) Monitor serum electrolytes.
    E) Monitor serial CBC with differential with platelet count. Myelosuppression (eg, leukopenia, neutropenia, thrombocytopenia, anemia, and pancytopenia) is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks.
    F) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    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).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor renal function and liver enzymes.
    4) Monitor serum electrolytes.
    5) Monitor serial CBC with differential with platelet count. Myelosuppression (eg, leukopenia, neutropenia, thrombocytopenia, anemia, and pancytopenia) is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks.
    6) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) NEUTROPENIA
    1) Patients with severe neutropenia should be in protective isolation.
    2) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997). They should be administered to any patient who receives an chlorambucil overdose.
    3) ANTIBIOTIC PROPHYLAXIS: Treat high risk patients with fluoroquinolone prophylaxis, if the patient is expected to have prolonged (more than 7 days), profound neutropenia (ANC 100 cells/mm(3) or less). This has been shown to decrease the relative risk of all cause mortality by 48% and or infection-related mortality by 62% in these patients (most patients in these studies had hematologic malignancies or received hematopoietic stem cell transplant). Low risk patients usually do not routinely require antibacterial prophylaxis (Freifeld et al, 2011).
    D) MYELOSUPPRESSION
    1) Myelosuppression is the dose-limiting toxicity of chlorambucil and has an onset of 1 to 14 days. Leukopenia, thrombocytopenia, neutropenia, and anemia have been reported (Ezlindi & Stutzman, 1965; Galton, 1961; Masturon, 1960). Blood counts continue to fall after discontinuing therapy; a nadir is usually reached in 10 days to 2 weeks (Prod Info LEUKERAN(R) oral tablets, 2011; Knoben & Anderson, 1988b).
    2) NEUTROPENIA
    a) DOSING
    1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or IV infusion (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period. Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    b) Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    3) HIGH-DOSE THERAPY
    a) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose.
    b) FILGRASTIM: In patients receiving bone marrow transplant (BMT), the recommended dose of filgrastim is 10 mcg/kg/day given as an IV infusion of 4 or 24 hours, or as a continuous 24 hour subQ infusion. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010):
    1) When ANC is greater than 1000/mm(3) for 3 consecutive days; reduce filgrastim to 5 mcg/kg/day.
    2) If ANC remains greater than 1000/mm(3) for 3 more consecutive days; discontinue filgrastim.
    3) If ANC decreases again to less than 1000/mm(3); resume filgrastim at 5 mcg/kg/day.
    c) In BMT studies, patients received up to 138 mcg/kg/day without toxic effects. However, a flattening of the dose response curve occurred at daily doses of greater than 10 mcg/kg/day (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010).
    d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008).
    4) SPECIAL CONSIDERATIONS
    a) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).
    E) FEBRILE NEUTROPENIA
    1) SUMMARY
    a) Due to the risk of potentially severe neutropenia following overdose with chlorambucil, all patients should be monitored for the development of febrile neutropenia.
    2) CLINICAL GUIDELINES FOR ANTIMICROBIAL THERAPY IN NEUTROPENIC PATIENTS WITH CANCER
    a) SUMMARY: The following are guidelines presented by the Infectious Disease Society of America (IDSA) to manage patients with cancer that may develop chemotherapy-induced fever and neutropenia (Freifeld et al, 2011).
    b) DEFINITION: Patients who present with fever and neutropenia should be treated immediately with empiric antibiotic therapy; antibiotic therapy should broadly treat both gram-positive and gram-negative pathogens (Freifeld et al, 2011).
    c) CRITERIA: Fever (greater than or equal to 38.3 degrees C) AND neutropenia (an absolute neutrophil count (ANC) of less than or equal to 500 cells/mm(3)). Profound neutropenia has been described as an ANC of less than or equal to 100 cells/mm(3) (Freifeld et al, 2011).
    d) ASSESSMENT: HIGH RISK PATIENT: Anticipated neutropenia of greater than 7 days, clinically unstable and significant comorbidities (ie, new onset of hypotension, pneumonia, abdominal pain, neurologic changes). LOW RISK PATIENT: Neutropenia anticipated to last less than 7 days, clinically stable with no comorbidities (Freifeld et al, 2011).
    e) LABORATORY ANALYSIS: CBC with differential leukocyte count and platelet count, hepatic and renal function, electrolytes, 2 sets of blood cultures with a least a set from a central and/or peripheral indwelling catheter site, if present. Urinalysis and urine culture (if urinalysis positive, urinary symptoms or indwelling urinary catheter). Chest x-ray, if patient has respiratory symptoms (Freifeld et al, 2011).
    f) EMPIRIC ANTIBIOTIC THERAPY: HIGH RISK patients should be admitted to the hospital for IV therapy. Any of the following can be used for empiric antibiotic monotherapy: piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK patients should be placed on an oral empiric antibiotic therapy (ie, ciprofloxacin plus amoxicillin-clavulanate), if able to tolerate oral therapy and observed for 4 to 24 hours. IV therapy may be indicated, if patient poorly tolerating an oral regimen (Freifeld et al, 2011).
    1) ADJUST THERAPY: Adjust therapy based on culture results, clinical assessment (ie, hemodynamic instability or sepsis), catheter-related infections (ie, cellulitis, chills, rigors) and radiographic findings. Suggested therapies may include: vancomycin or linezolid for cellulitis or pneumonia; the addition of an aminoglycoside and switch to carbapenem for pneumonia or gram negative bacteremia; or metronidazole for abdominal symptoms or suspected C. difficile infection (Freifeld et al, 2011).
    2) DURATION OF THERAPY: Dependent on the particular organism(s), resolution of neutropenia (until ANC is equal or greater than 500 cells/mm(3)), and clinical evaluation. Ongoing symptoms may require further cultures and diagnostic evaluation, and review of antibiotic therapies. Consider the use of empiric antifungal therapy, broader antimicrobial coverage, if patient hemodynamically unstable. If the patient is stable and responding to therapy, it may be appropriate to switch to outpatient therapy (Freifeld et al, 2011).
    g) COMMON PATHOGENS frequently observed in neutropenic patients (Freifeld et al, 2011):
    1) GRAM-POSITIVE PATHOGENS: Coagulase-negative staphylococci, S. aureus (including MRSA strains), Enterococcus species (including vancomycin-resistant strains), Viridans group streptococci, Streptococcus pneumoniae and Streptococcus pyrogenes.
    2) GRAM NEGATIVE PATHOGENS: Escherichia coli, Klebsiella species, Enterobacter species, Pseudomonas aeruginosa, Citrobacter species, Acinetobacter species, and Stenotrophomonas maltophilia.
    h) HEMATOPOIETIC GROWTH FACTORS (G-CSF or GM-CSF): Prophylactic use of these agents should be considered in patients with an anticipated risk of fever and neutropenia of 20% or greater. In general, colony stimulating factors are not recommended for the treatment of established fever and neutropenia (Freifeld et al, 2011).
    F) VOMITING
    1) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING
    a) Treat patients with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. It may be necessary to treat with multiple concomitant agents, from different drug classes, using alternating schedules or alternating routes. In general, rectal medications should be avoided in patients with neutropenia.
    b) DOPAMINE RECEPTOR ANTAGONISTS: Metoclopramide: Adults: 10 to 40 mg orally or IV and then every 4 or 6 hours, as needed. Dose of 2 mg/kg IV every 2 to 4 hours for 2 to 5 doses may also be given. Monitor for dystonic reactions; add diphenhydramine 25 to 50 mg orally or IV every 4 to 6 hours as needed for dystonic reactions (None Listed, 1999). Children: 0.1 to 0.2 mg/kg IV every 6 hours; MAXIMUM: 10 mg/dose (Dupuis & Nathan, 2003).
    c) PHENOTHIAZINES: Prochlorperazine: Adults: 25 mg suppository as needed every 12 hours or 10 mg orally or IV every 4 or 6 hours as needed; Children (2 yrs or older): 20 to 29 pounds: 2.5 mg orally 1 to 2 times daily (MAX 7.5 mg/day); 30 to 39 pounds: 2.5 mg orally 2 to 3 times daily (MAX 10 mg/day); 40 to 85 pounds: 2.5 mg orally 3 times daily or 5 mg orally twice daily (MAX 15 mg/day) OR 2 yrs or older and greater than 20 pounds: 0.06 mg/pound IM as a single dose (Prod Info COMPAZINE(R) tablets, injection, suppositories, syrup, 2004; Prod Info Compazine(R), 2002). Promethazine: Adults: 12.5 to 25 mg orally or IV every 4 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed (Prod Info promethazine hcl rectal suppositories, 2007). Chlorpromazine: Children: greater than 6 months of age, 0.55 mg/kg orally every 4 to 6 hours, or IV every 6 to 8 hours; max of 40 mg per dose if age is less than 5 years or weight is less than 22 kg (None Listed, 1999).
    d) SEROTONIN 5-HT3 ANTAGONISTS: Dolasetron: Adults: 100 mg orally daily or 1.8 mg/kg IV or 100 mg IV. Granisetron: Adults: 1 to 2 mg orally daily or 1 mg orally twice daily or 0.01 mg/kg (maximum 1 mg) IV or transdermal patch containing 34.3 mg granisetron. Ondansetron: Adults: 16 mg orally or 8 mg IV daily (Kris et al, 2006; None Listed, 1999); Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
    e) BENZODIAZEPINES: Lorazepam: Adults: 1 to 2 mg orally or IM/IV every 6 hours; Children: 0.05 mg/kg, up to a maximum of 3 mg, orally or IV every 8 to 12 hours as needed (None Listed, 1999).
    f) STEROIDS: Dexamethasone: Adults: 10 to 20 mg orally or IV every 4 to 6 hours; Children: 5 to 10 mg/m(2) orally or IV every 12 hours as needed; methylprednisolone: children: 0.5 to 1 mg/kg orally or IV every 12 hours as needed (None Listed, 1999).
    g) ANTIPSYCHOTICS: Haloperidol: Adults: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).
    G) BLOOD AND FLUIDS PRECAUTIONS
    1) Caution should be used when handling urine or vomitus in patients who have ingested chlorambucil. It has been suggested that protective clothing should be worn for up to 48 hours after ingestion when handling urine from these patients (Reeves et al, 1985).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Chlorambucil is not dialyzable (Prod Info LEUKERAN(R) oral tablets, 2011).

Abstracts

Case Reports

    A) INFANT
    1) A 22-month-old girl developed drowsiness with episodes of extreme agitation, staring spells, myoclonic-like muscle jerks of her extremities, an exaggerated startle reflex, and vomiting shortly after an accidental acute ingestion of 3.2 mg/kg of chlorambucil. Bone marrow depression was mild during the following 3 weeks (Vandenberg et al, 1988).

Range Of Toxicity

Summary

    A) TOXICITY: Dosages ranging from 0.125 to 6.8 mg/kg in children and 5 to 250 mg/day in adults have resulted in seizures. Irreversible bone marrow damage and neutropenia may occur at doses greater than 6.5 mg/kg total dose. THERAPEUTIC DOSE: ADULTS; varies by course; initial or short course, 0.1 to 0.2 mg/kg/day (about 4 to 10 mg/day for the average patient) orally for 3 to 6 weeks. Intermittent, biweekly, or once-monthly pulse course, initially with a single dose of 0.4 mg/kg orally, increased by 0.1 mg/kg to produce mild hematologic toxicity, until control of lymphocytosis, or toxicity. CHILDREN: Safety and effectiveness in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) Varies by course; initial or short course, 0.1 to 0.2 mg/kg/day (about 4 to 10 mg/day for the average patient) orally for 3 to 6 weeks. Intermittent, biweekly, or once-monthly pulse course, initially with a single dose of 0.4 mg/kg orally, increased by 0.1 mg/kg to produce mild hematologic toxicity, until control of lymphocytosis, or toxicity (Prod Info LEUKERAN(R) oral tablets, 2011).
    7.2.2) PEDIATRIC
    A) Safety and effectiveness in pediatric patients have not been established (Prod Info LEUKERAN(R) oral tablets, 2011).

Maximum Tolerated Exposure

    A) NEUROTOXICITY
    1) High dose chlorambucil (2 to 4 mg/kg/day) in autologous bone marrow transplantation for ovarian carcinoma was associated with the development of reversible central nervous system toxicity in 3 adults (Ciobanu et al, 1987).
    B) SEIZURES
    1) In children, chlorambucil dosages which have caused seizures are reported to range from 0.125 to 6.8 mg/kg.
    2) In adults, these doses range from 5 to 250 mg/day (Alberts et al, 1979; McLean et al, 1979; Shotton & Monie, 1963; Knisley et al, 1971; Salloum et al, 1997).
    3) In one case report, 250 mg of chlorambucil taken in a single dose caused seizures and acute renal failure. No permanent sequelae were noted (Blank et al, 1983).
    C) NEUTROPENIA
    1) Neutropenia is usually present in patients receiving in excess of 6.5 mg/kg in a total dose (Prod Info LEUKERAN(R) oral tablets, 2011).
    2) PEDIATRIC DOSING: Chlorambucil was used to induce remission within 6 months in 41 (52%) pediatric patients with juvenile chronic arthritis. Chlorambucil was initiated stepwise to a maximum dose of 0.2 mg/kg/day. Long-term remission (median follow-up 8.5 years) was attained in 14 (18%) patients. Chlorambucil was withdrawn in 16 patients due to side effects of either rash or bone marrow depression. Two patients developed leukemia and 17 (22%) experienced 1 to 3 occurrences of herpes zoster infection. At long-term follow-up (8.5 years), 14 (18%) patients were in complete remission without drugs (Savolainen, 1999).
    D) IRREVERSIBLE BONE MARROW DAMAGE
    1) May be seen at doses of greater than 6.5 milligrams/kilogram total dose given therapeutically (Prod Info LEUKERAN(R) oral tablets, 2011).
    E) PANCYTOPENIA
    1) In a case report, 280 mg (4.1 mg/kg) was accidentally ingested over a 5-day period in an adult. Only mild pancytopenia was seen (Enck & Bennett, 1977).

Workplace Standards

    A) ACGIH TLV Values for CAS305-03-3 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS305-03-3 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS305-03-3 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    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): 1 ; Listed as: Chlorambucil
    a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
    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 ): K ; Listed as: Chlorambucil
    a) K : KNOWN = Known to be a human carcinogen

    D) OSHA PEL Values for CAS305-03-3 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 30 mg/kg (RTECS , 1999)
    B) LD50- (ORAL)MOUSE:
    1) 101 mg/kg (RTECS , 1999)
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 115 mg/kg (RTECS , 1999)
    D) LD50- (INTRAPERITONEAL)RAT:
    1) 14 mg/kg (RTECS , 1999)
    E) LD50- (ORAL)RAT:
    1) 76 mg/kg (RTECS , 1999)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Chlorambucil is an aromatic nitrogen mustard derivative and alkylating agent that interferes with DNA replication. Chlorambucil also induces cellular apoptosis by accumulation of cytosolic p53 and activation of BAX, an apoptosis promoter (Prod Info LEUKERAN(R) oral tablets, 2011).

Toxicologic Mechanism

    A) SEIZURES
    1) Predhan & Marsan (1963) while experimenting with cats, postulated the seizure activity of chlorambucil originated in the subcortical regions and therefore the activity of the drug involved subcortical structures. They also postulated that the mechanism was chemical, rather than a structural lesion. The definite mechanism in which the chlorambucil exerts its neurological toxicity is yet unknown (Pradhan & Marsan, 1963).

Physicochemical

Physical Characteristics

    A) This compound exists as flattened needles from petroleum ether (Budavari, 1989).

Molecular Weight

    A) 304.23

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) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    14) Alberts DS, Chang SY, & Chen HS: Pharmacokinetics and metabolism of chlorambucil in man: a preliminary report. Cancer Treat Rev 1979; 6:9.
    15) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    16) Ammenti A, Reitter B, & Muller-Wiefel DE: Chlorambucil neurotoxicity: report of two cases. Helv Paediatr Acta 1980; 35:281-287.
    17) Ando S, Tanaka O, & Tatewaki R: Comparative study on the pathogenesis of drug-induced and spontaneously developed neural tube defects (NTDs) in mouse embryos. Senten Ijo 1990; 30:271.
    18) Ashby J & Tinwell H: Clastogenicity of chlorambucil to the mouse bone marrow: consideration in relation to its genetic specificity of action in some assays. Mutagenesis 1993; 8:373-375.
    19) Aymard JP, Frustin J, & Witz F: Acute leukaemia after prolonged chlorambucil treatment for non-malignant disease: report of a new case and literature survey. Acta Haematol 1980; 63:283-285.
    20) Aymard JP, Lederlin P, & Witz F: Acute leukaemia following prolonged chlorambucil treatment for non-neoplastic disease - a study of two cases and literature review. Acta Clin Belg 1983; 38:228-235.
    21) Barone C, Cassano A, & Astone A: Toxic epidermal necrolysis during chlorambucil therapy in chronic lymphocytic leukaemia. Eur J Cancer 1990; 26:1262.
    22) Bean CL & Galloway SM: Evaluation of the need for a late harvest time in the assay for chromosome aberrations in Chinese hamster ovary cells. Mutat Res 1993; 292:3-16.
    23) Berger MR, Habs M, & Schmahl D: Long-term toxicology effects of prednimustine in comparison with chlorambucil, prednisolone, and chlorambucil plus prednisolone in Sprague-Dawley rats. Semin Oncol 1986; 13(Suppl 1):8-13.
    24) Berk PD, Goldberg JD, & Silverstein MN: Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981; 304:441-447.
    25) Bermas BL & Hill JA: Effects of immunosuppressive drugs during pregnancy. Arthritis Rheum 1995; 38:1722-1732.
    26) Blanc AP, Gastaut JA, & Sebahoun G: Acute leukaemia during immunosuppressive treatment. One case. Nouv Presse Med 1981; 10:1717-1719.
    27) Blank DW, Nanji AA, & Schreiber DH: Acute renal failure and seizures associated with chlorambucil overdose. J Toxicol Clin Toxicol 1983; 20:361-365.
    28) Boivin JF, Hutchison GB, & Zauber AG: Incidence of second cancers in patients treated for Hodgkins disease. J Nat Cancer Inst 1995; 87:732-741.
    29) Braunwald E, Isselbacher KJ, & Petersdorf RG: Harrison's Principles of Internal Medicine, 12th ed, McGraw-Hill Book Company, New York, NY, 1990a.
    30) Braunwald E, Isselbacher KJ, Petersdorf RG, et al (Eds): Harrison's Principles of Internal Medicine, 12th. McGraw-Hill Book Company, New York, NY, 1990.
    31) Briggs GG, Freeman RK, & Yaffe SJ: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 4th ed, Williams & Wilkins, Baltimore, MD, 1994.
    32) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    33) Brummett ES & Johnson EM: Morphological alterations in the developing fetal rat limb due to maternal injection of chlorambucil. Teratology 1979; 20:279-287.
    34) Buriot D, Prieur AM, & Lebranchu Y: Acute leukemia in 3 children with chronic juvenile arthritis treated with chlorambucil. Arch Fr Pediatr 1979; 36:592-598.
    35) Byrne TN Jr, Moseley TA III, & Finer MA: Myoclonic seizures following chlorambucil overdose. Ann Neurol 1981; 9:191-194.
    36) Cameron S: Chlorambucil and leukemia. N Engl J Med 1977; 296:1065.
    37) Cannon GW: Pulmonary complications of antirheumatic drug therapy. Semin Arthritis Rheum 1990; 19:353-364.
    38) Cannon GW: Pulmonary complications of antirheumatic drug therapy. Semin Arthritis Rheum 1990a; 19:353-364.
    39) Carr ME Jr: Chlorambucil induced pulmonary fibrosis: report of a case and review. VA Med 1986; 113:677-680.
    40) Cavaliere A, Pietropaoli N, & Alberti PF: Chlorambucil carcinogenesis in BALB/c mice. Cancer Lett 1990; 55:115-120.
    41) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    42) Chang SY: Modification of HPLC analysis of melphalan in plasma. J Pharm Sci 1978; 67:679-681.
    43) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    44) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    45) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    46) Ciobanu N, Runowicz C, & Gucalp R: Reversible central nervous system toxicity associated with high-dose chlorambucil in autologous bone marrow transplantation for ovarian carcinoma. Cancer Treat Rep 1987; 71:1324-1325.
    47) Clark ST, Radford JA, & Crowther D: Gonadal function following chemotherapy for Hodgkins disease - a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol 1995; 13:134-139.
    48) Crestani B, Jaccard A, & Israel-Biet D: Chlorambucil-associated pneumonitis. Chest 1994a; 105:634-636.
    49) Crestani B, Jaccard A, Israel-Biet D, et al: Chlorambucil-associated pneumonitis. Chest 1994; 105:634-636.
    50) 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.
    51) Dorr RT & Fritz WL: Cancer Chemotherapy Handbook, Elsevier, New York, NY, 1980.
    52) Dumont J, Thiery JP, & Mazabraud A: Acute myeloid leukemia following non-Hodgkin's lymphoma: danger of prolonged use of chlorambucil as maintenance therapy. Nouv Rev Fr Hematol 1980; 22:391-404.
    53) Dupuis LL & Nathan PC: Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs 2003; 5(9):597-613.
    54) 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/.
    55) Ehrsson H, Lonroth U, & Wallin I: Degradation of chlorambucil in aqueous solution - influence of human albumin binding. J Pharm Pharmacol 1981; 33:313.
    56) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    57) Elzouki AY, al Nassar K, & al Ali M: Sister chromatid exchange analysis in monitoring chlorambucil therapy in primary nephrotic syndrome of childhood. Pediatr Nephrol 1991; 5:59-61.
    58) Enck RE & Bennett JM: Inadvertent chlorambucil overdose in adults. State J Med 1977; 77:1480-1481.
    59) Ezlindi EZ & Stutzman L: Chlorambucil therapy for lymphomas and chronic lymphocytic leukemia. JAMA 1965; 191:444.
    60) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    61) Ferguson LR, Palmer BD, & Denny WA: Microbial mutagenicity of chlorambucil, its half-mustard and mitomycin C: a modified screening strategy for genetic toxicology of bis-alkylating anti-tumour drugs. Anticancer Drug Des 1988; 3:67-76.
    62) Flaherty L, Messer A, & Russell LB: Chlorambucil-induced mutations in mice recovered in homozygotes. Proc Natl Acad Sci USA 1992; 89:2859-2863.
    63) Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52(4):e56-e93.
    64) Galton DAG: The use of chlorambucil and steroids in treatment of chronic lymphocytic leukemia. Br J Haematol 1961; 7:73.
    65) Generoso WM, Witt KL, & Cain KT: Dominant lethal and heritable translocation tests with chlorambucil and melphalan in male mice. Mutat Res 1995; 345:167-180.
    66) Giles FJ, Smith MP, & Goldstone AH: Chlorambucil lung toxicity. Acta Haematol 1990; 83:156-158.
    67) Goldhirsch A, Pirovino M, & Coninx S: Acute erythroleukemia following chemotherapy for Hodgkin's disease. Am J Med Sci 1980; 280:53-56.
    68) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    69) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    70) Grant WM: Toxicology of the Eye, 3rd ed, Charles C Thomas, Springfield, IL, 1986, pp 252.
    71) Green AA & Naiman JL: Chlorambucil poisoning. Am J Dis Child 1968; 116:190-191.
    72) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 1996; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    73) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    74) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    75) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    76) Hitchins RN, Hocker GA, & Thomson DB: Chlorambucil allergy - a series of three cases. Aust NZ J Med 1987; 17:600-602.
    77) Hoorn AJ, Custer LL, & Myhr BC: Detection of chemical mutagens using Muta Mouse: a transgenic mouse model. Mutagenesis 1993; 8:7-10.
    78) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    79) 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.
    80) 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.
    81) 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.
    82) 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.
    83) 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.
    84) 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.
    85) IARC: Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, 9, International Agency for Research on Cancer, World Health Organization, Geneva, Switzerland, 1975, pp 127-131.
    86) Ichida F, Konishi T, & Asada R: Chlorambucil central nervous toxicity: a significant side effect of chlorambucil therapy in childhood nephrotic syndrome. Eur J Pediatr 1985; 144:283-286.
    87) 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.
    88) 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.
    89) JEF Reynolds : Martindale: The Extra Pharmacopoeia. The Pharmaceutical Press. London, England (Internet Version). Edition expires 1996; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    90) Kaldor JM, Day NE, & Pettersson F: Leukemia following chemotherapy for ovarian cancer [see comments]. N Engl J Med 1990; 322:1-6.
    91) Kauppi MJ, Savolainen HA, & Anttila VJ: Increased risk of leukaemia in patients with juvenile chronic arthritis treated with chlorambucil. Acta Paediatr 1996; 85:248-250.
    92) Kavlock RJ, Rehnberg BF, & Rogers EH: Chlorambucil induced congenital renal hypoplasia: Effects on basal renal function in the developing rat. Toxicology 1986; 40:247-258.
    93) Kavlock RJ, Rehnberg BF, & Rogers EH: Critical prenatal periods for chlorambucil-induced functional alterations of the rat kidney. Toxicology 1987; 43:51-64.
    94) Knisley RE, Settipane GA, & Albala MM: Unusual reaction to chlorambucil in a patient with chronic lymphocytic leukemia. Arch Dermatol 1971; 104:77.
    95) Knoben JE & Anderson PO (Eds): Handbook of Clinical Drug Data, 6th. Drug Intelligence Publications, Inc, Hamilton, IL, 1988b.
    96) Knoben JE & Anderson PO: Handbook of Clinical Drug Data, 6th ed, Drug Intelligence Publications, Inc, Hamilton, IL, 1988.
    97) Knoben JE & Anderson POKnoben JE & Anderson PO (Eds): Handbook of Clinical Drug Data, 6th. Drug Intelligence Publications, Inc, Hamilton, IL, 1988a.
    98) Krakoff IH: Growth-inhibiting drugs: their anticancer, anti-immune, and teratogenic effects. Drill's Pharmacology in Medicine, 1971, 1971.
    99) Kris MG, Hesketh PJ, Somerfield MR, et al: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
    100) LaDelfa I, Bayer N, & Myers R: Chlorambucil-induced myoclonic seizures in an adult. J Clin Oncology 1985; 3:1691-1692.
    101) Lawler SD & Lele KP: Chromosomal damage induced by chlorambucil in chronic lymphocytic leukemia. Scand J Hematol 1972; 9:603.
    102) Lerner HJ: Acute myelogenous leukemia in patients receiving chlorambucil as long-term adjuvant chemotherapy for stage II breast cancer. Cancer Treat Rep 1978; 62:1135-1138.
    103) Littlefield LG, Colyer SP, & Sayer AM: Sister-chromatid exchanges in human lymphocytes exposed during Go to four classes of DNA-damaging chemicals. Mutat Res 1979; 67:259-269.
    104) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    105) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    106) Masturon JG: Clinical study of the use of chlorambucil in treatment of carcinoma of ovary. Am J Obstet Gynecol 1960; 79:1002.
    107) McLean A, Woods RL, & Catovsky D: Pharmacokinetics and metabolism of chlorambucil in patients with malignant disease. Cancer Treat Rev 1979; 6:33.
    108) Menkes CJ, Levy JP, & Weill B: Acute leukemia with megakaryoblasts. Incidence following immunosuppressive treatment of rheumatoid polyarthritis (French). Nouv Presse Med 1975; 4:2869-2871.
    109) Mortelmans K, Haworth S, & Lawlor T: Salmonella mutagenicity tests. 2. Results from the testing of 270 chemicals. Environ Mutagen 1986; 8(Suppl 7):1-119.
    110) Mueller W & Brandis M: Acute leukemia after cytotoxic treatment for nonmalignant disease in childhood. A case report and review of the literature. Eur J Pediatr 1981; 136:105-108.
    111) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    112) 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.
    113) 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.
    114) 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.
    115) 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.
    116) 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.
    117) 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.
    118) 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.
    119) 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.
    120) 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.
    121) 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.
    122) 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.
    123) 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.
    124) 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.
    125) 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.
    126) 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.
    127) 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.
    128) 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.
    129) 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.
    130) 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.
    131) 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.
    132) 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.
    133) 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.
    134) 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.
    135) 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.
    136) 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.
    137) 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.
    138) 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.
    139) 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.
    140) 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.
    141) 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.
    142) 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.
    143) 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.
    144) 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.
    145) 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.
    146) 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.
    147) 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.
    148) 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.
    149) 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.
    150) 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.
    151) 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.
    152) 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.
    153) 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.
    154) 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.
    155) 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.
    156) 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.
    157) 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.
    158) 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.
    159) 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.
    160) 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.
    161) 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.
    162) 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.
    163) 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.
    164) 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.
    165) 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.
    166) 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.
    167) 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.
    168) 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.
    169) 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.
    170) 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.
    171) 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.
    172) 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.
    173) 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.
    174) 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.
    175) 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.
    176) 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.
    177) 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.
    178) 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.
    179) 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.
    180) 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.
    181) 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.
    182) 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.
    183) 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.
    184) 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.
    185) 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.
    186) 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.
    187) 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.
    188) 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.
    189) 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.
    190) 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.
    191) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    192) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    193) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    194) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    195) Naysmith A & Robson RH: Focal fits during chlorambucil therapy. Postgrad Med J 1979; 55:806-807.
    196) None Listed: ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 1999; 56(8):729-764.
    197) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    198) Oppitz MM, Musch E, & Malek M: Studies on the pharmacokinetics of chlorambucil and prednimustine in patients using a new high-performance liquid chromatographic assay. Cancer Chemother Pharmacol 1989; 23:208-212.
    199) Palmer RG, Smith-Burchnell CA, & Dore CJ: Thioguanine-resistant mutations induced by cytotoxic drugs in lymphocytes of patients with connective tissue diseases. Br J Rheumatol 1986; 25:376-379.
    200) Patapanian H, Graham S, & Sambrook PN: The oncogenicity of chlorambucil in rheumatoid arthritis. Br J Rheumatol 1988; 27:44-47.
    201) Peterman A & Braunstein B: Cutaneous reaction to chlorambucil therapy (Letter). Arch Dermatol 1986; 122:1358-1360.
    202) Pieper RO & Erickson LC: DNA adenine adducts induced by nitrogen mustards and their role in transcription termination in vitro. Carcinogenesis 1990; 11:1739-1746.
    203) Pietrantonio F, Moriconi L, & Torino F: Unusual reaction to chlorambucil: a case report. Cancer Lett 1990; 54:109-111.
    204) Polenakovic M & Grcevska L: Development of bronchial adenocarcinoma 11 years after the onset of membranous nephropathy associated with chlorambucil therapy. Nephron 1995; 69:335-336.
    205) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    206) Povirk LF & Shuker DE: DNA damage and mutagenesis induced by nitrogen mustards. Mutat Res 1994; 318:205-226.
    207) Pradhan SN & Marsan CA: Chlorambucil toxicity and EEG "centrecephalic" patterns. Epilepsia 1963; 4:1-14.
    208) Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.
    209) Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    210) Product Information: LEUKERAN(R) oral tablets, chlorambucil oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2006.
    211) Product Information: LEUKERAN(R) oral tablets, chlorambucil oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2011.
    212) Product Information: LEUKINE(R) subcutaneous, IV injection, sargramostim subcutaneous, IV injection. Bayer Healthcare, Seattle, WA, 2008.
    213) Product Information: Leukeran(R), chlorambucil. Burroughs Wellcome Co, Research Triangle Park, NC, 1990.
    214) Product Information: NEUPOGEN(R) IV, subcutaneous injection, filgrastim IV, subcutaneous injection. Amgen Manufacturing, Thousand Oaks, CA, 2010.
    215) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    216) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    217) Product Information: promethazine hcl rectal suppositories, promethazine hcl rectal suppositories. Perrigo, Allegan, MI, 2007.
    218) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 1996; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    219) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 1999; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    220) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    221) Reeves BR, Casey G, & Harris H: Long-term cytogenetic follow-up study of patients with uveitis treated with chlorambucil. Carcinogenesis 1985; 6:1615-1619.
    222) Rodriguez-Arnaiz R, Soto PO, & Oyarzun JCG: Analysis of mitotic recombination induced by several mono- and bifunctional alkylating agents in the Drosophila wing-spot test. Mutat Res 1996; 351:133-145.
    223) Rudd P, Fries JF, & Epstein WV: Irreversible bone marrow failure with chlorambucil. J Rheumatol 1975; 2:421-429.
    224) Russell LB, Hunsicker PR, & Cacheiro NL: Chlorambucil effectively induces deletion mutations in mouse germ cells. Proc Natl Acad Sci USA 1989; 86:3704-3708.
    225) Russell LB, Hunsicker PR, & Shelby MD: Chlorambucil and bleomycin induce mutations in the specific-locus test in female mice. Mutat Res 1996; 358:25-35.
    226) Sacanella E, Cervantes F, & Navarro M: Chronic myeloid leukemia after chemotherapy treatment for non-Hodgkin's lymphoma (Spanish). Med Clin (Barc) 1992; 99:145-146.
    227) Salder TW & Kochhar DM: Teratogenic effects of chlorambucil on in vivo and in vitro organogenesis in mice. Teratology 1975; 12:71-78.
    228) Salloum E, Khan KK, & Cooper DL: Chlorambucil-induced seizures. Cancer 1997; 79:1009-1013.
    229) Savolainen HA: Chlorambucil in severe juvenile chronic arthritis: longterm followup with special reference to amyloidosis. J Rheumatol 1999; 26(4):898-903.
    230) Schiffman FJ, Uehara Y, & Fisher JM: Potentiation of chlorambucil activity by phenylbutazone. Cancer Lett 1978; 4:211-216.
    231) Schreiber ZA, Axelrod MR, & Abebe LS: Coexistence of chronic myelogenous leukemia and chronic lymphocytic leukemia. Cancer 1984; 54:697-701.
    232) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    233) Shotton D & Monie IW: Possible teratogenic effect of chlorambucil on a human fetus. JAMA 1963; 186:74.
    234) Singh B & Gupta RS: Comparison of the mutagenic responses of 12 anticancer drugs at the hypoxanthine-guanine phosphoribosyl transferase and adenosine kinase loci in Chinese hamster ovary cells. Environ Mutagen 1983; 5:871-880.
    235) Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24(19):3187-3205.
    236) Sotrel G, Jafari K, & Lash AF: Acute leukemia in advanced ovarian carcinoma after treatment with alkylating agents. Obstet Gynecol 1976; 47:67S-71S.
    237) Speit G, Menz W, & Roescheisen C: Cytogenetic and molecular characterization of the mutagenicity of chlorambucil in V79 cells. Mutat Res 1992; 283:75-81.
    238) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2010; 14(2):162-168.
    239) Stachowiak J, Gorin NC, & Najman A: Acute leukemia after prolonged treatment with chlorambucil: study of 2 cases. Ann Med Interne Paris 1976; 127:584-589.
    240) Steege JR & Caldwell DS: Renal agenesis after first trimester exposure to chlorambucil. South Med J 1980; 73:1414.
    241) Stevenson AC & Patel C: Effects of chlorambucil on human chromosomes. Mutat Res 1973; 18:333.
    242) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    243) Tanaka O, Yoshioka N, & Yoshioka T: Effects of chlorambucil on the brain development in mice during post-neurulation period. Senten Ijo 1991; 31:141-152.
    244) Tripathy NK, Wurgler FE, & Frei H: Genetic toxicity of six carcinogens and six non-carcinogens in the Drosophila wing spot test. Mutat Res 1990; 242:169-180.
    245) 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.
    246) 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.
    247) 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-.
    248) 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.
    249) 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.
    250) 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.
    251) 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.
    252) 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-.
    253) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    254) 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.
    255) Vandenberg SA, Kulig K, & Spoerke DG: Chlorambucil overdose: accidental ingestion of an antineoplastic drug. J Emerg Med 1988; 6:495-498.
    256) Weber E, Berger S, & Weber S: Rapid desensitization for chlorambucil drug fever. Haematologica 2007; 92(7):e77-.
    257) Westberg NG & Swolin B: Acute myeloid leukemia appearing in two patients after prolonged continuous chlorambucil treatment for Wegener's granulomatosis. Acta Med Scand 1976; 199:373-377.
    258) Westin J: Chromosome abnormalities after chlorambucil therapy of polycythaemia vera. Scand J Haematol 1976; 17:197-204.
    259) Williams SA, Makker SP, & Grupe WE: Seizures: a significant side effect of chlorambucil therapy in children. J Pediatr 1978; 93:516-518.
    260) Witz F, Lederlin P, & Aymard JP: Acute myeloblastic leukemia following chlorambucil treatment: 2 new cases (French). Nouv Presse Med 1978; 7:2392.
    261) Wolfson S & Olney MB: Accidental ingestion of a toxic dose of chlorambucil. JAMA 1957; 239-240.
    262) Woodruff RC, Mason JM, & Valencia R: Chemical mutagenesis testing in Drosophila. V. Results of 53 coded compounds tested for the National Toxicology Program. Environ Mutagen 1985; 7:677-702.
    263) Wyllie ARJ, Bayliff CD, & Kovacs MJ: Myoclonus due to chlorambucil in two adults with lymphoma. Ann Pharmacother 1997; 31:171-174.
    264) Yamada M, Sofuni T, & Nohmi T: Preferential induction of AT-TA transversion, but not deletions, by chlorambucil at the hisG428 site of Salmonella typhimurium TA102. Mutat Res 1992; 283:29-33.
    265) Yiannakis PH & Larner AJ: Visual failure and optic atrophy associated with chlorambucil therapy. Br Med J 1993; 306:109.