Brain - Adverse Effects
Fluorinated and Fluoride Pesticides

beginning with
A-E • F-G H-P Q-Z
 
 
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.

A 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 metabolism.
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.

There are two basic subtypes, GABA-a and GABA-b.
GABA-a is 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 ...

The 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.
Ref: http://www.unifr.ch/biochem/DREYER/Neurotransmitters/gaba.htm


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.

Acifluorfen, sodium - 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.
http://www.epa.gov/oppsrrd1/reregistration/acifluorfen/newrisk.pdf

-- 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).
Ref: Overview of Sodium Acifluorfen Risk Assessment April 4, 2002. USEPA. http://www.fluorideaction.org/pesticides/acifluorfen.na.epa.apr.02.pdf

TABLE 3. Doses and Toxicological Endpoints Selected for Various Exposure Scenarios
EXPOSURE SCENARIO DOSE (mg/kg/day) ENDPOINT STUDY
Acute Dietary (Female 13-50) NOAEL=20
UF=100
FQPA SF=10

Decreased fetal weight and increased incidences of dilated lateral ventricles of the brain at 90 mg/kg/day

DevelopmentalŠ rat

Acute PAD = 0.02 mg/kg/day

(a) Dermal (short and intermediate-term, females 13-50) NOAEL=20
MOE=100
FQPA SF=10
(Females 13-50)
 
Decreased fetal weight and increased incidences of dilated lateral ventricles of the brain at 90 mg/kg/day
(b) Inhalation (short and intermediate-term, females 13-50)
(a) = Since an oral NOAEL was selected, a dermal absorption factor of 20% of oral absorption should be used in route-to-route extrapolation.
(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.
Ref: January 15, 2002. MEMORANDUM. SUBJECT: SODIUM ACIFLUORFEN. HED Chapter for the Reregistration Eligibility Decision Document. US EPA. Office of Prevention, Pesticides, and Toxics Substances. http://www.fluorideaction.org/pesticides/acifluorfen.na.a.red.jan.02.pdf

Ammonium bifluoride - Wood Preservative - CAS No. 1341-49-7

Ingestion: 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 1 oz.
Ref: Analytyka. Material Safety Data Sheet. Online as of September 15, 2003.

http://www.analytyka.com.mx/tabla%20periodica/MSDS/N/AMMONIUM%20BIFLUORIDE.htm

Ammonium fluoride - 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.
http://www.fluoridealert.org/pesticides/ammonium.f.msds.htm

Bromethalin - Rodenticide - CAS No. 63333-35-7

• Note: This pesticide contains both bromine and fluorine; a combination that has the potential to produce severe adverse effects - particularly to the brain.
• Other fluorinated pesticides that contain both bromine and fluorine are:

Chlorfenapyr
Fluazolate
Fluorophene
Halfenprox

1H-Pyrrole-3-carbonitrile, 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl
Thifluzamide

-- 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.

http://www.fluoridealert.org/pesticides/bromethalin.red.epa..1998.pdf

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 astrocytes, 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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1632057&dopt=Abstract or http://www.fluoridealert.org/pesticides/bromethalin-medline.htm

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.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2094433&dopt=Abstract

Abstract: Bromethalin 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 The 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.

Chlorfenapyr - Acaricide, Insecticide - CAS No. 122453-73-0

• Note: This pesticide contains both bromine and fluorine; a combination that has the potential to produce severe adverse effects - particularly to the brain.
• Other fluorinated pesticides that contain both bromine and fluorine are:

Bromethalin
Fluazolate
Fluorophene
Halfenprox

1H-Pyrrole-3-carbonitrile, 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl
Thifluzamide

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 and/or 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.

http://www.epa.gov/opprd001/chlorfenapyr/memohed2.pdf

Note: 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."
http://www.epa.gov/opprd001/chlorfenapyr/chlorfenapyr.pdf

Note: 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:
http://www.fluorideaction.org/pesticides/chlorfenapyr.us.residuefood.htm

-- 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 in females.
-- 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 consumption (males)
-- 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 c
onsumption (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 developing young.

Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

-- 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, 7/29/96)
-- 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)
Ref:
August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at:
http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf

Also see the following.

December 22, 2004, US EPA's response to FAN's Comments on Chlorfenapyr effects on brain - see
http://www.fluorideaction.org/pesticides/chlorfenapyr.2005.epa.response.pdf
-
(Online at US EPA Docket OPP-2004-0362-0002)

August 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). http://www.fluorideaction.org/pesticides/chlorfenapyr.comments.aug03.htm -
(Online at US EPA Docket OPP-2003-0205)

September 17, 2003, reply to comments from FAN's Pesticide Project, from Daniel J. O'Byrne, Product Registrations Manager, BASF Corporation. http://www.fluorideaction.org/pesticides/chlorfenapyr.basf.sept.2003.pdf -
(O
nline at US EPA Docket OPP-2003-0205)

1-Chloro-1,1-Difluoroethane (Freon 142; Freon 142B) - List 2 Inert; Solvent -CAS No. 75-68-3

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:
http://toxnet.nlm.nih.gov/

Chlorodifluoromethane - Insecticide, Fungicide, Propellant - CAS No. 75-45-6

Ref: The Registry of Toxic Effects of Chemical Substances
Methane, chlorodifluoro -
RTECS #: PA6390000
NIOSH - National Institute for Occupational Safety and Health
ROUTE/ ORGANISM DOSE EFFECT REFERENCE
inhalation mouse lowest published toxic concentration: 50 gm/m3/6 hour/43 week- intermittent Brain and Coverings: Other degenerative changes

Spinal Cord: Other degenerative changes

Behavioral: Alteration of classical conditioning

Trudy Leningradskogo Sanitarno-Gigienicheskogo Meditsinskogo Instituta. (Leningrad, Russia).
V 75: 231,1963.

oral rat lowest published toxic dose: 2,457 mg/kg/26 week- intermittent

Brain and Coverings: Other degenerative changes

Blood: Changes in other cell count (unspecified)

Nutritional 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): 69,1983.

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 inhalation.
Ref: Fitzgerald RL et al; J Forensic Sci 38 (2): 477-483 (1993); cited in the TOXNET profile from the Hazardous Substances Data Bank.

http://www.fluoridealert.org/pesticides/chlorodifluoromethan.toxnet.htm

Cyfluthrin - 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 39.

http://www.fluoridealert.org/pesticides/cyfluthrin.who.tox.eval.97.htm

Cyhalothrin, 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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15288513

Abstract (1990). 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.

Abstract (2003). 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.]

DFP: Diisopropyl fluorophosphate - Insecticide - CAS No. CAS No. 55-91-4

Note: More abstracts are available on DFP

Abstract: The features of organophosphate-induced brain injuries were investigated. Rats were poisoned intraperitoneally with 9 mg/kg (1.8 LD50) of diisopropylfluorophosphate [synonym for DFP] . 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 production.
Ref: 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

Abstract: ... 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); by TiV Damodaran et al. Neurochemical Research 25 (6): 809-816, June 2000.

Astroglial: "The astroglial cell mass constitutes a prominent part of the total brain cell number and volume..." See full paper: Astroglial Pharmacology by Elisabeth Hansson et al. Paper available online at http://www.acnp.org/g4/GN401000079/Ch079.html

Abstract:Daily 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 motor function.
Ref: 1994 - 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).

Abstract: 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.
Ref: C-fos 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 [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 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 [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

Pub 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.
Ref:
Brain 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, Sweden).

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.
Ref:
2002 Neurochem Res Mar;27(3):183-93. 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): 110-8 (1996)]
Ref: TOXNET Hazardous Substances Data Base for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-toxnet.htm

The effects 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.

The Morris 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]
Ref: 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 Service.

The biodisposition 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]
Ref: 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.

The effect 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.
Ref: 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.

Cholinesterase (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.

Dichlofluanid - 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 reported.
Ref: January 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:

http://www.pesticides.gov.uk/citizen/Evaluations/206_dichlofluanid.pdf

Dichlorodifluoromethane - 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

http://www.fluoridealert.org/pesticides/dichlorodifluorometh.toxnet.htm

Chronic 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).
Ref: 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.

Dichlorotetrafluoroethane (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. 575]
Ref: 1,2-DICHLORO-1,1,2,2-TETRAFLUOROETHANE. CASRN: 76-14-2. TOXNET profile from Hazardous Substances Data Base.
http://www.fluorideaction.org/pesticides/dichlorotetrafluoroe.toxnet.htm

Diflufenzopyr - 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.
Ref: Federal Register, January 28, 1999. Diflufenzopyr; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/diflufenzopyr.fr.jan.1999.htm

Dimefox - Acaricide, 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. Abstract available at FAN's abstracts for Dimefox:

http://www.fluorideaction.org/pesticides/dimefox.abstracts.htm

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
Ref: Lehotzky 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:
http://www.fluorideaction.org/pesticides/dimefox.abstracts.htm

 
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