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DFP: Diisopropyl fluorophosphate. TOXNET Hazardous Substances Data Base.
From TOXNET
see for
Updates: http://www.toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB
Human Health Effects:
Human Toxicity Excerpts:
... A 12-month-old boy, who had received one drop of 0.1% DFP in each eye
daily for 2 months, experienced two brief apneic spells, with probable seizure
activity for 1 or 2 minutes each time ... miotic, unreactive pupils, profuse
nasal discharge & possible motor weakness /noted/. Eight hr after admin,
he had a typical grand mal convulsion lasting 2 to 3 minutes. ... The cholinesterase
activity of serum collected 60 hr after the last eye drop was below the range
of normal & 44% of the average normal.
TREATMENT OF GLAUCOMA WITH POTENT, LONG-ACTING ANTICHOLINESTERASE AGENTS (INCLUDING
... ISOFLUROPHATE) FOR 6 MONTHS OR LONGER CARRIES HIGH RISK OF THE DEVELOPMENT
OF A SPECIFIC TYPE OF CATARACT, WHICH BEGINS AS ANTERIOR SUBCAPSULAR VACUOLES.
ALTHOUGH FORMATION OF SPONTANEOUS CATARACTS IS QUITE COMMON WITHIN COMPARABLE
AGE GROUPS, THE INCIDENCE OF LENTICULAR OPACITIES UNDER SUCH CIRCUMSTANCES CAN
BE AS HIGH AS 50%; THE HAZARD IS APPARENTLY INCREASED IN PROPORTION TO THE STRENGTH
OF SOLUTION, FREQUENCY OF INSTILLATION, DURATION OF THERAPY, & AGE OF THE
PATIENT. THE UNDERLYING MECHANISM REMAINS ELUSIVE ... MISCELLANEOUS OCULAR SIDE
EFFECTS THAT MAY OCCUR FOLLOWING LOCAL INSTILLATION OF ANTICHOLINESTERASE AGENTS
ARE HEADACHE, BROW PAIN, BLURRED VISION, PHACODINESIS, PERICORNEAL INJECTION,
CONGESTIVE IRITIS, VARIOUS ALLERGIC REACTIONS, &, RARELY, RETINAL DETACHMENT.
... DFP ... has the property of inducing a ... delayed neurotoxicity. ...
The clinical picture is that of a severe polyneuritis that begins several days
after exposure to a sufficient single or cumulative amt of the toxic cmpd. It
is manifested initially by mild sensory disturbances, ataxia, weakness, and
ready weakness of the legs, accompanied by reduced tendon reflexes & ...
muscle twitching, fasciculation, & tenderness to palpation. In severe cases,
the weakness may progress eventually to complete flaccid paralysis that, over
the course of weeks or months, is often succeeded by a spastic paralysis with
a concomitant exaggeration of reflexes. During these phases, the muscles show
marked wasting. Recovery may require 2 or more yr.
Do not inhale vapors. Avoid contact with skin. Even traces of the vapor cause
myosis. Highly toxic; cholinesterase inhibitor.
This compound is a cholinesterase inhibitor, a neurotoxin, and has reproductive
effects.
The onset of the clinical manifestation of organophosphate poisoning usually
occurs within 12 /hours/ of exposure.
Drug Warnings:
... Should be used cautiously in patients with bronchial asthma, bradycardia,
or hypotension. An increase in blood pressure may occur occasionally due to
a nicotinic effect on sympathetic ganglia.
Because of their cataractogenic properties & other toxicity, /diisopropyl
fluorophosphate/ should be reserved for patients refractory
to short-acting miotics, epinephrine, beta-blocking drugs, & possibly, carbonic
anhydrase inhibitors. /Long-acting miotics, including floropryl/
Medical Surveillance:
The assessment of exposure to the organophosphate pesticides, bromophos and
dicrotophos, can be accomplished through measurement of these compounds in the
blood. However, since organophosphate pesticides are rapidly cleared from the
blood, it is difficult to be able to detect the pesticides in blood unless very
large quantities have been absorbed. This test may be useful for identification
of the compound in cases of severe exposure, although documented tests for measurement
of specific organophosphate pesticides in blood are very limited. Blood Reference
Ranges: Normal - None detected; Exposed - Not detected; Toxic - Not established.
Serum or Plasma Reference Ranges: Normal - Not established; Exposed - Not established;
Toxic - Not established. Urine: The assessment of organophosphate pesticide
exposure can be accomplished through measurement of the following alkyl phosphate
metabolites: dimethylphosphate, diethylphosphate, dimethylthiophosphate, diethylthiophosphate,
dimethyldithiophosphate, and diethyldithiophosphate. ... The one limitation
to measurement of urinary alkyl metabolites is that this test is only useful
for assessing recent exposure, due to the short half-life of organophosphate
pesticides. Urine Reference Ranges: Normal - Note established; Exposed - Not
established; Toxic - Not established. /Organophosphate Pesticides/
Initial Medical Examination: A complete history and physical examination:
The purpose is to detect pre-existing conditions that might place the exposed
employee at increased risk, and to establish a baseline for future health monitoring.
... Examination of the respiratory system, nervous system, cardiovascular system,
eyes, and attention to the cholinesterase levels in the blood should be stressed.
The skin should be examined for evidence of chronic disorders. ... The cholinesterase
activity in the serum and erythrocytes should be determined by using medically
acceptable biochemical tests prior to any new period of exposure. /Parathion/
Populations at Special Risk:
Persons with a history of reduced pulmonary function, convulsive disorders,
or recent exposure to anticholinesterase agents would be expected to be at an
increased risk. /Parathion/
Probable Routes of Human Exposure:
Occupational exposure to diisopropyl fluorophosphate
may occur through dermal contact with this compound at workplaces
where diisopropyl fluorophosphate is
produced or used. (SRC)
Emergency Medical Treatment:
Emergency Medical Treatment:
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The following Overview, *** DIISOPROPYL FLUOROPHOSPHATE ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted.
|
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o Diisopropyl fluorophosphate (DFP) is an organophosphate
compound used as an insecticide, a substrate for the
production of organophosphate military "nerve" gases
and formerly as a topical miotic medication in
ophthalmology. The following are symptoms of
organophosphates in general, due to the
anticholinesterase activity of this class of compounds.
All of these effects may not be documented for DFP, but
could potentially occur in individual cases.
1. DFP forms HYDROGEN FLUORIDE is the presence of
moisture (Refer to the HYDROFLUORIC ACID MEDITEXT(R)
Medical Management for more information).
2. DFP has been used as an experimental agent in
neuroscience because of its ability to inhibit
cholinesterase and cause delayed peripheral
neuropathy. It has been also used as a miotic agent
in the treatment of glaucoma. Although DFP has caused
experimental distal anoxopathy, no cases of peripheral
neuropathy have been reported in patients treated with
this agent for glaucoma.
3. Cataracts may occur following treatment of 6 or more
months duration with DIFP.
4. Two workers with occupational inhalation and dermal
DFP exposure developed dim vision, difficulty in
focusing vision, excessive lacrimation, small pupils,
pain behind the eyes, nausea, vomiting, and diarrhea.
o MUSCARINIC (PARASYMPATHETIC) EFFECTS may include
bradycardia, bronchospasm, bronchorrhea, salivation,
lacrimation, diaphoresis, vomiting, diarrhea, and
miosis. NICOTINIC (SYMPATHETIC AND MOTOR) EFFECTS may
include tachycardia, hypertension, fasciculations,
muscle cramps, weakness, and RESPIRATORY PARALYSIS.
CENTRAL EFFECTS may include CNS depression, agitation,
confusion, delirium, coma, and seizures.
o Children may have different predominant signs and
symptoms than adults: CNS depression, stupor,
flaccidity, dyspnea, and coma are the most common signs
in children.
VITAL SIGNS
0.2.3.1 ACUTE EXPOSURE
o Fever, bradycardia, hypotension, tachycardia, and
hypertension may occur.
o A self-limited decrease in body temperature was noted
in rats administered DFP.
HEENT
0.2.4.1 ACUTE EXPOSURE
o Miosis, lacrimation, and blurred vision are common;
mydriasis may occur in severe poisonings. Opsoclonus
has been reported in one case. Excessive salivation
commonly occurs.
0.2.4.2 CHRONIC EXPOSURE
o Decreased visual acuity and persistent photophobia may
be seen.
o DFP has been used as a miotic agent for the treatment
of glaucoma. Rarely, angle-closure glaucoma has been
provoked by treatment with such agents.
1. Patients treated with anticholinesterase medications
(such as DFP) for glaucoma have rarely had retinal
detachment.
CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
o Bradycardia, hypotension, and chest pain may occur.
Tachycardia and hypertension may also be noted.
Arrhythmias and conduction defects may occur in severe
poisonings. Myocarditis may develop.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Dyspnea, rales, bronchorrhea, bronchospasm, or
tachypnea may be noted. Noncardiogenic pulmonary edema
may occur in severe cases. Chemical pneumonitis may be
seen, especially following pulmonary aspiration of
hydrocarbon-based diluents.
o Bronchospasm may occur in previously sensitized
asthmatics or as a muscarinic pharmacological effect.
o Acute respiratory insufficiency is the main cause of
death in acute poisonings.
NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
o Headache, dizziness, muscle spasms, and profound
weakness are common. Alterations of level of
consciousness, anxiety, paralysis, seizures, and coma
may occur. Seizures may be more common in exposed
children.
1. Seizures, apneic spells, miosis, profuse nasal
discharge, and muscle weakness were noted in a
12-month-old boy treated with DFP eye drops daily for
2 months; serum cholinesterase level 60 hours after
the last drop was instilled was 44% of normal.
o Peripheral neuropathy of the mixed sensory-motor type
may be delayed in onset by 6 to 21 days following
exposure to some organophosphates. Recovery may be
slow or incomplete.
o Dyskinesias may develop. Abnormal neuropsychiatric
tests and EEGs may persist for months following acute
exposure.
0.2.7.2 CHRONIC EXPOSURE
o DIFP has been used as an experimental agent in
neuroscience because of its ability to inhibit
cholinesterase and cause delayed peripheral neuropathy.
Delayed peripheral neuropathy has been especially
demonstrated in the standard hen assay.
o DIFP has been used as a miotic agent for treatment of
glaucoma, but no cases of peripheral neuropathy have
been reported in patients so treated.
GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
o Vomiting, hypersalivation, diarrhea, fecal
incontinence, and abdominal pain may occur.
o Intussusception has been reported in a single pediatric
organophosphate poisoning case.
GENITOURINARY
0.2.10.1 ACUTE EXPOSURE
o Increased urinary frequency and urinary incontinence
have occurred.
o Immune-complex nephropathy with proteinuria and/or
amorphous crystalluria may occur.
o Reversible renal tubular dysfunction unrelated to
cholinesterase inhibition has been demonstrated in
rats.
ACID-BASE
0.2.11.1 ACUTE EXPOSURE
o Metabolic acidosis has occurred in several severe
poisonings.
HEMATOLOGIC
0.2.13.1 ACUTE EXPOSURE
o Alteration in prothrombin time and/or tendency to
bleeding may occur. Clinically significant bleeding or
hypercoagulability are rare.
o The hallmark of organophosphate poisoning is inhibition
of plasma pseudocholinesterase and erythrocyte
acetylcholinesterase.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Sweating is a consistent, but not universal, sign.
0.2.14.2 CHRONIC EXPOSURE
o Dermal sensitization may occur.
MUSCULOSKELETAL
0.2.15.1 ACUTE EXPOSURE
o Muscle weakness, fatigability, and fasciculations are
common findings, and may be delayed in onset by several
days. Muscle paralysis may occur.
ENDOCRINE
0.2.16.1 ACUTE EXPOSURE
o Hyperglycemia and glycosuria without ketosis may be
present.
METABOLISM
0.2.17.1 ACUTE EXPOSURE
o Hyperglycemia and glycosuria without ketosis may occur
in severe poisoning.
PSYCHIATRIC
0.2.18.1 ACUTE EXPOSURE
o Decreased vigilance, defects in expressive language and
cognitive function, impaired memory, depression,
anxiety, irritability, and psychosis have been
reported, more commonly in persons having other
clinical signs of organophosphate poisoning or
pre-existing psychological conditions.
o Abnormal neuropsychiatric tests and EEGs may persist
for months after acute exposure. During chronic
therapy with DFP for glaucoma, aggravation of
pre-existing psychiatric symptoms and development of
new psychiatric symptoms in normal individuals may
occur, and can persist for up to several months after
the medication is withdrawn.
IMMUNOLOGIC
0.2.19.2 CHRONIC EXPOSURE
o Chronic skin exposure to some organophosphates may lead
to dermal sensitization.
REPRODUCTIVE HAZARDS
o In rodents, stillbirths, metabolic, and behavioral
effects have been observed. DFP was not teratogenic in
rats.
o No information about possible male reproductive effects
was found in available references at the time of this
review.
CARCINOGENICITY
0.2.21.3 ANIMAL OVERVIEW
o At the time of this review, no studies were found on
the possible carcinogenic effects of diisopropyl
fluorophosphate in humans.
o Sixteen of 100 rats administered DIFP at a dose of 0.5
mg/kg every 72 hours for 730 days developed chromophobe
adenomas of the pituitary gland, a tumor with a rare
spontaneous incidence.
GENOTOXICITY
o Cytogenetic studies of organophosphate-exposed workers
have suggested possible increases in frequencies of
chromosome aberrations, but the evidence is not
compelling.
|
| Laboratory: |
o Determine plasma and red blood cell cholinesterase
activities. While there may be poor correlation between
cholinesterase values and clinical effects, depression in
excess of 50% activity is generally associated with severe
symptoms. Correlation between cholinesterase levels and
clinical effects in milder poisonings may be poor.
o If respiratory tract irritation, excessive bronchial
secretions, or bronchospasm occur following exposure,
monitor arterial blood gases.
o If respiratory tract irritation, excessive bronchial
secretions, or bronchospasm occur following exposure,
monitor chest x-ray.
|
| Treatment Overview: |
ORAL EXPOSURE
o EMESIS -
1. Because of potential seizures and coma, inducing emesis
is CONTRAINDICATED.
o GASTRIC LAVAGE -
1. GASTRIC LAVAGE: Consider after ingestion of a
potentially life-threatening amount of poison if it can
be performed soon after ingestion (generally within 1
hour). Protect airway by placement in Trendelenburg
and left lateral decubitus position or by endotracheal
intubation. Control any seizures first.
a. CONTRAINDICATIONS: Loss of airway protective reflexes
or decreased level of consciousness in unintubated
patients; following ingestion of corrosives;
hydrocarbons (high aspiration potential); patients at
risk of hemorrhage or gastrointestinal perforation;
and trivial or non-toxic ingestion.
o ACTIVATED CHARCOAL/CATHARTIC -
1. ACTIVATED CHARCOAL/CATHARTIC: Administer charcoal
slurry, aqueous or mixed with saline cathartic or
sorbitol. The FDA suggests 240 mL of diluent/30 g of
charcoal. Usual charcoal dose is 25 to 100 grams in
adults and adolescents, 25 to 50 grams in children (1
to 12 years old), and 1 gram/kilogram in infants less
than 1 year old.
a. Routine use of cathartics is NOT recommended. If
used, administer only ONE dose of cathartic.
Administer one dose of a cathartic, mixed with
charcoal or given separately. See "Treatment:
Prevention of Absorption" in the main document.
o SUCTION ORAL SECRETIONS - until atropinization.
o ATROPINE THERAPY - If symptomatic from
anticholinesterase poisoning, administer IV atropine
until atropinization is achieved (See details in main
Treatment Section). ADULT - 2 to 5 mg every 10 to 15
minutes; CHILD - 0.05 mg/kg every 10 to 15 minutes.
Atropinization may be required for hours to days
depending on severity.
o PRALIDOXIME (PROTOPAM, 2-PAM) - Severe
anticholinesterase poisoning, characterized by profound
weakness and respiratory depression, should also be
treated with 2-PAM. ADULT - 1 to 2 g IV at 0.5 g per
min; CHILD - 25 to 50 mg/kg over 5 to 30 minutes; may
repeat in one hour and every 6 to 12 hours if muscle
weakness is not relieved or if patient is comatose.
CONTINUOUS INFUSION - (Controversial) - ADULT - 500
mg/hr. Pralidoxime may need to be administered over
several days.
o SEIZURES: Administer a benzodiazepine IV; DIAZEPAM
(ADULT: 5 to 10 mg, repeat every 10 to 15 min as
needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min
as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05
to 0.1 mg/kg).
1. Consider phenobarbital if seizures recur after diazepam
30 mg (adults) or 10 mg (children > 5 years).
2. Monitor for hypotension, dysrhythmias, respiratory
depression, and need for endotracheal intubation.
Evaluate for hypoglycemia, electrolyte disturbances,
hypoxia.
o PULMONARY EDEMA (NONCARDIOGENIC): Maintain ventilation
and oxygenation and evaluate with frequent arterial
blood gas or pulse oximetry monitoring. Early use of
PEEP and mechanical ventilation may be needed.
o HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid,
place in Trendelenburg position. If hypotension
persists, administer dopamine (5 to 20 mcg/kg/min) or
norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to
desired response.
o CONTRAINDICATIONS - Succinylcholine and other
cholinergic agents are contraindicated.
INHALATION EXPOSURE
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
o If respiratory tract irritation or respiratory
depression is evident, monitor arterial blood gases,
chest x-ray, and pulmonary function tests.
o Carefully observe patients with inhalation exposure for
the development of any systemic signs or symptoms and
administer symptomatic treatment as necessary.
o Suction oral secretions until atropinization.
o ATROPINE THERAPY - If symptomatic from
anticholinesterase poisoning, administer IV atropine
until atropinization is achieved (See details in main
Treatment Section). ADULT - 2 to 5 mg every 10 to 15
minutes; CHILD - 0.05 mg/kg every 10 to 15 minutes.
Atropinization may be required for hours to days
depending on severity.
o PRALIDOXIME (PROTOPAM, 2-PAM) - Severe
anticholinesterase poisoning, characterized by profound
weakness and respiratory depression, should also be
treated with 2-PAM. ADULT - 1 to 2 g IV at 0.5 g per
min; CHILD - 25 to 50 mg/kg over 5 to 30 minutes; may
repeat in one hour and every 6 to 12 hours if muscle
weakness is not relieved or if patient is comatose.
CONTINUOUS INFUSION - (Controversial) - ADULT - 500
mg/hr. Pralidoxime may need to be administered over
several days.
o SEIZURES: Administer a benzodiazepine IV; DIAZEPAM
(ADULT: 5 to 10 mg, repeat every 10 to 15 min as
needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min
as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05
to 0.1 mg/kg).
1. Consider phenobarbital if seizures recur after diazepam
30 mg (adults) or 10 mg (children > 5 years).
2. Monitor for hypotension, dysrhythmias, respiratory
depression, and need for endotracheal intubation.
Evaluate for hypoglycemia, electrolyte disturbances,
hypoxia.
o PULMONARY EDEMA (NONCARDIOGENIC): Maintain ventilation
and oxygenation and evaluate with frequent arterial
blood gas or pulse oximetry monitoring. Early use of
PEEP and mechanical ventilation may be needed.
o HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid,
place in Trendelenburg position. If hypotension
persists, administer dopamine (5 to 20 mcg/kg/min) or
norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to
desired response.
o CONTRAINDICATIONS - Succinylcholine and other
cholinergic agents are contraindicated.
EYE EXPOSURE
o DECONTAMINATION: Irrigate exposed eyes with copious
amounts of tepid water for at least 15 minutes. If
irritation, pain, swelling, lacrimation, or photophobia
persist, the patient should be seen in a health care
facility.
o If respiratory tract irritation or respiratory
depression is evident, monitor arterial blood gases,
chest x-ray, and pulmonary function tests.
o Carefully observe patients with inhalation exposure for
the development of any systemic signs or symptoms and
administer symptomatic treatment as necessary.
o SUCTION ORAL SECRETIONS - until atropinization.
o ATROPINE THERAPY - If symptomatic from
anticholinesterase poisoning, administer IV atropine
until atropinization is achieved (See details in main
Treatment Section). ADULT - 2 to 5 mg every 10 to 15
minutes; CHILD - 0.05 mg/kg every 10 to 15 minutes.
Atropinization may be required for hours to days
depending on severity.
o PRALIDOXIME (PROTOPAM, 2-PAM) - Severe
anticholinesterase poisoning, characterized by profound
weakness and respiratory depression, should also be
treated with 2-PAM. ADULT - 1 to 2 g IV at 0.5 g per
min; CHILD - 25 to 50 mg/kg over 5 to 30 minutes; may
repeat in one hour and every 6 to 12 hours if muscle
weakness is not relieved or if patient is comatose.
CONTINUOUS INFUSION - (Controversial) - ADULT - 500
mg/hr. Pralidoxime may need to be administered over
several days.
o SEIZURES: Administer a benzodiazepine IV; DIAZEPAM
(ADULT: 5 to 10 mg, repeat every 10 to 15 min as
needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min
as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05
to 0.1 mg/kg).
1. Consider phenobarbital if seizures recur after diazepam
30 mg (adults) or 10 mg (children > 5 years).
2. Monitor for hypotension, dysrhythmias, respiratory
depression, and need for endotracheal intubation.
Evaluate for hypoglycemia, electrolyte disturbances,
hypoxia.
o PULMONARY EDEMA (NONCARDIOGENIC): Maintain ventilation
and oxygenation and evaluate with frequent arterial
blood gas or pulse oximetry monitoring. Early use of
PEEP and mechanical ventilation may be needed.
o HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid,
place in Trendelenburg position. If hypotension
persists, administer dopamine (5 to 20 mcg/kg/min) or
norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to
desired response.
o CONTRAINDICATIONS - Succinylcholine and other
cholinergic agents are contraindicated.
DERMAL EXPOSURE
o DECONTAMINATION: Remove contaminated clothing and
jewelry. Wash the skin, including hair and nails,
vigorously; do repeated soap washings. Discard
contaminated clothing.
o If respiratory tract irritation or respiratory
depression is evident, monitor arterial blood gases,
chest x-ray, and pulmonary function tests.
o Carefully observe patients with inhalation exposure for
the development of any systemic signs or symptoms and
administer symptomatic treatment as necessary.
o Suction oral secretions until atropinization.
o ATROPINE THERAPY - If symptomatic from
anticholinesterase poisoning, administer IV atropine
until atropinization is achieved (See details in main
Treatment Section). ADULT - 2 to 5 mg every 10 to 15
minutes; CHILD - 0.05 mg/kg every 10 to 15 minutes.
Atropinization may be required for hours to days
depending on severity.
o PRALIDOXIME (PROTOPAM, 2-PAM) - Severe
anticholinesterase poisoning, characterized by profound
weakness and respiratory depression, should also be
treated with 2-PAM. ADULT - 1 to 2 g IV at 0.5 g per
min; CHILD - 25 to 50 mg/kg over 5 to 30 minutes; may
repeat in one hour and every 6 to 12 hours if muscle
weakness is not relieved or if patient is comatose.
CONTINUOUS INFUSION - (Controversial) - ADULT - 500
mg/hr. Pralidoxime may need to be administered over
several days.
o SEIZURES: Administer a benzodiazepine IV; DIAZEPAM
(ADULT: 5 to 10 mg, repeat every 10 to 15 min as
needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min
as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05
to 0.1 mg/kg).
1. Consider phenobarbital if seizures recur after diazepam
30 mg (adults) or 10 mg (children > 5 years).
2. Monitor for hypotension, dysrhythmias, respiratory
depression, and need for endotracheal intubation.
Evaluate for hypoglycemia, electrolyte disturbances,
hypoxia.
o PULMONARY EDEMA (NONCARDIOGENIC): Maintain ventilation
and oxygenation and evaluate with frequent arterial
blood gas or pulse oximetry monitoring. Early use of
PEEP and mechanical ventilation may be needed.
o HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid,
place in Trendelenburg position. If hypotension
persists, administer dopamine (5 to 20 mcg/kg/min) or
norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to
desired response.
o CONTRAINDICATIONS - Succinylcholine and other
cholinergic agents are contraindicated.
|
| Range of Toxicity: |
o Acute toxicity is variable and depends strongly upon the
kinetics of absorption and whether or not metabolic
activation is required. Sudden absorption of a less toxic
compound may have a more severe effect.
o Seizures, apneic spells, miosis, profuse nasal discharge,
and possible muscle weakness were noted in a 12-month-old
boy treated with one drop of 0.1% DIFP eye drops in each
eye daily for 2 months; a serum cholinesterase level 60
hours after the last drop was instilled was 44% of normal.
o A single intraarterial injection of 2 mg/kg of DIFP caused
a delayed peripheral neuropathy in the injected limb in
cats. Muscle fasciculations without other typical signs
of cholinergic poisoning were seen in monkeys administered
as little as 0.03 mg/kg twice weekly. In dogs, similar
findings occurred at dosages of 0.05 mg/kg twice weekly;
in rats, a dose of 0.5 mg/kg twice weekly produced similar
results.
o Reversible renal tubular dysfunction unrelated to
cholinesterase inhibition was seen in rats administered a
single dose of 2 to 4 mg/kg of DIFP.
|
Antidote and Emergency Treatment:
... Since thermoregulatory disturbance may itself contribute to the morbidity
and mortality in individuals exposed to cholinesterase inhibitors, and since
this may be independent of the effect of the toxin on cholinesterase activity,
treatment should be instituted to correct hypothermia as well as to combat cholinergic
stimulation directly.
... Hexamethonium, trimethaphan, and mecamylamine are ganglionic blockers
which can reduce acetylcholine (ACh) release presynaptically. All these agents
are capable of protecting mice from diisopropyl fluorophosphate
(DFP) intoxication by prolonging the latent period of death
or by completely preventing death. Combinations of these agents with 2-pyridine
aldoxime methochloride (2-PAM) (50 mg/kg) improved prophylactic action even
further even further. These results indicate that reduction of ACh release presynaptically
plus neutralization of organophosphates with 2-PAM could be an effective way
to reduce mortality in patients exposed to organophosphorus poisons.
... Mice were injected with several drugs which have in common the ability
to block sodium-channels. Drugs tested were ketamine, phenobarbital, lidocaine,
morphine, prednisolone, and lithium. All mice were injected with DFP (7.6 mg/kg)
plus atropine; the treatment groups were simultaneously injected with the test
drug, while controls received an equal volume of physiological saline. All the
test drugs, at one or more doses, revealed protection, not only in terms of
prolonging symptom onset but also in terms of mortality. The reduction in mortality
was quantitatively similar for each drug. Although the various drugs could have
protected by many different, coincidental mechanisms, a more parsimonious explanation
is that the effect could have been due to one property which all had in common;
namely, sodium-channel blockade.
Maintaining adequate respiratory function should be the first treatment measure
taken. In cases of ingestion, activated charcoal is indicated. Atropine is the
drug of first choice ...
... /Authors/ showed that the carbamate anticholinesterase physostigmine could
protect cat cholinesterase against inactivation by DFP in vivo ... .
Animal Toxicity Studies:
Non-Human Toxicity Excerpts:
... IN ANIMALS POISONED WITH DFP, PLASMA CHOLINESTERASE ACTIVITY RETURNS TO
NORMAL WITHIN SEVERAL DAYS TO A FEW WK, BECAUSE IT IS RELATIVELY RAPIDLY REPLACED
BY NEW ENZYME SYNTHESIZED IN THE LIVER. THE ACETYLCHOLINESTERASE ACTIVITY OF
ERYTHROCYTES, HOWEVER, REMAINS DEPRESSED FOR DURATION OF RED CELL'S LIFE.
IN SEVERE POISONING, MOTOR FIBERS ARE INVOLVED, & THERE IS PARALYSIS &
EXTENSIVE DAMAGE TO RHOMBENCEPHALON & SPINAL CORD WITH DEGENERATION OF SPINOCEREBELLAR
TRACTS, CEREBELLAR PONTINE NUCLEI, & VENTRAL LUMBAR, THORACIC, & CERVICAL
TRACTS.
DIISOPROPYL FLUOROPHOSPHATE ADMIN
IM TO WISTAR RATS, 0.5 MG/KG EVERY 72 HR FOR 730 DAYS, PRODUCED 16/100 PITUITARY
TUMORS (CHROMOPHOBE ADENOMA). SPONTANEOUS INCIDENCE "RARE". /FROM TABLE/
THE ACUTE AND DELAYED BEHAVIORAL EFFECTS OF DFP WERE STUDIED IN WHITE-LEGHORN
HENS TRAINED TO KEY-PECK UNDER A MULTIPLE FIXED-RATIO, FIXED-INTERVAL (MULT
FR F1) SCHEDULE OF FOOD PRESENTATION. ACUTE EFFECTS CONSISTED OF DOSE-RELATED
RESPONSE-RATE DECREASES WHICH WERE SIMILAR FOR BOTH FR AND FI SCHEDULE COMPONENTS.
FOLLOWING A RETURN TO CONTROL RESPONDING FOR NO LESS THAN 7 DAYS, DELAYED EFFECTS
OCCURRED. BEHAVIORAL EFFECTS PRECEDED NEUROTOXIC EFFECTS. THESE LATTER EFFECTS
FIRST APPEARED AS ATAXIA AND PROGRESSED TO LEG PARALYSIS AND SOMETIMES DEATH.
DELAYED EFFECTS FOLLOWED BOTH ACUTE (0.5-1.0 MG/KG) DOSES AS WELL AS DOSES (0.125-0.25
MG/KG) HAVING NO OR LITTLE ACUTE BEHAVIORAL EFFECTS.
THE FINE STRUCTURE OF THE CAT SOLEUS NEUROMUSCULAR JUNCTION WAS STUDIED FOLLOWING
A SINGLE INTRAARTERIAL INJECTION OF DFP. DFP INDUCED SEPARATE SUBACUTE &
DELAYED MORPHOLOGIC CHANGES IN SOLEUS NONMYELINATED MOTOR NERVE TERMINALS. THREE
DAYS AFTER DFP ADMIN MOTOR NERVE TERMINALS WERE REDUCED IN NUMBER. ONE WEEK
FOLLOWING SOME INITIAL REGENERATION, SOLEUS MOTOR NERVE TERMINALS UNDERWENT
A DELAYED TRANSIENT DEGENERATION, FOLLOWED BY REINNERVATION OF DAMAGED ENDPLATES
6-8 WK FOLLOWING DFP.
Dosages as low as 0.05 mg/kg twice/wk in dogs, 0.03 mg/kg twice/wk in monkeys,
& 0.50 mg/kg twice/wk in rats led to muscular fasciculations soon after
individual doses, but to no other typical signs of poisoning. Three of four
monkeys developed bronchopneumonia, which investigators ... associated with
excessive secretions. Cardiospasm often associated with dilatation of esophagus
was seen in three dogs receiving dosages of 0.1, 0.3, & 0.5 mg/kg twice/wk,
& this led to malnutrition at the higher dosages. Partial urinary incontinence
was observed in the dogs on the two higher dosage levels. Both cardiospasm &
urinary incontinence were considered related to inhibition of cholinesterase.
Finally, hind leg paralysis developed during or before the 10th wk of dosing
in dogs receiving 0.3 & 0.5 mg/kg twice/wk.
/Rats admin ip/ ... 1 to 4 mg/kg on days 8, 9, or 12 /of pregnancy/ ... no
/fetal/ defects /found/, but perinatal mortality was increased & weight
gain postnatally was reduced. Treatment on days 7, 8, 9, & 10 did not increase
the resorption rate.
Muscarinic receptors were down-regulated in Wistar rats after repeated exposure
to DFP. The density of receptors was decr to 60-85% of the controls. Redn was
observed in cortex, caudate-putamen, lateral septum, hippocampal formation,
superior colliculus, and pons. The density of muscarinic receptors was unchanged
in thalamic and hypothalamic nuclei, periaqueductal grey, cerebellum, inferior
colliculus & reticular formation of the brain
stem.
The effect of chronic admin of DFP on the levels & forms of plasma cholinesterase
were studied in male Wistar albino rats. The enzymatic activity was evaluated
for butyrylcholinesterase (BuChE) & for acetylcholinesterase (AChE). At
1.5 and 24 hr after the treatments, BuChE was considerably more depressed than
AChE. Moreover, the recovery of BuChE proceeded more slowly, its activity being
restored only 7 days after the last treatment, while the recovery of AChE was
completed 72 hr after the end of the treatments.
The effect of a single dose of DFP (1.1 mg/kg sc) admin to rats during pregnancy
was evaluated by measuring postpartum maternal & newborn brain-soluble
and total acetylcholinesterases (AChE) & their molecular forms @ intervals
of 1, 2, 3, 4 & 10 days between treatment & sacrifice. Subsequently,
the effects of DFP were studied in 18-day-pregnant rats, fetuses & placentae
@ 90 min & 24 hr after treatment. The inhibition of postpartum maternal
enzymatic activity did not differ from that previously found in adult males,
while inhibition was considerably less pronounced in newborns at all time intervals,
with a nearly complete recovery already at 48 hr after treatment. An even faster
recovery of brain enzyme was observed in
18-day fetuses from DFP-treated mothers (24-hr interval between treatment &
sacrifice). In this expt, a comparable inhibition was observed at 90 min after
treatment in the adult & the developing brain,
excluding a major influence of disposition factors in the differential recovery
phenomena.
DFP in doses of 1-4 mg/kg was tested on renal function in rats. A single dose
(2, 3, or 4 mg/kg) caused an incr flow of urine of low osmolality over 6 hr
after the admin of the drug with essentially a return to control status by 24
hr after either of the lower doses. The incr urine flow assoc with decr inulin
clearance (4 mg/kg) and renal blood flow (3 or 4 mg/kg) suggests a direct effect
of DFP on renal tubular function. These effects do not appear to be related
to inhibition of cholinesterase.
The effects of acute admin of DFP (1.1 mg, sc) on sol brain
acetylcholinesterase (AChE) were studied in male rats sacrificed at time intervals
ranging from 3 hr to 25 days after admin. Three main molecular forms of AChE
were separated. In the brain of untreated
animals, the slow-, medium-, and fast-migrating forms accounted, respectively,
for 64, 18, and 18% of the sol AChE activity. At 3 hr after treatment with DFP,
the relative contribution of slow-migrating forms to the residual enzymic activity
was decr, while that of medium-forms was incr. These changes became gradually
more pronounced and reached their max at 4 days, when AChE had recovered to
approx 50% of control level. Subsequently, the distribution of the molecular
forms showed a progressive return toward the control pattern. The partial recovery
in the initial period after max enzyme depression was mainly due to an incr
of medium-migrating forms. Thus, these may be precursors of the biosynthesis
of slow-migrating forms and/or there may be functional specialization of different
forms.
The effects were studied of DFP, paraoxon, and parathion on the activity of
ATPase of rat heart myofibers and mitochondria. The organophosphates had an
inhibitory effect on ATPases. The inhibition was correlated with the duration
of poisoning, the dose of the poison, and the type of the organophosphate. DFP
had the highest inhibitory effects. Ca-dependent ATPase was more
sensitive than the Na-K-dependent ATPase.
A single injection of DFP (2 mg/kg) into a cat femoral artery produced a delayed
neuropathy in the injected leg. Clinical neurotoxic signs in the DFP-treated
leg were most prominent at 21-28 days after DFP admin: a high-step gait with
some tip-toe walking. During that time, the capacity of the cat soleus alpha-motor
nerve terminals to generate a stimulus-evoked repetitive discharge, known as
SBR, was greatly attenuated. At that time, the ultrastructure of the motor nerve
terminals demonstrated prominent alterations that correlated well with the motor
nerve terminal SBR deficit. These alterations incl the presence of extensive
whorls in nerve terminals and axoplasms, the retraction and disruption of nerve
terminals from the synaptic cleft, and a widening of secondary junctional folds.
From the sampled population, the incidence of normal terminals in soleus muscles
of the DFP-treated leg was only 2%.
A number of organophosphates produced delayed neurotoxicity in man which may
be modeled ... in several animal species ... /such as/ the adult hen Gallus
domesticus. The development of delayed neurotoxicity was studied in adult white
Leghorn hens after a single, oral dose (1.0 mg/kg) of diisopropylfluorophosphate
and after the administration of repeated low-level oral doses (125 mug/kg, 5
days/wk; 1.0-5.0 mg/kg, total dose) of DFP. The relationship of dosage, time,
and frequency of administration of subneurotoxic doses of DFP under conditions
of a multiple-dose procedure was examined. The comparative activities of hen
brain and sciatic nerve neurotoxic esterase
(NTE) were studied. The percentage inhibition of NTE paralleled the incr in
the degree of severity of the acute pharmacological response. The chronic dosing
regimen resulted in a small, yet definite, inhibitory effect of DFP on brain
NTE and cholinesterase activities. A maximum level of brain
NTE inhibition occurred followed by a decrease and eventual leveling off of
the inhibitory effect. The comparative NTE studies demonstrate that substrate
hydrolysis by hen sciatic nerve preparations was considerably less when compared
with hen brain extracts using equivalent
tissue weights. The percentage of NTE of the total paraoxon-resistant activity
was lower in sciatic nerve preparations compared with brain
preparations. The effects of DFP on the NTE activities from brain
and sciatic nerve preparations were definitely inhibitory, and quantitative
differences exist between NTE content and activity in peripheral and central
nervous systems.
The effects following oral and intramuscular injection of diisopropyl
fluorophosphate (DFP) were studied in chickens and pigeons responding
under a multiple fixed-ratio, fixed-interval schedule of food presentation.
The effects for both routes for DFP were also studied in chickens responding
on a multiple fixed-ratio, time-out schedule of food presentation. The effects
of intramuscular DFP were studied in a rhesus monkey responding under a chain
fixed-ratio, fixed-ratio schedule of sucrose presentation. The effects of DFP
generally depressed fixed-ratio, fixed-interval, and time-out responding with
no mean response rate increases. Doses producing behavioral effects also produced
acute cholinergic effects in the chicken and the rhesus monkey but not in the
pigeon. The potency and duration of DFP effects depended on the species and
route of administration. The monkey was the most sensitive animal with the lowest
active intramuscular dose (0.1 mg/kg) disrupting for 5 days. A higher dose (0.125
mg/kg) disrupted responding for 8 days. Intramuscular DFP disrupted responding
in the chicken in a dose-related manner and with 0.25 mg/kg being the lowest
active dose. Higher doses (0.5 and 0.75 mg/kg) disrupted responding for 2 days
after administration. Oral DFP was much less potent than the intramuscular route
in chickens and pigeons, with a marginally active dose being 1 mg/kg. Effects
following oral administration lasted < 1 day. Potency was the same in the
pigeon by both the oral and intramuscular routes.
In an attempt to learn more about the proteolytic enzymes responsible for
protein turnover in cells, the effects of various protease inhibitors on protein
catabolism in Escherichia coli were examined. Diisopropyl
fluorophosphate, phenylmethane sulfonyl fluoride, and toluenesulfonyl
fluoride were found to decrease protein breakdown in E coli, starved for a carbon
source. These compounds partially inhibited protein breakdown at doses which
did not inhibit growth on minimal medium. Protein breakdown in starving cells
could also be inhibited reversibly by the aromatic diamidines, dibromopropamidine,
and pentamidine, which are potent trypsin inhibitors. The effects of pentamidine
and p-toluenesulfonyl fluoride did not require concomitant protein synthesis.
Other data presented suggest that there may exist at least two proteolytic systems
in E coli; one operating in all cells, which can degrade abnormal proteins,
and one found in starving cells which is sensitive to sulfonyl fluorides and
aromatic diamidines.
The effects of DFP on the release of endogenous dopamine from rat brain
striatum in vitro were compared with those of the cholinergic muscarinic agonist
oxotremorine, the cholinergic nicotinic agonist nicotine, the cholinergic antagonists
mecamylamine and atropine, and the cholinesterase inhibitor physostigmine to
elucidate the mechanisms involved in the neurotoxicity of DFP and possibly other
organophosphates. DFP (1x10(-3) M) inhibited both spontaneous release and K+-stimulated
dopamine release, the effect on the latter being greater than that of the former.
At 10(-5) and 10(-4) M the inhibitory effects of physostigmine and oxotremorine
on the K+-stimulated dopamine release were similar to DFP. Also, the apparent
stimulatory effects of DFP at 10(-5) and 10(-4) M on spontaneous dopamine release
were similar to those of physostigmine and oxotremorine. However, the inhibitory
effects of 10(-3) M DFP on spontaneous and induced dopamine release was not
observed. Apparently moderate concentrations of DFP affect dopamine release
via an effect of increased acetylcholine on muscarinic receptors on dopaminergic
neurons, whereas high DFP concentrations might directly attack protein sites
involved in neurotransmitter release.
... The results show that DFP ... initially increases rat sciatic nerve conduction
and reduces refractoriness. Continued exposure had a diminished effect with
nerve excitability eventually returning to control. During recovery, the nerve
membrane responsiveness to potassium-induced depolarization significantly changed
in a manner which would indicate either decreased Na, K-ATPase activity, or
decreased potassium ion transmembrane flux. The data suggest that compensatory
changes occcur in rat nerve in response to organophosphorus exposure, and further,
that these compensatory changes involve alteration in membrane ion fluxes.
Thirty-five pregnant Wistar rats (Charles River Italia) were (DFP) injected
sc with 0 or 1.1 mg/kg diisopropylfluorophosphate in arachis oil on day 6 of
pregnancy, and with subsequent doses of 0.7 mg/kg each (25% LD50) on alternate
days up to day 20 of pregnancy. DFP treatment was toxic to dams and caused weight
reduction but not mortality. Pups of 4 DFP-treated litters were stillborn or
died shortly after delivery, and 8 additional litters were lost within 48 hr
after birth. The levels of brain cholinesterase
(ChE) in DFP-exposed newborns did not differ from those of controls. In another
experiment, 15 DFP-treated pregnant rats and 15 controls were killed either
90 min, 24 hr, or 48 hr after the last injection. Total ChE in maternal brain
was consistently depressed without recovery from 90 min to 48 hr, while in fetuses
an almost complete recovery occurred at 48 hr. Maximal number of 3 H quinuclinidyl
benzylate binding sites was significantly decreased in maternal brain
and in 21-day fetal brain.
... DFP was tested as an unconditioned stimulus in the conditioned taste aversion
(CTA) test /rats/. DFP caused a dose-dependent conditioned taste aversion in
rats which did not induce any other signs of toxicity. ... The conditioned taste
aversion test appears to be a sensitive indicator of neurobehavioral effects
of mild exposure to organophosphates. ...
The LD50 and ED50 for inhibition of acetylcholinesterase in whole mouse brain
were determined after intravenous administration of diisopropyl
fluorophosphate over a 10 sec period at a volume of 0.1 ml/10
g body weight. The LD50 was 3.4 mg/kg. Recovery of acetylcholinesterase activity
in whole mouse brain after subLD50 doses
was slow and did not reach control values by 14 days after intravenous administration.
Acetylcholinesterase activity was inhibited in a dose dependent manner in whole
mouse brain as well as in six brain
regions (cortex, hippocampus, striatum, midbrain,
medulla/pons, and cerebellum). None of these brain
areas were particularly sensitive to acetylcholinesterase inhibition by the
organophosphate compound. The EC50 was 0.649 mg/kg or 19% of th LD50.
The luminal and mucosal de-esterification of the prodrug ester cefpodoxime
proxetil and effects of esterase inhibitors such as physostigmine (eserine),
isoflurophate (diisopropylfluorophosphate), edetic acid (EDTA), dithiothreitol,
and mercuric chloride and drug ester competitors such as enalapril, bacampicillin,
and aspirin (acetylsalicylic acid) on the hydrolysis of the prodrug were studied
in vitro in New Zealand rabbit intestine, and the intestinal absorption of the
prodrug was studied in vitro in white New Zealand rabbit jejunum. In rabbit
intestine, enzymatic hydrolysis of the prodrug was observed in both luminal
washing and mucosal homogenate. In rabbit jejunum, extensive hydrolysis of the
prodrug occurred in the mucosal compartment and the accumulation of cefpodoxime
in the serosal compartment was very slow. Physostigmine and isoflurophate were
potent inhibitors of prodrug hydrolysis in both luminal washing and mucosal
homogenate. Edetic acid was a moderate inhibitor, and dithiothreitol showed
no inhibition. The luminal and mucosal activities were equally sensitive to
mercuric chloride and aspirin inhibition, but slight differences were observed
concerning the 50% inhibitory concentrations of bacampicillin and enalapril.
The results showed that luminal choline esterases participated in the hydrolysis
of cefpodoxime proxetil.
Involvement of dorsal and ventral root activity for the depressant action
of diisopropylfluorophosphate (DFP) on synaptic transmission was examined using
in vitro spinal cord/root preparations. Superfusion of DFP produced a dose-dependent
depression of monosynaptic reflex (MSR) and maximal depression of about 80%
occurred at 1000 uM. The concentration to produce 50% of the maximal inhibition
was about 100 microM of diisopropylfluorophosphate. The diisopropylfluorophosphate
(100 uM)-induced depression of monosynaptic reflex was reversed by atropine
(0.5 uM) but not by mecamylamine (0.5 uM). Contrary to the action on monosynaptic
reflex, diisopropylfluorophosphate potentiated the ventral root potential and
1st peak of dorsal root potential. The maximal potentiation was about 25% of
control in both the root potentials at 100 uM of diisopropylfluorophosphate.
However, the second peak of dorsal root potential was slightly depressed (10-20%
of control) by diisopropylfluorophosphate (1-1000 uM). Further, the cords treated
with diisopropylfluorophosphate (100 uM) showed significant decrease in the
cholinesterase (ChE) activity (27% of control). Results suggest that the diisopropylfluorophosphate-induced
depression was mediated at least by two different mechanisms, one through the
inhibition of ChE activity and the other through the activation axonal activity
having inhibitory inputs to the segmental synaptic transmission. These inputs
mediate their action through muscarinic receptors.
The contribution of carboxylesterase (CarbE) to toxicity and tolerance to
the organophosphorus anticholinesterases (OP-antiChE) paraoxon (diethyl p-nitrophenyl
phosphate) and DFP (diisopropylphosphorofluoridate) was investigated in rats.
Daily injections (20 days) of paraoxon (0.33 umol/kg) or diisopropylfluorophosphate
(2.72 umol/kg) reduced AChE activity in brain
to 29 or 16% and in diaphragm to 58 or 54%, respectively. The animals tolerated
an accumulated 6-fold LD50 dose and survived an LD90 dose of carbachol, indicating
tolerance to this cholinergic agonist. A single dose of paraoxon or diisopropylfluorophosphate
significantly reduced carboxylesterase activity of plasma, lung and liver. After
paraoxon, rapid recovery was seen of plasma and liver carboxylesterase while
recovery after diisopropylfluorophosphate was much slower. Daily pretreatment
with the carboxylesterase inhibitors CBDP (2-[o-cresyl]-4H-1,2,3-benzodioxa-
phosphorin-2-oxide) (7.22 micromol/kg, s.c.) or iso-OMPA (tetraisopropylpyrophosphoramide)
(8.76 umol/kg, i.p.), followed by paraoxon (0.33 micromol/kg, s.c.) 30 min later,
prevented the development of tolerance to paraoxon and potentiated its toxicity.
Rats died on day four of the combined treatment. The carboxylesterase inhibitors
neither potentiated the diisopropylfluorophosphate toxicity, nor prevented tolerance
development to diisopropylfluorophosphate. We conclude that rat plasma CarbE
provides a significant protection against paraoxon toxicity because its rapid
reactivation can reduce the toxicity of repeated paraoxon applications and thus
contribute to tolerance development. This same mechanism does not apply to diisopropylfluorophosphate
toxicity, as inhibition of carboxylesterase of plasma, liver and lung neither
potentiated its toxicity, nor prevented tolerance development. These findings
confirm previous observations that CarbE detoxification is of greater importance
for highly toxic OP-antiChEs such as nerve agents and paraoxon than for less
toxic ones such as diisopropylfluorophosphate.
Rats were repeatedly administered with a low dose of diisopropylfluorosphosphate
(DFP; 0.2 mg/kg/day, SC, for 9 or 21 days), an irreversible cholinesterase (ChE)
inhibitor. Control rats received a daily injection of oil vehicle. Neurochemical
changes occurring in the pontomesencephalic tegmentum (PMT), a brain
stem region critically involved in behavioral state control, were evaluated
at various times of treatment and after diisopropylfluorosphosphate withdrawal.
First, enzyme assay revealed a profile of cholinesterase inhibition 6 days (74-82%
inhibition). The inhibition was less pronounced in the locus coeruleus (49%).
Third,(3H)QNB autoradiography showed that muscarinic receptor density was unchanged
in any of the pontomesencephalic tegmentum areas selected. These results are
discussed regarding the question of regional variation in susceptibility to
anti-cholinesterase agents. To what extent behavioral state alterations occur
concomitantly with cholinesterase activity changes is assessed in the companion
article.
Rats were repeatedly administered with low doses of diisopropylfluorophosphate
(DFP; 0.2 mg/kg/day, SC), an irreversible cholinesterase (ChE) inhibitor. Control
rats received a daily injection of oil vehicle or of saline. Recordings of the
sleep-wake states were obtained in the 6 hr following 1, 3, 6, 9, 13, 17, and
21 injections, as well as 2, 4, and 19 days after 9-day treatment. Diisopropylfluorophosphate
administration increased waking at the expense of slow-wave sleep (SWS), but
not of paradoxical sleep (PS); as a . In contrast, after diisopropylfluorophosphate
withdrawal, behavioral states returned to control values more rapidly (in 2-4
days) than did cholinesterase activity. These results are discussed regarding
the promoting role of cholinergic neurotransmission in brain-activated
states.
Humans acutely exposed to anticholinesterase (anti-ChE) pesticides often become
febrile, whereas rats and other rodents become markedly hypothermic. The rat
may nonetheless be a useful model for anti-cholinesterase toxicity because recent
work using radiotelemetry demonstrated an elevation in core temperature of unrestrained
rats for several days following acute exposure to the anti-cholinesterase, diisopropyl
fluorophosphate (DFP). To discern the mechanisms of diisopropyl
fluorophosphate-induced hypothermia and hyperthermia, various
pharmacological agents were administered acutely or chronically to rats injected
with 1.5 mg/kg diisopropyl fluorophosphate (SC).
Core temperature, heart rate, and motor activity were monitored continuously
via radiotelemetry. Methylscopolamine, a peripheral muscarinic antagonist, attenuated
the diisopropyl fluorophosphate-induced
hypothermia by 1.0 degree C and reversed the diisopropyl
fluorophosphate-induced bradycardia. Chronic scopolamine, a
central and peripheral muscarinic antagonist, delivered via a subcutaneously
implanted minipump (9.5 mg/kg/day) blocked diisopropyl
fluorophosphate-induced hypothermia and hyperthermia. Propranolol
(10 mg/kg; SC), a general beta blocker, augmented the bradycardic effects of
diisopropyl fluorophosphate but had
no effect on body temperature. Sodium salicylate (200 and 300 mg/kg; IP), an
antipyretic that inhibits prostaglandin synthesis, administered during the period
of diisopropyl fluorophosphate-induced
hyperthermia produced a transient recovery in body temperature. Overall, diisopropyl
fluorophosphate-induced hypothermia and hyperthermia in the
rat appear to be mediated via cholinergic activation in the CNS because both
are blocked by scopolamine. The decrease in core temperature following sodium
salicylate suggests that prostaglandin release is involved in the manifestation
of diisopropyl fluorophosphate-induced
hyperthermia. The elevation in core temperature after diisopropyl
fluorophosphate appears to involve neurochemical pathways similar
to that of fever.
This study compared the neurotoxic effects of triphenyl phosphite (TPP) in
the rat with those seen after exposure to diisopropylphosphorofluoridate (DFP),
a compound known to produce organophosphorus-induced delayed neurotoxicity (OPIDN).
Animals received either three subcutaneous injections of triphenyl phosphite
(1184 mg/kg body wt each dose) administered at 3-day intervals or a single subcutaneous
injection of diisopropylphosphorofluoridate (4 mg/kg body wt). Triphenyl phosphite-induced
clinical signs were initially observed 2 to 18 days after the last injection
and included ataxia, flaccid paresis, stereotyped alternating side-to-side movements,
and circling behavior. Axonal and terminal degeneration were present in the
cerebellum, vestibular nuclear complex, cochlear nuclei, and superior and inferior
colliculi. The subthalamic nucleus, substantia nigra, septal region, hypothalamus,
thalamus, hippocampus, and cerebral cortex also contained degenerating axons
and terminals. Degeneration was particularly evident in the sensorimotor cerebral
cortex, mediodorsal, ventromedial, and medial geniculate thalamic nuclei and
in the magnocellular preoptic and medial mammillary nuclei of the hypothalamus.
Very light degeneration was present in the gracile fasciculus and nucleus. In
contrast, rats injected with diisopropylphosphorofluoridate showed moderate
degeneration in the gracile fasciculus and nucleus but did not display degeneration
in any other brain region. Injections of
diisopropylphosphorofluoridate did not produce delayed onset clinical signs.
The results indicate that in the rat, different central nervous system cell
groups are affected by these two organophosphorus compounds and that triphenyl
phosphite affects nuclei and tracts at all levels of the neuraxis, including
those associated with higher-order processing and cognitive functions. In addition,
the distinct degeneration patterns produced by these two compounds support the
view that triphenyl phosphite-induced neurotoxicity should not be considered
as a type of organophosphorus-induced delayed neurotoxicity, but rather as a
separate category of organophosphorus-induced neurotoxicity.
... Daily dosing of DFP /to rats/ in a concn (0.5 mg/kg, sc) that as a single
dose did not cause symptoms, produced onset of fasciculations on the third day
associated with a reduced number of muscle fiber lesions. Further administration
of DFP (14 days) caused disappearance of fasciculations and loss of sensitivity
to necrotizing actions in all muscles tested (diaphragm, soleus, and extensor
digitorum longus). Activity of all molecular forms of AChE was reduced to 20-24%
of control when symtoms of cholinergic hyperactivity appeared. Continuous injections
of DFP (0.5 mg/kg/day, sc) up to 14 days did not cause greater inhibition of
AChE activity. Instead, recovery of enzyme activity, especially of the 4S and
10S forms, was seen. During this period choline acetyltransferase activity (ChAT)
was increased in muscle (intramuscular nerves) while post-synaptic nicotinic
acetylcholine receptor (nAChR) density (Bmax) was decreased to 44% without a
change in the affinity constant (KD). It is concluded that neuromuscular adaptation
to DFP is caused by recovery of AChE activity due to de novo synthesis and reduction
in the number of nAChR.
Non-Human Toxicity Values:
LD50 Rat oral 5 mg/kg
TSCA Test Submissions:
The inhibition of nonspecific esterase activity, and/or inhibition of aromatic
amino acid esterase activity, and/or potential effects on specific cellular
functions (phagocytosis, immunoglobulin G synthesis, and inflammatory and immune
mediator release) were evaluated with organic chemicals added to human peripheral
blood monocytes. Diisopropyl phosphorofluoridate at a concentration of 1.5 mM
inhibited monocyte alpha-naphthyl acetate esterase activity by 65% (assay method
not reported).
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
HEN EGG-WHITE LYSOZYME WAS ALLOWED TO REACT WITH AN EXCESS OF DFP @ 25 DEG
C & AT PH VALUES RANGING FROM 9.5 TO 11.0. ANALYSIS INDICATED THAT ALKYLPHOSPHORYLATION
OF TYROSYL HYDROXYL GROUPS HAD OCCURRED & ... SOME OTHER AMINO ACID RESIDUES
HAD ALSO BEEN PHOSPHORYLATED. SIMILAR RESULTS ... OBTAINED WITH STEM BROMELAIN,
TAKA-AMYLASE A, & PAPAIN.
... DIISOPROPYL FLUOROPHOSPHONATE, UNDERGOES DEFLUORINATION IN BOTH MAMMALS
& BACTERIA.
DFP is rapidly metabolized to diisopropylphosphate & is excreted, mainly
in the urine. Less than 1% is eliminated by bile & lung within the first
2 hr.
WHEN SMALL AMOUNTS (0.1 MG/KG) OF DFP WERE ADMIN TO GUINEA PIGS, DFP WAS ...
CONVERTED IN PART TO DIISOPROPYL PHOSPHATE (DP) ... DFP WAS DEGRADED BY PSEUDOMONAS
MELOPHTHORA BUT NO METABOLITES WERE IDENTIFIED. BLUEGILL (LEPOMIS MACROCHIRUS
RAFINESQUE) & CHANNEL CATFISH (ICTALURUS PUNCTALUS WALBAUM) CONVERTED DFP
TO DIISOPROPYL PHOSPHATE.
An enzyme in Escherichia coli hydrolyzes isofluorophate. A superficially similar
but distinctly different enzyme is found in squid nerve. The results of this
study suggest that while several tissues of the squid contain only this second
kind of DFP hydrolyzing enzyme, termed squid type DFPase, many other sources
incl E coli contain a mixt of squid type DFPase (the name not strictly indicative
of source) and the other DFP hydrolyzing enzyme, now termed Mazur type DFPase.
Absorption, Distribution & Excretion:
WHEN SMALL AMOUNTS (0.1 MG/KG) OF DFP WERE ADMIN TO GUINEA PIGS, DFP WAS PREFERENTIALLY
BOUND BY SERUM & BY THE LUNGS. ADMIN OF LARGE AMOUNTS (3-6 MG/KG) PRODUCED
UNIFORM BODY DISTRIBUTION & ACCUMULATION IN KIDNEYS & LIVER. DFP WAS
CONVERTED IN PART TO DIISOPROPYL PHOSPHATE (DP). BOTH DFP & DP WERE EXCRETED
MAINLY IN THE URINE. SOME APPEARED IN BILE.
TRANSPLACENTAL PASSAGE OF MORE POLAR INSECTICIDES, DFP ... HAS BEEN INFERRED
FROM FETAL CHOLINESTERASE INHIBITION.
... Its high lipid solubility, low molecular weight, and volatility facilitate
inhalation and transdermal absorption. DFP also readily penetrates the central
nervous system.
The effects of skin metabolism on percutaneous penetration of drugs with high
lipophilicity were studied in vitro using rat skin pretreated with and without
an esterase inhibitor, isoflurophate (diisopropylphosphofluoridate; DFP). Without
diisopropylphosphofluoridate, about 96% of the total penetrated amount appeared
as metabolized p-hydroxybenzoic acid in the receptor fluid after application
of butylparaben, whereas about 30% penetrated as intact form after application
of propylparaben. On the other hand, metabolized p-hydroxybenzoic acid was not
detected in the receptor fluid under pretreatment with DFP. DFP significantly
decreased the total amount that penetrated after application of butylparaben,
but it did not significantly affect that of propylparaben. It was concluded
that skin metabolism directly affected the total amount that penetrated in the
case of highly lipophilic drugs, and that the higher the metabolic rate to hydrophilic
drugs, the greater the amount that penetrated the skin.
Biological Half-Life:
Following iv injection of tritium-labeled DFP, the concn in arterial serum
declined in two exponential phases with t1/2 of about 7 & 200 minutes, respectively,
reflecting, first, fast accumulation of the compound & its metabolites in
the tissue &, second, elimination.
Mechanism of Action:
Passive avoidance retention and cortical (3)H-quinuclidinyl benzilate (QNB)
binding were exam in rats that were chronically treated with isofluorophate.
Retention of a passive avoidance response was significantly lower when compared
to vehicle-treated controls. Passive avoidance retention decr from 93% in control
animals to 68% in DFP-treated rats. QNB binding studies revealed the density
of muscarinic receptors in cortical homogenates was significantly reduced from
0.95 +/- 0.04 pmol/mg protein in controls to 0.72 +/- 0.04 pmol/mg protein in
DFP-treated rats. Based on data that DFP causes a redn in cholinergic receptors,
this study supports the hypothesis that central cholinergic receptors are assoc
with mechanisms involved in memory storage.
The organophosphorus inhibitors, such as DFP, serve as true hemisubstrates,
since the resultant conjugate with the active center serine phosphorylated or
phosphonylated is extremely stable. ... If the alkyl groups in the phosphorylated
enzyme are ethyl or methyl, a significant degree of spontaneous regeneration
of active enzyme requires several hours. Secondary (as in DFP) or tertiary alkyl
groups enhance the stability of the phosphorylated enzyme, & significant
regeneration of active enzyme is not observed. Hence, the return of acetylcholinesterase
activity depends on synthesis of new enzyme.
The characteristic pharmacological effects of the anticholinesterase agents
are due primarily to the prevention of hydrolysis of acetylcholine by acetylcholinesterase
at sites of cholinergic transmission. The transmitter thus accumulates, &
the action of acetylcholine that is liberated by cholinergic impulses that leak
from the nerve ending is enhanced. With most of the organophosphorus agents,
such as DFP, virtually all the acute effects of moderate doses are attributable
to this action. For example, the characteristic miosis that follows local application
of DFP to the eye is not observed after chronic postganglionic denervation of
the eye because there is no effective source of endogenous acetylcholine.
Rats were treated with DFP using 1 or 2 mg/kg acutely, or with 1 mg/kg daily
for 4, 14 or 28 days. Tremors, chewing movements and hind-limb abduction induced
by DFP incr in a steeply dose-dependent manner. Tremor occurred in a complex
spectrum of slow to intense fast types. Except for chewing, tolerance developed
for these parameters, but at different rates. After acute treatment striatal
dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels were altered and
the DOPAC/DA ratios were consistently incr within about the first 2 hr, suggesting
an incr turnover of DA. It is suggested that the changes in DA metab arose secondarily
to an elevation of brain acetylcholine following
cholinesterase inhibition. A prolonged change in the levels or turnover of DA
could be responsible for incr of postsynaptic DA receptor density previously
found, which might then partly mediate the behavioral tolerance to DFP.
DFP (1X10-3 M) inhibited both spontaneous release and K+-stimulated dopamine
release from rat brain striatum in vitro,
the effect on the latter being greater than that on the former. At 1X10-5 and
1X10-4 M the inhibitory effects of physostigmine and oxotremorine on K+-stimulated
dopamine release were similar to those of DFP. Also, the apparent stimulatory
effects of DFP at 1X10-5 and 1X10-4 M on spontaneous dopamine release were similar
to those of physostigmine and oxotremorine. However, the inhibitory effect of
1X10-3 M DFP on spontaneous and induced dopamine release was not observed following
physostigmine or oxotremorine. Apparently, moderate DFP concn affect dopamine
release via an effect of incr acetylcholine on muscarinic receptors of dopaminergic
neurons, whereas high DFP concn might directly attack protein sites involved
in neurotransmitter release.
The effects of DFP on neuromuscular transmission were explored using intracellular
recording techniques in a vascular perfused rat phrenic nerve-hemidiaphragm
prepn. The presence of DFP (4X10-5 M) in the perfusion medium yielded greater
than 97% inhibition of acetylcholinesterase activity and resulted in a slight
incr in amplitude as well as a prolongation of the decay phase of spontaneous
miniature endplate potentials and evoked endplate potentials. Quantal content
of evoked acetylcholine release was unaltered by DFP. Therefore, DFP appears
to be an appropriate acetylcholinesterase inhibitor for studies involving the
release of endogenous acetylcholine from phrenic nerve-hemidiaphragm.
/A study concerned/ with the feasibility of a general approach of chemical
modification of an enzyme for decreasing the reactivity with organophosphorus
inhibitors relative to activity towards substrate, and potential prophylaxis,
has been demonstrated. Chemical modification of chymotrypsin decreases its reactivity
to organophosphorus compounds. The ratios of rates of inhibition of native to
modified chymotrypsin are 3:2 for sarin, 2:1 for diisopropyl
fluorophosphate, 6.7:1 for soman, and 7.1:1 for cyclohexylmethylphosphonofluoridate.
The bulkier the organophosphorus compound, generally the more potent its inhibition
of native chymotrypsin, the slower its relative rate of inhibition of modified
chymotrypsin. Inhibited native chymotrypsin could be reactivated by pralidoxime
chloride more rapidly than could inhibited modified chymotrypsin. The ratios
of half-times of reactivation when comparing native to modified enzymes were
2:1 for sarin and 7.8:1 for soman inhibitions. Native chymotrypsin inhibited
by soman can be reactivated twice as fast as when inhibited by sarin, whereas
the reverse occurs with modified ehymotrypsin.
Perfusion of the hemidiaphragm with 10 or 100 mu M of DFP reduced choline
efflux by 39% and 69%, respectively. DFP administration to rats (6 mg/kg) also
lowered the in vitro release of choline by 33%. The rate of ACh release from
hemidiaphragm preparations perfused with DFP was lower than the rate of release
from the preparations perfused with physostigmine, an acetylcholinesterase inhibitor
which had no effect on choline efflux. The addition of choline (10-30 muM) to
the perfusion medium restored the rate of ACh release from DFP-treated hemidiaphragms
but did not further elevate ACh release from physostigmine-treated preparations.
Thus, DFP inhibits choline efflux from the isolated hemidiaphragm and apparently
by limiting the availability of choline for ACh synthesis, DFP reduces the rate
of ACh release.
Diisopropyl fluorophosphate ... is
widely used as an enzyme inhibitor.
Organophosphate insecticides such as ... DFP are potent cholinesterase enzyme
inhibitors that act by interfering with the metabolism of acetylcholine, resulting
in the accumulation of acetylcholine at neuroreceptor transmission sites.
Interactions:
IN SOME CASES ANOTHER PARASYMPATHOMIMETIC AGENT SUCH AS CARBACHOL ... MAY
ENHANCE THE EFFECT OF ISOFLUROPHATE. HOWEVER, ACTION OF ISOFLUROPHATE IS INHIBITED
BY PRIOR INSTILLATION OF PHYSOSTIGMINE.
Phenyl methyl sulfonyl fluoride (PMSF) was able to protect hens from delayed
neurotoxicity when given 4 hr before 1.7 mg/kg sc DFP. However, PMSF was ineffective
at preventing paralysis when given later than 4 hr before DFP admin. These results
support the notion that PMSF acts at the same site as the organophosphorus esters.
Using the hot-plate test in mice di-isopropylfluorophosphate potentiates the
antinociceptive activity of alfentanil but has no effect on the activity of
morphine or fentanyl.
Skin penetration of the alkyl phophates, diisopropyl
fluorophosphate (DFP) and N,N-dimethylamino-o-ethylcyanophosphate
(Tabun), was investigated, in vitro and in vivo, in guinea pigs and rats. As
a basis for the development of skin barrier creams (formulations), a series
of polyethylene glycols was chosen. For some formulations a short-time inhibition
of Tabun-penetration in vitro was found, which could not be verified in vivo.
In vivo all formulations gave an enhancement of penetration. Mixed with Tabum
(10:1) polyethylene glycol 400 strongly diminished the penetration of the former
substance.
Exptl Therapy: The delayed organophosphorus neuropathy caused by diisopropyl
fluorophosphate (DFP) can be prevented by pretreatment with
phenylmethanesulfonyl fluoride (PMSF). A single injection of DFP (2 mg/kg) into
a cat femoral artery produced a delayed neuropathy in the injected leg. Cats
which received PMSF (30 mg/kg, ip) 4 hr before DPF administration did not develop
any neurotoxic signs.
... Diazepam,with atropine and obidoxime, substantially raised the LD50 of
diisopropyl phosphorofluoridate (DFP) in rats.
DFP injected into the femoral artery of cats causes a localized organophosphorus-induced
delayed neuropathy (OPIDN). Gait disturbances develop in the treated leg 14
days after DFP exposure and reaches a maximum at 21 to 28 days after DFP. In
vivo high-frequency conditioning of soleus motor nerve endings evokes stimulus-bound
repetitive neural discharges (SBR) and an obligatory potentiation of the muscle
contractile response (PTP). In this OPIDN model, SBR and PTP are maximally suppressed
at 21 to 28 days after DFP. A high-dose regimen of methylprednisolone started
30 to 40 minutes after DFP exposure and lasting for 20 days prevented the development
of OPIDN. In the methylprednisolone-DFP treated cats, SBR and PTP functions
were not suppressed and not different from those in untreated normal cats.
Pharmacology:
Therapeutic Uses:
Cholinesterase Inhibitors; Miotics; Parasympathomimetics; Protease Inhibitors
OCCASIONALLY BY PHYSICIANS (OPHTHALMOLOGISTS) FOR TREATMENT OF GLAUCOMA.
IT IS USED TOPICALLY IN TREATMENT OF PRIMARY OPEN-ANGLE GLAUCOMA, BUT ONLY
WHEN SHORT-ACTING MIOTICS HAVE FAILED. ... ALSO USED IN TREATMENT OF APHAKIC
GLAUCOMA & ACCOMMODATIVE ESOTROPIA. WITHIN A DAY INTRAOCULAR TENSION DROPS,
& ... MAY REMAIN DEPRESSED FOR A ... WK. MIOSIS LASTS 2 TO 4 WK.
IRREVERSIBLE ANTICHOLINESTERASE ... ISOFLUROPHATE ... /IS/ ONLY OF HISTORICAL
INTEREST IN TREATMENT OF MYASTHENIA GRAVIS ... UNSATISFACTORY BECAUSE OF ...
TOXICITY.
MEDICATION (VET): ... /IS/ COMMONLY USED ... /LOCALLY TO CONSTRICT THE PUPIL
FOR TREATMENT OF GLAUCOMA/ IN DOGS. EFFECTS ... ARE RELATIVELY LONG LASTING
& DOSAGE MUST BE CAREFULLY CONTROLLED.
Of the organophosphorus agents, DFP has the longest duration of action &
is extremely potent when applied locally; solutions in peanut or sesame oil
require instillation from once daily to once weekly, & may control intraocular
pressure in severe cases that are resistant to other drugs. The oily vehicle
is unpleasant to most patients. Consequently, DFP has largely been replaced
by echothiophate.
MEDICATION: CHOLINERGIC (OPHTHALMIC)
Medication: An organophosphate anticholinesterase ... used topically in the
treatment of primary open-angle glaucoma, but only when short acting miotics
have failed. It is also used in the treatment of aphkic glaucoma and accomodative
estropia.
MEDICATION (VET): HAS BEEN USED AS A MIOTIC
This compound is used to treat glaucoma.
Drug Warnings:
... Should be used cautiously in patients with bronchial asthma, bradycardia,
or hypotension. An increase in blood pressure may occur occasionally due to
a nicotinic effect on sympathetic ganglia.
Because of their cataractogenic properties & other toxicity, /diisopropyl
fluorophosphate/ should be reserved for patients refractory
to short-acting miotics, epinephrine, beta-blocking drugs, & possibly, carbonic
anhydrase inhibitors. /Long-acting miotics, including floropryl/
Interactions:
IN SOME CASES ANOTHER PARASYMPATHOMIMETIC AGENT SUCH AS CARBACHOL ... MAY
ENHANCE THE EFFECT OF ISOFLUROPHATE. HOWEVER, ACTION OF ISOFLUROPHATE IS INHIBITED
BY PRIOR INSTILLATION OF PHYSOSTIGMINE.
Phenyl methyl sulfonyl fluoride (PMSF) was able to protect hens from delayed
neurotoxicity when given 4 hr before 1.7 mg/kg sc DFP. However, PMSF was ineffective
at preventing paralysis when given later than 4 hr before DFP admin. These results
support the notion that PMSF acts at the same site as the organophosphorus esters.
Using the hot-plate test in mice di-isopropylfluorophosphate potentiates the
antinociceptive activity of alfentanil but has no effect on the activity of
morphine or fentanyl.
Skin penetration of the alkyl phophates, diisopropyl
fluorophosphate (DFP) and N,N-dimethylamino-o-ethylcyanophosphate
(Tabun), was investigated, in vitro and in vivo, in guinea pigs and rats. As
a basis for the development of skin barrier creams (formulations), a series
of polyethylene glycols was chosen. For some formulations a short-time inhibition
of Tabun-penetration in vitro was found, which could not be verified in vivo.
In vivo all formulations gave an enhancement of penetration. Mixed with Tabum
(10:1) polyethylene glycol 400 strongly diminished the penetration of the former
substance.
Exptl Therapy: The delayed organophosphorus neuropathy caused by diisopropyl
fluorophosphate (DFP) can be prevented by pretreatment with
phenylmethanesulfonyl fluoride (PMSF). A single injection of DFP (2 mg/kg) into
a cat femoral artery produced a delayed neuropathy in the injected leg. Cats
which received PMSF (30 mg/kg, ip) 4 hr before DPF administration did not develop
any neurotoxic signs.
... Diazepam,with atropine and obidoxime, substantially raised the LD50 of
diisopropyl phosphorofluoridate (DFP) in rats.
DFP injected into the femoral artery of cats causes a localized organophosphorus-induced
delayed neuropathy (OPIDN). Gait disturbances develop in the treated leg 14
days after DFP exposure and reaches a maximum at 21 to 28 days after DFP. In
vivo high-frequency conditioning of soleus motor nerve endings evokes stimulus-bound
repetitive neural discharges (SBR) and an obligatory potentiation of the muscle
contractile response (PTP). In this OPIDN model, SBR and PTP are maximally suppressed
at 21 to 28 days after DFP. A high-dose regimen of methylprednisolone started
30 to 40 minutes after DFP exposure and lasting for 20 days prevented the development
of OPIDN. In the methylprednisolone-DFP treated cats, SBR and PTP functions
were not suppressed and not different from those in untreated normal cats.
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Diisopropyl fluorophosphate's production
and use as a cholinergic and miotic may result in its release to the environment
through various waste streams. If released to air, an estimated vapor pressure
of 0.54 mm Hg at 25 deg C indicates diisopropyl fluorophosphate
will exist solely in the vapor-phase in the ambient atmosphere.
Vapor-phase diisopropyl fluorophosphate will
be degraded in the atmosphere by reaction with photochemically-produced hydroxyl
radicals; the half-life for this reaction in air is estimated to be 5 hrs. If
released to soil, diisopropyl fluorophosphate is
expected to have very high mobility based upon an estimated Koc of 31. Volatilization
from moist soil surfaces is expected to be an important fate process based upon
an estimated Henry's Law constant of 3.2X10-6 atm-cu m/mole. Diisopropyl
fluorophosphate will not volatilize from dry soil surfaces based
upon its vapor pressure. If released into water, diisopropyl
fluorophosphate is not expected to adsorb to suspended solids
and sediment based upon the estimated Koc. Volatilization from water surfaces
is expected to be an important fate process based upon this compound's estimated
Henry's Law constant. Estimated volatilization half-lives for a model river
and model lake are 250 hrs and 120 days, respectively. An estimated BCF of 1
suggests the potential for bioconcentration in aquatic organisms is low. Diisopropyl
fluorophosphate does undergo hydrolysis to HF and diisopropyl
phosphate; half-lives range from 16.7 hrs to 2.2 days at temperatures of 37
to 25 deg C and 72 hrs to several days at temperatures of 15 to 30 deg C. Occupational
exposure to diisopropyl fluorophosphate may
occur through dermal contact with this compound at workplaces where diisopropyl
fluorophosphate is produced or used. (SRC)
Probable Routes of Human Exposure:
Occupational exposure to diisopropyl fluorophosphate
may occur through dermal contact with this compound at workplaces
where diisopropyl fluorophosphate is
produced or used. (SRC)
Artificial Pollution Sources:
Diisopropyl fluorophosphate's production
and use as a cholinergic and miotic (in veterinary medicine)(1) may result in
its release to the environment through various waste streams(SRC).
Environmental Fate:
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value
of 31(SRC), determined from a structure estimation method(2), indicates that
diisopropyl fluorophosphate is expected
to have very high mobility in soil(SRC). Volatilization of diisopropyl
fluorophosphate from moist soil surfaces is expected to be an
important fate process(SRC) given an estimated Henry's Law constant of 3.2X10-6
atm-cu m/mole(SRC), using a fragment constant estimation method(3). Diisopropyl
fluorophosphate does undergo hydrolysis to HF and diisopropyl
phosphate; half-lives range from 16.7 hrs-2.2 days at temperatures of 37-25
deg C(5,6) and 72 hrs-several days at temperatures of 15-30 deg C(7,8). Diisopropyl
fluorophosphate is not expected to volatilize from dry soil
surfaces(SRC) based upon an estimated vapor pressure of 0.54 mm Hg(SRC), determined
from a fragment constant method(4).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value
of 31(SRC), determined from an estimation method(2), indicates that diisopropyl
fluorophosphate is not expected to adsorb to suspended solids
and sediment(SRC). Volatilization from water surfaces is expected(3) based upon
an estimated Henry's Law constant of 3.2X10-6 atm-cu m/mole(SRC), developed
using a fragment constant estimation method(4). Using this Henry's Law constant
and an estimation method(3), volatilization half-lives for a model river and
model lake are 250 hr and 120 days, respectively(SRC). Diisopropyl
fluorophosphate does undergo hydrolysis to HF and diisopropyl
phosphate; half-lives range from 16.7 hrs-2.2 days at temperatures of 37-25
deg C(8,9) and 72 hrs-several days at temperatures of 15-30 deg C(10,11). According
to a classification scheme(5), an estimated BCF of 1(SRC), from an estimated
log Kow of 1.13(6) and a regression-derived equation(7), suggests the potential
for bioconcentration in aquatic organisms is low.
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile
organic compounds in the atmosphere(1), diisopropyl
fluorophosphate, which has a vapor pressure of 0.54 mm Hg at
25 deg C(2), is expected to exist solely in the vapor-phase in the ambient atmosphere.
Vapor-phase diisopropyl fluorophosphate is
degraded in the atmosphere by reaction with photochemically-produced hydroxyl
radicals(SRC); the half-life for this reaction in air is estimated to be 5 hrs(SRC),
calculated from its rate constant of 8.0X10-11 cu cm/molecule-sec at 25 deg
C(3) determined using a structure estimation method(3).
Environmental Biodegradation:
Microbial cell-free extracts were found to contain lysase enzymes capable
of hydrolyzing diisopropyl fluorophosphate(1).
This indicates that intact microorganisms in the environment may also be capable
of biodegrading diisopropyl fluorophosphate. One
study reported that Pseudomonas melophthora could degrade diisopropyl
fluorophosphate in the presence of yeast extract, mannitol,
and acetone(2). Diisopropyl fluorophosphate was
found to be rapidly degraded (no quantitative rate was given) in ruminal fluid(3),
which contains anaerobic microorganisms.
Environmental Abiotic Degradation:
The rate constant for the vapor-phase reaction of diisopropyl
fluorophosphate with photochemically-produced hydroxyl radicals
has been estimated as 8.0X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a
structure estimation method(1). This corresponds to an atmospheric half-life
of about 5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals
per cu cm(1). Diisopropyl fluorophosphate does
undergo hydrolysis. Diisopropyl fluorophosphate in
a 0.03 m bicarbonate buffer with a pH of 7.4 at a temperature of 37 deg C had
a half-life of 16.7 hours(2). Extrapolation of these data to 25 deg C(3) gives
a half-life of approximately 2.2 days. Other researchers report a half-life
of several days at 30 deg C and pH 7.6 and that in dilute solutions (pH not
indicated) hydrolysis goes to completion in 72 hr at 15 deg C(4,5). A kinetic
study of the hydrolysis of diisopropyl fluorophosphate
in neutral and acid aqueous solutions found the reaction to
be autocatalytic and catalyzed by hydrogen ions for an initial rate of 0.6%/hr
that was independent of the initial concentration of diisopropyl
fluorophosphate and produced diisopropyl phosphate and HF(5).
Cupric ions are extremely effective at catalyzing the hydrolysis of diisopropyl
fluorophosphate although other ions are less effective or without
effect(4). This suggests that some soils may catalyze hydrolysis but experimental
data are lacking.
Environmental Bioconcentration:
An estimated BCF of 1 was calculated for diisopropyl
fluorophosphate(SRC), using an estimated log Kow of 1.13(1)
and a regression-derived equation(2). According to a classification scheme(3),
this BCF suggests the potential for bioconcentration in aquatic organisms is
low.
Soil Adsorption/Mobility:
Using a structure estimation method based on molecular connectivity indices(1),
the Koc for diisopropyl fluorophosphate can
be estimated to be 31(SRC). According to a classification scheme(2), this estimated
Koc value suggests that diisopropyl fluorophosphate
is expected to have very high mobility in soil.
Volatilization from Water/Soil:
The Henry's Law constant for diisopropyl fluorophosphate
is estimated as 3.2X10-6 atm-cu m/mole(SRC) using a fragment
constant estimation method(1). This Henry's Law constant indicates that diisopropyl
fluorophosphate is expected to volatilize from water surfaces(2).
Based on this Henry's Law constant, the volatilization half-life from a model
river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated
as 250 hours(SRC). The volatilization half-life from a model lake (1 m deep,
flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 120 days(SRC).
Diisopropyl fluorophosphate's Henry's
Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC).
Diisopropyl fluorophosphate is not expected
to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.54
mm Hg(SRC), determined from a fragment constant method(3).
Environmental Standards & Regulations:
CERCLA Reportable Quantities:
Persons in charge of vessels or facilities are required to notify the National
Response Center (NRC) immediately, when there is a release of this designated
hazardous substance, in an amount equal to or greater than its reportable quantity
of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In
the Washington D.C. metropolitan area (202) 426-2675. The rule for determining
when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b).
Releases of CERCLA hazardous substances are subject to the release reporting
requirement of CERCLA section 103, codified at 40 CFR part 302, in addition
to the requirements of 40 CFR part 355. Isofluorphate is an extremely hazardous
substance (EHS) subject to reporting requirements when stored in amounts in
excess of its threshold planning quantity (TPQ) of 100 lbs.
RCRA Requirements:
P043; As stipulated in 40 CFR 261.33, when diisopropyl
fluorophosphate, as a commercial chemical product or manufacturing
chemical intermediate or an off-specification commercial chemical product or
a manufacturing chemical intermediate, becomes a waste, it must be managed according
to federal and/or state hazardous waste regulations. Also defined as a hazardous
waste is any container or inner liner used to hold this waste or any residue,
contaminated soil, water, or other debris resulting from the cleanup of a spill,
into water or on dry land, of this waste. Generators of small quantities of
this waste may qualify for partial exclusion from hazardous waste regulations
(40 CFR 261.5(e)).
Chemical/Physical Properties:
Molecular Formula:
C6-H14-F-O3-P
Molecular Weight:
184.15
Color/Form:
Liquid
CLEAR, COLORLESS OR FAINTLY YELLOW LIQUID
Oily liquid
Odor:
Very weak fruity odor
Boiling Point:
62 deg C @ 9 mm Hg; 46 deg C @ 5 mm Hg; 183 deg C @ 760 mm Hg (by extrapolation)
Melting Point:
-82 deg C
Density/Specific Gravity:
1.055
Solubilities:
Solubility in water @ 25 deg C: 1.54% wt/wt; sol in vegetable oils; not very
sol in mineral oils
Sol in ether
SOL IN ALCOHOL
Soluble in organic solvents, fuel and lubricants.
Spectral Properties:
Index of refraction: 1.3830 @ 25 deg C/D
MAX ABSORPTION (ALCOHOL): 243 NM (LOG E = 0.28); 255 NM (LOG E = 0.33); 261
NM (LOG E = 0.30)
UV: 2-79 (Organic Electronic Spectral Data, Phillips et al, John Wiley &
Sons, New York)
Vapor Density:
6.4 (Air= 1)
Vapor Pressure:
0.579 mm Hg @ 20 deg C
Other Chemical/Physical Properties:
Forms hydrogen fluoride in presence of moisture; decomp in water @ pH about
2.5
DFP yields phosphate as a result of decomposition with sulfuric acid.
Oil/water partition coefficient: log= 0.93
Carbon tetrachloride/water partition coefficient: 1.57-1.58
The anhydride compd or oil solns are stable in glass containers at room temp.
Chemical Safety & Handling:
DOT Emergency Guidelines:
Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin.
Inhalation or contact with some of these materials will irritate or burn skin
and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors
may cause dizziness or suffocation. Runoff from fire control or dilution water
may cause pollution. /Organophosphorus pesticide, liquid, flammable, poisonous;
Organophosphorus pesticide, liquid, flammable, toxic; Organophosphorus pesticide,
liquid, poisonous, flammable; Organophosphorus pesticide, liquid, toxic, flammable/
Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks
or flames. Vapors may form explosive mixtures with air. Vapors may travel to
source of ignition and flash back. Most vapors are heavier than air. They will
spread along ground and collect in low or confined areas (sewers, basements,
tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Some
may polymerize (P) explosively when heated or involved in a fire. Runoff to
sewer may create fire or explosion hazard. Containers may explode when heated.
Many liquids are lighter than water. /Organophosphorus pesticide, liquid, flammable,
poisonous; Organophosphorus pesticide, liquid, flammable, toxic; Organophosphorus
pesticide, liquid, poisonous, flammable; Organophosphorus pesticide, liquid,
toxic, flammable/
Public safety: Call Emergency Response Telephone Number. ... Isolate spill
or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in
all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low
areas. Ventilate closed spaces before entering. /Organophosphorus pesticide,
liquid, flammable, poisonous; Organophosphorus pesticide, liquid, flammable,
toxic; Organophosphorus pesticide, liquid, poisonous, flammable; Organophosphorus
pesticide, liquid, toxic, flammable/