Sciatic Nerve - Adverse Effects
Fluorinated and Fluoride Pesticides

The sciatic nerve is the largest nerve in the human body, about the diameter of a finger.

Sciatic nerve fibers begin at the 4th and 5th lumbar vertebra (L4, L5) and the first few segments of the sacrum. The nerve passes through the sciatic foramen just below the Piriformis muscle (rotates the thigh laterally), to the back of the extension of the hip and to the lower part of the Gluteus Maximus (muscle in the buttock, thigh extension). The sciatic nerve then runs vertically downward into the back of the thigh, behind the knee branching into the hamstring muscles (calf) and further downward to the feet.

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.
When time allows more information will be added.

Cyfluthrin - Insecticide - CAS No. 68359-37-5

-- Cyfluthrin. Neurotoxicity oral studies--hen. In the single-dose study, at 5,000 mg/kg, five of the ten hens died. Moderate fiber alterations (axon fragmentation, occasional swelling and eosinophilia of the axon fragments and vacuolation of the myelin sheaths) in the sciatic nerve were observed in two hens. Six hens at 2,500 mg/kg showed signs of excitation during the first 3 days following treatment. In the two-dose study, hens showed initial signs of intoxication during the first 3 days but were normal until the second dose was administered when four hens died. Symptoms following the second treatment subsided; however, a second set of symptoms developed in 4/30 hens. These symptoms resembled delayed type neurotoxicity. Nerve fiber degeneration was present in the majority of the hens. The myelin sheath was distended and the myelin sheath was described as being optically void or granularly disintegrated. The axons were described as swollen or fragmented and in some areas activated or proliferated Schwann's cells were noted. The nerves also contained macrophages in which cytoplasm contained granular material. In the 5-day study, 4/10 hens died. All hens showed initial toxic responses which eventually disappeared. Behavioral disorders accompanied by drowsiness and a cramped gait were observed in 3 of the 6 survivors. Mottled kidneys and brittle livers were noted at necropsy. Treatment-related fiber degeneration (distension or granular disintigration of the medullary sheath, swollen or fragmented axis cylinders and proliferated Schwann's cell in the sciatic nerve were reported. One hen had similar lesions in the spinal marrow.
-- Cyfluthrin. Neurotoxicity dermal studies--hen. In the first study there were 2 deaths on the 3rd and 10th day. All other hens had symptoms (apathy and disturbed behavior) but recovered. Local irritation and weight loss were also noted. Two hens had minimal segment-like nerve fiber degeneration (sciatic nerve), but this type is often found in hens. In the second study, the hens were apathetic. These symptoms disappeared after the first week in all hens except 2, in which they persisted until the 38th and 51st day after the start of the treatment, respectively. Local irritation and body weight loss were also observed. No other neurologic effects were observed, including microscopic.
Ref: Federal Register. September 27, 2002. Cyfluthrin; Pesticide Tolerance. Final

Diisopropyl fluorophosphate (DFP) - Former Insecticide - CAS No. 55-91-4

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

Flucythrinate - Acaricide; Insecticide - CAS No. 70124-77-5

Long-term studies. Mouse. Groups of 50 male and 50 female CD-1 mice received technical flucythrinate (80% pure) in the diet at 0, 30, 60, or 120 ppm daily for 18 months... Mild sciatic nerve degeneration occurred in all groups, but at slightly increased incidence in treated groups, especially high-dose males. There was no apparent dose-response relationship. The incidence of mild axonal degeneration was similar in all groups. The no-effect level for this study was therefore set at 30 ppm (Lang, 1981b).
Ref: Flucythrinate. 1985 World Health Organization Review.

Abstract: The neurotoxic action of six pyrethroid insecticides, four type II, (flucythrinate, deltamethrin, fenvalerate, fluvalinate) and two type I (cis- and trans-permethrin) was compared on the isolated sciatic nerve of frog. The nerve was exposed to pyrethroids for 30 min and action potentials were recorded for more than 45 hr after exposure. From the plots of the amplitude of the compound action potential vs time, it was possible to estimate, for each compound, the minimum effective concentration, the concentration which is required to reduce the amplitude of the compound action potential to 50% of its control value (mEC50). Flucythrinate was the most toxic compound, while toxicity decreased in the value: deltamethrin > fenvalerate > fluvalinate >> cis-permethrin > trans-permethrin. Low neurotoxicity of cis-permethrin and trans-permethrin (type I pyrethroids) was expected. The neurotoxicity of type I pyrethroids is mainly due to an action at the synapse, which are not present in the frog sciatic nerve preparation. The relative potencies of the four type II compounds agree with their acute toxicity estimated using the LD50.
Ref: Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1997 Sep;118(1):97-103. Neurotoxic action of six pyrethroid insecticides on the isolated sciatic nerve of a frog (Rana ridibunda).
Theophilidis G, Benaki M, Papadopoulou-Mourkidou E.

Flufenacet - Herbicide - CAS No. 142459-58-3

NOEL = 40 ppm [1.29 mg/kg/day in males and 1.14 mg/kg/day in females] LOEL = 800 ppm [27.75 mg/kg/day in males and 26.82 mg/kg/day in females] based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T3, T4 and ALT values in both sexes, and increased incidence of microscopic lesions in the brain [axonal degeneration], eye [vacuolization of the ciliary body epithelium], kidney [hyperplasia of the epithelial cells], spinal cord [axonal degeneration], sciatic nerve [axonal degeneration] and liver [hepatocytomegaly].
Ref: EPA Pesticide Fact Sheet, April 1998.

-- Chronic toxicity dogs: NOAEL = 1.29(m), 1.14(f) mg/kg/day LOAEL = 27.75 (m), 26.82(f) mg/kg/day based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T3, T4, and ALT values in both sexes, and increased incidences of microscopic lesions in the brain, eye, kidney, spinal cord, sciatic nerve, and liver.
Ref: Federal Register. Flufenacet (Bayer). June 25, 2003. Pesticide Tolerances. Final Rule.

Isoxaflutole - Herbicide - CAS No. 141112-29-0

-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

Mefluidide and its potassium and diethanolamine salts - Herbicide, Plant growth regulator - CAS Nos. 53780-34-0, 53780-36-2, 83601-83-6)

21-Day Dermal toxicity - rabbit (4 rabbits/sex/dose). Acceptable/Non-guideline (NOAEL was not observed). Systemic LOAEL = 240 mg/kg/day, based on clinical chemistry (increased alkaline phosphatase and alanine aminotransferase) and organ weights (decreased spleen weight in females and increased liver weights in males). Edema and swelling with myelin loss in sciatic nerve was seen in 720 and 2400 mg/kg/day dose group. Dehydration observed at 2400 mg/kg/day dose. Dermal and systemic NOAELs were not established.
Ref: USEPA. Mefluidide - Toxicology section for the Reregistration Eligibility Decision Document (RED) (January 31, 2007)

Mipafox - Acaricide, Insecticide - CAS No. 371-86-8

Abstract: Abstract: Bioclinical effects induced by local application of neuropathic organophosphates to the sciatic nerve were studied in adult red-hens. Diisopropyl-phosphorofluoridate (55914) (DFP), mipafox (371868), cresylsaligenyl-phosphate (CSP), or phenylsaligenyl-phosphate (4081236) (PSP) were applied locally to 1 or 1.5 centimeter segments of the common trunk of surgically exposed sciatic nerves in one leg of each hen. Doses ranged up to 1790, 17500, 108, or 526 micrograms (microg), respectively. The contralateral leg served as the control. Fifteen minutes later, the treated segments, the adjacent proximal and distal portions, and the most distal segments of the peroneal branch were dissected out and assayed for neuropathy-target-esterase (NTE) activity. DFP and mipafox caused greater than 90% inhibition of NTE activity in the treated sciatic nerve segments. A 40% inhibition of NTE activity was induced by DFP and mipafox in the adjacent proximal and distal segments. Less than 20% NTE inhibition was induced in the terminal segments. PSP and CSP did not significantly affect sciatic NTE activity. Since only DFP and mipafox significantly inhibited NTE activity these were used to investigate clinical symptomatology and histopathological changes induced in the sciatic nerve. Hens with surgically exposed sciatic nerves were treated locally in one or both legs with 27 to 110microg DFP or 18 to 182microg mipafox. Some hens were pretreated with 30mg/kg phenylmethanesulfonyl-fluoride (PMSF) subcutaneously. Hens were observed for clinical signs of toxicity for 15 to 25 days then killed on day 25. Peroneal nerves were removed and examined for histopathological changes. All hens treated in both legs with DFP or mipafox lost the avian retraction reflex. Only birds treated with the maximum DFP or mipafox doses in both legs developed gait abnormalities. Following application to one leg only, hens treated with 110microg DFP showed loss of the avian retraction reflex. No clinical signs of toxicity were seen in birds pretreated with PMSF. DFP or mipafox caused axon swelling, accumulation of endoplasmic reticulum, and intraaxonal and intramyelinal vacuolation. The authors conclude that the peripheral neuropathological effects of locally applied DFP or mipafox appear to be mediated by their effects on NTE.
Ref: Toxicology and Applied Pharmacology, Vol. 117, No. 2, pages 218-225, 31 references, 1992.
Local Application of Neuropathic Organophosphorus Compounds to Hen Sciatic Nerve: Inhibition of Neuropathy Target Esterase and Peripheral Neurological Impairments. by Carrera V, Barril J, Mauricio M, Pellin M, Vilanova E. -from

Abstract. Neuropathy target esterase (NTE) is a protein suggested to be involved in the initiation mechanism of organophosphorus-induced delayed neuropathy (OPIDP). We previously described two different forms of NTE activity in hen sciatic nerve: a particulate form (P-NTE) representing 40-50% of total NTE activity in sciatic nerve, and a remaining soluble component (S-NTE). In brain tissue on the other hand, more than 90% of NTE activity was recovered as P-NTE. In this work we studied the in vivo inhibition of both NTE forms with different doses of mipafox and the results were compared with sensitivity to mipafox in vitro. The highest dose with no observable neuropathic effects (1.5 mg/kg mipafox p.o.) inhibited 33% P-NTE and 55% S-NTE activity. The difference between P-NTE and S-NTE activity was statistically significant (P < 0.001, n = 9). Higher doses (3 mg/kg) induced neuropathy and inhibited NTE more than 75%, but differences between P- and S-NTE were not significant (P > 0.5). The greater inhibition of S-NTE than P-NTE in vivo contrasts with the observation that S-NTE is less sensitive in vitro.
Ref: Toxicol Lett 1994 Mar;71(1):47-51 In vivo inhibition by mipafox of soluble and particulate forms of organophosphorus neuropathy target esterase (NTE) in hen sciatic nerve. Carrera V, Diaz-Alejo N, Sogorb MA, Vicedo JL, Vilanova E.

Abstract: Considerable evidence exists suggesting that the so-called neuropathy target esterase (NTE) is involved in the mechanisms responsible for organophosphorus-induced delayed polyneuropathy (OPIDP). Earlier studies in the adult hen, the habitually employed experimental model in OPIDP, have shown that most NTE activity in the brain is centered in particulate fractions, whereas approximately 50% of this activity in the sciatic nerve is encountered in soluble form, with the rest being particulate NTE. In the present work, we have studied the particulate and soluble fractional distribution of paraoxon-resistant phenylvalerate esterase activity (B activity), paraoxon- and mipafox-resistant phenylvalerate esterase activity (C activity), and NTE activity (B-C) according to ultracentrifugation criteria (100,000 g for 1 h). To this effect, two sensitive (adult hen and cat) and two scarcely sensitive (rat and chick) models were used. In all four experimental models, the distribution pattern was qualitatively similar: B activity and total NTE were much greater in brain (900-2,300 nmol/min/g of tissue) than in sciatic nerve (50-100 nmol/min/g of tissue). The proportion of soluble NTE in brain was very low (< 2%), whereas its presence in sciatic nerve was substantial (30-50%). The NTE/B ratio in brain was high for the particulate fraction (> 60%) and low in the soluble fraction (7-30%); in sciatic nerve the ratio was about 50% in both fractions.(ABSTRACT TRUNCATED AT 250 WORDS)
Ref: J Neurochem 1993 Dec;61(6):2164-8. Soluble and particulate organophosphorus neuropathy target esterase in brain and sciatic nerve of the hen, cat, rat, and chick. Tormo N, Gimeno JR, Sogorb MA, Diaz-Alejo N, Vilanova E.

Tembotrione - Herbicide - CAS No. 335104-84-2

• In a combined chronic/carcinogenicity study (MRID 46695708) Wistar male rats/dose in the diet at dose levels of 0, 1, 20, 200 or 800 ppm (equivalent to 0, 0.04, 0.79, 8.3 or 31.7 mg/kg bw/day) in the diet for 104 weeks. In the sciatic nerve, minimal to slight nerve fiber degeneration was significantly increased (p≤0.05) in the 20, 200 and 800 ppm groups (73%, 73% and 75%, respectively), when compared to controls (53%). This change was described as multiple fiber degeneration, loss of stain intensity, decreased density and definition of the nerve fiber and/or demyelination. In addition, sometimes associated with sciatic nerve atrophy was a minimal to moderate chronic inflammatory response and/or minimal to moderate mineralization of the vessels within the nerve. In general, these changes were noted in animals that survived to the terminal sacrifice, indicating a late onset of the exacerbation of this lesion (page 71-72).
• Thyroid gland toxicity was observed in the 21/28-day dermal toxicity study in the rat and chronic oral toxicity study in the dog. Dermal exposure (21/28-day study) resulted in colloid alteration and hypertrophic follicular epithelium in the thyroid gland in the rat. Also observed were degenerative changes in the pancreas, increased proteinacious material in the Ratche pouch in the pituitary gland and basophilic tubules in the kidneys. Pigmentation of the thyroid gland along with
hematological changes and microscopic changes in the sciatic nerve were observed in the dog.
Dose and Endpoint for Establishing RfD:
(page 22)
------ Study Selected: Chronic Toxicity/Carcinogenicity (Feeding)/Rat MRID No.: 46695708
------ The NOAEL of 0.04 mg/kg/day was based on neovascularization and edema of the cornea and snow flake-like corneal opacity, unilateral or bilateral keratitis of the eye, decreased mean body weight and mean body-weight gain, increased total cholesterol, higher ketone levels and lower pH values, higher protein levels, increased kidney weight, kidney to body weight and kidney to brain weight ratios, chronic nephropathy and atrophy of the sciatic nerve observed in the male at 0.79 mg/kg/day (LOAEL).
------ UF(s): An UF of 100 was applied to account for interspecies extrapolation (10X)
------ Comments about Study/Endpoint/UF: This study provided the lowest NOAEL in the database (most sensitive endpoint) and will also provide the most protective limits for human effects.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.

Triflusulfuron-methyl - Herbicide - CAS No. 126535-15-7

Groups of 62 rats/sex were fed diets containing 0, 10, 100, 750 or 1500 ppm DPX-66037- 24 (95.6% purity) (equal to 0.406, 4.06, 30.6 or 64.5 mg/kg bw/d for males and 0.546, 5.47, 41.5 and 87.7 mg/kg bw/d for females) for 22 months. The NOEL for this study was 100 ppm (4.06 mg/kg bw/d). At 750 ppm, body weights and body-weight gains were lower than controls in both sexes and males had lower erythrocyte counts than controls at most time points and an increased incidence of Leydig cell hyperplasia compared to controls. The incidence of myelin/axonal degeneration of the sciatic nerve was increased compared to controls in the 1500-ppm group of females (25/48 versus [vs] 42/49)...
Ref: Dec 3, 1999 - Report on Triflusulfuron methyl. Regulatory Note REG99-03. Pest Management Regulatory Agency, Health Canada, Ottawa.

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