Brain Structures |
Function |
From the excellent
website: Neuroscience
for Kids |
Cerebral
Cortex |
* Thought
* Voluntary movement
* Language
* Reasoning
* Perception |
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. |
Cerebellum |
* Movement
* Balance
* Posture |
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.
|
Brain stem |
* Breathing
* 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. |
Hypothalamus |
* Body Temperature
* Emotions
* Hunger
* Thirst
* 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. |
Thalamus |
* Sensory processing
* Movement |
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. |
Limbic System |
* Emotions |
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. |
Hippocampus |
* Learning
* Memory |
The hippocampus is one part of the limbic system
that is important for memory and learning. |
Basal Ganglia |
* Movement |
The basal ganglia are a group of structures,
including the globus pallidus, caudate nucleus, subthalamic
nucleus, putamen and substantia nigra, that are important in
coordinating movement. |
Midbrain |
* Vision
* Audition
* 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. |
|
The
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
is available.
--
Food and Agricultural Organization of the United Nations
|
Note:
This is not an exhaustive list.
As time allows more information will be added.
Gliftor -
Rodenticide - Rodenticide - CAS No. 8065-71-2
Abstract. Acute poisoning with gliftor, a pesticide composed
of 30% glycerol chlorofluorohydrin and 70% glycerol difluorohydrin,
was studied in three tractor drivers who, mistaking it for alcohol,
ingested 30 ml each of this liquid. Motor
disorders comprising complex chloreiform hyperkinesis (Kulenkampff-Tarnow
syndrome) due to lesions in the cortical and subcortical structures
of the corpus striatum and of the limbicoreticular portion of
the brain, were the principal poisoning symptoms. There
were no symptoms of fluorine poisoning. One patient, who
presented the first symptoms 48 hr after ingestion of the poison,
died in respiratory collapse 6 days later. Leukocytosis (up to
20% rod neutrophilis) hyperglycemia, a serum potassium level of
2.7 mEq/liter, proteinuria, pyuria, and hematuria were observed.
Histopathological examination revealed acute
circulatory disturbances in the internal organs, parenchymatous
dystrophy, and dystrophic changes in the central nervous system.
Ref: Three cases of gliftor poisoning;
by Kovalenko LI, Bulkina VA, Panteleev RI. Gig. Tr. Prof. Zabol.
(12): 53-54; 1975. [Abstract from Toxline at Toxnet.]
Indoxacarb
- Insecticide - CAS No. 173584-44-6
•
Pyrazoline-type insecticides (PTIs) are potent neurotoxicants
that cause cessation of feeding, abnormal movement, and paralysis
in arthropods. Indoxacarb,
the first insecticide in this class to achieve commercial registration,
is a proinsecticide that is selectively activated in insects to
form the insecticidal N-decarbomethoxyllated metabolite, DCJW
is another pyrazoline-type compound that is an effective insecticide
but was not registered for use due to its unacceptable mammalian
toxicity ([Meier et al., 1992], [Silver and Soderlund, 2005a]
and [Silver and Soderlund, 2005b]).
Ref: Silver KS, Soderlund DM (2007). Point
mutations at the local anesthetic receptor site modulate the state-dependent
block of rat Nav1.4 sodium channels by pyrazoline-type insecticides.
NeuroToxicology 28:3 655-663. (Available at ScienceDirect.)
•
See also: Action of pyrazoline-type insecticides at neuronal
target sites. Silver
KS, Soderlund DM (2007). Pesticide Biochemistry and Physiology
81:2 136-143. (Available at ScienceDirect.)
52425-040
162205 ŇOncogenicity Study with DPX-JW062-106 (50% DPX-KN128,
50% DPX-KN127) Eighteen-Month Feeding Study in MiceÓ(Frame, S.
832-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 799-96, 3/24/97). DPX-JW062-106
technical (Batch DPX-JW062-106, approximately 48% DPX-KN128)
was given in the diet daily to 70 Crl:CD ¨ -1(ICR)BR mice/sex/dose
at 0, 20, 100, or 125/150/200 ppm for 18 months (200 ppm level
reduced to 150 ppm on day 126 and to 125 ppm on day 287 due to
excessive mortality). The cause of death was either central nervous
system disorder (determined from clinical signs of abnormal gait/mobility
and head tilt) or heart inflammation/ necrosis (males only) ...
Non-neoplastic changes were noted in the brain
of both sexes and in the heart of males only of mice that died
or were sacrificed in extremis. Neuronal
necrosis was reported in two high-dose males and two females
and in one female at 100 ppm. Both high-dose males were sacrificed
in extremis, one while receiving the 150 ppm diet (day 133) and
the other while receiving the 125 ppm diet (test day 302). The
two affected females died or were killed in extremis (day 83 and
108, respectively) while receiving 200 ppm.
Residual vacuolation of the piriform cortex was observed in 2
female high-dose mice that survived to the 18-month scheduled
sacrifice.
Ref: March
11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Based on animal data
from DPX-JW062 (50% KN128
[Indoxacard], Active Ingredient), the following chronic effects
may occur in animals with DPX-MP062.
Ingestion of DPX-JW062 by dogs for one-year caused hemolytic
anemia with secondary histopathological changes and decreased
body weights. The NOEL for both male and female dogs was 40 ppm.
Effects in male and female rats that were fed DPX-JW062 in their
diets for two-years include decreased body weight, in addition
females also had some hemolysis. The NOEL for the two-year rat
feeding study was 60 ppm for male rats and 40 ppm for female rats.
Male and female mice fed DPX-JW062 for eighteen months had decreased
body weight, in addition females showed signs of neurotoxicity,
some mortality, and a few incidences of histopathologic
changes in the brain (probably secondary to seizures).
The NOEL for the eighteen month mouse feeding study was 20 ppm
in male and female mice.
Ref: Dupont's Material Safety Data Sheet
for STEWARD insecticide. January 2001.
http://www.fluoridealert.org/pesticides/dpx-mp062.msds.steward.htm
Abstract: Indoxacarb
is a newly developed insecticide with high insecticidal activity
and low toxicity to non-target organisms. Its metabolite, DCJW,
is known to block compound action potentials in insect nerves
and to inhibit sodium currents in cultured insect neurons. However,
little is known about the effects of these compounds on the sodium
channels of mammalian neurons. We compared the effects of indoxacarb
and DCJW on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant
(TTX-R) sodium channels in rat dorsal root ganglion neurons by
using the whole-cell patch clamp technique. Indoxacarb and DCJW
at 1-10 microM slowly and irreversibly blocked both TTX-S and
TTX-R sodium channels in a voltage-dependent manner. The sodium
channel activation kinetics were not significantly modified by
1 microM indoxacarb or 1 microM DCJW. The steady-state fast and
slow inactivation curves were shifted in the hyperpolarization
direction by 1 microM indoxacarb or 1 microM DCJW indicating a
higher affinity of the inactivated sodium channels for these insecticides.
These shifts resulted in an enhanced block at more depolarized
potentials, thus explaining voltage-dependent block, and an apparent
difference in the sensitivity of TTX-R and TTX-S channels to indoxacarb
and DCJW near the resting potential. Indoxacarb
and its metabolite DCJW cause toxicity through their action on
the sodium channels.
Ref:
Zhao X et al. (2003). Voltage-dependent block of sodium channels
in mammalian neurons by the oxadiazine insecticide indoxacarb
and its metabolite DCJW. Neurotoxicology. Jan;24(1):83-96.
Abstract: The effects of the oxadiazine insecticide
indoxacarb and its N-decarbomethoxylated
metabolite (DCJW) on tetrodotoxin-resistant (TTX-R)
voltage-gated sodium channels in rat dorsal
ganglion neurons were studied using the whole-cell patch
clamp technique. Indoxacarb and DCJW suppressed
the peak amplitude of action potentials, and DCJW exhibited a
faster time course and higher potency than indoxacarb in the blocking
effects. In voltage-clamp experiments, indoxacarb and DCJW suppressed
TTX-R sodium currents in a time-dependent manner without a steady-state
level of suppression. IC50 values for indoxacarb and DCJW on TTX-R
sodium currents were estimated to be 10.7 and 0.8 microM after
25 min of bath application, respectively. DCJW was about 10 times
more potent than indoxacarb in blocking TTX-R sodium currents.
Although the suppressive effects of indoxacarb were partially
reversible after washout with drug-free external solution, no
recovery of sodium current was observed in DCJW treated neurons
after prolonged washout. In current-voltage relationships, both
indoxacarb and DCJW blocked the sodium currents to the same degree
in the entire range of membrane potentials. The sodium conductance-voltage
curve was not shifted along the voltage axis by indoxacarb and
DCJW at 10 microM. In contrast, the steady-state inactivation
curves were shifted in the hyperpolarizing direction by indoxacarb
as well as by DCJW. Based on these results, it was concluded that
indoxacarb and DCJW potently blocked the TTX-R sodium channel
in rat DRG neurons with hyperpolarizing shifts of the steady-state
inactivation curves, suggesting preferential association of the
insecticides to the inactivated state of sodium channels.
The small structural variation between indoxacarb
and DCJW resulted in clear differences in potency for blocking
sodium channels and reversibility after washout.
Ref: Tsurubuchi Y, Kono Y (2003).
Modulation of sodium channels by the oxadiazine insecticide indoxacarb
and its N-decarbomethoxylated metabolite in rat dorsal root ganglion
neurons. Pest Manag Sci. Sep;59(9):999-1006.
Methanesulfonyl
fluoride - Fumigant, Insecticide -
CAS
No. 558-25-8
Abstract: TD3: This
citation summarizes a one-page announcement of technology available
for utilization. Chemicals that markedly inhibit
the enzyme cholinesterase (ChE) in the rat brain but relatively
little in other tissues have been discovered by Dr. Donald E.
Moss and his colleagues at the University of Texas at EL Paso
(UTEP). Dr. Moss and his colleagues found that phenylmethanesulfonyl
fluoride (PMSF) and methanesulfonyl fluoride
(MSF) inhibited 90 percent of ChE activity in the rat brain
but less than 35 percent in other tissues. The enzyme hydrolyzes
acetylcholine, a vital neurotransmitter. Acetylcholine
is markedly deficient in the brains of patients with Alzheimer
disease, due at least in part to decreased synthesis, Dr.
Moss points out. 'A therapeutic strategy, therefore, would be
to cut down ChE's destructive action so that the little bit of
neurotransmitter that is being synthesized lasts longer,' he says.
Dr. Moss points out that a big advantage of MSF and PMSF over
other drugs is their apparent l
Ref: New
Chemicals Markedly Inhibit Cholinesterase. Authors:
Anon. Author Address: National Institutes of Health, Bethesda,
MD. Source: Govt Reports Announcements & Index (GRA&I), Issue
23, 1986. Order Number: NTIS/NTN86-0746,
FOR ADDITIONAL INFORMATION: Contact: Research Resources Information
Center, 1601 Research Blvd, Rockville, MD; (301)984-2870, Refer
to X, No. 1., 1p. As cited at Toxnet.
BIOSIS
COPYRIGHT: BIOL ABS. Mice were injected with an anticholinesterase,
methanesulfonyl fluoride (MSF, 1.5 mg/kg) or O,O-dimethyl O-(2,2-dichlorovinyl)
phosphate (DDVP, 10 mg/kg) singly or repeatedly and examined for
synaptic activities on the cerebral cholinergic system and behavior.
MSF inhibited the activity of cerebral acetylcholinesterase
(AChE) more slowly but more irreversibly than DDVP. Although
a single injection of DDVP increased the concentrations of total,
extraterminal, intraterminal and cytoplasmic acetylcholine (ACh)
remarkably shortly after injection, MSF was still as effective
at 24 h as 3 h after administration in increasing the concentrations
of fractional ACh. Repeated injection of MSF for 3 d showed a
significant reduction in the activity of AChE one day after cessation
with a slight recovery 5 d later. Repeated administration of DDVP
for 10 days showed a less significant reduction in the ac tivity
of AChE one day after cessation with considerable recovery 14
d later. Although a single injection of DDVP showed suppressive
effects on locomotor activity, rectal temperature and rotarod
performance in mice, the administration of MSF did not produce
any significant effects, while DDVP suppressed locomotor activity
and rectal temperature during and after the term of repeated injection.
MSF showed a significant suppressive effect only at the 3rd day
without causing any other changes during or after the term of
repeated injection. In conclusion, MSF causes
similar, but longer lasting effects on cholinergic mechanisms
than DDVP and has fewer suppressive effects on behavioral parameters
than DDVP.
Ref: KOBAYASHI H et al. (1999). Effects
of a central anticholinesterase, methanesulfonyl fluoride on the
cerebral cholinergic system and behavior in mice: Comparison with
an organophosphate DDVP. JOURNAL OF HEALTH SCIENCE; 45 (4). 1999.
191-202. As cited on Toxnet.
Mipafox
- Acaricide, Insecticide
- CAS No. 371-86-8
There
are many abstracts pertaining to Mipafox effects on brain - see
http://www.fluoridealert.org/pesticides/mipafox.pubmed.htm
Excerpts: ... At ten
times the concentration of mipafox that causes a 50% inhibition
of NTE (5x10-5 M/day) mipafox was found to significantly
decrease neurite length in differentiated cells while paraoxon
and OPH-hydrolyzed paraoxon at the same concentration did not.
... While some organophosphorus (OP) compounds including paraoxon
produce acute toxicity through acetylcholinesterase inhibition,
others such as mipafox produce OP-induced delayed neurotoxicity
(OPIDN), which is characterized anatomically by Wallerian-type
"dying back" neuropathy in the axon and myelin.
... Protein expression of NF200 was shown
to be a new biomarker by which the neurotoxic effects of
mipafox and paraoxon on SY5Y cells were distinguishable at the
molecular level.
... The current study shows that organophosphorus compounds produce
not only antiesterase activity but also modifications
in protein. Evidence presented suggests that mipafox caused
shortening of neurites in differentiated SY5Y cells by a degeneration
process, whereas paraoxon inhibited neurite growth in the cells.
Ref: Research
Project (April 2001 - April 2006): Organophosphate Insecticide
Damage to the Mature and Developing Nervous Systems: in Vitro
Systems for Detection and Remediation. Principal Investigator:
E. Tiffany-Castiglioni. Texas
A&M University.
http://www.tard.state.tx.us/index.php?mode=Listing&rl_id=639
...ACETYLCHOLINESTERASE
INHIBITOR, LIKE PARATHION. AFTER ACUTE PHASES OF POISONING, DEGENERATIVE
LESIONS MAY BECOME APPARENT IN CENTRAL &
PERIPHERAL NERVOUS SYSTEMS. [Gosselin, R.E., H.C. Hodge,
R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial
Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-196]
Ref. Hazardous Substances Data Bank for
MIPAFOX CASRN: 371-86-8. Available at Toxnet.
... 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 [176]. 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 phosphates
- for 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 [p 40].
Ref: Delayed Toxic Effects of Chemical Warfare
Agents. A SIPRI (Stockholm international Peace Research Institute)
Monograph. 1975. ISBN 91-85114-29-4.
http://projects.sipri.se/cbw/research/cw-delayed.pdf
PubMed abstract: A
single injection of mipafox was administered
to both Long-Evans hooded rats and White Leghorn hens in dosages
which inhibited the activity of brain neurotoxic esterase 30-50%,
60-80%, or greater than 80% four hr after intoxication. All animals
were monitored for clinical evidence of organophosphorus induced
delayed neuropathy for 21 days, euthanatized, and regions of the
nervous system were histologically evaluated. Only hens manifested
clinical signs of neuropathy; however, light and electron microscopic
lesions were present in the nervous systems of both species. In
rats, these lesions were well developed in only the highest dosage
group and confined to the rostral level of the fasciculus gracilis
in the medulla oblongata. Swollen axons containing a single vacuole
filled with flocculent material were the most prominent lesion
in rats. Hens manifested more extensive and varied fiber
breakdown in multiple spinal cord tracts, with the intensity of
degeneration increasing with increasing dosages of mipafox. Both
marked Wallerian-like degeneration and swollen axons filled with
aggregates of cellular debris were observed in the nervous systems
of hens. This study indicates that both rats and hens are
susceptible to OPIDN. However, there are qualitative and quantitative
differences in both clinical manifestations and histologic appearances
between the two species.
Ref: Comparative
dose-response studies of organophosphorus ester-induced delayed
neuropathy in rats and hens administered mipafox; by Dyer KR,
Jortner BS, Shell LG, Ehrich M. Neurotoxicology 1992 Winter;13(4):745-55.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1302301&dopt=Abstract
PubMed abstract: Adult
male Long-Evans rats and White Leghorn hens were given 30 mg/kg
mipafox ip. Administration of this
organophosphorus ester resulted in > or = 89% inhibition of
brain and spinal cord neurotoxic esterase activity in both species
4 hr after dosing. Our sequential, comparative study of the bilateral
mipafox-induced neuropathy in the
medulla and cervical spinal cord
in hens and rats demonstrated that the rats
had well-developed, vacuolar axonopathic lesions in the fasciculus
gracilis by post-dosing day 7. Severely affected rats with
such lesions were noted through day 21, but not subsequently (days
28 and 35). The hen had a slower developing, but more severe,
consistent and longer lasting neuropathy than the rat. In these
birds, lesions in the medulla and rostral cervical spinal cord
levels were more extensive, involving large regions of both the
spinocerebellar tracts and fasciculus gracilis. Neuropathic changes,
including myelinated fiber axonopathy and Wallerian-like degeneration,
were prominent from days 14 - 35 in hens, and were associated
with prominent gliosis in the later stages.
Ref: Comparative
evolution of mipafox-induced delayed neuropathy in rats and hens;
by Carboni D, Ehrich M, Dyer K, Jortner BS. Neurotoxicology 1992
Winter;13(4):723-33.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1302299&dopt=Abstract
•
Definitions:
Fasciculus
gracilis.
White matter in the dorsal, medial area of the spinal cord.
It forms the entire dorsal column in the lumbar and sacral levels
and the medial division of the dorsal column in the thoracic
and cervical regions. It carries sensory information from the
lower extremities. In the thoracic and cervical regions it is
located between the fasciculus cuneatus and the dorsal median
fissure. In the lumbar and sacral regions it is found between
the dorsal horn and the dorsal median fissure.
Gliosis.
The production of a dense fibrous network
of neuroglia; includes astrocytosis, which is a proliferation
of astrocytes in the area of a degenerative lesion.
Gliosis
- excerpt from PubMed Abstract:
... Our results show that chronic gliosis
is associated with altered processing of the amyloid precursor
protein in vivo and thus may initiate or exacerbate pathological
changes associated with Alzheimer's disease.
Ref: Bates KA et al (2002). Chronic gliosis
triggers Alzheimer's disease-like processing of amyloid precursor
protein. Neuroscience: 113(4):785-96.
Medula
lower or hindmost part of the brain; continuous
with spinal cord; (`bulb' is an old term for medulla oblongata);
"the medulla oblongata is the most vital part of the brain because
it contains centers controlling breathing and heart functioning"
Abstract:
The effects of multiple low doses of ecothiopate (513100), paraoxon
(311455), and mipafox (371868) on organophosphate target enzymes
in the brain and diaphragm were studied in mice. Male albino-mice
were injected subcutaneously once with 0 or 110 micromoles per
kilogram (micromol/kg) mipafox, 0.5micromol/kg ecothiopate, or
1.5micromol/kg paraoxon or with 0 or 44micromol/kg mipafox, 0.2micromol/kg
ecothiopate, or 0.6micromol/kg paraoxon daily for 5 days or 27.5micromol/kg
mipafox daily for 8 day s. The mice were killed 3 hours (hr) after
the single dose or 3 or 24hr after each of the multiple doses
and the brain and diaphragms were removed... Mipafox
and paraoxon inhibited brain AChE activity by 55 and 73%, respectively...
Only mipafox inhibited brain NTE activity,
by 66%. Brain AChE activity was progressively inhibited
by 17 to 46% by multiple dosing with 27.5micromol/kg mipafox,
by 23 to 49% by multiple injection with 44micromol/kg mipafox,
and by 20 to 55% by multiple dosing with paraoxon... Mipafox
also produced a progressive inhibition of brain NTE activity,
the cumulative inhibitory effect, 74 and 76%, being similar after
the two dosing protocols. The authors conclude that exposure to
multiple low doses of mipafox, ecothiopate, and paraoxon produces
additive inhibition of AChE activity. These results have implications
for humans as humans are generally exposed to low levels of organophosphates
for extended periods of time.
Ref: Williams
FM et al (1997. The Effects of Multiple Low Doses of Organophosphates
on Target Enzymes in Brain and Diaphragm in the Mouse. Human and
Experimental Toxicology, Vol. 16, No. 2, pages 67-71. Abstract
available at
http://www.fluorideaction.org/pesticides/mipafox.pubmed.htm
Nissol
(also known as MNFA or MNAF) - Acaricide, Insecticide - CAS
NO. 5903-13-9
Abstract.
The relationship between the characteristic electroencephalographic
findings and the blood sugar levels in Nissol (N-methyl-N (10naphthyl)
monofluoroacetamide) poisoning has been noted recently. States
of both acute and chronic intoxication by Nissol were produced
in male albino rabbits to study the compound's effects on the
brain, together with hematologic, renal and postmortem histological
manifestations. In the acute experiment, 2 ml of a 25% emulsion
was applied to the skin surface. In the chronic toxicity test,
a 1000-fold dilution of the 25% emulsion was applied to the skin
once daily until the animals succumbed. In the acute toxicity
test, there were no remarkable findings in the blood cell count,
hemoglobionmetry or livr function tests but the blood sugar decreased
from the pretreatment level of 122 to 78 and 56 mg/dl in 3 and
7 hr, respectively. In
the chronic toxicity test, the erythrocyte count decreased to
3,310,000 and hemoglobin dropped to 50% in 8 months.
The liver function tests, blood sugar analysis and electrocardiography
did not show any remarkable changes. The electroencephalogram
in the acute toxicity test exhibited a transient convulsive wave
in all leads 5 hr following the application of Nissol which then
gradually lapsed to a slow-voltage pattern, while the blood sugar
level dropped to 56 mg/dl. In the chronic experiment, the electroencephalographic
tracings showed a low-voltage pattern which fell into regular
waves in the eighth month without convulsions or a decrease in
blood sugar levels. I.P. injection of 20% glucose caused the temporary
development of an alpha wave. The visceral
organs were characterized by congestion, atrophy and degeneration
both in the chronic and the acute toxicity tests,
Ischemic changes in the cerebral cortex, hippocampus and Purkinje
cells of the cerebellum were more pronounced in the chronic experiment.
From
the above studies, it is concluded that there is a cause-effect
relationship between the fall of the blood sugar level, the electroencephalographic
findings and the ischemic changes in the brain in Nissol intoxication.
Ref:
Organic fluorine poisoning, by Nanba M JR et al. Nippon Rinsho;
29(2):864-70 1971. [Abstract from Toxnet.]
Abstract. The accumulation of citrate
was studied in spider-mites, house-flies and mice after treatment
with the acaricide Nissol (5903139). Male Swiss-Webster-mice were
injected with various concentrations of Nissol. House-flies were
treated topically with Nissol at various concentrations or received
thoracic injections. A slide/dip technique was used to dose two-spotted-spider
mites with Nissol. Mortality was recorded at 24 hours after treatment
and the median lethal dose (LD50) was calculated for each species.
The citric-acid (77929) content was determined in homogenates
of whole mice in brains, hearts, livers, and kidneys photospectrometrically.
Citric-acid content was also determined in homogenates of flies
and mites. The LD50 for intraperitoneal administration in mice
was 200 milligrams per kilogram (mg/kg). The topical LD50 in house-flies
was 525mg/kg and the injected LD50 was 14mg/kg. The LD50 for contact
administration to spider mites was 250 parts per million. Citric-acid
increased substantially in each species even by 3 hours after
dosing. The maximum accumulation in mice occurred at 6 hours.
Flies and mites continued to show increased accumulation through
12 hours. In the mouse citric-acid was accumulated
in decreasing order in the heart, kidney, brain, and liver. The
authors conclude that mites, flies and mice accumulate citrate
when treated with Nissol. The toxicity of
this acaricide may be related to inhibition of aconitase which
catalyzes transformation of citric-acid.
Ref. Citrate Accumulation In Twospotted
Spider Mites, House Flies, And Mice Following Treatment With The
Acaricide 2-Fluoro-N-methyl-N-(1-naphthyl) Acetamide; by Johannsen
FR. Knowles CO. Journal of Economic Entomology, Vol. 65, No. 6,
pages 1754-1756, 14 references, 1972.
Abstract. The effects of a single dose and repeated doses of
N-methyl-N- ( 1- naphthyl ) monofluoroacetamide (MNFA) on the
fluctuation of citrate in animals and the replationship between
the activity of MNFA hydrolysis and the acute toxicity of MNFA
in various species were investigated. MNFA
was administered intraperitoneally at 25 mg/kg to male Wistar
strain rats, 2.0 mg/kg to guinea pigs and 300 mg/kg to monkeys.
At specified periods after dosing, the animals were sacrificed
and the citrate content of heart, kidneys, liver and brain was
determined. For the multiple dose study, MNFA was administered
orally to male rats at doses of 0.625, 1.25, 2.5, 5.0 and 10.0
mg/kg/ day for 180 days and the citrate content was determined
in the brain, heart, liver, kidney, testis and blood.
In the rat, after a single dose of MNFA, the citrate level increased
to 27, 10,
10 and negligible times the
normal value in heart, kidneys,
brain and liver, respectively. In the chronic
toxicity experiment, the only increase (3 times
the control value) was in the testes of rats receiving
10 mg/ kg/day of MNFA. In all other
groups, the level in liver and kidney decreased significantly
in comparison with the levels in animals receiving a single dose.
It is suggested that this difference was due to metabolism and
to the detoxification mechanism of the liver
and kidney which may have been accelerated by the chronic administration
of MNFA. The citrate level in the monkeys after a single dose
was much lower than in the rat. In guinea pigs it
increased to the maximum at 9 hr when it reached 30 times the
control value in the kidney, 10 times in the heart,
6 times in the brain while no appreciable
increase was found in the liver. The hydrolysis of MNFA by liver
homogenates was closely related to the acute toxicity and the
product of the hydrolysis was determined as N-methyl-1-naphthylamine.
The enzyme activity in the guinea pig was about 35 times that
of the rat or mouse. The LD50 of MNFA was 3.1 times that
of N- ( 1-naphthyl ) monofluoroacetamide ( NFA ) and the amount
hydrolyzed after 30 min incubation was about one- fifth.
Ref: Studies of the biochemical lesions
caused by a new fluorine pesticide, N-methyl-N- ( 1-naphthyl )
monofluoroacetamide; by Noguchi T, Hashimoto Y, Miyata H. Toxicol.
Appl. Pharmacol.; 13(2), 189-98, 1968.
Abstract. The selective toxicity of N-methyl-N- ( 1-naphthyl
) monofluoroacetamide ( MNFA ) in various species of animals and
the effects of the compound on the central action, the peripheral
action and the fluctuations in the cardiovascular and respiratory
systems were investigated. Tabulated data present the physiological
function or activity investigated, the test animal, the dosage
of MNFA administered and the route of administration. Results
showed that below the toxic level, MNFA had little or no general
pharmacologic effect and only a minute effect on the central and
peripheral nervous systems and various peripheral organs of the
differenct animals tested. When a toxic dose of MNFA was administered,
respiratory depression, a fall of blood pressure and body temperature
and a decrease in heart rate were generally observed.
Both the rat and cat developed convulsions.
Just prior to death, a flat wave was observed
in the electrical activity of the brain which was indicative of
a serious impediment. A
drop in blood pressure of about 30% was observed at 24
hr in rats that received 50 mg/kg of MNFA orally.
Cardiac response revealed the characteristic feature of this compound
to be cardiac depression in every species tested. In
addition, among animals that have a high sensitivity to MNFA,
such as the guinea pig, dog and cat, bigeminal or trigeminal ventricular
premature beats were observed. An enhancement of epinephrine
activity by MNFA was also noted. MNFA had a slight effect on the
red cell count, but the white cell count
in rabbits decreased markedly accompanied by a decrease of pseudoeosinophils
and an increase of lymphocytes. The blood
sugar level in mice showed an initial increase prior to a final
decrease, while in rats and guinea pigs there was a decrease
and the value remained unchanged in rabbits and dogs. Ketone bodies
were only detected in the mouse.
Ref. Some pharmacologic properties
of a new fluorine pesticide, N-methyl- N- ( 1-Naphthyl ) monofluoroacetamide;
by Hasimoto Y, Noguchi T, Mori T, Kitagawa H. Toxicol. Appl. Pharmacol.;
13(2), 174-88, 1968.
TOXICITY
Ref: ChemIDplus for Nissol. Available
at Toxnet. |
Organism
|
Test
Type |
Route |
Reported
Dose (Normalized Dose) |
Effect |
Source |
cat |
LD50 |
skin |
4mg/kg
(4 mg/kg) |
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
BEHAVIORAL:
EXCITEMENT |
Nippon
Yakurigaku Zasshi. Japanese Journal of Pharmacology. Vol.
65, Pg. 182, 1969.
Link
to PubMed |
dog |
LD50 |
skin |
2750ug/kg
(2.75 mg/kg) |
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
BEHAVIORAL:
EXCITEMENT |
Nippon
Yakurigaku Zasshi. Japanese Journal of Pharmacology. Vol.
65, Pg. 182, 1969.
Link to PubMed |
dog |
LDLo |
intraperitoneal |
2mg/kg
(2 mg/kg) |
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
BEHAVIORAL:
EXCITEMENT |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
guinea
pig |
LD50 |
skin |
5mg/kg
(5 mg/kg) |
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
guinea
pig |
LDLo |
subcutaneous |
1mg/kg
(1 mg/kg) |
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
monkey |
LDLo |
intraperitoneal |
100mg/kg
(100 mg/kg) |
BEHAVIORAL:
"HALLUCINATIONS, DISTORTED PERCEPTIONS"
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
monkey |
LDLo |
skin |
800mg/kg
(800 mg/kg) |
BEHAVIORAL:
"HALLUCINATIONS, DISTORTED PERCEPTIONS"
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
monkey |
LDLo |
subcutaneous |
150mg/kg
(150 mg/kg) |
BEHAVIORAL:
"HALLUCINATIONS, DISTORTED PERCEPTIONS"
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
mouse |
LD50 |
intraperitoneal |
164mg/kg
(164 mg/kg) |
BEHAVIORAL:
EXCITEMENT
BEHAVIORAL: COMA |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
mouse |
LD50 |
subcutaneous |
216mg/kg
(216 mg/kg) |
BEHAVIORAL:
EXCITEMENT
BEHAVIORAL:
COMA |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
rabbit |
LD50 |
oral |
1500ug/kg
(1.5 mg/kg) |
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD |
Experimental
Animals. Jikken Dobutso Iho. Vol. 21, Pg. 88, 1972. |
rabbit |
LDLo |
intravenous |
5mg/kg
(5 mg/kg) |
BEHAVIORAL:
CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
rat |
LD50 |
subcutaneous |
41mg/kg
(41 mg/kg) |
BEHAVIORAL:
EXCITEMENT
BEHAVIORAL: COMA |
Toxicology
and Applied Pharmacology. Vol. 12, Pg. 536, 1968. |
Noviflumuron
-Insecticide - CAS No. 121451-02-3
-- REPRODUCTION, RAT. “XDE-007: Two-Generation
Dietary Reproduction Toxicity Study in CD Rats,”
(Carney, E.W., Zablotny, C.L., Liberacki, A.B., Yano, B.L.;Toxicology
& Environmental Research and Consulting, The Dow Chemical
Company, Midland, MI; 3/22/04). XDE -007 (97.9% pure) was fed
in diet to Crl:CD (SD) IGS BR rats (30/sex/dose/generation)
at 0, 0.5, 5 or 25 mg/kg/day continuously from pre-mating of
parental generation 1 (P1) through weaning of offspring through
2 generations (2 matings for P2 generation) to F2b weaning.
. ... . F2a male weanlings had statistically
significantly decreased body weights,
relative brain
and absolute spleen weights at
25 mg/kg. Neonates
at 25 mg/kg in both F1 and F2 generations showed tonoclonic
convulsions, as well as in 1 litter of F2a at 5.0 mg/kg. P2
females (1, 1, 5 and 7 at 0, 0.5, 5.0 and 25 mg/kg, respectively)
failed to litter, so the female is considered
to be an affected sex.) Possible adverse effects on reproduction,
fertility and pup survival, along with numerous other toxicologically
relevant effects. M. Silva, 6/18/04
-- “XDE-007: Two-year Dietary Chronic
Toxicity/Oncogenicity and Chronic Neurotoxicity Study in Fischer
344 Rats,” (Yano, B.L., Dryzga, M.D., Thomas, J.;
Toxicology & Environmental Research and Consulting, The
Dow Chemical Company, Midland, MI; Laboratory Project Study
ID: 011168; 4.22.05). Noviflumuron ((N-[3,5-dichloro-2-fluoro-4(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-N’-(2,6-difluorobenzoyl)urea;
XDE-007, 97.9% pure) was fed in diet to Fischer 344 rats (75/sex/dose)
for 90 days, 1 or 2 years at 0, 0.1, 1.0, 75 or 300 mg/kg/day.
Subchronic toxicity was assessed after 90 days of treatment
on 10/sex/dose at 0 and 1.0 mg/kg/day doses only. At 1 year,10/sex/dose
(chronic toxicity group), and 5/sex/dose (chronic neurotoxicity
group) were necropsied. The remaining 50/sex/dose were necropsied
after 2 years (oncogenicity group). Chronic NOEL = 1.0 mg/kg/day
(At > 75 mg/kg/day there were decreased body weights and
body weight gains along with increases
or decreases in absolute and/or relative organ weights
(liver, kidney, brain, heart, adrenal,
testes, spleen, epididymides were affected) at 12 and/or 24
months.
Ref:
August 2005 - Summary of toxicological data. California EPA,
Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/noviflumuron.ca.epa.2005.pdf
-- 52905-009 186501,
"XR-007: Whole Embryo Culture Teratogenicity
Screen", (E. W. Carney, Health and Environmental
Research Laboratories, The Dow Chemical
Company, Midland, MI, Report # 971083, 31 July 1997).
Seven non-pregnant female rats (serum donors) received 1000
mg/kg/day of the test article (XR-007, 98%) in 0.5% Methocel
by gavage for 3 consecutive days. Four hours after the last
dose, rats were exsanguinated and their blood centrifuged to
obtain serum. Six control rats were similarly treated with vehicle
and bled... Statistically significant
increases in crown-rump length and somite number for treated
embryos were reportedly due to a lower than usual growth
rate in control embryos. Morphological
abnormality was limited to an abnormal curvature of the anterior
neural tube which distorted the head in one treated embryo
(8.3%). No historical control data. This is supplemental information.
(Green and Gee, 10/3/02).
Ref:
September 26, 2002. Summary of Toxicology Data for Noviflumuron
((XDE-007) or N-(((3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl)amino)carbonyl)-2,6-
diflurobenzamide. California EPA, Department of Pesticide Regulation,
Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/noviflumuron.ca.epa.2002.pdf
• Note from FAN- some definitions:
"Predominately anterior neural tube
defects, occuring early in gestation. The anterior neural
tube fails to close properly, or does not divide into two hemispheres.
The generic name for this category of malformations is arrhinencephaly.
Ref: Developmental and Perinatal Disorders of the CNS. Weill
Medical College of Cornell University. http://edcenter.med.cornell.edu/CUMC_PathNotes/Neuropathology/Neuropath_II/dev2.html
-- "... trisomy 13 is closely linked to midline malformations,
including arrhinencephaly,
agenesis of the corpus callosum, and holoprosencephaly, and
is the single most common chromosomal defect underlying holoprosencephaly."
- http://128.100.71.82/neurosurgery/developmental.html
-- "Trisomy 13 Syndrome is
a genetic disorder with onset before birth. It occurs approximately
1/5000 live births. Infants affected with Trisomy 13 tend to
be small at birth. Spells of interrupted breathing (apnea) in
early infancy are frequent, and mental retardation is usually
severe. Many affected children appear to be deaf. A moderately
small head (microcephaly) with sloping forehead, wide joints
and openings between parietal bones of the head are present.
Gross anatomic defects of the brain, especially failure of the
forebrain to divide properly (holoprosencephaly) are common.
A hernial protrusion of the cord and its meninges through a
defect in the vertebral canal (myelomeningocele) is found in
almost 50% of cases. The entire eye is usually small (microphthalmia),
and a defect of the iris tissue (coloboma), and faulty development
of the retina (retinal dysplasia) occur frequently. The supraorbital
ridges are shallow and palapebral fissures are usually slanted.
Cleft lip, cleft palate, or both are present in most cases.
The ears are abnormally shaped and unusually low-set."
- http://www.trisomy.org/html/trisomy_13_facts.htm
Oxyfluorfen
- Herbicide - CAS No. 42874-03-3
Absolute and relative
thymus weights were decreased in mid-dose males (-14%/-10%)and
high-dose males (-32%/- 18%)...Vacuolation of the adrenal cortex
was present in high-dose females. Thymic atrophy occurred in high-dose
males and females.... Fine vacuolation of adrenal glands (slight)and
cortical atrophy of the thymus (slight) were increased in high-dose
males... Absolute and/or relative organ weights in the high-dose
groups that showed statistically significant
changes relative to control weights (thyroid gland in both
sexes and kidney in females at 12 months and brain,
pituitary, and spleen in females sacrificed at 24 months) had
no microscopic correlates and are not considered toxicologically
significant.
Ref: US EPA. Toxicology Chapter for RED.
August 8, 2001.
http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf
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