ORGANIC POLLUTANTS: An Ecotoxicological Perspective - Chapter 10 pot

193 10 Organophosphorus and Carbamate Insecticides 10.1 BACKGROUND Organophosphorus insecticides (OPs) and carbamate insecticides are dealt with here in a single chapter because they share a common mode of action: cholinesterase (ChE) inhibition. Unlike DDT and most of the cyclodiene insecticides, they do not have long biological half-lives or present problems of biomagnication along food chains. When OCs such as DDT and dieldrin began to be phased out during the 1960s, they were often replaced by OPs or carbamates, which were seen to be more readily biodegradable and less persistent, although not necessarily as effective for controlling pests, parasites, or vectors of disease. They replaced OCs as the active ingredients of crop sprays, sheep dips, seed dressings, sprays used for vector control, and various other insecticidal preparations. When OCs were phased out, the less persistent insecticides that replaced them were thought to be more “environment friendly.” However, some of the insecticides that were used as replacements also presented problems because of very high acute toxicity. The insecticides to be discussed in this chapter illustrate well the ecotoxi- cological problems that can be associated with compounds that have low persistence but high neurotoxicity. OPs were rst developed during World War II, both as insecticides and chemical warfare agents. During this time, several new insecticides were synthesized by G. Schrader working in Germany, prominent among which was parathion, an insecti- cide that came to be widely used in agriculture after the war. In the postwar years, many new OPs were introduced and used for a wide range of applications. Early insecticides had only “contact” action when applied to crops in the eld, but later ones, such as dimethoate, metasystox, disyston, and phorate, had systemic proper- ties. Systemic compounds can enter the plant, to be circulated in the vascular system. Sap-feeding insects, such as aphids and whitey, are then poisoned by insecticides (or their toxic metabolites) that circulate within the plant. Some OPs were developed that were highly selective between mammals and insects, and showed low mam- malian toxicity (e.g., malathion and pirimiphos-methyl), making them suitable for certain veterinary uses, and protecting stored grain against insect pests. The rapid growth in the use of OPs and the proliferation of new active ingredients and formulations was not without its problems. Some OPs proved to be too hazard- ous to operators because of very high acute toxicity. A few were found to cause delayed neurotoxicity, a condition not caused by ChE inhibition (e.g., mipafox, lepto- phos). There was also the problem of the development of resistance, for example, by © 2009 by Taylor & Francis Group, LLC 194 Organic Pollutants: An Ecotoxicological Perspective, Second Edition cereal aphids. In due course, other insecticides, such as carbamates, were developed, and came to replace OPs for certain uses where there were problems. New carbam- ate insecticides were introduced and came to take a signicant share of the market. Some had the advantage of being nematicides or molluskicides as well as being insecticides. Some had systemic action (e.g., aldicarb and carbofuran). Sometimes, they overcame problems of resistance that had arisen because of the intensive use of OPs in cereal aphids, such as Myzus persicae. Unfortunately, some carbamates also caused environmental problems because of high vertebrate toxicity. In the following account, OPs will be discussed before considering carbamates. 10.2 ORGANOPHOSPHORUS INSECTICIDES The chemical and biological properties of the OPs are described briey in the next three sections. More detailed accounts are given by Eto (1974), Ballantyne and Marrs (1992), and Fest and Schmidt (1982). 10.2.1 CHEMICAL PROPERTIES The OPs to be discussed here correspond to one or other of the two following struc- tural formulas: R1 R2 XP [1] R1 R2 XP [2] O S Compounds corresponding to structure [1] are referred to as oxons. R1, R2, and X are all linked to P through oxygen, and the compound is a triester of orthophosphoric acid that may be termed a phosphate. If only one or two of these links are through oxygen, then the compounds are termed phosphinate or phosphonate, respectively. Compounds corresponding to structure [2] are termed thions; R1, R2, and X are all linked to P through oxygen. Compounds of this type are triesters of phosphorothioic acid (phosphorothioates). If one of the links to P is through S, then the molecule is a phosphorodithioate. R1 and R2 are usually alkoxy groups, whereas X is usually a more complex group, linked to P through oxygen or sulfur. X is sometimes termed the leaving group, because it can be removed by hydrolytic attack, either chemically or biochemically. Some properties of OPs are given in Table 10.1 and some structures in Figure 10.1. There is some variation in the values quoted for the aforementioned properties in the literature, reecting purity of sample, accuracy of method, etc. The foregoing are repre- sentative values, and are not necessarily the most accurate ones for the purest samples. Of the compounds listed in Table 10.1, all except dimethoate and azinphos-methyl exist as liquids at normal temperature and pressure. Looking through the table, it can be seen that there is considerable variation in both water solubility and vapor © 2009 by Taylor & Francis Group, LLC Organophosphorus and Carbamate Insecticides 195 pressure. Thus, dimethoate and demeton-S-methyl have appreciable water solubility and show marked systemic properties whereas parathion, chlorfenvinphos, and azin- phos-methyl have low water solubility and are not systemic. Disulfoton, although of low water solubility in itself, undergoes biotransformation in plants to yield more polar metabolites, including sulfoxides and sulfones, which are systemic. In general, OPs are considerably more polar and water soluble than OCs. The relatively high vapor pressure of most OPs limits their persistence when sprayed on to exposed surfaces (e.g., on crops, seeds, or farm animals). Some, such as chlorfenvinphos, have relatively low vapor pressure, and consequently tend to be more persistent than most OPs. Chlorfenvinphos has been used as a replacement for OC compounds both as an insecticidal seed dressing and as a sheep dip. O Parathion   NO 2 S C 2 H 5 O C 2 H 5 O P OC Chlorfenvinphos Cl Cl Cl H O C C 2 H 5 O C 2 H 5 O P O CH 3 CH 3 CH 3 N CH N Diazinon S C 2 H 5 O C 2 H 5 O P S CH 2 CONHCH 3 Dimethoate S CH 3 O CH 3 O P S CH 2 CH 2 S C 2 H 5 Disyston (disulfoton) S C 2 H 5 O C 2 H 5 O P S CH 2 CH 2 S CH 2 CH 3 Demeton-S-methyl O CH 3 O CH 3 O P S CHCOOC 2 H 5 CH 2 COOC 2 H 5 Malathion S CH 3 O CH 3 O P N O N N S CH 2 Azinphos-methyl (gusathion) S CH 3 O CH 3 O P FIGURE 10.1 Some OPs. TABLE 10.1 Properties of Some Organophosphorus Insecticides Compound Water Solubility (μg/mL @ 25nC) log K ow Vapor Pressure (mmHg @ 25nC) Parathion 11 3.83 6.7 × 10 −6 Diazinon 40 3.40 1.4 × 10 −4 Dimethoate 5000 8.5 × 10 −6 Azinphos-methyl 33 3.8 × 10 -4 Malathion 145 2.36 3.98 × 10 −5 Disyston 25 1.8 × 10 −4 Demeton-S-methyl 3300 1.32 3.6 × 10 −4 Chlorfenvinphos 145 3 × 10 −6 © 2009 by Taylor & Francis Group, LLC 196 Organic Pollutants: An Ecotoxicological Perspective, Second Edition The environmental fate and behavior of compounds depends on their physical, chemical, and biochemical properties. Individual OPs differ considerably from one another in their properties and, consequently, in their environmental behavior and the way they are used as pesticides. Pesticide chemists and formulators have been able to exploit the properties of individual OPs in order to achieve more effective and more environment-friendly pest control, for example, in the development of com- pounds like chlorfenviphos, which has enough stability and a sufciently low vapor pressure to be effective as an insecticidal seed dressing, but, like other OPs, is read- ily biodegradable; thus, it was introduced as a more environment-friendly alternative to persistent OCs as a seed dressing. Of the compounds shown in Figure 10.1, six are thions and only two (demeton- S-methyl and chlorfenvinphos) are oxons. Four of the thions possess two sulfur linkages to P and are therefore phosphorodithionates. The oxons tend to be more unstable and reactive than the thions, and they are much better substrates for esterases, including acetylcholinesterase (AChE). Oxygen has stronger electron- withdrawing power than sulfur; so, oxons tend to be more polarized than thions. In fact, the thions are not effective anticholinesterases in themselves and need to be converted to oxons by monooxygenases before toxicity is expressed (see Chapter 10, Section 10.2.4). As technical products, thions have an advantage over most oxons in being more stable. Organophosphorus insecticides as a class are chemically reactive and not very stable either chemically or biochemically. The leaving group (X in structural for- mula) can be removed hydrolytically, and OPs generally are readily hydrolyzed by strong alkali. Examples of enzymic hydrolysis are given in Figure 10.3. After OPs have been released into the environment, they undergo chemical hydrolysis in soils, sediments, and surface waters. The rate of hydrolysis depends on pH; in most cases, the higher the pH, the faster the hydrolysis of the OP. Demeton-S-methyl, for exam- ple, shows half-lives in aqueous solution of 63, 56, and 8 days at pH values of 4, 7, and 9, respectively (Environmental Health Criteria 197). Thus, most OPs are not very persistent in alkaline soils or waters. Thions are prone to oxidation, and can be converted to oxons under environ- mental conditions. Also, some OPs can undergo isomerization under the inuence of sunlight or high temperatures, a well-documented example being the conversion of malathion to isomalathion. Although malathion is a thion of low mammalian toxicity, isomalathion is an oxon of high mammalian toxicity. Cases of human poisoning have been the consequence of malathion undergoing this conversion in badly stored grain. Another group of organophosphorus anticholinesterases deserving brief mention, which have not been employed as insecticides, are certain chemical warfare agents, often termed nerve gases (Box 10.1). Examples include soman, sarin, and tabun. These compounds have, as bets their intended purpose, very high mammalian tox- icity and high vapor pressure. All the examples given are oxons, which tend to have greater mammalian toxicity than thions. Also, they are phosphinates rather than phosphates, having only one P linkage through oxygen or sulfur. © 2009 by Taylor & Francis Group, LLC Organophosphorus and Carbamate Insecticides 197 10.2.2 METABOLISM As examples of OP metabolism, the major metabolic pathways of malathion, diazi- non, and disyston are shown in Figure 10.2, identifying the enzyme systems involved. OPs are highly susceptible to metabolic attack, and metabolism is relatively complex, involving a variety of enzyme systems. The interplay between activating transfor- mations on the one hand, and detoxifying transformations on the other, determines toxicity in particular species and strains (see Walker 1991). Because of this complex- ity, knowledge of the metabolism of most OPs is limited. Further information on OP metabolism may be found in Eto (1974), Fest and Schmidt (1982), and Hutson and Roberts (1999). All three insecticides shown in Figure 10.2 are thions, and all are activated by conversion to their respective oxons. Oxidation is carried out by the P450-based microsomal monooxygenase system, which is well represented in most land verte- brates and insects, but less well represented in plants, where activities are very low. Oxidative desulfuration of thions to oxons does occur slowly in plants, and may be due to monooxygenase attack and peroxidase attack (Drabek and Neumann 1985; Riviere and Cabanne 1987). Compounds, such as disyston, which have thioether bridges in their structure, can undergo sequential oxidation to sulfoxides and sulfones. Other examples are demeton-S-methyl (Figure 10.1) and phorate. The oxon forms of OP sulfoxides and sulfones can be potent anticholinesterases, and sometimes make an important contribution to the systemic toxicity of insecticides, such as demeton- S-methyl, disyston, and phorate. The oxidation of OPs can bring detoxication as well as activation. Oxidative attack can lead to the removal of R groups (oxidative dealkylation), leaving behind P-OH, which ionizes to PO − . Such a conversion looks supercially like a hydrolysis, and was sometimes confused with it before the great diversity of P450-catalyzed biotransfor- mations became known. Oxidative deethylation yields polar ionizable metabolites and generally causes detoxication (Eto 1974; Batten and Hutson 1995). Oxidative demethy- lation (O-demethylation) has been demonstrated during the metabolism of malathion. The bond between P and the “leaving group” (X) of oxons is susceptible to esterase attack, the cleavage of which represents a very important detoxication mechanism. Examples include the hydrolysis of malaoxon and diazoxon (see Figure 10.2). Such hydrolytic attack depends on the development of d + on P as a consequence of the electron-withdrawing effect of oxygen. By contrast, thions are less polarized and are not substrates for most esterases. Two types of esterase interact with oxons (see Chapter 2, Figure 2.9 and Section 2.3.2.3). A-esterases continuously hydrolyze them, yielding a substituted phosphoric acid and a base derived from the leaving group as metabolites. B-esterases, on the other hand, are inhibited by them, the oxons acting as “suicide substrates.” With cleavage of the ester bond and release of the leaving group, the enzyme becomes phosphorylated and is reactivated only very slowly. If “aging” occurs it is not reactivated at all. Thus, continuing hydrolytic breakdown of oxons by B-esterases is, at best, slow and inefcient. Nevertheless, B-esterases produced in large quantities by resistant aphids can degrade or sequester OPs to a sufcient extent to substantially lower their toxicity and thereby provide a resistance © 2009 by Taylor & Francis Group, LLC 198 Organic Pollutants: An Ecotoxicological Perspective, Second Edition O CH 3 CH 3 CH 3 N CH 3 N Diaz inon MO Glutathione - dependent desethylase S C 2 H 5 O C 2 H 5 O P –OH O CH 3 CH 3 CH 3 N CH N CH 3 CH 3 CH 3 N CH HO N Diazoxon Uncharac terised metabo lites MO MO MO MO Mainly ‘A’ esterase O C 2 H 5 O C 2 H 5 O P SCH 2 CH 2 SC 2 H 5 Disyston Oxon form S C 2 H 5 O C 2 H 5 O P SCH 2 CH 2 SC 2 H 5 S O C 2 H 5 O C 2 H 5 O P SCH 2 CH 2 SC 2 H 5 O C 2 H 5 O C 2 H 5 O P Sulphoxide SCH 2 CH 2 SC 2 H 5 S O O C 2 H 5 O C 2 H 5 O P SCH 2 CH 2 SC 2 H 5 O O C 2 H 5 O C 2 H 5 O P Sulphone OH CH 2 CH 2 HS + SC 2 H 5 S O O S O O C 2 H 5 O C 2 H 5 O P OH HSCH 2 CH 2 + SC 2 H 5 O O O C 2 H 5 O C 2 H 5 O P SCH 2 CH 2 SC 2 H 5 O C 2 H 5 O C 2 H 5 O P SH + S CH 3 O CH 3 O P OH S CH 3 O CH 3 O P S CHCOOC 2 H 5 Malathion monoacid Malathion CH 2 COOH S CH 3 O CH 3 O P S CHCOOC 2 H 5 CH 2 COOC 2 H 5 S CH 3 O * CH 3 O * P MO MO MO Principally ‘A’ esterase Carboxyesterase (‘B’ esterase) MO Malaoxon S CHCOOC 2 H 5 CH 2 COOC 2 H 5 O CH 3 O * CH 3 O * Removable by MO attack * P OH O CH 3 O CH 3 O P Principally ‘A’ esterase FIGURE 10.2 Metabolism of OPs. © 2009 by Taylor & Francis Group, LLC Organophosphorus and Carbamate Insecticides 199 mechanism (Devonshire and Sawicki 1979; Devonshire 1991). AChE, the site of action of OPs, is a B-esterase, which is highly sensitive to inhibition by oxons. In addition to ester bonds with P (Section 10.2.1, Figures 10.1 and 10.2), some OPs have other ester bonds not involving P, which are readily broken by esteratic hydroly- sis to bring about a loss of toxicity. Examples include the two carboxylester bonds of malathion, and the amido bond of dimethoate (Figure 10.2). The two carboxylester bonds of malathion can be cleaved by B-esterase attack, a conversion that provides the basis for the marked selectivity of this compound. Most insects lack an effec- tive carboxylesterase, and for them malathion is highly toxic. Mammals and certain resistant insects, however, possess forms of carboxylesterase that rapidly hydrolyze these bonds, and are accordingly insensitive to malathion toxicity. OP compounds are also susceptible to glutathione-S-transferase attack. Both R groups and X groups can be removed by transferring them to reduced glutathione to form a glutathione conjugate. As with oxidative dealkylation, an ionizable P-OH group remains after removal of the substituted group, and the result is detoxication. Diazinon, for example, can be detoxied by glutathione-dependent desethylase in mammals and resistant insects. Looking at the overall pattern of OP metabolism, it can be seen that there is often competition between activating and detoxifying metabolic processes. Moreover, many of these processes occur relatively rapidly. There are often marked differences in the balance of these processes between species and strains, differences that may be reected in marked selectivity. As mentioned earlier, malathion is highly selective between insects and mammals because most insects lack a carboxylesterase that can detoxify the molecule. Some strains of insects (e.g., of Tribolium castaneum) owe their resistance to the presence of such an esterase. Inhibition of B-esterase activity with another OP (e.g., EPN) can remove this resistance mechanism and make the resistant strain susceptible to malathion. Likewise, malathion becomes highly toxic to mammals if administered together with a B-esterase inhibitor. The inhibitor acts as a synergist. When rapid detoxication by carboxylesterase is blocked, consider- able quantities of malathion are activated by monooxygenase to form malaoxon, and toxicity is enhanced. Diazinon, and the related insecticides pirimiphos-methyl and pirimiphos-ethyl, are selectively toxic between birds and mammals (Environmental Health Criteria 198). All possess leaving groups derived from pyrimidine, and their oxon forms are excellent substrates for mammalian A-esterases. Selectivity is largely explained by the absence of signicant A-esterase activity from the plasma of birds, an activ- ity well represented in mammals (Machin et al. 1975; Brealey 1980; Brealey et al. 1980; Walker 1991; Machin et al. 1975). A-esterase activity is also low in avian liver relative to that in mammalian liver. Diazinon is activated to diazoxon in the liver, and toxicity then depends on the efciency with which the latter can be transported by the blood to its site of action (primarily AChE in the brain). In mammals, rapid detoxication of oxons in the liver and blood gives effective protection against low doses of these OPs. Birds are not so well protected; many species lack detectable plasma A-esterase activity against oxon substrates (Mackness et al. 1987) and, on available evidence, activity in liver is relatively low (Brealey 1980; Walker 1991). Other OPs whose oxons are not good substrates for A-esterase (e.g., parathion) do © 2009 by Taylor & Francis Group, LLC 200 Organic Pollutants: An Ecotoxicological Perspective, Second Edition not show such selectivity between birds and mammals, providing further evidence for the importance of A-esterase activity in determining the relatively low toxicity of diazinon and related insecticides to mammals. A number of cases of diazinon resis- tance have been reported in insects (Brooks 1972). Resistance mechanisms include detoxication by deethylation of diazinon mediated by glutathione-S-transferase, and oxidative detoxication of diazoxon mediated by monooxygenase. 10.2.3 ENVIRONMENTAL FATE In general, the OPs differ from the persistent OCs in their environmental fate and dis- tribution. Because they are degraded relatively rapidly by most animals, they tend not to undergo biomagnication in the higher levels of terrestrial or aquatic food chains. However, some of them can be bioconcentrated by aquatic invertebrates from ambi- ent water. Chlorpyrifos, for example, can be bioconcentrated by the eastern oyster (Crassostrea virginica) some 225-fold in comparison with ambient water (Woodburn et al. 2003). This is in keeping with the very limited metabolic capacity of mollusks (see Box 4.1). They appear to lack the effective esterases and monooxygenases, which rapidly biotransform OPs to polar metabolites in terrestrial animals. Interestingly, a lipophilic metabolite was bioconcentrated to a somewhat greater extent than the parent compound by the oysters. This metabolite, O,O,diethyl,-O-(3,5-dichloro-6- methylthio-2-pyridyl-O-phosphorothioate), was evidently formed as a result of gluta- thione-mediated dechlorination of the leaving group (see Chapter 2, Figure 2.15 for examples of dechlorination reactions mediated by reduced glutathione). OPs are not very persistent in soils; hydrolysis, volatilization, and metabolism by soil microorganisms and soil animals ensure relatively rapid removal. Persistence in surface waters and sediments is also limited because of relatively rapid degrada- tion and metabolism. Although most OPs do tend to volatilize as a consequence of their appreciable vapor pressures, they are susceptible to photodecomposition and to hydrolysis when in the atmosphere. Thus, they are not stable enough to undergo extensive long-range transport (cf. many polyhalogenated compounds). For these reasons, most harmful effects produced by OPs are likely to be limited both in time and space; limited, that is, to the general area in which they are applied, and to a relatively short period of time following their release. The release of OPs into the environment has been very largely intentional, with the objective of controlling pests, parasites, and vectors of disease, mainly on land. Invertebrate pests of crops, forest trees, and stored products, as well as invertebrate vectors of disease, have been the principal targets. The organisms in question are mainly insects, but other types of invertebrates (e.g., Acarina) are sometimes con- trolled with OPs. Some (e.g., chlorfenvinphos) have been used to control ectopara- sites of sheep and other livestock and there have been problems arising from the illegal disposal of residual sheep dips into water courses. A further limited use of OPs on land has been for the control of vertebrate pests. Birds regarded as pests (e.g., Quelea spp. in Africa) have been controlled by aerial spraying of roosts with para- thion and fenthion (Bruggers and Elliott 1989). The use of poisoned bait contain- ing phosdrin to control predators of game birds has become a contentious issue in Western countries. In Britain, the poisoning of protected species, such as the red kite © 2009 by Taylor & Francis Group, LLC Organophosphorus and Carbamate Insecticides 201 (Milvus milvus) and the golden eagle (Aquila chrysaetos), is illegal, and gamekeep- ers following this practice have been prosecuted and ned. Although OPs have mainly been used for pest or vector control on land, there has been limited use of them in the aquatic environment, for example, to control parasites of salmon farmed in the marine environment (Grant 2002). Dichlorvos and azamethiphos have been used for this purpose, although this practice has been restricted by legislation to protect the environment in certain countries. OPs of relatively low mammalian toxicity (e.g., malathion) have sometimes been released into surface waters to control insect pests, for example, in water cress beds. Apart from the very small direct application of OPs to surface waters, there is continuing concern about unintentional contamination. Overspraying of surface waters, runoff from land, and movement of insecticides through ssures in agricultural soil and so into water courses are all potential sources of contamination with OPs, as indeed they are for agricultural pesticides more generally. OPs are often applied as sprays. Commonly, the formulations used for spraying are emulsiable concentrates, where the OP is dissolved in an organic liquid that acts as a carrier. OPs are also used as seed dressings and as components of dips used to protect livestock against ectoparasites. Some highly toxic OPs have been incorpo- rated into granular formulations for application to soil or to certain crops. Some OPs, such as chlorfenvinphos, are more persistent than most, having greater chemical stability and lower vapor pressures than is usual. Such compounds have been used where some persistence in the soil is desirable, as in the case of insecti- cidal seed dressings. Also, some OPs have been formulated in a way that increases their persistence. Thus, the highly toxic compounds disyston and phorate are formu- lated as granules for application to soil or directly to certain crops. The insecticides are incorporated within a granular matrix from which they are only slowly released, to become exposed to the usual processes of chemical and biochemical degrada- tion. Insecticidal action may thereby be prolonged for a period of 2–3 months, much longer than would occur if they were formulated in other ways (e.g., as emulsiable concentrates), where release into the environment is more rapid. Notwithstanding the limited persistence of OPs generally, and the fact that they do not tend to biomagnify in the higher trophic levels, they have sometimes been implicated in the poisoning of predatory birds (for examples from the United States, United Kingdom, and Canada, see Mineau et al. 1999). Most reported cases have involved OPs of very high acute toxicity. Cases of poisoning as the result of approved use of insecticides have been explained on the grounds of a few predisposing causes. These have included direct contact of predators with spray residues and consump- tion of prey carrying sufciently high pesticide burdens to poison the predators. The latter may be the consequence of prey (e.g., large insects or earthworms), immedi- ately after OP spraying, carrying quantities of insecticide externally which are far in excess of the levels needed to poison them. If predation occurs very soon after exposure of prey to OP, tissue levels of insecticide in prey may sometimes be high enough to cause poisoning because there has been insufcient time for effective detoxication. Even though insects generally are poor vectors of insecticides because of their sensitivity to them, some strains have acquired resistance to OPs as they have insensitive forms of ChE (see Section 10.2.4) so are able to tolerate relatively high © 2009 by Taylor & Francis Group, LLC 202 Organic Pollutants: An Ecotoxicological Perspective, Second Edition tissue levels of insecticide. Consequently, the development of this type of resistance may increase the risk of secondary poisoning of insectivores by OPs. Thus, a number of different routes of transfer need to be taken into account when considering the fate of OP insecticides applied on agricultural land. BOX 10.1 ORGANOPHOSPHORUS “NERVE GASES” Chemical warfare agents, such as soman and sarin, sometimes termed nerve gases, are powerful anticholinesterases, which bear some resemblance in structure and properties, to the OP insecticides. A major difference from most insecticides is their high volatility. These agents were possessed by the major powers during World War II, although they were never employed in warfare. More recently, with the end of the Cold War, there has been a reduction in their stockpiles, in keeping with arms reduction treaties. At the same time, it has come to light that badly disposed canisters containing chemical weapons and originating from World War II are still around, for example, in some areas of the Baltic Sea. Thus, questions have been asked about their possible impor- tance as environmental pollutants. There continues to be public concern about the possibility of their being used in future. When Saddam Hussein was in power in Iraq, there was evi- dence that a chemical weapon of this type was used against Kurdish villag- ers. Subsequently, it was widely believed that these were among the weapons of mass destruction held by Saddam Hussein’s regime; weapons that failed to materialize after the invasion of Iraq in 2003. Since these events, there has been concern that weapons of this type may be in the possession of “rogue” states— or individual terror groups. There have been suspected cases of human exposure to these compounds. One issue has been the possible exposure of soldiers to them during the Gulf War of 1991. Some have suggested that this may have contributed to what has been termed the Gulf War syndrome, a condition reported in some NATO soldiers serving in the Gulf War. Also, during the post–Cold War era, there has been discussion about the safe disposal of the large stockpiles of chemical weapons held by the major powers (see also Chapter 1). 10.2.4 TOXICITY The primary site of action of OPs is AChE, with which they interact as suicide sub- strates (see also Section 10.2.2 and Chapter 2, Figure 2.9). Similar to other B-type esterases, AChE has a reactive serine residue located at its active site, and the ser- ine hydroxyl is phosphorylated by organophosphates. Phosphorylation causes loss of AChE activity and, at best, the phosphorylated enzyme reactivates only slowly. The rate of reactivation of the phosphorylated enzyme depends on the nature of the X groups, being relatively rapid with methoxy groups (t 50 1–2 h), but slower with larger © 2009 by Taylor & Francis Group, LLC [...]... shown (from Sussman et al 1991) © 2009 by Taylor & Francis Group, LLC 204 Organic Pollutants: An Ecotoxicological Perspective, Second Edition Synaptic cleft Presynaptic membrane Postsynaptic membrane AcCH release Vesicles containing acetyl choline Cholinergic receptors Acetyl cholinesterase bound to membrane Direction of neurotransmission FIGURE 10. 4 Diagram of cholinergic synapse BOX 10. 2 ANTIDOTES TO... Being an assay based on FIGURE 10. 5 Stages in the progression of OP intoxication © 2009 by Taylor & Francis Group, LLC 206 Organic Pollutants: An Ecotoxicological Perspective, Second Edition the principal molecular mechanism of toxicity, it has the advantage of providing an index of the different stages of the manifestation of toxicity, including early neurophysiological and behavioral effects; it can... resistance as an indication of the environmental impact of insecticides Thus, the development of esteratic resistance mechanisms by aquatic invertebrates may provide a measure of the environmental impact of OPs in freshwater (Parker and Callaghan 1997) © 2009 by Taylor & Francis Group, LLC 212 Organic Pollutants: An Ecotoxicological Perspective, Second Edition 10. 3 CARBAMATE INSECTICIDES The chemical and... monooxygenase activity found in these and many other species of birds compared with the activity in the rat (see Chapter 2) Detoxication O H O C N OH CH3 ChE OH + O ChE H + O C N CH3 Carbaryl FIGURE 10. 8 Carbamylation of cholinesterase © 2009 by Taylor & Francis Group, LLC Carbamylated enzyme I-Naphthol 216 Organic Pollutants: An Ecotoxicological Perspective, Second Edition TABLE 10. 4 Toxicity of Some Carbamates... active anticholinesterases Carbofuran is detoxified by both hydrolytic and oxidative attack 10. 3.3 ENVIRONMENTAL FATE CBs have been widely used in agriculture as insecticides, molluskicides, and acaricides They have been applied as sprays and as granules or pellets Highly toxic compounds, such as aldicarb and carbofuran, are usually only available as granules, © 2009 by Taylor & Francis Group, LLC 214 Organic. .. 218 Organic Pollutants: An Ecotoxicological Perspective, Second Edition granules were found to lose their effectiveness in some “problem” soils where the insecticide was regularly used The soils showed enhanced capacity to degrade carbofuran, an effect attributed to either or both of the following: (1) the increase in numbers of preexisting species or strains capable of metabolizing the carbamate and,... Carbamates, Butterworth/Heinemann, Oxford—Gives an indepth account of the toxicology of both groups of compounds including some information about the so-called nerve gases Eto, M (1974) Organophosphorus Insecticides: Organic and Biological Chemistry, CRC Press, Cleveland, OH Fest, C and Schmidt, K.-J (1982) Chemistry of the Organophosphorus Pesticides, Springer, Berlin—This and the Eto book are valuable... Group, LLC 210 Organic Pollutants: An Ecotoxicological Perspective, Second Edition residues in carcasses of animals or birds found in the field do not provide reliable evidence of the cause of death (cf the persistent OCs) Supporting evidence, such as inhibition of brain AChE activity, is usually needed to establish causality From an ecological point of view, such compounds appear less hazardous than compounds... (Section 10. 2.4) According to the model, all the changes would cause steric hindrance of the relatively bulky insecticides, but not to any important extent of acetylcholine itself Thus, the insensitive enzyme could continue to function as AChE The existence of more than one of these point mutations brings a higher level of resistance than does a single-point mutation Apart from the importance of OP resistance... 1989), and canopy-living birds were poisoned by fenitrothion applied to forests in New Brunswick, Canada, to control spruce bud worm (see Chapter 15 in Walker et al 2006) Mammals have also been affected by OPs in the field Sheffield et al (2001) review a number of cases of such lethal and sublethal poisoning of free-living lagomorphs and rodents © 2009 by Taylor & Francis Group, LLC Organophosphorus and . sulfoxides and sulfones. Other examples are demeton-S-methyl (Figure 10. 1) and phorate. The oxon forms of OP sulfoxides and sulfones can be potent anticholinesterases, and sometimes make an important. metabolite, O,O,diethyl,-O-(3,5-dichloro- 6- methylthio-2-pyridyl-O-phosphorothioate), was evidently formed as a result of gluta- thione-mediated dechlorination of the leaving group (see Chapter 2, Figure. (Parker and Callaghan 1997). © 2009 by Taylor & Francis Group, LLC 212 Organic Pollutants: An Ecotoxicological Perspective, Second Edition 10. 3 CARBAMATE INSECTICIDES The chemical and biological