Humans cholinesterases

Substrate (6 X KT mol/liter) Purified horse cholinesterase Horse cholinesterase Human cholinesterase... 

Soon after DFP was discovered, it was demonstrated that it had the capacity of inhibiting AChE irreversibly. One of the earliest published reports of a systematic study of the inhibitory properties of DFP was that of Koelle and Gilman (1946). In vitro log p/50 was reported to be 6.5 for serum BuChE and 4.2, 4.5, 4.8 for AChE from rat erythrocyte, brain, and muscle, respectively, with similar values in dogs. In vivo studies after intramuscular injection in rats, dogs, and monkeys were performed and inhibition, toxic effects and AChE regenerations were evaluated. Levels in the range of 0.05-1 mg/kg showed significant inhibition of serum ChE and doses of 1-5 mg/kg caused a total inhibition of erythrocyte cholinesterase. Human exposure to a dose of 0.5-2 mg/60 kg caused marked inhibition of serum BuChE, without any inhibition of erythrocyte AChE and/or toxic symptoms. 

Often, absorption occurs by multiple routes in humans. Dean et al. (1984) reported deaths and toxic effects as well as lowered blood cholinesterase levels and excretion of urinary 4-nitrophenol in several children who were exposed by inhalation, oral, and possibly dermal routes after the spraying of methyl parathion in a house. In the same incident (Dean et al. 1984), absorption was indicated in adults who also excreted 4-nitrophenol in the urine, though at lower levels than some of the children, and in the absence of other evidence of methyl parathion exposure. In this study, the potential for age-related differences in absorption rates could not be assessed because exposure levels were not known and the children may have been more highly exposed than the adults. Health effects from multiple routes are discussed in detail in Section 3.2. 

Based on the rapid appearance of clinical signs and cholinesterase inhibition, methyl parathion appears to be readily absorbed by humans and animals following inhalation, oral, and dermal exposure. Following oral administration of methyl parathion to animals, the extent of absorption was at least 77-80% (Braeckman et al. 1983 Hollingworth et al. 1967). No studies were located regarding the extent of absorption following inhalation and dermal exposure, or the mechanism of absorption. 

Following exposure of humans to organophosphates, but not specifically methyl parathion, restoration of plasma cholinesterase occurs more rapidly than does restoration of erythrocyte cholinesterase (Grob et al. 1950 Midtling et al. 1985). These findings are supported by studies of methyl parathion in animals. Erythrocyte cholinesterase levels are representative of acetylcholinesterase levels in the nervous system, and, therefore, may be a more accurate biomarker of the neurological effects of chronic low level exposure of humans to methyl parathion (Midtling et al. 1985 NIOSH 1976). 

Garcia-Lopez JA, Monteoliva M. 1988. Physiological changes in human erythrocyte cholinesterase as measured with the "pH-stat". Clin Chem 34 2133-2135. 

Moeller HC, Rider JA. 1959. The effects of various organic phosphate insecticides on RBC and plasma cholinesterase in humans [Abstract]. Fed Proc 18 424. 

Nigg HN, Knaak JB. 2000. Blood cholinesterases as human biomarkers of organophosphorus pesticide exposure. Rev Environ Contam Toxicol 163 29-112. 

TharrD. 1998. Rapid assessment of organophosphate-induced cholinesterase depression A comparison of laboratory and field kit methods to detect human exposure to organophosphates. Appl Occup Environ Hyg 13 265-268. 

Other additional studies or pertinent information that lend sunnort to this MRL Methyl parathion affects the nervous system by inhibiting acetylcholinesterase activity. Cholinesterase inhibition and neurological effects have been observed in humans and animals, for all exposure routes and durations (for example. Dean et al. 1984 Desi et al. 1998 EPA 1978e Gupta et al. 1985 Nemec et al. 1968 Suba 1984). 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

DF and its precursor, DC are organophosphonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. Because DF and DC are relatively volatile compounds, the primary route of exposure is expected to be the respiratory system. However, ingestion also results from inhalation exposures in animals and could occur in humans. DF and DC vapors have a pungent odor and may cause severe and painful irritation of the eyes, nose, throat, and lungs. Data provided is for DF only, DC has similar properties. 

Most chemical agents are essentially cumulative in their effects. The reason is that the human body detoxifies them very slowly or not at all. For example, a 1-h exposure to HD or CG followed within a few hours by another 1-h exposure has about the same effect as a single 2-h exposure. Continued exposure to low concentrations of HD may cause sensitivity to very low concentrations of HD. Other chemical agents also have cumulative effects. For example, an initial exposure to a small (less than lethal) amount of Sarin (GB) would decrease cholinesterase levels a second quantity less than the FDS0... 

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... 

There are different types of cholinesterases in the human body, and they differ in their location in tissues, substrate affinity, and physiological function. The main ones are ACHE, present in nervous tissue and red blood cells (RBC-ACHE), and plasma cholinesterases (PCHE), present in glial cells, plasma, and liver. The physiological functions of RBC-ACHE and PCHE, if any, are unknown. 

Based on the data from controlled human studies, the NOEL for plasma cholinesterase inhibition for a single dose of chlorpyrifos is between 0.1 and 0.5 mg/kg bw/day, and the more conservative 0.1 mg/kg bw/day (100 pg/kg bw/day) is used in this assessment as the acute NOEL for chlorpyrifos. The repeated dose NOEL in humans is 0.03 mg/kg bw/day (30 pg/kg bw/day), based on plasma cholinesterase activity, and this is the basis for the establishment of the reference dose of 0.003 mg/kg bw/day (3 pg/kg bw/day) used by the EPA in assessing dietary risk to chlorpyrifos. For the work described here, both NOELs are used as bases for assessing risks to persons who have the potential for non-dietary exposure to chlorpyrifos. For exposures that are infrequent or of short duration, the 100 pg/kg bw/day NOEL is assumed to be the more appropriate value, and the lower 30 pg/kg bw/day will be used in those situations in which exposure may be considered to be more frequent. ... 

T Anders, LA Svensson. Bambuterol, a carbamate ester prodrug of terbutaline, as inhibitor of cholinesterases in human blood. Drug Metabol Dispos 16(5) 759-763,... 

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