Erythrocyte cholinesterase inhibition

In one study with common marmosets, the animals were dosed with diazinon (10, 90, or 130 mg/kg i.m.) and measnrements of erythrocyte cholinesterase inhibition... 

In another part of this study, soman, 10-40 mg in 0.5-mg droplets, was placed on the forearms of 32 subjects. The mean erythrocyte cholinesterase inhibition increased from 13% to 27% as the... 

In another study, 105 subjects inhaled Cts ranging from 2.4 to 19.6 mg min m-3 (retained doses of 0.1-3.1 pg kg-1). There was a mean erythrocyte cholinesterase inhibition of 30% at a retained dose of 2.2 pg kg-1 and a rough correlation of enzyme inhibition with retained dose. However, although measures of pulmonary function varied widely both above and below baseline, none changed consistently with dose. Measures used included resting tidal volume, exercise tidal volume, maximum breathing capacity and vital capacity (MOD18). 

Also with a single-breath technique, 25 subjects inhaled 0.5-5.0 pg kg-1 of sarin and had fewer symptoms than usually seen after these amounts (MOD20). There was a correlation between the amount retained and erythrocyte cholinesterase inhibition, with a maximal inhibition of 27% at 5.0 pg kg-1. The half-time for inhibition of the enzyme was about 90 s, and inhibition was complete in about 10 min. 

PbB has long been used as the standard index of dose in estimating dose-effect and dose-response relationships. Some would argue that it is perhaps less valid than certain other measurements which reflect in quantitative fashion the bioavailable fraction of PbB, much as erythrocyte cholinesterase inhibition reflects the toxic impact of exposure to organophosphate insecticides. Indeed, it has been reported that inhibition of erythrocyte membrane Na, K-ATPase activity is better correlated with lead toxicity than erythrocyte lead concentration (Raghavan ei al, 1981). This was attributed to the fact that the subjects had variable concentrations of a low molecular weight lead binding protein which influenced the bioavailable fraction of PbB. It is possible that EP reflects bioavailable lead in a similar fashion. 

Neurologic signs did not occur over a 30-day period in male prisoner volunteers in California who ingested daily doses of methyl parathion ranging from 1.0 to 19 mg. There were no uniform changes in plasma or erythrocyte cholinesterase levels at any of these doses (Rider et al. 1969). By increasing concentrations of methyl parathion administered to the same experimental population and using the same protocol, a dose that inhibited cholinesterase values was established. These additional studies were published nearly 20 years ago in abstract form only therefore, they are not discussed in this section. 

Mice that were exposed dermally to residues of methyl parathion in emulsifiable concentrate on foliage, and were muzzled to prevent oral intake, developed inhibition of plasma cholinesterase and erythrocyte cholinesterase after two 10-hour exposures (Skinner and Kilgore 1982b). For the organophosphate pesticides tested in this study, cholinergic signs generally were seen in mice with cholinesterase inhibition >50% results for this end point were not broken down by pesticide. 

Diagnosis of organophosphate poisoning (including methyl parathion) can be confirmed by evaluation of serum (plasma) cholinesterase and erythrocyte cholinesterase. However, cholinesterase inhibition is not specific for organophosphates. For example, carbamate insecticides also result in cholinesterase inhibition, which is usually transitory. Erythrocyte cholinesterase measurement is a specific test for... 

EPA has derived an RfD of. 00025 mg/kg/day, based on a NOAEL of 0.025 for reduced hematocrit, erythrocyte counts, and hemoglobin (cholinesterase inhibition was also listed as a critical effect but the reason for this was not explained). This NOAEL appears to be from the same study as for the ATSDR chronic-duration oral MRL, although the study is referenced differently (IRIS 2001). 

All doses inhibited erythrocyte cholinesterase levels by 45-95%. All groups tolerated 16.6 mg/kg BW. Severe toxicosis in the two high-dose groups (9 of 20) in bulls but not in heifers and steers 7 of the 9 bulls died or had to be euthanized necropsy showed severe pulmonary edema... 

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

The MRL is based on a NOAEL of 0.5 mg/m3 for decreased acetylcholinesterase activity in rats exposed to disulfoton 4 hours/day for 5 days in a study by Thyssen (1978). The NOAEL was adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). Inhibition of erythrocyte cholinesterase activity and unspecified behavioral disorders were observed at 1.8 mg/m, and unspecified signs of cholinergic toxicity were observed at 9.8 mg/m. Similar effects were observed in rats or mice exposed to higher concentrations for shorter duMtions (Doull 1957 Thyssen 1978). The NOAEL value of 0.5 mg/m is supported by another study, in which no significant decrease in the activity of brain, serum, or submaxillary gland cholinesterase was found in rats exposed to 0.14-0.7 mg/m for 1 hour/day for 5-10 days (DuBois and Kinoshita 1971). Mild depression of erythrocyte cholinesterase activity was reported in workers exposed by the inhalation and dermal routes (Wolfe et al. 1978). 

Because cholinesterase inhibition is a very sensitive biomarker for other chemicals, it is not always conclusive evidence of disulfoton exposure. However, depression of cholinesterase activity can alert a physician to the possibility of more serious neurological effects. Erythrocyte acetylcholinesterase activity more accurately reflects the degree of synaptic cholinesterase inhibition in nervous tissue, while serum cholinesterase activity may be associated with other sites (Goldfrank et al. 1990). In addition, a recent study showed that after rats received oral doses of disulfoton for 14 days, acetylcholinesterase levels in circulating lymphocytes correlated better with brain acetylcholinesterase activity than did erythrocyte cell cholinesterase activities during exposure (Fitzgerald and Costa 1993). However, recovery of the activity in lymphocytes was faster than the recovery of activity in the brain, which correlated better with the activity in erythrocytes. Animal studies have also demonstrated that brain acetylcholinesterase depression is a sensitive indicator of neurological effects (Carpy et al. 1975 Costa et al. 1984 Schwab and Murphy 1981 Schwab et al. 1981, 1983) however, the measurement of brain acetylcholinesterase in humans is too invasive to be practical. 

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