Inhibition cholinesterase, exposure

Organophosphates, such as methyl parathion, are known to inhibit cholinesterase activity. A method has been developed to measure the extent of this inhibition and relate it to organophosphate exposure (EPA 1980d Nabb and Whitfield 1967). In this EPA-recommended method, blood is separated into plasma and red blood cell fractions. The fractions are treated with saline solution, brought to pH 8 with sodium hydroxide, and dosed with acetylcholine perchlorate. The ensuing acetic acid releasing enzyme reaction... 

May cause severe and painful irritation of the eyes, nose, throat, and lungs. Severe exposure can cause accumulation of fluid in the lungs (pulmonary edema). Inhalation toxicity similar to HC1 and HF. May cause second or third degree burns upon short contact with skin surfaces. Oral ingestion may result in tissue destruction of the gastrointestinal tract. High overexposure may inhibit cholinesterase. 

Pharmacologically, carbofuran inhibits cholinesterase, resulting in stimulation of the central, parasympathetic, and somatic motor systems. Sensitive biochemical tests have been developed to measure cholinesterase inhibition in avian and mammalian brain and plasma samples and are useful in the forensic assessment of carbamate exposure in human and wildlife pesticide incidents (Bal-lantyne and Marrs Hunt and Hooper 1993). Acute toxic clinical effects resulting from carbofuran exposure in animals and humans appear to be completely reversible and have been successfully treated with atropine sulfate. However, treatment should occur as soon as possible after exposure because acute carbofuran toxicosis can be fatal younger age groups of various species are more susceptible than adults (Finlayson et al. 1979). Carbofuran labels indicate that application is forbidden to streams, lakes, or ponds. In addition, manufacturers have stated that carbofuran is poisonous if swallowed, inhaled, or absorbed through the skin. Users are cautioned not to breathe carbofuran dust, fumes, or spray mist and treated areas should be avoided for at least 2 days (Anonymous 1971). Three points are emphasized at this juncture. First, some carbofuran degradation... 

Disulfoton and its breakdown products can be measured in the blood, urine, feces, liver, kidney, or body fat of exposed people. In cases of occupational or accidental exposure to disulfoton, the breakdown products are often measured in the urine. The breakdown products are relatively specific for disulfoton and a few other similar organophosphate pesticides and can be detected in urine for up to one week after people were last exposed. Because disulfoton inhibits cholinesterase in blood and in blood cells, inhibition of this enzyme activity may also suggest exposure to disulfoton. Cholinesterase activity in blood and in blood cells may remain inhibited for as long as 1-2 weeks after the last exposure. Because other organophosphate pesticides also inhibit cholinesterase activity in blood and blood cells, this test is not specific for disulfoton. The measurement of cholinesterase in blood and blood cells and the amount of disulfoton breakdown products in the urine cannot always predict how much disulfoton you were exposed to. Your doctor can send samples of your blood or urine to special laboratories that perform these tests. Chapters 2 and 6 provide more information about medical tests. 

SPMD sample extracts, e.g., certain organochlorine pesticides (OCPs), are known to inhibit cholinesterase activity. Therefore, these results were not unexpected. However, it was surprising that a similar response was not observed with brain cholinesterase activity. It is possible that brain cells can more readily metabolize the chemicals, that the chemicals did not pass the brain blood barrier or that the effects occurred earlier in the exposure period, effectively allowing the activity to recover. Considering the numerous neurotoxic chemicals potentially entering aquatic ecosystems or present as airborne vapor phase chemicals, the neurotoxic mode of action related to exposure to contaminants is of increasing interest. Evidence presented in this work demonstrate that SPMDs concentrate members of this class of toxicants. 

The general chemical structure of N-methyl carbamate is shown in Fig. 4.4. Common N-methyl carbamates in use today include aldicarb, carbofuran, methiocarb, oxamyl, and carbaryl. N-methyl carbamates share with organophosphates the capacity to inhibit cholinesterase enzymes and, therefore, share similar symptomology during acute and chronic exposure. 

With irreversible interactions, however, a single interaction will theoretically be sufficient. Furthermore, continuous or repeated exposure allows a cumulative effect dependent on the turnover of the toxin-receptor complex. An example of this is afforded by the organophosphorus compounds, which inhibit cholinesterase enzymes (see Aldridge (7) and chap. 7). 

Long-term exposure to azinphos-methyl, above the average 8-hour standard set by the Occupational Safety and Health Administration (OSHA), can impair concentration and memory, and cause headache, irritability, nausea, vomiting, muscle cramps, and dizziness. Cholinesterase inhibition from exposure to azinphos-methyl may persist for 2 to 6 weeks. Repeated exposure to small amounts may... 

TMS derivative by GC/FPD in urine collected over 7 days from casualties of the Tokyo attack (43). Concentrations were not reported but the estimated exposures were 0.13-0.25 mg of sarin in a comatose patient and 0.016-0.032 mg in less severely intoxicated patients. Using LC/MS/MS and a more rigorous method of quantitation, /-PrMPA was detected underivatized in serum at concentrations of 3-136ng/ml in four casualties of the Matsumoto incident and 2-100ng/ml in 13 casualties of the Tokyo attack (59). All samples were taken within 2.5 hours of hospitalization. High levels of /-PrMPA correlated with low levels of butyryl-cholinesterase activity. Other positive analyses associated with these incidents were obtained by identification of inhibited cholinesterase, and are reported in Part B. 

Relative potency of nerve agents can also be expressed in terms of the in vivo dose necessary to produce the same level of cholinesterase inhibition by a specific exposure route. As would be expected, the effectiveness of the agents in inhibiting cholinesterase is closely correlated with their acute toxicity (see Appendix A). 

Unlike the nonspecific effects and uncommon occurrence of direct mortality observed in wildlife exposed to chlorinated hydrocarbon pesticides, several studies have documented direct mortality from exposure to OP and carbamate insecticides. The method by which the OPs and carbamate insecticides affect wildlife is quite different from the method by which the chlorinated hydrocarbon insecticides effect wildlife. The OPs and carbamates inhibit cholinesterase, primarily acetylcholinesterase (AChE), which is an enzyme that functions in the breakdown of the neurotransmitter acetylcholine. Acetylcholine functions in the transmission of nerve impulses. Therefore, when AChE is inhibited by an OP or carbamate insecticide, it can no longer breakdown acetylcholine and there is continued transmission of nerve impulses that eventually leads to nerve and muscle exhaustion. The respiratory muscles are a critical muscle group that is affected, often leading to respiratory paralysis as the immediate cause of death. A major difference in the mode of action between OPs and carbamates is that the inhibition of AChE by OPs is, from a biological standpoint, irreversible, while the inhibition from exposure to carbamates is reversible in a biologically relevant time frame. There... 

The incident described in the letter most likely was a result of applying in terrorist purposes of highly toxic substance (similar to chemical warfare agents inhibited cholinesterase), and by physicochemical properties similar to sarin. Exposure of people occurred by penetration of chemical substance via respiratory apparatus as no setting fine aerosol or vapour. Aerosol may be obtained using specially equipped tailpipe of a car as an aerosol generator. 

The forearm or the entire arm of 29 subjects was exposed to Cts of 7-681 mg min m 3 of VX vapor (Cresthull et al., 1963). Blood was taken for whole blood cholinesterase activity once before exposure and once at 20 h after exposure. (Because the VX-inhibited cholinesterase reactivates rapidly during the first hours after inhibition, this may not be a good measure of the maximal amount of inhibition.) The enzyme activity was inhibited in a dose-related fashion from 3% to 43%. There were neither signs nor symptoms. 

With irreversible interactions, however, a single interaction will theoretically be sufficient. Furthermore, continuous or repeated exposure allows a cumulative effect dependent on the turnover of the toxin-receptor complex. An example of this is afforded by the organophosphorus compounds which inhibit cholinesterase enzymes (see Aldridge, 1996, and Chapter 7). This inhibition involves reaction with the active site of the enzyme which is often irreversible. Resynthesis of the enzyme is therefore a major factor governing the toxicity. Toxicity only occurs after a certain level of inhibition is achieved (around 50%). The irreversibility of the inhibition allows cumulative toxicity to occur after repeated exposures over an appropriate period of time relative to the enzyme resynthesis rate. 

Fish serum and brain cholinesterase activity, serum glucose, serum protein, or total scrum lipid contents are measured bi(x hemically to monitor the strength of pesticide exposure in fish (Lockhart et /., 1951). Since most OP pesticides are known to inhibit cholinesterase, monitoring of this enzyme activity is of prime importance. 

Mioduszewski et al. (2001) estimated the probability of sarin vapor-induced lethality in Sprague-Dawley rats exposed to various combinations of exposure concentration and duration in a whole-body dynamic chamber. In this study, the onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Miosis was the initial clinical sign observed at the start of the exposure. The authors have reported that the interaction of LC50X time (LCT 50) values increased with each exposure duration and found poor correlation of cholinesterase inhibition to exposure conditions or to the severity of clinical signs. 

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