Organophosphates, neurotoxic effects

Intermediate-duration inhalation exposures to aerosols of a few organophosphate ester hydraulic fluids (Durad MP280 and "triaryl phosphate ester") produced lethal neurotoxic effects in chickens and rabbits (MacEwen and Vemot 1983 Siegel 1965). Rats and hamsters appear to be less susceptible to the neurotoxic action of organophosphate esters tests of several organophosphate fluids produced no deaths in rats exposed to substantial aerosol concentrations. 

Organophosphate Ester Hydraulic Fluids. A number of studies have been conducted on organophosphate ester hydraulic fluids because of the well known neurotoxic effects caused by organophosphorus insecticides, organophosphorus nerve gases, and tri-ort/w-cresyl phosphate (TOCP). The following manifestations of acute exposure to organophosphorus compounds have been described ... 

No NOAELs or LOAELs were identified for toxic effects in humans after inhalation exposure to organophosphate ester hydraulic fluids. Reliable NOAELs and LOAELs for acute inhalation exposure are restricted to 4-hour NOAELs for systemic effects in rats exposed to Fyrquel 220 or Durad MP280 and 4-hour LOAELs for mild lethargy in rats exposed to Durad MP280 and Fyrquel 220 (Gaworski et al. 1986). The study identifying these NOAEL and LOAEL values did not measure cholinesterase inhibition, did not allow sufficient follow-up time for the development of delayed neurotoxic effects, and used a... 

The inhibition of two cholinesterase activities in blood can also be used to confirm exposure to certain organophosphate ester compounds. Red blood cell acetylcholinesterase is the same cholinesterase found in the gray matter of the central nervous system and motor endplates of sympathetic ganglia. Synonyms for this enzyme include specific cholinesterase, true cholinesterase, and E-type cholinesterase. Plasma cholinesterase is a distinct enzyme found in intestinal mucosa, liver, plasma, and white matter of the central nervous system. Synonyms for this enzyme include nonspecific cholinesterase, pseudocholinesterase, butyrylcholinesterase, and S-type cholinesterase (Evans 1986). Nonspecific cholinesterase is thought to be a very poor indicator of neurotoxic effects. 

Slotkin, T.A., Levin, E.D. and Seidler, F.J. (2006) Comparative developmental neurotoxicity of organophosphate insecticides effects on brain development are separable from systemic toxicity. Environ. Health Perspect., 114 (5), 746-751. 

The subcommittee considered other possible toxicity end points, notably neurotoxicity, associated with GD exposure. Organophosphate compounds like GD may act directly on nerve cell receptors or, by inhibiting neural AChE, interfere with neuromuscular transmission and produce delayed-onset subjunctional muscle damage. In addition, some organophosphate compounds cause a neurotoxic effect (organophosphate-induced delayed neuropathy, or OPIDN) that is not associated with ChE inhibition. Emerging research in this area might indicate alternative... 

Burchfiel, J.L. and F.H. Duffy. 1982. Organophosphate neurotoxicity chronic effects of sarin on die electroencephalogram of monkey and man. Neurobehav. Toxicol. Teratol. 4 767-778. 

Notes Human SH-SY5Y neuroblastoma cells were Incubated for 1 h with different concentrations of each organophosphate (OP). Cytotoxicity was measured by the neutral red assay. Results represent the IC50 values for inhibition of AChE and NTE activities and for cytotoxicity. DBVP = 0,0-dibutyl 0-(2,2-dlchlorovlnyl) phosphate DOVP = 0,0-dloctyl 0-(2,2-dlchlorovlnyl) phosphate. A high ratio of NTE IC50/AChE IC50 Indicates that the OP is likely to cause acute rather than delayed neurotoxic effects in vivo. 

Numerous neurotoxic chemicals have been identified. These include pesticides (particularly, but not limited to, organophosphates and carbamates), aliphatic and aromatic hydrocarbons, alcohols, ethers, ketones, heavy metals (including lead, mercury, manganese, and others), and mixtures of these. Hundreds of individual chemicals are established or suspected neurotoxins. The EPA Guidelines for Neurotoxicity Risk Assessment and the Scorecard list of neurotoxicantsl5 contain partial lists of neurotoxic chemicals. The actual number of chemicals with neurotoxic potential has been estimated to range between 3% and 28% of all the approximately 80,000 chemicals in use (2400-22,400) Clearly, the number of mixtures possible is infinite, though little attention has been devoted to the neurotoxic effects of mixtures. 

In a study on laboratory animals, it was shown that a mixture of five organophosphate pesticides produced greater than additive neurotoxic effects J6°l The five pesticides were... 

As can be seen, even though all of the pesticides are organophosphates, they vary widely in K. It is hypothesized that the lipophilic species (chlorpyrifos, diazinon, and malathion) facilitate the absorption of the hydrophilic species (dimethoate and acephate) and thereby multiply the neurotoxic effects. 

Maneb (Kqw = 0.62), a dithiocarbonate, and paraquat (Kow = -2.71), an organophosphate, show potentiated neurotoxic effects in animal studies when co-exposure to these occurs during gestation. These pesticides also... 

Jamal, G.A., Long-term neurotoxic effects of organophosphate compounds. Adverse Drug React. Toxicol. Rev., 14, 85, 1995. 

WoodW, GabicaJ, Brown HW, et al Implication of organophosphate pesticide poisoning in the plane crash of a duster pilot. Aerospace Medicine 42 1111-1113,1971 Xintaras C, Burg JR, Johnson BL, et al Neurotoxic effects of exposed chemical workers. Ann N Y Acad Sci 329 30-38,1979... 

In human populations, serum PON1 exhibits a substrate-dependent polymorphism to the neurotoxic effects of organophosphates in those susceptible individuals that are deficient in PON1 (i.e., PM phenotype) (55). The PON1 catalyzes the hydrolysis of paraoxon, chlorpyrifos (Dursban), and other orgahophosphates. 

The delayed neurotoxic effect, also called OrganoPhosphate Induced Delayed Neurotoxicity (Neuropathy) (OPIDN), is characterized by sensoric and motoric disturbances of the peripheral nervous system (degeneration of... 

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