Organophosphates, delayed neurotoxicity

See also Cholinesterase Inhibition Neurotoxicity Organophosphate Poisoning, Delayed Neurotoxicity Organophosphate Poisoning, Intermediate Syndrome Organophosphates. 

See also A-Esterases Cholinesterase Inhibition Organophosphate Poisoning, Delayed Neurotoxicity Organophosphates. 

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 available inhalation data for Durad MP280, Fyrquel 220, Cellulube 220, Skydrol 500B-4, and cyclotriphosphazene (reviewed in the next paragraph) are inadequate to derive intermediate-duration MRLs for these individual fluids, principally because the studies were conducted in species (rats or rabbits) that are generally considered to be insensitive to the delayed neurotoxicity of acute exposure to organophosphate esters. Cats, dogs, or nonhuman primates more accurately model the human expression of OPIDN than rats and rabbits, and studies in these species would provide a better basis for MRL derivation. 

One of the main human health concerns about organophosphate esters is the potential for neurotoxicity reactions, in particular a condition known as organophosphate-induced delayed neurotoxicity (OPIDN). Tri-ort/20-cresyl phosphate (TOCP) has been identified as one of the more potent OPIDN neurotoxins in humans, and was formerly a constituent in some organophosphate ester hydraulic fluid products (Marino 1992 Marino and Placek 1994). Production processes now routinely remove virtually all the TOCP. For instance, tricresyl phosphate (TCP) products now typically are manufactured to contain over 98% meta and para isomers and virtually no TOCP (Marino and Placek 1994). Products containing these compounds associated with OPIDN have now entirely disappeared from commercial use, and the vast majority of the industrial organophosphate esters are based on triaryl phosphates with no halogenated components (Marino 1992). At waste disposal sites, however, site contaminants from older product formulations containing the ortho form may be encountered. 

Baron RL. 1981. Delayed neurotoxicity and other consequences of organophosphate esters. Ann Rev Entomol 26 29-48. 

No studies were located regarding organophosphate-induced delayed neurotoxicity (OPIDN) in humans or in animals after inhalation exposure to diazinon. 

Diazinon MG-8 (purity 87%) has been tested for organophosphate-induced delayed neurotoxicity in chickens (Jenkins 1988). Ten hens (Red Heavy breed) were used as a control group and received... 

The ideal animal for studying organophosphates would be one without hair, fur or feathers capable of contracting delayed neurotoxicity. Such a creature is the scaleless chicken, a mutant with a defect in feather and scale development (2,3), developed and maintained by Dr. Ursula K. Abbott of the Department of Avian Sciences, University of California, Davis. (Figure 3) Its absence of feathers makes it an excellent animal for studies of dermally applied toxicants. Renden and Abbott found that the scaleless mutant was more sensitive to applications of trithion in mineral oil than were either normal chickens or another mutant "ichthyiotic", in a study of mineral oil-induced dermatitis ( ). 

Studies on the scaleless chicken are underway examining its suitability as a model for assessing toxicity of organophosphates. The first compound selected for field trials was the defoliant DEF (S,S,S-tributylphosphorotrithioate) used during the harvesting of cotton in California and Arizona in the fall (October-November) when air movements are frequently restricted by inversions. DEF has been the subject of sufficient complaints to place it on the pre-RPAR list, although there are no reports of acute or delayed neurotoxicity in humans when it and related chemicals are used according to recommendations. It both inhibits cholinesterases and causes delayed neurotoxicity in hens (3,6). 

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). 

Abou-Donia, M.B. (1992). Tri-phenyl phosphite a type II organophosphoras compound-induced delayed neurotoxic agent. In Organophosphates Chemistry, Fate, and Effects (J.E. Chambers, P.E. Levi, eds), pp. 327-51. Academic Press, San Diego. 

Johnson, M.K. (1977). Improved assay of neurotoxic esterase for screening organophosphates for delayed neurotoxicity potential. Toxicol. 37 113-15. 

Johnson, M.K. (1990). Organophosphates and delayed neurotoxicity - is NTE alive and well Toxicol. Appl. Pharmacol. 102 385-99. 

Johnson, M.K., Lotti, M. (1980). Delayed neurotoxicity caused by chronic feeding of organophosphates requires a high point of inhihition of neurotoxic esterase. Toxicol. Lett. 5 99-102. 

Richardson, R.J. (2005). Organophosphate poisoning, delayed neurotoxicity. In Encyclopedia of Toxicology, 2nd edition (4 vols) (P. Wexler, ed.), Vol. 3, pp. 302-6. Elsevier, Oxford. 

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. 

Cholinesterase inhibition can sometimes persist for weeks thus, repeated exposures to small amounts of this material may result in accumulation of acetylcholinesterase inhibition with possible sudden-onset acute toxicity. Chlorpyrifos may be capable of causing organophosphate-induced delayed neurotoxicity in humans a massive overdose resulted in signs characteristic of delayed neurotoxicity. Animal studies generally indicate, however, that doses several times higher than the LD50 would be required to initiate delayed neurotoxicity. 

---