Methamidophos toxicity

Pathway a in Fig. 9.15 is one of amide hydrolysis mediated by a carboxy-amidase. The metabolite thus produced is methamidophos, the toxic species formed predominantly in insects and far less in mammals. Pathways b and c lead to an O-demethyl and a demethylthio metabolite, respectively. The re-... 

M. Mahajna, G. B. Quistad, J. E. Casida, Acephate Insecticide Toxicity Safety Conferred by Inhibition of the Bioactivating Carboxyamidase by the Metabolite Methamidophos , Chem. Res. Toxicol. 1997, 10, 64-67. 

The reaction between a phosphoramidothioate and N-chlorosulfenylcarbamate described in Figure 2 has been applied to methamidophos. In Figure 2, the reaction was used to derivatize a toxic me thyIcarhamate ester by a non-toxic phosphora-midothioate however, in the case of methamidophos the reaction was used to derivatize a toxic phosphoramidothioate with a nontoxic carbamate moiety. The IJ-alkoxycarbonyl-IJ -alkylamino-sulfenyl derivatives of methamidophos thus prepared, where R... 

Methamidophos is toxic to birds, aquatic organisms, and insects, and has a half life in water of up to 309 days . 

Another example of insecticide selectivity is shown in Figure 9.12. Acephate is a proinsecticide that has to be converted to methamidophos, an active insecticide, by a carboxy-lamidase. It has been shown that this hydrolase is much more active in insects than in mammals. This explains why acephate is very toxic to insects but not to mammals. 

Acephate is moderately toxic to mammals with an acute oral LD50 of 850-950 mg kg in rats, whereas its metabolite methamidophos is highly toxic to mammals. The common symptoms of acephate poisoning include salivation, nasal discharge, vomiting, diarrhea, nausea, blurred vision, difficulty in breathing, headache, and muscle weakness. Convulsions, coma, and death may occur in cases of severe acute poisoning. 

Both acephate and its metabolite, methamidophos, pose a high acute and chronic risk to birds. Studies in insects have shown that acephate is highly toxic to honey bees and other beneficial insects. Methamidophos is also very highly toxic to freshwater invertebrates. 

Methamidophos has high mammalian toxicity. The oral LD50 value in rats is 20 mg kg Dermal... 

Methamidophos may cause harm to nontarget species with approved applications. Field studies indicate bird mortality can occur with methamidophos use. Methamidophos residues on food that birds may eat (e.g., leaves, insects, invertebrates) show high acute and persistent exposure. In addition, residue data on food that wild mammals may eat indicate that there would be sufficient persistent residues to cause adverse chronic effects. Methamidophos is highly toxic to bees and some beneficial insects. Freshwater and estuarine invertebrate aquatic species may be affected with normal use of methamidophos but acute risks to fish are minimal. 

Glutathione conjugation. The involvement of glutathione transferases in OP metabolism was realized in the early 1960 s (35. 361. It was difficult to establish this fact because of similarities between glutathione transferase-and carboxylesterase-produced metabolites. Induction of glutathione transferase activity in the fall armyworm caused a 2- to 3-fold decrease in the toxicity of diazi-non, methamidophos, and methyl parathion (37.) This shows indirectly the importance of glutathione transferase activity in the detoxification of these OPs. 

Acephate is an organophosphate with high activity toward insects, but it seems to have low toxicity to other animals. It is systemic and is metabolized in plants to metamidophos, which has a much higher toxicity. But this activation does not seem to be so important in mammals. Methamidophos is also used as an insecticide/nematicide. Table 8.5 shows the high difference in toxicity toward acephate and its metabolite. 

OP insecticide-induced intermediate syndrome (IMS) was reported for the first time in human patients in Sri Lanka in 1987 (Senanayake and Karalliede, 1987). Since then, this syndrome has been diagnosed in OP-poisoned patients in South Africa (1989), Turkey (1990), Belgium (1992), the United States (1992), Venezuela (1998), France (2000), and elsewhere. IMS is usually observed in individuals who have ingested a massive dose of an OP insecticide either accidentally or in a suicide attempt. IMS is clearly a separate clinical entity from acute toxicity and delayed neuropathy. A similar syndrome has also been observed in dogs and cats poisoned maliciously or accidentally with massive dosc.s of certain OPs. OPs that are known to cause IMS include bromophos, chlorpyrifos, diazinon, dicrotophos, dimethoatc, fenthion, malathion, merphos, methamidophos, methyl parathion, monocrotophos, omethoate, parathion, phosmet, and trichlorfon. These compounds and IMS are discussed further in Chapter 26. 

Methyl parathion, methamidophos, and methidathion, all too often found in dead bee samples, are hazardous both for the environment and for man and reflect a non-professional approach to farming and above all a lack of respect for the territory. There is also the issue of fenoxycarb. The sale and use of this compound is banned throughout Italy (Ministerial Decree 8.8.1995 G.U. n. 189 of 14.8.1995, an exception being made only for the province of Bolzano), in view of its toxic effects on beneficial ento-mofauna. Nonetheless, residues of this compound were found in a bee sample taken from station OZZ 3 in June. 

Risk assessment is the process that is used to evaluate the potential for exposure and the likelihood that the toxic effects of a substance will occur under specific exposure conditions. There are limitations and uncertainties in estimating the potential risk to human health. The degree or magnitude of the uncertainty varies depending on the availability and quality of the data and the exposure scenarios being assessed (15). Specific areas of uncertainty associated with this risk assessment for methamidophos are described, as follows. 

There is a possibility that an individual could be exposed to multiple chemicals sharing the same mechanism of toxicity. An effort is to be made under FQPA to attempt to combine these "cumulative exposure(s)" to related chemicals (23). In the case of methamidophos, such multiple chemical exposure(s) will include exposure to acephate, as well as other ACME inhibitors. 

Seven developmental toxicity studies (four rat, three rabbit) failed to show fetal or embryonic toxicity at doses of methamidophos less than those affecting dams. No evidence was forthcoming from these experiments that there was an increase in sensitivity among fetal/embryonic animals compared with adults. It is therefore unlikely that an additional factor will be required to protect against increased pre-/post natal sensitivity to methamidophos. The recently completed developmental neurotoxicity study of methamidophos also indicates that fetal/young rats are not more sensitive than adults. However, there must remain a degree of uncertainty about the precise dosage received by the pups in the reproductive toxicity and developmental neurotoxicity studies. 

In a 2-generation (SD) rat reproductive toxicity study, reduced body weight was reported in adults and piq>s with the same LOEL and NOEL values. Because inhibition of AChE appeared to be more marked in adults than pups, it is therefore unlikely that methamidophos has adverse effects on reproduction. 

The aquatic toxicity of chiral organophosphorous (OP) compounds has received increasing attention. Lin et al. reported that the (+)-enantiomer of methamidophos was 7.0 times more toxic than its (—)-enantiomer against Daphnia magna in 48 h tests [82]. The acute aquatic toxicity of trichloronate against Daphnia magna was also found to be selective the (-)-form was 8-11 times more toxic than its (+)-form, while the raceme showed intermediate toxicity [83]. 

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