||From the excellent
* Voluntary movement
|The word "cortex" comes from the
Latin word for "bark" (of a tree). This is because
the cortex is a sheet of tissue that makes up the outer layer
of the brain. The thickness of the cerebral cortex varies from
2 to 6 mm. The right and left sides of the cerebral cortex are
connected by a thick band of nerve fibers called the "corpus
callosum." In higher mammals such as humans, the cerebral
cortex looks like it has many bumps and grooves. A bump or bulge
on the cortex is called a gyrus (the plural of the word gyrus
is "gyri") and a groove is called a sulcus (the plural
of the word sulcus is "sulci"). Lower mammals, such
as rats and mice, have very few gyri and sulci.
|The word "cerebellum" comes from
the Latin word for "little brain." The cerebellum
is located behind the brain stem. In some ways, the cerebellum
is similar to the cerebral cortex: the cerebellum is divided
into hemispheres and has a cortex that surrounds these hemispheres.
* Heart Rate
* Blood Pressure
|The brain stem is a general term for the area
of the brain between the thalamus and spinal cord. Structures
within the brain stem include the medulla, pons, tectum, reticular
formation and tegmentum. Some of these areas are responsible
for the most basic functions of life such as breathing, heart
rate and blood pressure.
||* Body Temperature
* Circadian Rhythms
|The hypothalamus is composed of several different
areas and is located at the base of the brain. Although it is
the size of only a pea (about 1/300 of the total brain weight),
the hypothalamus is responsible for some very important functions.
One important function of the hypothalamus is the control of
body temperature. The hypothalamus acts as a "thermostat"
by sensing changes in body temperature and then sending signals
to adjust the temperature. For example, if you are too hot,
the hypothalamus detects this and then sends a signal to expand
the capillaries in your skin. This causes blood to be cooled
faster. The hypothalamus also controls the pituitary.
||* Sensory processing
|The thalamus receives sensory information and
relays this information to the cerebral cortex. The cerebral
cortex also sends information to the thalamus which then transmits
this information to other areas of the brain and spinal cord.
||The limbic system (or the limbic areas) is
a group of structures that includes the amygdala, the hippocampus,
mammillary bodies and cingulate gyrus. These areas are important
for controlling the emotional response to a given situation.
The hippocampus is also important for memory.
|The hippocampus is one part of the limbic system
that is important for memory and learning.
||The basal ganglia are a group of structures,
including the globus pallidus, caudate nucleus, subthalamic
nucleus, putamen and substantia nigra, that are important in
* Eye Movement
* Body Movement
|The midbrain includes structures such as the
superior and inferior colliculi and red nucleus. There are several
other areas also in the midbrain.
little background on GABA
Synthesis, storage and release
GABA was identified in the mammalian brain in 1950's. It
is believed to be the major inhibitory neurotransmitter
in the brain. It is this role which is of interest to the
neuropsychiatrist. GABA is synthesized from Glutamate. The
marker enzymeis Glutamic acid decarboxylase (GAD). GAD is
a pyridoxal cofactor dependent enzyme. A congential form
of B-6 vitamin deficiency is known to predispose to seizures
which are B-6 responsive. Glutamate is a pivotal amino acid
in the brain. It is dervied from alpha keto glutarate which
is one of the intermediates in the Krebs cycle by way of
the addition of an amine group. Glutamate also undergoes
transamination to form glutamine by addition of another
amine group. Glutamine then proceeds to the liver where
it is deaminated to regenerated glutamate which then returns
to the brain. This is brain's nitorgen cycle. In situations
where the liver is unable to deaminate the glutamine the
brain must obtain glutamate by draining the Kreb's cycle
intermediates. This in turn begins to impair cerebral energy
Following release GABA can be taken back up by the neurons
or by astrocytes. It appears that the release of GABA is
also under autoreceptor control. GABA is metabolized by
the enzym GABA transaminase (GABA-T) to form succinic acid
semialdehyde. Succinic acid semialdehyde is metabolized
further to form succinic acid which is also a Kreb's cycle
intermediate. GABA-T is inhibited by valproic acid. This
is the basis for the belief that valproic acid is GABAergic.
There are other alternative pathways for GABA metabolism.
are two basic subtypes, GABA-a and GABA-b.
the most prevalent in the mammalian brain. The GABA-a receptor
is similar to acetylcholine receptor in that it is related
to an ion channel. In the case of GABA-a it is the chloride
ionophore. Binding of GABA to this receptor increases the
permeability to chloride ion which causes a hyperpolarization
of the neuron or inhibition. The GABA-a receptor has four
basic subunits, 2-alpha and 2 beta peptides which surround
a chloride channel. There are three basic binding sites
on this complex. The first is the GABA site. The second
is a benzodiazepine site. The third is in the channel and
is essentially a barbiturate site ...
GABA-b receptor is
a G-protein related receptor which is distinct from the
GABA-a sites. The highest concentrations of GABA-b receptors
is in the interpeduncular nuclie and cerebellum. It appears
that one of its prinicple effects is to increase the efflux
of K+ from the cell. This would result in a hyperpolarization.
Pharmacologically baclofen is considered a GABA-b agonist.
The principle effect of GABA-b agonism is muscle relaxation.
A significant relationship of dopamine and GABA exists.
In general GABA acts to reduce the firing of the dopaminergic
neurons in the tegmentum and substantia nigra. It forms
the basis for the use of benzodiazepines as augmentation
strategies in the treatment of psychosis. In addition benzodiazepines
may be helpful in cases where there is an over activity
of dopamine in the motor striatum such as Huntington's Chorea
or Tardive Dyskinesia. It is believed that they act by increasing
the feedback inhibition. The feedback inhibition from the
GABA neurons of the globus pallidus and putamen to the dopaminergic
neurons of the substantia nigra is an important modulating
force on the activity of the dopamine neurons.
use of high doses increases the likelihood that potentially
significant toxic effects will be identified. Findings of
adverse effects in any one species do not necessarily indicate
such effects might be generated in humans. From a conservative
risk assessment perspective however, adverse findings in
animal species are assumed to represent potential effects
in humans, unless convincing evidence of species specificity
Food and Agricultural Organization of the United Nations
This is not an exhaustive list.
As time allows more information will be added.
Herbicide - CAS No. 62476-59-9
The toxicity database
is adequate for selecting toxicity endpoints for risk assessments,
although a developmental neurotoxicity study is required because
of neurotoxicity which occurred in a developmental rat study (dilated
lateral ventricles of the brain)... A developmental toxicity
study in rats found qualitative evidence of increased susceptibility
of offspring because developmental toxicity (increased resorptions,
reduced fetal weights, slightly dilated
lateral ventricles of the brain, hemorrhage in the eyeball,
slight dilation of the renal pelvis, hemorrhage in peritoneal
cavity and subcutaneous spaces, and changes in ossification) was
accompanied by minimal maternal toxicity (excess salivation and
piloerection)... the Hazard Identification Assessment Review Committee
recommended that a developmental neurotoxicity study in rats be
conducted based on neurotoxicity observed in a developmental toxicity
study in rats (increased incidence of dilated
lateral ventricles of the fetal brain, MRID 00122743).
In addition, no neurotoxicity studies are available for acifluorfen
or for structurally related compounds which might provide an understanding
on the effects of acifluorfen on the developing nervous system.
Ref: EPA, Sodium Acifluorfen. HED Chapter
for the Reregistration Eligibility Decision. April 27, 2001.
For "females 13-50 years," a NOAEL of 20 mg/kg/day was
established based on effects of decreased fetal weight and increased
incidence of dilated lateral ventricles of the brain
observed in a rat developmental toxicity study. Both the decreased
fetal weight and
the brain malformations are presumed
to occur after a single exposure (dose), and thus, are appropriate
for this acute risk assessment. These effects were observed at
90 mg/kg/day (LOAEL).
Overview of Sodium Acifluorfen Risk Assessment April 4, 2002.
3. Doses and Toxicological Endpoints Selected for Various
Dietary (Female 13-50)
fetal weight and increased incidences
of dilated lateral ventricles of the brain at 90 mg/kg/day
PAD = 0.02 mg/kg/day
Dermal (short and intermediate-term, females 13-50)
fetal weight and increased incidences
of dilated lateral ventricles of the brain at 90 mg/kg/day
Inhalation (short and intermediate-term, females 13-50)
= Since an oral NOAEL was selected, a dermal absorption factor
of 20% of oral absorption should be used in route-to-route
(b) = Since an oral NOAEL was selected, an inhalation absorption
factor of 100% of oral absorption (default value) should be
used in route-to-route extrapolation.
January 15, 2002. MEMORANDUM. SUBJECT: SODIUM ACIFLUORFEN.
HED Chapter for the Reregistration Eligibility Decision Document.
US EPA. Office of Prevention, Pesticides, and Toxics Substances.
- CAS No. 1341-49-7
May cause salivation,
nausea, vomiting, diarrhea, and abdominal pain, followed by symptoms
of weakness, tremors, shallow respiration,
carpopedal spasm, convulsions, and coma.
May cause brain and kidney damage. Affects
heart and circulatory system. Death may be caused by respiratory
paralysis. Lethal dose estimated at between 1 teaspoonful and
Analytyka. Material Safety Data Sheet. Online as of September
- Wood Preservative - CAS No. 12125-01-8
If inhaled or swallowed,
this compound can cause fluoride poisoning. Early symptoms include
nausea, vomiting, diarrhea, and weakness. Later effects include
central nervous system effects, cardiovascular effects and death.
Ingestion: May cause salivation, nausea, vomiting, diarrhea, and
abdominal pain, followed by weakness, tremors, shallow respiration,
cardopedal spasm, convulsions, and coma. May
cause brain and kidney damage. Death may be caused by respiratory
paralysis. Affects heart and circulatory system.
Ref: 1999 Material Safety Data Sheet prepared
by Mallinckrodt Baker, Inc.
- Rodenticide - CAS No. 63333-35-7
-- Subchronic Toxicity.
Sprague Dawley rats (10/sex/group)
received daily gavage doses of 0 (25% polyethylene glycol in H
O), 5, 25, or 125 micrograms/kg/day (ug/kg/day) of bromethalin
technical for 13 2 weeks. Parameters evaluated included daily
observation, weekly body weight and food consumption, ophthalmoscopy,
clinical pathology, necropsy, organ weights, and histopathology.
The NOEL is 25 µg/kg/day. The LOEL is 125 µg/kg/day, based
on spongy degeneration (leukoencephalomyelopathy) observed in
most of the central white fiber tracts of the brain, cerebellum,
pons, brain stem, and thoracic spinal cord of both sexes and optic
nerves of males. There were no effects on mortality, clinical
chemistry, ophthalmoscopy, body weight, food consumption, clinical
pathology and histopathology of other tissues (MRID 43582102).
-- In a second 90-day study, groups of 4 male and 4 female beagle
dogs were orally dosed by gavage for 90 days at levels
of 0, 5, 25, 125, or 200 ug/kg/day with bromethalin technical.
Observations included daily clinical evaluations, ophthalmoscopy,
body weight, food consumption, clinical pathology evaluations
at weeks 6 and 13, necropsy, organ weights and histopathology.
The NOEL is 25 µg/kg/day. The LOEL is 125 µg/kg/day
based on spongy degeneration observed in nervous tissue components
(cervical, thoracic, and lumbar spinal cord, brain stem, right
and left optic nerves, frontal and median brain, pons, and cerebellum)
in both sexes of dogs. At the high dose, 3 male dogs displayed
the following neurotoxic signs before death or being sacrificed
moribund: salivation and hypoactivity, followed by trembling,
myoclonia, hyperesthesia, groaning, and decubitus... (MRID 43582101).
-- The following information is in the AgencyÕs [EPA] files and
are supportive of the endpoint of toxicological concern identified
in the above studies. Ph.D. Dissertation entitled "Bromethalin-Based
Rodenticides: Mode of Action, Toxicity, Clinical Effects, and
Treatment Efficacy in Rats, Dogs, and Cats", by D. Dorman, University
of Illinois, Dept. of Veterinary Biosciences (MRID 42759602).
This dissertation is a summary of information found in the literature.
According to the summary page of the dissertation, "The purpose
of these studies was to define the toxicity of bromethalin-based
rodenticides, develop treatments, and determine new modes of action
of bromethalin..... Sublethal doses of bromethalin to dogs and
cats resulted in delayed CNS depression, hind-limb ataxia, paresis,
and paralysis. Higher doses given to dogs resulted in rapid severe
muscle tremors and generalized seizures. Bromethalin toxicosis
was also associated with increased cerebrospinal fluid pressure
and cerebral edema. Bromethalin toxicosis
produced acute and chronic EEG changes.
Predominant abnormal EEG changes included spike and spike-and-wave
EEG patterns; high voltage slow wave activity; photoconvulsive
or photoparoxysmal irritative responses, and marked voltage depression.
Histologic lesions included diffuse white
matter spongiosis, mild microgliosis, and optic nerve vacuolization.
Ultramicroscopic examination of brainstem revealed occasional
swollen axons, intramyelenic vacuolization, and myelin splitting
at the intraperiod line."
Ref: US EPA Reregistration Eligibility Decision
(RED) Rodenticide Cluster. EPA738-R-98-007. July 1998.
Abstract: Ten random
source male domestic shorthair cats, 2 to 6 years old and 3.0-4.4
kg body weight, were each given a single oral dose (1.5 mg/kg)
of bromethalin (cat Nos. 1-5) or bait vehicle carrier (cat Nos.
6-10). Bromethalin-dosed cats developed a toxic syndrome characterized
by ataxia, focal motor seizures, vocalization,
decerebrate* posture, decreased
conscious proprioception, recumbency, depression, and semicoma.
Bromethalin-dosed cats were euthanatized if seizure activity or
hindlimb paralysis developed. Survival times were 48 hours (cat
No. 1), 89 hours (cat No. 2), 90 hours (cat No. 3), and 97 hours
(cat No. 4). Control cats (cat Nos. 6-10) and one bromethalin-dosed
cat (cat No. 5) were euthanatized on day 20 after dosing. Spongy
change (edema--characterized by the formation of vacuoles
in extracellular spaces and myelin
lamellae), hypertrophied fibrous
and hypertrophied oligodendrocytes
were observed in the white matter of the
cerebrum, cerebellum, brain stem,
spinal cord, and optic nerve of all bromethalin-dosed cats.
Spongy change occasionally extended
into contiguous cerebellar Purkinje
cell layer and cerebral cortical gray matter.
The severity of lesions varied among cats but was most pronounced
in cat No. 5 (480 hours after dosing). A leukocytic inflammatory
response, gitter cell (macrophage) response, or
axonal degeneration was not observed in the vacuolated areas.
Ultrastructural findings included separation
of myelin lamellae at the interperiod lines with
the formation of intramyelinic vacuoles (intramyelinic edema),
rupture and coalescence of intramyelinic vacuoles into larger
extracellular spaces (spongy change),
and pronounced cytosolic edema of astrocytes
and oligodendroglial cells.
PMID: 1632057 [PubMed - indexed for MEDLINE]
Ref: Vet Pathol 1992 Mar;29(2):139-44. Neuropathologic
findings of bromethalin toxicosis in the cat. Dorman DC, Zachary
JF, Buck WB.
Abstract: Dogs given
a single oral dose of bromethalin at 6.25 mg/kg developed a toxic
syndrome characterized by hyperexcitability, tremors, seizures,
depression, and death within 15-63 hours after bromethalin administration.
Gross lesions included mild cerebral edema
(2/5) and mild pulmonary congestion (2/5). Histologic lesions
included diffuse white matter spongiosis
(5/5), mild microgliosis (3/5), optic nerve vacuolization
(3/5), mild thickening of Bowman's capsule (2/5), and occasional
splenic megakaryocytes (2/5). Ultramicroscopic examination of
midbrain stem revealed occasional swollen
axons, intramyelinic vacuolization,
and myelin splitting at the intraperiod line. Bromethalin was
detected in kidney, liver, fat, and brain
tissues, using gas chromatography with electron capture
detection. Photodegradation of extracted bromethalin may limit
accurate quantification of tissue residues.
Ref: J Vet Diagn Invest 1990 Apr;2(2):123-8.
Diagnosis of bromethalin toxicosis in the dog; by Dorman DC, Simon
J, Harlin KA, Buck WB.
is a new rodenticide for the control of commensal rodents. Doses
in excess of the LD50 (2 mg/kg in rats) will cause death within
8-12 hr and it is preceded by one to three episodes of clonic
convulsions with death usually due to respiratory arrest. Multiple
low doses or sublethal intoxication yields hind leg weakness and
loss of tactile sensation in rodents. Histopathology of the brain
and spinal cord of these animals revealed a spongy
degeneration of the white matter which was shown upon ultramicroscopic
examination to be intramyelenic edema.
No inflammation or cellular destruction of neuronal tissue was
noted. LD50 values ranged from 1.8 mg/kg in the cat to approximately
13 mg/kg in rabbits. The only apparent nonsusceptible species
was the guinea pig which could tolerate doses in excess of 1000
mg/kg without effect. Identification of the desmethyl metabolite
was demonstrated in the blood and liver of treated animals by
comparison of chromatographic retention times to that of a reference
standard, but direct mass spectral identification was unsuccessful
in part due to the low dose which could be administered. Therefore,
the metabolism of bromethalin was studied by indirect means. Animals
were pretreated with three inducers of microsomal drug metabolism:
phenobarbital, 3-methylcholanthrene (3MC), and Aroclor 1254 (Aroclor)
and one inhibitor, SKF-525A. Pretreated mice or rats were given
an LD50 dose of bromethalin or the desmethyl analog and the percentage
of surviving animals was determined. (ABSTRACT TRUNCATED AT 250
WORDS) PMID: 3229590
Ref: Fundam Appl Toxicol 1988 Nov;11(4):664-72
toxicity and mechanism of action of bromethalin: a new single-feeding
rodenticide. van Lier RB, Cherry LD. Toxicology Division,
Lilly Research Laboratories, Greenfield, Indiana 46140.
Acaricide, Insecticide - CAS No. 122453-73-0
ii. Subchronic Oral
Toxicity in Mice... Spongiform encephalopathy
was noted in the brain and myelin of the spinal cord of both males
and females receiving the 320 ppm treatment level. The LEL is
14.8 mg/kg/day (80 ppm) for male mice and 40.0 mg/kg/day (160
ppm) for female mice, based on hepatic cell hypertrophy in 20%
of the test animals at this treatment level. The NOEL is 7.1 mg/kg/day
(40 ppm)... The RfD Committee also recommended that a special
developmental neurotoxicity study be conducted based upon the
effects of a spongyform myelopathy
vacuolation seen in the brain and spinal cord
of treated rats and mice. They concluded that the registrant should
also conduct a mechanistic study to determine the cause/relationship
of CNS/myelinopathic alterations to neurotoxicity (including developmental)...
Chronic-Term (greater than several months) Occupational/Residential
Dermal NOEL: 3 mg/kg/day (decreased body weight gains brain
lesions (vacuolation) and/or
scabbing of the skin in a 1 year neurotoxicity study in rats and
a chronic/carcinogenicity study in mice) Acceptable MOE = 1000
(includes FQPA Factor)
Ref: US EPA, Feb 12, 1998: Chlorfenapyr
- 129093: Health Effects Division Risk Characterization for Use
of the Chemical Chlorfenapyr.
Page 19-20: "Other chronic effects. For other chronic effects,
a Reference Dose (RfD) has been established at 0.003 mg/kg/day
based on decreased body weight gains and brain
lesions (vacuolation) observed in the 1-year rat neurotoxicity
study. An uncertainty factor (UF) of 1000 was applied to account
for interspecies extrapolation, intraspecies variability and
the additional FQPA Factor of 10. The FQPA factor has been retained
because chlorfenapyr has produced central nervous system lesions
in several studies in both rats and mice. It will be reevaluated
after the developmental neurotoxicity study has been submitted."
Ref: US EPA. March 13, 2000. "Denial of
Registration of Chlorfenapyr for Use on Cotton."
In a search of EPA's OPP database <http://www.epa.gov/pesticides/search.htm>
for "spongiform encephalopathy" - "spongyform
myelopathy" and "spongyform" - , the only
substance cited was Chlorfenapyr. Mad Cow Disease is also called
Bovine spongiform encephalopathy (BSE) which is a chronic, degenerative
disorder affecting the central nervous system of cattle. In
the US, up until 2002, there were 19 tolerances for residues
of Chlorfenapyr in or on: Cotton,
Milk, Cattle, Hog, Sheep, Horse, and Goat - see:
MRID No. 42770219 (1993)-- 90-Day oral toxicity rats.
NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform
myelopathy in the brain and spinal cord of male
rats, decreased body weight
gain and increased relative liver weight in males and females,
increased absolute liver weight in females, and decreased hemoglobin
-- MRID No. 43492830 (1994). 90-Day oral toxicity mouse
. NOAEL = 27.6/40, M/F. LOAEL = 62.6/78, M/F, based on reduced
body weights/body weightgains, and spongiform
encephalopathy in both sexes.
-- MRID No. 43492838 (1994). Carcinogenicity mouse.
NOAEL = 2.8/3.7 mg/kg/day, M/F. LOAEL = 16.6/21.9 mg/kg/day, M/F,
based on decreased body weight gains,
brain vacuolation, and scabbing of the skin
(males) No evidence of carcinogenicity.
-- MRID No. 43492833 (1994). Chronic neurotoxicity rat.
NOAEL = 2.6/3.4 mg/kg/day, M/F. LOAEL = 13.6/18 mg/kg/ day, M/F,
based on the presence of myelinopathic alterations
in the central nervous system (CNS) in male rats and
decreased average body weights/body weight gains,
food efficiency, absolute food consumption (females) and water
-- Chronic neurotoxicity study - rat.
LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic
alterations in the CNS in male rats
and decreased average body weights, body
weigh gains, food efficiency,
absolute food consumption
(F), and water
consumption (M). Supporting this endpoint are similar CNS
lesions and skin lesions observed in the
mouse carcinogenicity study (NOAEL = 2.8).
-- Conditions: A developmental neurotoxicity study to determine
the cause/relationship of potential central
nervous system/myelinopathic alterations to neurotoxicity in the
Federal Register: September 26, 2003. Chlorfenapyr; Pesticide
Tolerance. Final Rule.
-- ONCOGENICITY, MOUSE
. 066; 147076; "A Chronic Dietary Toxicity
and Oncogenicity Study with AC 303,630 in Mice" (L. Bernier,
Bio-Research Lab., Ltd., Quebec, Canada, Project # 84580, 8/22/94).
AC 303,630 (Batch AC-7504-59A, 94.5% purity) administered orally
in the diet to 65 CD-1 mice/sex/dose for 80 weeks at 0, 20, 120,
or 240 ppm (Males: 0, 2.8, 16.6, or 34.5 mg/kg/day; Females: 0,
3.7, 21.9, or 44.5 mg/kg/day). Reduced survival rate was noted
in high dose females (60% vs. 80%, p < 0.05). However, overall
survival rate of this group was more comparable to that of the
historical controls. Treatment with AC 303,630 resulted in reduced
mean body weight gain in high dose males and females and in mid
dose females (Males: 70% of control, p < 0.01, Females: 86% of
control, p < 0.05 for mid and high dose groups). Food consumption
was also reduced in mid and high dose animals. Histopathology
revealed vacuolation of the white matter of the brain in animals
treated at mid and high dose levels. Also, vacuolation was detected
in spinal cord sections as well as optic nerve tissues in mice
at 240 ppm. There was no evidence of carcinogenicity. NOAEL
(M/F) = 240 ppm [No adverse effect]. NOEL (M/F) = 20 ppm (2.8
and 3.7 mg/kg/day for males and females, respectively; based on
histopathological changes in the brain, optic nerve and spinal
cord). acceptable (Leung, 7/24/96)
-- NEUROTOXICITY ** 061; 147070; "A One-Year
Dietary Neurotoxicity Study with AC 303,630 in Rats"; (J.A.
Foss; Argus Research Laboratories, Inc., Horsham, PA; Study No.
101-019; 5/10/94); AC 303,630 technical (purity: 94.5%) was administered
in the diet to 25 animals/sex/group at doses of 0, 60, 300, and
600 ppm for up to 52 weeks ((M)-0, 2.6, 13.6, 28.2 mg/kg/day,
(F)-0, 3.4, 18.0, 37.4 mg/kg/day). Surviving animals were observed
for an additional 16 weeks of a recovery phase. No treatment-related
effects were noted in the functional observational battery or
the motor activity evaluation. In the neurohistopathology,
myelin sheath swelling of the spinal nerve roots was evident in
the males of the 600 ppm treatment group after 13 and 52
weeks of treatment. Extensive vacuolar myelinopathy
was noted in the brain and spinal cord of the 300 and 600 ppm
males after 52 weeks of treatment. These effects were no
longer present after the 16 week recovery period. No treatment-related
lesions were noted in the females. No adverse effects were evident.
NOEL: (M) 60 ppm (based upon the incidence of extensive vacuolar
myelinopathy in the central nervous system); (F) 600 ppm;
NOAEL: 600 ppm (based on recovery). Study acceptable. (Moore,
-- SUBCHRONIC STUDIES ** 010, 031; 125163; "AC 303,630: "A
13 Week Dietary Toxicity Study in the Albino Rat", J.E.
Fischer; 821; Rat; American Cyanamid Co., Agricultural Research
Division, Toxicology Department, Princeton, NJ; Study No. T-0316;
4/8/93; AC 303,630 Technical (purity: 93.6%); 20 animals/sex/group;
Doses: 0, 150, 300, 600, 900, 1200 ppm (M: 0, 10.9, 22.0, 44.9,
69.5, 92.2 mg/kg/day, F: 0 11.7, 24.1, 48.4, 72.5, 97.5 mg/kg/day),
in the diet, 13 weeks; No treatment-related mortality; Clinical
Observations: red. body wgt. gain (M,F-900, 1200 ppm), red. food
consumption (M-600 ppm and up); Ophthalmology, Urinalysis: no
treatment-related effects; Hematology: red. hematocrit (M,F-1200,
F-900 ppm), red. hemoglobin (M,F-1200, F-600, 900 ppm), red blood
cells (M,F-1200, F-900 ppm), Clinical Chemistry: incr. BUN (M,F-1200
ppm, week 6, M-1200 ppm, week 13), incr. alk. phosphatase activity
(M,F-900, 1200 ppm, week 13); Necropsy: incr. mean abs. liver
wgt. (F-600 ppm and up), red. abs. kidney wgt (M,F-900, 1200 ppm),
incr. abs. spleen wgt. (M,F-900, 1200 ppm), incr. rel. liver wgt.
(M,F-600, 900, 1200, M-300 ppm), increased relative spleen weight
(M,F-900, 1200 ppm); Histopathology: spongiform
myelopathy in brain, spinal cord (M-(2/20), 1200, 900 ppm, (1/20),
600 ppm), lesion present in sciatic nerve (M-(1/20), 1200
ppm), lymphoid cell infiltrate in kidneys (M,F-900, 1200 ppm);
Target organ: central nervous system;
Adverse Effect: spongiform myelopathy in
the nervous system; NOEL: (M) 300 ppm (occurance of spongiform
myelopathy in the nervous system of the 600 ppm group) (F)
300 ppm (based on increased mean abs. liver wgt. in 600 ppm group);
(Study previously unacceptable, possibly upgradeable with submission
of GLP compliance and QA audit statements (Moore, 2/1/95)) requested
information submitted; Study acceptable. (Moore, 8/9/95)
24, 2001 - Summary
of Toxicological Data. California EPA.
Department of Pesticide Regulation. Medical Toxicology Branch.
Also available at:
see the following.
22, 2004, US EPA's response to FAN's Comments on Chlorfenapyr
effects on brain - see
(Online at US EPA Docket OPP-2004-0362-0002)
11, 2003, comments submitted to US EPA by FAN's Pesticide
Project on the pesticide petition from BASF Corporation
to establish a tolerance for residues of chlorfenapyr on
all food items in food handling establishments where food
products are held, processed, and/or prepared at 0.01 parts
per million (ppm).
at US EPA Docket OPP-2003-0205)
17, 2003, reply to comments from FAN's Pesticide Project,
from Daniel J. O'Byrne, Product Registrations Manager, BASF
at US EPA Docket OPP-2003-0205)
(Freon 142; Freon 142B) - List 2 Inert; Solvent -CAS No.
Two short-term in vitro
tests for mutagenicity (Salmonella reverse mutation and BHK21
cell transformation) were conducted on a series of fluorocarbons.
Some of these materials (FC22, FC31, FC142b,
FC143 and FC143a) were found to be positive
in 1 or both of the tests and could therefore be considered as
being potentially carcinogenic to animals.
Ref: Longstaff E et al. (1984). Genotoxicity
and carcinogenicity of fluorocarbons: Assessment by short-term
in vitro tests and chronic exposure in rats. TOXICOL APPL PHARMACOL;
72 (1). 15-31.
From Toxline at TOXNET:
Insecticide, Fungicide, Propellant - CAS No. 75-45-6
Registry of Toxic Effects of Chemical Substances
Methane, chlorodifluoro - RTECS
NIOSH - National Institute for Occupational
Safety and Health
lowest published toxic concentration: 50 gm/m3/6 hour/43 week-
and Coverings: Other degenerative changes
Spinal Cord: Other degenerative changes
Behavioral: Alteration of classical conditioning
Leningradskogo Sanitarno-Gigienicheskogo Meditsinskogo Instituta.
V 75: 231,1963.
published toxic dose: 2,457 mg/kg/26 week- intermittent
and Coverings: Other degenerative changes
Changes in other cell count (unspecified)
and Gross Metabolic: Weight loss or decreased weight gain
Gigiena i Sanitariya. For English translation, see HYSAAV.
(V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR). V 48(8):
Reports on fatalities
of chlorofluorocarbons usually involve chlorotrifluoroethane,
trichlorofluoromethane, dichlorodifluoromethane or chlorodifluoromethane,
where analysis was done using packed column gas chromatography.
In this case a death was caused by an azeotropic mixture of chlorodifluoromethane
& chloropentafluoroethane, a combination that has not previously
been reported in the forensic literature. This report details
the analysis using mass selective detection employing capillary
gas chromatography columns currently used in many toxicology laboratories.
Postmortem toxicology revealed blood concns of chlorodifluoromethane
& chloropentafluoroethane of 71 mg/L & 0.30 mg/L, respectively.
Brain, liver, & lung concns of chlorodifluoromethane
were (mg/kg) 2.8, 4.4, and 1.6, respectively. Brain,
liver, & lung concns of chloropentafluoroethane were (mg/kg)
0.80, 0.80, & 0.11, respectively. The victim's blood contained
5.5 mg/L caffeine. Lidocaine, used in resuscitation attempts,
was also present in the victim's blood. No other alkali-extractable
drugs or volatile alcohols were detected in the victim's blood.
The cause of death was acute respiratory arrest due to chlorofluorocarbon
Ref: Fitzgerald RL et al; J Forensic Sci
38 (2): 477-483 (1993); cited in the TOXNET profile from the Hazardous
Substances Data Bank.
Insecticide - CAS No. 68359-37-5
... A group of 12 hens
received a single oral dose of cyfluthrin in PEG 400 at 4300 mg/kg
bw and were observed for three weeks. A second group of 16 hens
received two doses of 4300 mg/kg bw three weeks apart by gavage
and were allowed to recover for eight weeks. A final group of
12 hens received doses of 1500 mg/kg bw per day by gavage for
five consecutive days and were allowed to recover for eight weeks.
All animals were autopsied after the recovery periods.
Neurotoxic esterase activity was determined
in the brains and spinal cords from five hens of each group
24, 48, and 72 h and seven days after treatment.
... Groups of five male and five female Wistar (SPF-Cpb) rats
received cyfluthrin at 0 or 60 mg/kg bw per day for two weeks
by gavage, and a supplementary group of male rats received doses
of 0 or 50 mg/kg bw per day... Symptoms of acute toxicity were
observed in all treated animals, including tremor, altered gait,
and increased vocalization. Four males at 60 mg/kg bw per day
died between treatment days 5 and 8, but gross pathologicam examination
revealed no specific alterations. The body-weight gain of females
was not affected by treatment, but decreases were seen for males
at 50 or 60 mg/kg bw per day. Small, fresh brain
haemorrhages were seen in all four males that died on test.
The authors concluded that the 'most likely explanation is that
these are the result of a terminal cardiovascular disorder with
necrosis of the vascular walls'. Since this finding was not seen
in control animals, a treatment-related effect could not be ruled
out. A NOEL was not identified (Heimann & Kaliner, 1983).
Ref: Toxicological evaluation of certain
veterinary drug residues in food. 1997. WHO FOOD ADDITIVES SERIES
lambda - Insecticide - CAS No. 91465-08-6
Abstract (2004). The
peripheral effects of pyrethroids on Na(+) channels are well known
but the effects on CNS neurotransmission are less known. In the
present study, type I and II pyrethroids were found to affect
the release of acetylcholine (ACh) from hippocampus in freely
moving rats as measured by in vivo microdialysis. The basal release
of ACh from the hippocampus of untreated rats was 6.6 pmol/10
microl/10 min. Allethrin had an interesting dual effect on ACh
release, increasing ACh efflux (to about 300% of baseline) at
the lower dose of 20 mg/kg i.p. with a peak time of 60 min and
decreasing the efflux (to about 40% of baseline) at the higher
dose of 60 mg/kg i.p. up to 3 h after administration.
Cyhalothrin 20 and 60 mg/kg i.p. inhibited the release (to about
30% of baseline) dose-dependently, with a peak time of 50-60 min
after administration. Deltamethrin 20 mg/kg i.p. increased
the efflux (to about 250% of baseline) with a peak time of 30
min after administration and 60 mg/kg i.p. increased the efflux
(to about 450% of baseline) and remained at a steady level during
the rest of the 3 h experiment. Control vehicle injections had
no effect on the efflux of ACh in any of the experiments. This
is the first report, using in vivo microdialysis, that pyrethroids
modulate the ACh release in the hippocampus of rat brain.
Ref: The modulatory effect of pyrethroids
on acetylcholine release in the hippocampus of freely moving rats;
by Hossain MM, Suzuki T, Sato I, Takewaki T, Suzuki K, Kobayashi
H. Neurotoxicology. 2004 Sep;25(5):825-33.
Ca2+ + Mg2+-ATPase from microsomal fractions of rat brain was
studied. The enzyme was activated by either Ca2+ or Mg2+ reaching
the peak at the Ca2+ concentration of 0.3 mM. Maximal activation
occurred at an ATP concentration of 5 mM with an apparent Km of
0.66 mM, a Vmax of 62.5 mumol inorganic phosphate/mg protein/hr,
and a pH between 8.1 and 8.5. The enzyme was found to be ouabain
insensitive but was inhibited by ruthenium red and lanthanum with
I50 values of 10-5 and 10-6 M, respectively. The enzyme was highly
sensitive to the actions of certain pyrethroid insecticides under
in vitro conditions. The cyano-containing
pyrethroids, karate and bathyroid, exerted a greater inhibitory
effect on the enzyme (Ki = 1.7 and 2 muM) than the non-cyano-containing
pyrethroids, permethrin and bioallethrin (Ki = 7 and 8.5 muM).
Ref: Properties of calcium, magnesium-ATPase
from rat brain and its inhibition by pyrethroids; by AL-RAJHI
DH. PESTIC BIOCHEM PHYSIOL; 37 (2). 1990. 116-120.
Lambda-cyhalohrin is one of synthetic pyrethroids of family of
compounds with a-cyano-3-phenoxybenzyl moiety. The aim
of the work was to evaluate the influence of lambda-cyhalothrin
on memory processes, movement co-ordination and spontaneous movement
activity in mice exposed to transient oligemic brain hypoxia in
BCCA model. There were four groups of animals examined: I) sham-operated,
II) after BCCA, III) sham-operated, treated with beta-cyfluthrin,
and IV) after BCCA, treated with beta-cyfluthrin. Bilateral clamping
of carotid arteries (BCCA) is an experimental model of transient
ischemic attacks (TIAs), that occur in humans. 24 hours after
the surgery, the mice had a training in the passive avoidance
task. The next day the animals from group
III and IV were injected with 0,1 LD50 lambda-cyhalothrin intraperitoneally.
30 minutes after administration the animals were examined in the
passive avoidance task. Then, their movement co-ordination
on a rota- rod was examined. After that the mice were placed in
a Y maze to examine their spontaneous movement alterations and
later, their spontaneous movement activity was checked. Results
obtained were analysed with Anova and the post hoc tests. There
is a statistically significant difference (p<0,05) in spontaneous
movement activity within first 30 minutes of examination in group
IV versus I and after 60 minutes in group IV vs all the others
and in group II vs sham.
Conclusions: 1. Memory
retention is most impaired by lambdacyhalothrin in sham-operated
animals whereas BCCA-procedure protects their brains from pesticide’s
toxic action.2. Lambdacyhalothrin’s
effect on fresh spatial memory and spontaneous motor activity
is enhanced by BCCA.
Ref: LAMBDA-CYHALOTHRIN’S INFLUENCE
ON MEMORY PROCESSES, MOVEMENT CO-ORDINATION AND SPONTANEOUS MOVEMENT
ACTIVITY IN MICE EXPOSED TO TRANSIENT OLIGEMIC BRAIN HYPOXIA IN
BCCA MODEL; by Barbara Nieradko, Andrzej Borzecki. Toxicology
Letters, Volume 144, Supplement 1, 28 September 2003, Page s147.
[From Science Direct.]
- Insecticide - CAS No. CAS No. 55-91-4
abstracts are available on DFP
features of organophosphate-induced brain injuries were investigated.
Rats were poisoned intraperitoneally with 9 mg/kg (1.8 LD50) of
. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitrate
(20 mg/kg), which are centrally inactive, were pre-treated intramuscularly
to reduce the mortality and eliminate peripheral signs. Diisopropylfluorophosphate
induced severe limbic seizures, and early necrotic and delayed
apoptotic brain injuries. The necrotic
brain injury was observed to be maximal as early as 1 h after
diisopropylfluorophosphate treatment predominently in hippocampus
and piriform/entorhinal cortices, showing a spongiform
change (malacia) of neuropils in severe cases.
In contrast, typical apoptotic (TUNEL-positive) cells started
to appear at 12 h in thalamus, and a mixed type in amygdala. Separately,
nitrite/nitrate content in cerebrospinal fluid was found to significantly
increase after 2 h, reaching a maximal level at 6 h. Pre-treatment
with -NG-nitroarginine, an inhibitor of nitric oxide synthase,
reduced nitrite/nitrate content and, noteworthy, attenuated only
apoptotic brain injury in all four brain regions without affecting
seizure intensity and necrotic injury. Taken together, the delayed
apoptotic injury of brain induced by diisopropylfluorophosphate
poisoning in rats might be mediated in part through nitric oxide
Organophosphate-induced brain injuries: delayed apoptosis mediated
by nitric oxide by Yun-Bae Kim et al. Environmental Toxicology
and Pharmacology Vol 7, Issue 2 , April 1999, Pages 147-152
... We studied the effect of DFP admimistration (1.7 mg/kg/s.c.)
on the expression of Intermediate Filament
(IF) proteins: Glial Fibrillary Acidic Protein (GFAP) and vimentin
which are known indicators of neurotoxicity and astroglial•
pathology. The hens were sacrificed at different time points
i.e. 1,2,5,10 and 20 days. Total RNA was extracted from the following
brain regions: cerebrum, cerebellum, and brainstem as well as
spinal cord. Northern blots prepared using standard protocols
were hybridized with GFAP and vimentin as well as [beta]-actin
and 18S RNA cDNA (controls) probes. The results indicate a differential/spatial/temporal
regulation of GFAP and vimentin levels which may
be due to the result of disruption of glial-neuronal network.
The GFAP transcript levels reached near control levels (88% and
95%) at 20 days post DFP treatment after an initial down-regulation
(60% and 73%) in highly susceptible tissues like spinal cord and
brainstem respectively. However vimentin transcript levels remained
down-regulated (61% and 53%) at 20 days after an early reduced
levels(47% and 55%) for spinal cord and brainstem respectively.
This may be due to the astroglial•
pathology resulting in neuronal alterations or vice-versa. In
cerebellum (less susceptile tissue) GFAP levels were moderately
down-regulated at 1,2 and 5 days and reached near control values
at 10 and 20 days. Vimentin was rapidly reinduced (128%) in cerebellum
at 5 days and remained at the same level at 10 days and then returned
to control values at 20 days after an initial down-regulation
at 1 and 2 days. Thus these alterations were less drastic in cerebellum
as indicated by initial susceptibility followed by rapid recovery.
On the other hand both GFAP and vimentin levels were upregulated
from 2 days onwards in the non-susceptible tissue cerebrum, implying
protective mechanisms from the beginning. Hence the
DFP induced astroglial•
pathology as indicated by the complex expression profile of GFAP
and vimentin mRNA levels may be playing an important role in the
delayed degeneration of axons or is the result of progressive
degeneration of axons in OPIDN.
Ref: Alterations in Levels of mRNAs Coding for Glial Fibrillary
Acidic Protein (GFAP) and Vimentin Genes in the Central Nervous
System of Hens Treated with Diisopropyl Phosphorofluoridate (DFP);
Damodaran et al. Neurochemical Research
25 (6): 809-816, June 2000.
astroglial cell mass constitutes a prominent part
of the total brain cell number
and volume..." See
Astroglial Pharmacology by Elisabeth Hansson et al.
Paper available online at http://www.acnp.org/g4/GN401000079/Ch079.html
subcutaneous (s.c) injections of the organophosphate diisopropylfluorophosphate
caused prolonged inhibition of cholinesterase (ChE) activity in
whole blood and brain and downregulation of muscarinic receptors
in the central nervous system; these changes were accompanied
by progressive, persistent deterioration of working memory and
- Repeated Inhibition of Cholinesterase by Chlorpyrifos in Rats:
Behavioral, Neurochemical and Pharmacological Indices of Tolerance;
by Bushnell PJ, Kelly KL, Ward TR. NTIS report no.NTIS/PB95-148979
[The National Technical Information Service).
A single dose of diisopropyl phosphorofluoridate (DFP), an organophosphorus
ester, produces delayed neurotoxicity (OPIDN) in hen. DFP
produces mild ataxia in hens in 7–14 days, which develops
into severe ataxia or paralysis as the disease progresses.
Since, OPIDN is associated with alteration in the expression of
several proteins (e.g., Ca2+/calmodulin-dependent protein kinase
II (CaM kinase II) [alpha]-subunit, tau, tubulin, neurofilament
(NF) protein, vimentin, GFAP) as well as their mRNAs (e.g., NF,
CaM kinase II [alpha]-subunit), we determined the effect of a
single dose of DFP on the expression of one of the best known
immediate-early gene (IEG), c-fos. C-fos expression was measured
by Northern hybridization in cerebrum, cerebellum, brainstem,
midbrain, spinal cord, and the sciatic nerves of hens at 0.5 hr,
1 hr, 2 hr, 1 day, 5 days, 10 days, and 20 days after a single
1.7 mg/kg, sc. injection of DFP. All the
tissues (cerebrum, 52%; cerebellum, 55%; brainstem, 49%; midbrain,
23%; spinal cord, 80%; sciatic nerve, 157%;)
showed significant increase in c-fos expression in 30 min
and this elevated level persisted at least up to 2 hr. Expressions
of [beta]-actin mRNA and 18S RNA were used as internal controls.
The significant increase
in c-fos expression in DFP-treated hens suggests that c-fos may
be one of the IEGs involved in the development of OPIDN.
mRNA Induction in the Central and Peripheral
Nervous Systems of Diisopropyl Phosphorofluoridate (DFP)-Treated
Hens; by RP
Gupta et al. Neurochemical Research 25 (3): 327-334, March 2000.
... In a study of alkyl
phosphate poisoning, Pasi and Leuzinger came to the conclusion
that delayed lesions only occur, if at all, after severe cerebral
anoxia . As regards anatomical
changes in the brain (demyelination), these delayed lesions correspond
to those caused by peripheral neuropathy in acute and chronic
ortho-tricresyl phosphate poisoning and are confined to fluorine-
containing alkyl phosphatesŃfor example, mipafox,
DFP, sarin and soman. A synoptic
evaluation of 536 civilian cases of alkyl phosphate poisoning
made by the above-mentioned authors led them to the conclusion
that acute poisoning by civilian alkyl phosphates did not result
in delayed lesions. It should be noted, however, that their period
of observation of two to three years was inadequate for investigations
of delayed lesions beside the scale of Spiegelberg and others
Ref: Delayed Toxic Effects of Chemical Warfare
Agents. A SIPRI (Stockholm international Peace Research Institute)
Monograph. 1975. ISBN 91-85114-29-4.
Med Abstract: The organophosphate Diisopropylfluorophosphate (DFP)
is a well-known inhibitor of cholinesterases. We have recently
observed that neonatal exposure to a single subsymptomal dose
of DFP induces permanent alterations in
muscarinic cholinergic receptors (MAChRs) and in spontaneous behaviour,
in the mice as adults. In order to determine if there is
a critical period for these effects, neonatal mice were given
a single oral dose of 1.5 mg/kg DFP b.wt. on postnatal day 3,
10 or 19, causing equal inhibition of AChE. At the adult age of
4 months the mice were tested for spontaneous motor behaviour,
and were subsequently sacrificed for measurement of density of
MAChRs and subpopulations of MAChRs in the cerebral cortex by
using the antagonist quinuclidinyl benzilate ([3H]QNB), and agonist
carbachol, respectively. At adult age, mice
exposed to DFP on postnatal day (PND) 3 or 10 showed significant
(P < or = 0.01) alterations in spontaneous motor behaviour
and a significant (P < or = 0.01) decrease in muscarinic
receptor density. There were no alterations mice exposed
on PND 19. The proportions and affinity-constants of high- and
low-affinity MAChR binding sites were not affected in mice showing
altered MAChR density. The lack of effect on mice exposed on PND
19 was not due to differences in AChE activity.
Res 1995 Apr 17;677(1):13-9. Exposure
to an organophosphate (DFP) during a defined period in neonatal
life induces permanent changes in brain muscarinic receptors and
behaviour in adult mice by Ahlbom J, Fredriksson A, Eriksson
P. (Department of Environmental Toxicology, Uppsala University,
PubMed abstract: Diisopropyl
phosphorofluoridate (DFP) produces
organophosphorus-ester-induced delayed neurotoxicity in sensitive
species. We studied the effect of single dose of DFP on the expression
of phosphorylated cAMP-response element
binding protein (p-CREB), which is a well known transcription
factor involved in several pathways mediating different types
of external stimuli. The hens were perfused with neutral buffered
formalin at different time points, i.e., 0.5, 1.0, and 2.0 hrs,
as well as 1, 2, 5, and 20 days after dosing. The central nervous
system regions of the whole brain were dissected and 7-micron
sections were stained for either p-CREB immunopositivity or with
hematoxylin and eosin. Results indicated an early differential
increase of p-CREB immunopositivity in susceptible regions such
as cerebellum, brainstem, and midbrain
within 2 hrs. These induced levels persisted upto 5 days in these
tissues, although the time course of p-CREB immunopositivity was
distinctly different for each region. In the cerebellum
induction of p-CREB was seen in the granular layer where both
the granulocytes and the glial
cells showed induction. Increased immunopositivity for
p-CREB in the Purkinje cells and
in some basket cells of the molecular layer was noticed over time,
but the induction was not as great as in the granular layer.
Of all the tissues cerebellum showed the strongest intensity of
immunopositivity of the cells as well as the highest (absolute)
number of pCREB-positive cells. The
brainstem showed a similar fluctuating pattern
like the cerebellum with the highest percentage
increase of the immunoreactive cells at 5 days preceded by the
lowest dip in immunopositivity at 2 days. In the midbrain, there
was a time-dependent increase in the immunopositivity from 0.5
hr onwards until reaching control levels at 20 days. Immunopositivity
was also noted in portions of the spina
medularis and spina oblongata. The cerebrum (non-susceptible
tissue) of DFP-treated hens did not show much deviation from the
controls. The endothelial cells of
the susceptible regions showed induction at early time points,
in contrast to the absence of induction in cerebrum. Spatial and
temporal differences in the immunopositivity pattern indicate
probable involvement of CREB-independent pathways also. Overall,
the complex induction pattern of p-CREB, along with our earlier
observations of the early induction of c-fos, c-jun and Protein
Kinase A (PKA) as well as the induction of Calcium2+/Calmodulin
dependent Protein Kinase II (CaM kinase II) at later periods,
strongly suggest an activator role of CREB mediated pathways that
may lead to the clinical development of delayed neurotoxicity.
Early differential elevation and persistence of phosphorylated
cAMP-response element binding protein (p-CREB) in the central
nervous system of hens treated with diisopropyl phosphorofluoridate,
an OPIDN-causing compound; by TV Damodaran TV et al.
-- 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)... 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. [Lehning EJ et al; Fundam Appl Toxicol 29 (1):
Ref: TOXNET Hazardous Substances Data Base
for DIISOPROPYL FLUOROPHOSPHATE.
of organophosphorus anti-cholinesterase (anti-ChE) agents, soman,
tabun, diisopropylfluorophosphate (DFP) and non-organophosphorus
anti-ChE agents, eserine and neostigmine on sympathetic neurons
and on ganglionic transmission were investigated. Intracellular
recordings were obtained from sympathetic neurons of isolated
rabbit and guinea pig superior cervical ganglia by means of glass
microelectrodes. DFP, soman and eserine
increased and blocked nicotinic cholinergic transmission at low
and high concentrations, respectively. These agents at lower concentrations,
i.e. 1 micro M or lower, facilitated nicotinic transmission by
inhibiting ganglionic cholinesterases. Whereas, these agents at
higher concentrations, i.e. 1 or 10 micro M appeared to block
nicotinic transmission by different mechanisms. ...
Ref: 1989 - Cellular Actions and Interactions
of Anticholinesterases and Their Antidotes in Mammalian Autonomic
Neurons; by Dun NJ. Report No. NTIS/AD-A215 077/9 from The National
Technical Information Service.
water task was used to measure the effects of chronic diisopropylfluorophosphate
(DFP) treatment on C57BL/6Ibg mice. Control mice showed good task
acquisition and searched accurately for the platform after it
was removed from the pool, suggesting that they had formed a spatial
map of the platform's location relative to distal cues.
In contrast, mice chronically treated with DFP prior to training
showed a marked deficit in spatial learning. Chronic DFP
treatment did not affect ability to locate a visible platform
and did not impair task retention in mice trained to find the
hidden platform prior to DFP treatment. The
chronic DFP treatment decreased muscarinic binding in cortex,
hippocampus, and striatum. These results indicate that
C57BL mice are capable of spatial learning in the water task.
The ability of chronic DFP treatment to
impair place but not cue learning suggests that the cholinergic
dysfunction produced by DFP is similar to those produced by lesions
of central cholinergic s [abstract truncated]
1987 - Effects of Chronic Diisopropylfluorophosphate Treatment
on Spatial Learning in Mice; by Upchurch M, Wehner JM. Report
No. NTIS/AD-A188 368/5 from The National Technical Information
of diisopropylfluorophosphate (DFP), soman, and sarin was studied
in the major organs of the mouse after i.v. administration of
sublethal but pharmacologically active doses. DFP was also administered
via inhalation, allowing comparison of disposition data between
the two routes of administration. Only trace quantities of parent
compounds were found in tissues. The major portion of the radioactivity
was determined to be vocalently bound or free metabolites of the
parent compounds. All compounds tested induced immediate hypothermia
and hypoactivity lasting at least 7 hr.
However, substantial quantities of radioactivity remained
in the brain following recovery from the pharmacological effects.
Cholinesterase inhibition was also not correlated with
either free agent or bound or free metabolites, suggesting that
non-cholinesterase binding of the parent compounds may play a
role in the depression of CNS activity. The pharmacological effects
of i.v. administered tabun were also evalu [abstract truncated]
1986 - Studies on the Biodisposition of Organophosphates in Mice;
by Martin BR. Report No. NTIS/AD-A183 850/7 from The National
Technical Information Service.
of diisopropylfluorophosphate (DFP) and several other organophosphates
on brain membranes was studied. DFP bound
to a wide range of proteins in synaptic plasma membranes (SPM),
but no effect was detected on cross-linking of these proteins
by several imidate reagents. DFP, soman,
sarin, and tabun administered in vivo significantly altered the
levels of endogenous opioids peptides in several brain regions.
A search for an endogenous enzyme in brain capable of inactivating
DFP was inconclusive, but suggested that one might be present
in the soluble fraction.
1986 - Neurochemical Mechanism of Organophosphorus Compounds:
Effect on Neuromembrane; by Lee NM. Report No. NTIS/AD-A217 464/7
from The National Technical Information Service.
(ChE) activity in selected brain regions and trunk blood was studied
20 min, 1 hr, and 24 hrs after bilateral injection of various
doses of diisopropylfluorophosphonate (DFP), soman and sarin into
the corpus striatum of male rats. Locomotor activity was measured
after bilateral intrastriatal injection of doses of DFP, soman
and sarin that reduced striatal ChE activity to 40% of control
or less, with a minimum of inhibition of ChE elsewhere in the
brain or blood. DFP appeared to diffuse
throughout the brain parenchyma more than soman and sarin, and
the latter two compounds appeared also to enter the peripheral
circulation. However, no gross signs of toxicity due to
peripheral ChE inhibition were observed. Locomotor
activity was reduced significantly 20 min after bilateral intrastriatal
administration of DFP (81.5 nmol). Keywords: Organophosphates,
Striatum, Cholinesterase. Annual rept. 30 Sep 83-29 Sep 84.
Ref: 1984 - Effect of Intracerebral
Injection of Organophosphates on Brain Neurochemistry and Peripheral
Physiology; by Robinson SE. Report No. NTIS/AD-B120-517/8 from
The National Technical Information Service.
- Wood Preservative, Antifoulant, Fungicide, Acaricide -
CAS No. 1085-98-9
-- Mouse Carcinogenicity
Study A 2-year OECD-compliant carcinogenicity study carried out
to GLP is available. Animals (SPF mice B63CF1 60 sex/group) received
dietary administration of either 0, 200, 1000 or 5000 ppm dichlofluanid
(89-93 % purity); equivalent to 50.1, 273.9 or 1731.3 and 63.7,
337 or 1872.7 mg kg -1 d -1 in females and males respectively.
The scheduled study termination was after 104 weeks, with an interim
kill at 52 weeks; all animals were necropsied plus any dying or
sacrificed intercurrently... There were effects on both the relative
and absolute organ weights. The following absolute organ weights
were reduced : brain (5 % males and 6 %
females), spleen (14 % females), and kidney (18 % females)
at the top dose.
-- There were effects on both the relative and absolute organ
weights. In males, at the top dose, there were significant
decreases in the absolute organ weights of the lung (20
%), brain (8 %) and testes (6 %).
In females at the top dose there were significant decreases in
the absolute organ weights of the brain
(8 %), spleen (42 %) and kidney (18 %). The relative organ
weights of the brain (13 %), liver
(44 %), spleen (36 %) and testes (5 %) were increased in males
at the top dose. In females the relative brain
(7 %) and liver (47 %) weights were increased and the kidney
(6 %) and ovary weights (28 %) were decreased. No incidences of
toxicologically significant histopathology (liver included) were
2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Also available at:
- Insecticide, Fungicide, Propellant, US EPA List 2 Inert -
CAS No. 75-71-8
There is a
significant accumulation of fluorocarbons in brain, liver
and lung compared to blood levels, signifying a tissue distribution
of fluorocarbons similar to that of chloroform. /Fluorocarbons/
[Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene
and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th
ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1203]
Ref: TOXNET profile from Hazardous Substances
Data Bank for DICHLORODIFLUOROMETHANE
effects ... In the occupational setting, chronic fluorocarbon
exposure has been associated with a syndrome of impaired psychomotor
speed, impaired memory and learning,
and emotional instability (Reprotext, 2003). Repeated or prolonged
skin contact may cause dermatitis (NIOSH, 2001E; NIOSH, 2001D).
September 24, 2003 (Revised)
- FREON [11, 12, 113].
Technical Support Document: Toxicology. Clandestine
Drug Labs/ Methamphetamine. Volume 1, Number 11. California EPA,
Office of Environmental Health Hazard Assessment (OEHHA), Department
of Toxic Substances Control.
(CFC-114) - Propellant,
Former EPA List 2 Inert - CAS No. 76-14-2
-- NEUROLOGIC 0.2.7.1
ACUTE EXPOSURE -Headache, dizziness, and disorientation are common.
Cerebral edema may be found on autopsy. A syndrome of impaired
psychomotor speed, impaired memory and learning, and emotional
lability has been described in workers with chronic occupational
exposure to fluorinated hydrocarbons.
-- THERE IS A SIGNIFICANT ACCUMULATION OF FLUOROCARBONS IN
BRAIN, LIVER & LUNG COMPARED TO BLOOD LEVELS, SIGNIFYING
A TISSUE DISTRIBUTION OF FLUOROCARBONS SIMILAR TO THAT OF CHLOROFORM.
/FLUOROCARBONS/ [Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial
Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology.
4th ed. New York, NY: John Wiley & Sons Inc., 1993-1994. 1203]
-- Aerosol sprays containing fluorocarbon propellants are another
source of solvent intoxication. Prolonged exposure or daily use
may result in damage to several organ systems. Clinical problems
include cardiac arrhythmias, bone marrow depression, cerebral
degeneration, and damage to liver, kidney, & peripheral
nerves. Death occasionally has been attributed to inhalant abuse,
probably via the mechanism of cardiac arrhythmias, especially
accompanying exercise or upper airway obstruction. /fluorocarbon
propellants/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W.
Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological
Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996.
1,2-DICHLORO-1,1,2,2-TETRAFLUOROETHANE. CASRN: 76-14-2. TOXNET
profile from Hazardous Substances Data Base.
- Herbicide - CAS No. 109293-97-2
In an acute rat neurotoxicity
study, diflufenzopyr was administered by gavage to Crl:CD BRR
rats (10/ sex/group) at dose levels of 0, 125, 500 or 2,000 mg/kg...
Lower mean brain weights in all female treatment groups.
Federal Register, January 28, 1999. Diflufenzopyr; Pesticide Tolerance.
Insecticide - CAS No. 115-26-4
Abstract: The toxicological
effects of schradan (152169), dimefox (115264),
and parathion (56382) were investigated in rats, pigs, and humans.
Schradan was given to rats on diet at concentrations from 0.05
to 5.0 parts per million (ppm) or by intraperitoneal (ip) injection
of 0.007 to 2.5 milligrams per kilogram (mg/kg). Pigs were fed
0.1 to 2.5ppm in diet. Human subjects were
given 1.4mg 5 days per week to a total of 44mg.
Brain and plasma cholinesterase (ChE) were determined
in animals. Blood
ChE was determined in humans. Rats were
fed 0.01 to 5.0ppm dimefox in diets for 28 to 287 days.
Pigs received 0.005 to 0.5ppm for 133 days.
Humans were given oral doses of 0.0014mg/kg for 14 days, then
0.004mg/kg for 95 days, or 0.0012, 0.002, or 0.0034mg/kg for 70
days. Inhibition of ChE was determined. For parathion,
rats were fed 0.05, 0.5, or 5.0ppm in diet for 84 days. Pigs were
fed 0.02 to 100ppm in increasing doses from 33 to 122 days. Humans
received oral doses of 0.6mg per day until week 4, then increased
to 4.8mg to week 13; 7.2mg for 6 weeks; or 1.2 or 2.4mg for 25
to 70 weeks. ChE inhibition was determined. The no effect concentrations
were determined for each of the compounds. For schradan, the no
effect dose was 0.02mg/kg per day for rats and pigs. In man, 3ppm
presented no hazard. Based on changes in
red cell ChE, the no effect concentrations of dimefox were 0.003,
0.006, and 0.002mg/kg per day for rat, pig, and man, respectively.
Obvious ill effects or illness in man would occur at about 100
times that concentration...
Ref: Edson EF (1964). Summaries of Toxicological
Data. No-Effect Levels of Three Organophosphates in the Rat, Pig
and Man. Food and Cosmetics Toxicology, Vol. 2, pages 311-316.
available at FAN's abstracts for Dimefox:
Excerpt from abstract:
The neurobehavioral toxicity of the organophosphate pesticides
sumithion (122145), dimefox (115264),
and trichlorphon (52686) was evaluated in rats. Rats were administered
perorally 10 milligrams per kilogram per day (mg/kg/day) sumithion,
0.25mg/kg/day dimefox... Acetylcholinesterase
activity decreased significantly in the case of dimefox
K (1982). Effect Of Pesticides On Central
And Peripheral Nervous System Function In Rats. Neurobehavioral
Toxicology and Teratology, Vol. 4, No. 6, pages 665-669. Abstract
available at FAN's abstracts for Dimefox: