Organophosphates neuropathy

McConnell, R., Delgado-Tellez, E., Cuadra, R., Torres, E., Keifer, M., Almendarez, J., Miranda, J., El-Fawal, H.A., Wolff, M., Simpson, D., Lundberg, I. (1999). Organophosphate neuropathy due to methamidophos biochemical and neurophysiological markers. Arch. Toxicol. 73 296-300. 

McConnell, R., Delgado-T411ez, E, Cuadra, R., et al., 1999. Organophosphate neuropathy due to methamidophos biochemical and neurophysiological markers. Arch. Toxicol. 73, 296-300. 

Johnson, M.K. (1992). Molecular events in delayed neuropathy Experimental aspects of neuropathy target esterase. In B. Ballantyne and T.C. Marrs, (1992). Clinical and Experimental Toxicology of Organophosphates and Carbamates 90-113. 

Acute oral exposure to several organophosphate ester hydraulic fluids produced deaths in rabbits, chickens, and cows. The deaths were associated with severe cholinergic symptoms or symptoms of organophosphorus induced delayed neuropathy (OPIDN). (See Section 22.2 A for further details on the neurological effects.)... 

Intermediate-duration oral exposure to Durad 110 produced deaths in chickens associated with the delayed development of neuropathy at dosage levels of 4,000 mg/kg/day in a 28-day study and 90 mg/kg/day in a 90-day study (FMC 1986). At 100 mg/kg/day over a 13-week period, 2 of 12 male and 1 of 12 female rats died with exposure to tri- -butyl phosphate (Healy et al. 1995). Dietary administration of Pydraul 90E for 90 days providing daily doses of 50 mg/kg/day produced no chemical-related deaths in rats (Monsanto 1979). An organophosphate ester hydraulic fluid designated MIL-H-83306 also caused death in 4 of 4 rats exposed by gavage to 1,000 mg/kg over a 26-day period (Mattie et al. 1993). 

Many of the studies on the neurological effects of oral exposure to organophosphate ester hydraulic fluids in animals have employed chickens as models instead of the more commonly used rodent models. For reasons that are not well understood, organophosphate-induced delayed neuropathy can be induced in chickens and cats, but not in mice or rats (Abou-Donia and Lapadula 1990). 

Acute exposure to certain organophosphate esters produces a slowly developing neuropathy in humans, OPIDN, that is functionally characterized by initial weakness and subsequent ataxia and paralysis in the lower limbs (8-14 days or longer, following exposure) (Ecobichon 1991 Johnson 1975 Murphy 1986). 

Reliable NOAELs and LOAELs for intermediate oral exposure are restricted to a 90-day NOAEL of 50 mg/kg/day for systemic toxicity in rats (a species that is not sensitive to the neuropathic effects of organophosphate esters) exposed to Pydraul 90E for 90 days and NOAELs and LOAELs for delayed neuropathy in chickens exposed to Durad 110. In chickens exposed to Durad 110 for 28 days, a NOAEL of444 mg/kg/day and LOAEL of 1,333 mg/kg/day were identified (FMC 1986) when the duration was increased to 90 days, the NOAEL was 20 mg/kg/day and the LOAEL was 90 mg/kg/day (FMC 1986). These data are inadequate for derivation of an intermediate oral MRL for organophosphate ester hydraulic fluids. As discussed under the acute-duration oral MRL section, there is uncertainty regarding extrapolation of chicken doses to human doses. 

The lack of corroborative case reports, epidemiological data, or animal data (see next paragraph) makes the association between dermal exposure to mineral oil hydraulic fluids and peripheral neuropathy uncertain. Nonetheless, the presence of organophosphate esters, some of which are demonstrated neurotoxic agents, in most mineral oil hydraulic fluids (they often are added as anti-wear agents) suggests that they may play a causative role if such an association exists. 

A third enzyme may have limited potential as a measure of exposure. Neurotoxic esterase, also known as neuropathy target esterase (NTE), is inhibited by certain organophosphate esters. When brain NTE is inhibited above 70% for acute or possibly as low as 50% for repeated exposures, there is a consensus that delayed neuropathy is likely. NTE also is found in lymphocytes and platelets (Lotti et al. 1984). The... 

Organophosphate Ester Hydraulic Fluid. The most widely examined target of organophosphate ester hydraulic fluids is the nervous system. Two types of neurological effects have been observed following exposure to certain organophosphate ester hydraulic fluids cholinergic symptoms associated with acetylcholinesterase inhibition and delayed neuropathy (OPIDN). 

Organophosphate Ester Hydraulic Fluids. The biomarkers of effects after exposure to organophosphate ester hydraulic fluids are well established in cases of delayed neuropathy (clinical signs of peripheral neuropathy). Further study would be helpful to determine whether certain effects (such as diarrhea after oral exposure) are due to direct action of the toxic agent on the target organ or to inhibition of acetylcholinesterase at the acetylcholine nerve receptor site on the organ. 

JohnsonMK. 1990. Organophosphates and delayed neuropathy Is NTE alive and well Toxicol Appl Pharmacol 102 355-399. 

Delayed neuropathy characterized by distal axonal degeneration is a systemic health effect caused by some organophosphate pesticides and is not due to anticholinesterase inhibition. EPN is neurotoxic to atropine-protected hens, producing polyneuropathy progressing to paralysis and some deaths after ingestion of 5-10mgA g/day. There are no reports, however, of neurotoxicity from EPN in humans. ... 

The fact that the birds developed delayed neurotoxicity under laboratory conditions indicates that the lack of it in the field study was not due to an inability of this mutant to develop the neuropathy. "Early warning" tests for delayed neurotoxicity are lacking. The laboratory data suggest that serum enzymes like CK may be useful markers for organophosphate exposure. However the conditions of this test must be controlled. The increase of CK in all birds taken to Visalia, regardless of their exposure to DEP in the field, suggests that the rigor of the trip may have stressed the birds and increased CK levels. Plasma CK activity in humans is known to increase under stress, such as after heavy exercise (12). 

Chronic exposure to certain organophosphate compounds, including some organophosphate cholinesterase inhibitors, causes neuropathy associated with demyelination of axons. 

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