Adverse Effects
DFP (Diisopropyl fluorophosphate)
CAS No. 55-91-4
 
 

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Abstracts
NTIS Reports

Activity: Former Insecticide (Organophosphate
Structure:


Adverse Effects:
Ataxia
Blood
Brain
CNS
Endocrine: Pituitary
Heart
Sciatic Nerve

DFP is a structural analog of sarin.
Ref: Sarin (nerve agent GB)-induced differential expression of mRNA coding for the acetylcholinesterase gene in the rat central nervous system; by Damodaran TV, Jones KH, Patel AG, Abou-Donia MB. Biochemical Pharmacology Volume 65, Issue 12 , 15 June 2003, Pages 2041-2047.


See 79 Reports available from The National Technical Information Service


Diisopropyl fluorophosphate (DFP) is an organophosphate compound used as an insecticide, a substrate for the production of organophosphate military "nerve" gases and formerly as a topical miotic medication in ophthalmology.

DFP has been used as an experimental agent in neuroscience because of its ability to inhibit cholinesterase and cause delayed peripheral neuropathy. It has been also used as a miotic agent in the treatment of glaucoma. Although DFP has caused experimental distal anoxopathy, no cases of peripheral neuropathy have been reported in patients treated with this agent for glaucoma.

Major Uses:

Not registered for current use in the U.S.

Therap cat: Cholinergic (ophthalmic)
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 883]

Therap Cat (Vet): Has been used as a miotic
[Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 883]

Insecticide (former use)
[Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 360]

Relatively mild poison
[Canadian Security Intelligence Service; Chemical and Biological Terrorism: The Threat According to the Open Literature. Author: Ron Purver, Strategic Analyst, CSIS. Chemical Terrorism. Available from http://www.csis-scrs.gc.ca/eng/miscdocs/chemtere.html as of Sept 19, 2000.]

Ref: TOXNET Hazardous Substances Data Base for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm


Apoptosis (click on for all fluorinated pesticides)

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

Ataxia (click on for all fluorinated pesticides)

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.

Blood (click on for all fluorinated pesticides)

The study examined the relationship between inhibition of cholinesterase activity (CA) and thermoregulatory response in the rat following exposure to the organophosphate (OP), diisopropyl fluorophosphate (DFP). Male Long-Evans rats were injected with DFP dissolved in peanut oil in doses ranging from 0 to 1.5 mg/kg (s.c.). Colonic T(sub col) and tail skin temperature T(sub tail) were recorded at 0, 1, 2, and 3 hr post-injection. At 3 hr post-injection the rat was sacrificed and a blood sample was taken by cardiac puncture and analyzed for CA. There was a biphasic dose effect of DFP on T(sub col) with slight but significant elevation in T(sub col) in the dose range of 0.01 to 0.5 mg/kg and a significant depression in T(sub col) at doses of 1.0 and 1.5 mg/kg. There was a dose-dependent fall in CA with DFP administration in the erythrocyte, plasma, and whole blood fractions. Hypothermia was associated with 80 to 87% inhibition in CA, whereas the elevation in T(sub col) was associated with 20 to 70% [abstract truncated]
Ref: 1991 - Relationship between Cholinesterase Inhibition and Thermoregulation Following Exposure to Diisopropyl Fluorophosphate in the Rat; by Gordon CJ, Fogelson L, Richards J, Highfill J. Report No. NTIS/PB92-158658 from The National Technical Information Service.

Brain (click on for all fluorinated pesticides)

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 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

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.

CNS (click on for all fluorinated pesticides)

Organophosphate insecticides such as ... DFP are potent cholinesterase enzyme inhibitors that act by interfering with the metabolism of acetylcholine, resulting in the accumulation of acetylcholine at neuroreceptor transmission sites. [Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 979]
-- MUSCARINIC (PARASYMPATHETIC) EFFECTS may include bradycardia, bronchospasm, bronchorrhea, salivation, lacrimation, diaphoresis, vomiting, diarrhea, and miosis. NICOTINIC (SYMPATHETIC AND MOTOR) EFFECTS may include tachycardia, hypertension, fasciculations, muscle cramps, weakness, and RESPIRATORY PARALYSIS. CENTRAL EFFECTS may include CNS depression, agitation, confusion, delirium, coma, and seizures.
-- Children may have different predominant signs and symptoms than adults: CNS depression, stupor, flaccidity, dyspnea, and coma are the most common signs in children.
-- ... Its high lipid solubility, low molecular weight, and volatility facilitate inhalation and transdermal absorption. DFP also readily penetrates the central nervous system. [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. 167]
Ref: TOXNET Hazardous Substances Data Base for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm

Abstract: Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester induced delayed neurotoxicity (OPIDN) in the hen, human and other sensitive species. We studied the effect of a single dose of DFP (1.7 mg/kg/sc) on the expression of c-jun, which is one of the heterodimerizing ITFs (Inducible Transcriptional Factors) of the AP-1 family. The hens were sacrificed at different time points ie 0.25,.0.50, 1 and 2 hrs. Total RNA was extracted from the following brain regions: cerebrum, cerebellum, brainstem, midbrain and as well as spinal cord. Northern blots prepared using standard protocols were hybridized with c-jun as well as b-actin and 18S RNA cDNA (control) probes. The results indicate differential regulation of c-jun levels which may be due to the activation of both cholinergic and non-cholinergic pathways of CNS, besides changing roles of c-jun (as mediator of degeneration or regeneration) depending on heterodimerization with other ITFs. In the highly susceptible tissues like brainstem and spinal cord c-jun transcript levels increased at 15 minutes and continued to increase gradually till it reached the maximum at 2 hrs. Overall spinal cord showed the maximum levels of c-jun induction (207%) at 2 hrs time point of all the CNS tissues. The enhancement of cholinergic transmisson by the inhibition of cholinestrase may be responsible for the gradual increase mediated by neural and vascular factors. In contrast, less susceptible tissue, cerebellum showed almost immediate induction to high level of (179%) at 15 minutes and the levels stayed more or less the same until it peaked to 185% at 2 hrs. Relatively low abundance of cholinergic neurons and high number of sensitized specialized cell types like Bergman glia and Purkinje cells may be responsible for the immediate higher induction. Non-susceptible tissue cerebrum did not show any changes in the c-jun levels. In midbrain the induction pattern was very similar to that of brainstem. This differential induction pattern of c-jun encomposing the differences in the quantity and time course was directly proportionate to the degree of susceptibility and cellular heterogeneity of different regions of CNS. The significant increase in c-jun levels along with our earlier observation on the increased c-fos levels indicate that AP-1 family of genes may be one of the IEGs involved in the long term changes which eventually lead to OPIDN.
Ref: Early Differential Induction of C-jun in the Central Nervous System of Hens Treated with Diisopropylphosphorofluoridate (DFP) by TV Damodaran et al. Neurochemical Research 25 (12): 1579-1586, December 2000.

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.

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: Behavioral effects of organophosphates (OPs) typically decrease with repeated exposure, despite persistence of OP-induced inhibition of acetylcholinesterase (AChE) and downregulation of muscarinic acetylcholine (ACh) receptors. To characterize this tolerance phenomenon, rats were trained to perform an appetitive operant task which allowed daily quantification of working memory (delayed matching-to-position), reference memory (visual discrimination) and motor function (choice response latencies and inter-response times (IRTs) during delay). Findings indicate that animals showing a definitive sign of tolerance to OP administration (subsensitivity to a cholinergic agonist) were also functionally impaired on both the motoric and mnemonic demands of a working memory task. The nature of this impairment suggests further that it results from compensatory changes in the CNS, e.g., muscarinic receptor downregulation, considered to produce 'tolerance' to OPs in exposed animals.
Ref: 1991 - Behavioral and Neurochemical Changes in Rats Dosed Repeatedly with Diisopropylfluorophosphate; by Bushnell PJ, Padilla SS, Ward T, Pope CN, Olszyk VB. Report No. NTIS/PB91-200238 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.

Endocrine: Pituitary (click on for all fluorinated pesticides)

Sixteen of 100 rats administered DIFP at a dose of 0.5 mg/kg every 72 hours for 730 days developed chromophobe adenomas of the pituitary gland, a tumor with a rare spontaneous incidence.
Ref: TOXNET Hazardous Substances Data Base for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm

Heart (click on for all fluorinated pesticides)

Organophosphate esters were studied in terms of their ability to affect neuropeptides in the rat central nervous system. The in vivo biosynthesis of enkephalin peptides in the basal ganglia and of vasopressin and oxytocin in the hypothalamus were studied and the effect of subcutaneous administration of diisopropylfluorophosphate (DFP) in the biosynthesis of these neuropeptides was assessed. It was found that DFP inhibited the biosynthesis of vasopressin and oxytocin. These results suggest that organophosphates exert their effects not only on cholinergic systems but also on neuropeptide systems important in endocrine and cardiovascular function. Annual rept. 1983-1984, {abstgract truncated]
Ref: 1986 - Effects of Organophosphate Esters on Neuropeptide Systems; by McKelvy JF. Report No. NTIS/AD-A186 594/8 from The National Technical Informatin Service.

Sciatic Nerve (click on for all fluorinated pesticides)

A number of organophosphates produced delayed neurotoxicity in man which may be modeled ... in several animal species ... /such as/ the adult hen Gallus domesticus. The development of delayed neurotoxicity was studied in adult white Leghorn hens after a single, oral dose (1.0 mg/kg) of diisopropylfluorophosphate and after the administration of repeated low-level oral doses (125 mug/kg, 5 days/wk; 1.0-5.0 mg/kg, total dose) of DFP. The relationship of dosage, time, and frequency of administration of subneurotoxic doses of DFP under conditions of a multiple-dose procedure was examined. The comparative activities of hen brain and sciatic nerve neurotoxic esterase (NTE) were studied. The percentage inhibition of NTE paralleled the incr in the degree of severity of the acute pharmacological response. The chronic dosing regimen resulted in a small, yet definite, inhibitory effect of DFP on brain NTE and cholinesterase activities. A maximum level of brain NTE inhibition occurred followed by a decrease and eventual leveling off of the inhibitory effect. The comparative NTE studies demonstrate that substrate hydrolysis by hen sciatic nerve preparations was considerably less when compared with hen brain extracts using equivalent tissue weights. The percentage of NTE of the total paraoxon-resistant activity was lower in sciatic nerve preparations compared with brain preparations. The effects of DFP on the NTE activities from brain and sciatic nerve preparations were definitely inhibitory, and quantitative differences exist between NTE content and activity in peripheral and central nervous systems.
[Olajos EJ et al; Ecotoxicol and Environ Safety 2 (3-4): 383-399 (1978)]
-- ... The results show that DFP ... initially increases rat sciatic nerve conduction and reduces refractoriness. Continued exposure had a diminished effect with nerve excitability eventually returning to control. During recovery, the nerve membrane responsiveness to potassium-induced depolarization significantly changed in a manner which would indicate either decreased Na, K-ATPase activity, or decreased potassium ion transmembrane flux. The data suggest that compensatory changes occcur in rat nerve in response to organophosphorus exposure, and further, that these compensatory changes involve alteration in membrane ion fluxes. [Anderson RJ, Dunham CB; Arch Toxicol 58 (2): 97-101 (1985)]
Ref: TOXNET Hazardous Substances Data Base. DIISOPROPYL FLUOROPHOSPHATE CASRN: 55-91-4

http://www.fluoridealert.org/pesticides/isofluorphate-toxnet.htm


NOTE FROM FAN: While DFP was found not to be a teratogen in rat studies, we include this abstract for whatever its worth - EC.

Teratogenic
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Abstract: Many organophosphorus (OP) insecticides are teratogenic to vertebrates, acting on acetylcholineesterase, kynurenine formamidase, and possibly other serine esterases. We sought to identify their protein targets in the yolk sac membrane (YSM) and to correllate their OP binding with developmental changes. OP compounds with different teratogenic potentials were administered to chicken eggs at day 4 and the eggs were incubated to day 10 when the YSMs were removed and homogenized. Cell free extracts were prepared and incubated with [3H]diisopropyl fluorophosphate. The reaction mixture was then boiled with sodium dodecylsulfate (SDS) and beta-mercaptoethanol and the proteins in it were resolved by SDS PAGE. The gels were fixed, stained and either autofluorographed or sliced and the amount of radioactivity in each slice was determined. There were 3 major DFP-binding proteins in the YSM, #1 94 KD; #2 83 KD; #3 72 KD, accounting for 8, 4 & 88% of the DFP binding, respectively. Pretreatment of the embryos with 1.6 umole/egg of EPN, a mildly teratogenic insecticide, completely suppressed DFP binding to peak 3 but suppressed binding to peaks 1 & 2 only 50%. An equal amount of diazinon, a highly teratogenic insecticide, suppressed binding to peak 3 by 50% and to peaks 1 & 2 by 80%. These and other findings suggest that OP binding to peak 3 does not have teratogenic implication but binding to peaks 1 & 2 does.
Ref: Yolk sac membrane targets of the organophosphorus insecticides; by Suntornwat O, Kitos P. FASEB J 1990;4(7):A2051

 
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