Drinking Water and Health, Volume 9 Selected Issues in Risk Assessment (1989) / Chapter Skim
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5 Acetylcholinesterase Inhibitors: Case Study of Mixtures of Contaminates with Similar Biologic Effects
5 Acetylcholinesterase Inhibitors: Case Study of Mixtures of Contaminates with Similar Biologic Effects
Pages 146-161
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From page 146... ...
The drug physostigmine, obtained from the calabar bean, is an aromatic carbamate ester that was first used therapeutically in 1877 in the treatment of glaucoma and still has some use for this purpose. Other related carbamates (such as neostigmine and edrophonium)
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From page 147... ...
Both the organophosphorus and carbamate classes of anticholinesterases contain compounds whose acute lethal dosages range from a few milligrams per kilogram to greater than a gram per kilogram (Murphy, 19861. The manifestation of cumulative toxic action is generally the same as that of the action produced by a large single dose.
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From page 148... ...
All the signs and symptoms described above can result from a single dose of an anticholinesterase agent that passes the blood-brain barrier, gains access to cells in the central nervous system, and acts at synapses of peripheral nerves. Smaller doses can be tolerated without these signs, but frequent repetition of the smaller doses can lead eventually to their onset when the accumulated inhibition of acetylcholinesterase allows acetylcholine to reach an excessive concentration.
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From page 149... ...
With the carbamate compounds, spontaneous reversal of cholinesterase inhibition occurs when the excessive inhibitor has been metabolized or otherwise removed generally within a few minutes to a few hours. The phospho~ylated acetylcholinesterase of the organophosphorus compounds tends to be much more stable, and spontaneous dephosphorylation and regeneration of the uninhibited enzyme can take many hours to several days.
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From page 150... ...
indicate that tests of subtle learned behaviors in laboratory animals can be altered with very little reduction in blood cholin esterase. Some organophosphorus and carbamate compounds are not strong inhibitors of acetylcholinesterases and are not properly classed with the anticholinesterases.
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From page 151... ...
Hence, factors that alter the rate of metabolism of these indirect inhibitors to their directly inhibiting forms can alter the toxicity of the compounds. Furthermore, many of the P=0 compounds can be attacked directly by hydrolases, sometimes called A-esterases, that split the (RO)
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From page 152... ...
Hence, compounds (including many insecticidal and noninsecticidal organophosphorus compounds) that inhibit carboxyl esterases can increase the toxicity of other organophosphorus compounds whose anticholinesterase activity depends on an intact carboxyl ester or carboxy amide linkage (DuBois, 1969; Murphy, 19691.
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From page 153... ...
Finally, it has been demonstrated that some organophosphorus triesters that are not always potent inhibitors of acetylcholinesterase can compete with other anticholinesterases for a noncritical group of enzymes, sometimes referred to as aliesterases (IX in Figure 5-11; these include nonspecific carboxyl esterases. The competition can block a sink of noncritical binding sites that normally act to spare acetylcholinesterase (the critical binding site)
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From page 154... ...
Inhibition of detoxification by tissue carboxyl esterases and amidases and competition for nonvital binding sites that normally act as a buffer system to spare the vital acetylcholinesterase appeared to be the two major mechanisms! involved in the synergism among or~anophosphorus compounds.
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From page 155... ...
The first reported example of substantial synergism among anticholinesterase compounds involved binary mixtures of malathion and EPN (Frawley et al., 19571. Both chemicals are anticholinesterase organophosphorothioate insecticides.
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From page 156... ...
degree of synergism of acute toxicity of oraanochosohorus insecticides given simultaneously as binary mixtures to laboratory animals. One criterion that appears to apply to most of the cases of reported synergism is that at least one of the compounds has a higher potency as a carboxyl esterase inhibitor than as an anticholinesterase.
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From page 157... ...
On the basis of that most-studied example of joint action by organophosphorus insecticides, it appears that no excess risk of cholinesterase inhibition in healthy men is likely if intake of EPN and malathion does not exceed the maximum that could result from legal food residues. No similar data base is available for other combinations of anticholinesterase organophosphorus or carbamate compounds.
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From page 158... ...
it appears likely, at least for the compounds discussed in this chapters that there are dosages below which interactions do not occur and that these can be predicted from data on individual compounds. With regard to the interaction resulting from the existence of cholinesterase inhibition as a common action, one would anticipate that at most this interaction would result in additive activity.
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From page 159... ...
· The role of inhibition of carboxyl esterases or other noncritical (silent) receptors in the loss of anticholinesterases, whether or not they involve carboxyl ester linkage, should be investigated further.
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From page 160... ...
1957. Marked potentiation in mammalian toxicity from simultaneous administration of two anticholinesterase compounds.
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From page 161... ...
1987. Potentiations of N-methylcarbamate toxicities by organophosphorus insecticides in male mice.
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