Click for next page ( 6


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 5
2 ANTICHOLINEUE"SES Antichollnesterases (anti-ChEs) are toxic to h''mans principally because they interfere with molecular and cellular mechanisms required for the normal functioning of the central nervous system (CNS) and peripheral nervous system (PNS). Their adverse health effects are related Costly to inhibition of acetylcholinesterase (AChE), a critically important CNS and PNS enzyme that hydrolyzea the neurotransmitter acetylcholi.ne (ACh). Chemical-warfare (COO) agents exploit the acute, life-threatening properties of profound AChE inhibition; some of the antl-ChEs precipitate other clinically si gnif leant de let eriou s e f f ec t ~ on sensory and neuromuscular function. All the ma jor anei--ChEs are chemically reactive and potentially capable of allylating a variety of biologic macromolecules, but the long-term health implications of these reactions are not well known. This chapter therefore focuses on the acute toxic effects of anti-ChEs and the possible long-term effects on CNS and PNS function. The fundamental cellular component of the nervous system, the neuron, has long ~ branching ~ cylindric processes (dendrites and axon) that extend from the cell body. Dendrites are modified for signal reception end transduction end form extensive networks that permit interneuronal communication, coordination, and integration of ner~rous-system function. The axon typically is a long extension of the neuron specialized f or transmission of electric signals and, at its distal end, for chemical communication of informaelon to other neurons or to muscle at sites termed synapses and neuromuscular junctions, re spectively. ACh is the chemical transmitter of information from both somatic ant autonomic (PNS) neurons. On the somatic side, the lower motor neuron uses ACn to convey excitatory impulses to voluntary muscle. Cholinergic neurons of the autonomic division of the PNS are grouped in craniosacral (parasympathetic) and thoracolumbar (sympa thetic) outflows from the spinal cord . Parasympathetic pathways use ACh at both preganglionic and postganglionic neurons; in the sympathetic system, ACh is restricted to the preganglionic effecter. These cholinergic-dependent autonomic neurons play an important role in regulating the function of various Maritally import ant e f f ec tor organs. Cholinergic pathways are widely distributed in CNS tissue, but their functions are less well understood than those in the PNS. AChE terminates the transmitter action of ACh. Drugs that inhibit or inactivate AChE (anti-ChE agents) cause ACh to accumulate at cholinocepeive sites and thus produce effects equivalent to continuous stimulation cuff cholinergic nerve fibers. Before World War ~ I, only "reversible" antl-ChE agents were generally known, of which physostigmine (eserine) is the outstanding example. Shortly before and during World War ~ I, a class of highly toxic chemicals, the organophosphorus compounds ~ OPs ), were developed , chiefly by Schrader of I.G. Parbenindustrie,first as agricultural insecticides and later as CW agents. The high potency of these compounds was found to be due to "irreversible" inhibition of AChE; thus, they produced effects for considerably longer periods than the classical s

OCR for page 5
inhibitors. Since the pharmacologic actions of both classes of anti-ChE agents are qualitatively similar, they are discusses as a group, and important features of individual pleases or compounds are noted. - CHEMISTRY OF ANTICHOLINESTERASES A complete fiat of anti-ChE compounds used in the Edgewood program is contained in the master file (Appendix A). Structure-activity relationships have been reviewed extenalvely for the "reversible inblbitors tl,2) the OF agent a (3,4) and both classes of compounds (5-7). " REVERSIBLE " INHIBITORS After the structure of physostigmine wee eatabliahet, Stedman (8,9) undertook a systematic lovestigatlon of a number of related synthetic c-ompouads. The essential moiety of the physostigaine molecule we. found to be the methy~carba~ate of a basically substituted, simple ooaminophenol. The quaterna~y ammonium - derivative, Deo~tig~iD@9 i~ a compound of greater stability and equal or greater potency. Retention of the dimethy~carbamate side chain in the mete position, but with incorporation of the quaternary nitrogen atom Into the ring to fore a pyrityl nucleus, results in compounds with anti-ChE and other pharmacologic properties similar to those of neostigmine. Pyridostlgmine is a drug of this clasaO Although the carbamates are the most familiar and the most commonly encountered anei-ChEs, members of other chemical classes are also capable of inhibiting AChE. For example, edrophonium, an analogue of the phenolic residue of neostlgmine, is used extensively in clinical medicine. It was not administered to the volunteers at Edgewood, but two other noncarbamates were: 1,2,3, 4tetrahydro-9-acridinamine (Tacrine) and hexafluorenium (Mylaxen). These compounds also are used in clinical medicine but are not as popular as neostigmine, pyridostigmine, or edrophonium. O RGANOP HO SP HORUS INHIBITORS The general formula for this class of cholinesterase inhibitors is shown in Figure 1. A great variety of substituents is possible: R1 and R2 may be alkyl, alkoxy, aryloxy, amido, mercapto, or other groups; and X (also called the "leaving group-) may be a halide, cyanide, thiocyanate, phenoxy, thiophenoxy' phosphate, alkyIthioethylmercaptide, dialkylaminoethyl~ercaptide, or carboxylate group. It is obviously impossible to discuss here more than a few representative compounds of the more than 50,000 that Fig. 1: Organophosphorus Compounds General Formula: R2 \ X Rl TO

OCR for page 5
have been prepared; a useful chemical classification f the compounds in this class that are of particular pharmacologic or toxicologic interest has been developed by Holmstedt (3, 4) . 1'ilsopropyl phosphorofluoridate (DEP3 is perhaps the best known and the mos ~ extensively studied compound . Generally, the most acutely toxic compounds are those with one carbon-phosphorus bond (phosphonates). The compounds studied by the Army (Appendix A), with the exception of OPP, con~aln this feature. In GA ~ rabun), the leaving group is cyanide . In GB ~ sarin), GO (soman) ~ snot OF, the leaving group is fluoride. In the V agents, OX and EA 3148 ~ the most potent agent atmintstered to the volunteers), the leaving group is a dialkylaminoalk~rImercaptide. ABSORPTION, FATE, ANI) EXCRETION OF ANTI-CHES . Physostigmine is readily absorbed from the gastrointestinal tract, subcutaneous tissues, and mucous membranes. It undergoes hydrolytic cleavage at the ester linkage by cholinesterases, renal excretion plays only a minor role in its disposal. In man, a Beg dose of physostigmi-ne injected subcutaneously is largely destroyed in 2 h. Neostig~ine and related qua ternary ammonium drugs are absorbed poorly after oral administration, and much larger doses are needed for effect than when they are administered by injection; both are metabolized by hepatic microsomal enzymes (IO) and excreted in the urine . The commonly encountered OP anti-ChE agents are, with some exceptions ~ e.g., echothiophate), highly soluble in lipids . Consequently ~ e hey are rapidly and effectively absorbed when administered by almost any route, including the gastrointestinal tract, the skin and mucous membranes after contact with the liquid form, and the lungs after inhalation of vapors, finely dispersed dust, or aerosols. Most OP compounds are excreted almost entirely as metabolites in urine. Between the time of-absorption and excre Lion, there are varied periods during which -the original compound or its metabolizes remain bound to proteins in the blood and tissues. Both hydrolytic and oxidative enzymes are involved in metabolism of the OP compounds. The OP anti-ChE agents are hydrolyzed in the body by a group of enzymes, the phosphory~phosphatases. These are widely distributed and hydrolyze a large number of OP compounds (e.g., DFP, tabun, satin, paraoxon, and tetraethyl pyrophosphate, or TEPP) by splitting the anhydride-like P-E (or P-CN) bond. They also hydrolyze several aliphatic esters (e.g., ethyl acetate) and aromatic esters (e.g., phenyl acetate). The enzymes are not irreversibly inhibited by OP compounds, presumably because the phosphory3-ated active site reacts rapidly with water to regenerate the free form, in contrast with its high stability in the case of the cholinesterases. Because of the above reactions, the effects of exposure to two OP insecticides may be synergistic. For example, when malathion is administered to animals in combination with O-ethyl O~-nitrophenyl pheny~phosphonothionate (EPN), the resulting toxicity is as much as 50 times that expected from the sum of their individual toxicities, this results primarily from the inhibition by EPN of enzyme 8y8te~s that normally metabolize malathion to inactive products. Other combinations of OP insecticides also have shown supra-addition of toxic effects. 7

OCR for page 5
Arc #ma - I - ~~ - Cx ACHED '0~ '0; I' 1 ~ it_ Cow Cal ~~ ~ f cat I~Y_ S - ~~ ~ h - ~~ Iel ll. [~ ~C3^C~. I DAYS Be_ C ~e til. ~~ - '~ ~0 _ _ ~ ~,0 ~~ V'~, Be_ 3~ - oe~.~ ~ ~ ~~ ~ ~ Con - C 't`~ #0 C - Ad ~. f`` '0 ~~ I =^ ~ j "^ ,~,0 Of - ~_~e Ho ,0 ~ _ +~50 ESCROW COCCI. Fig. 2: Steps involved in the hydrolysis of acetylcholine (ACh) by acetylcholinesterase (ACHE) All, and in the inhibition of AChE by reversible (I), carb~myl eager (all), and organophosphorus clot) agents. Heavy, I1ght, and dashed arrows represent extremely rapid, intermediate, and extremely slow or insignificant reactions, respectively. Reproduced from Koelle, G.B., In: The Pharmacologic Basis of Therapeutics (Goodman, L.S. and Gils'ian, A., eds.), 5th ado Macmillan Publ. Co., 1975, pg. 448. 8

OCR for page 5
MECHANISMS OF ACTION INHIBITION OF ACET~CHOLI~STE~SE BY ~ICHOLI~STE"SES The mechanisms of action of compounds that typify the three c lasses of anti-ChE agent s are show in Figure 2. They differ primarily in quantitative respects from the reaction between AChE and i ts noneal substrate, ACh. simple quaternary compounds, such as edrophonium, form electrostatic bonds with the anionic site of the enzyme and hydrogen bonds with the imidazole nitrogen atom of the esteratic site. In all such case., inhibition is rapidly reversible, and such drugs have a Very short duration of inhibitory action. It was at one -time generally assumed that physostig~ine, neostigmine, and related inhibitors that possess a carbamyl ester linkage or urethane structure, in addition to a tertiary amino or quaternary ammonium group, inhibit the enzyme in the same reversible fashion. However, careful kinetic studies showed that physostigaine and neostigmine are hydrolyzed by cholinesterase ~ Il-14 ~ O Initially, inhibitors of this class form complexes in which the inhibitor is attached to the enzyme at both anionic and esteratic sites; subsequently, hydrolysis proceeds in a manner analogous to that of ACh, and the alcoholic moiety is split off, leaving a carbamylated ant inhibited enzyme. I`ater, this enzyme reacts with water to release a substituted carbamic acid and the regenerated enzyme. The main difference between the reaction of the natural substrate, ACh, and that of the carbamate inhibitors is the velocity of the final step; the half-life of dimethy~carbamy! ACh35:, formed by the reaction with neostigmine, is more than 40 million times that of the acetylated enzyme: 30 min and 42,us, respectively (15~. The reaction between AChE and most OP inhibitors, such as OFF, occurs only at the esteratic site. It proceeds in a comparable fashion, except that, as a result of the initial hydrolysis, the enzyme becomes phosphorylated. The reaulting phosphorylated enzyme is extremely stable: if the attached allays groups are methyl or ethyl, substantial regeneration of the enzyme by hydrolytic cleavage requires several hours; with isopropyl groups, as in DFP, virtually no hydrolysis occurs, and the return of AChE activity depends on synthesis of new enzyme, which requires days to months. Some quaternary OP compounds (e.g., echothiophate) combine at both the e~teratic and anionic sites, and that probably contributes to their extreme potency and specificity (4,16~. From the foregoing account, it 1. apparent that the terms "reversible" and "irreversible, a as applied to the carbamy] ester and OP anti-ChE agents, respectively, reflect only quantitative differences and that both classes of drugs react with the enzyme in essentially the same manner as does ACh. REACTIVATION OF ACHE Although the phosphorylated esteratic site of AChE undergoes hydrolytic regeneration at a low or negligible rate, Wilson (17) f ound that the nucleophilic agent hydroxyla~ine ~ H2NOH) can reactivate the enzyme much more rapidly. In the subsequent search for more effective Deactivators, a large number of hydroxam~c acids 9

OCR for page 5
(RCONHOH) and oximes (RCH-NOB) was shown to have this property, e.g., tiacetyl monoxide, or DAM. From the data that accrued, it was predicted that highly effective reactivation should be produced by a molecule containing both a quaternary nitrogen atom ant an oxime group, Spaced at an appropriate distance. Thla goal was achieved (18) with pryidlne~2-aldoxime meehy! chloride ( 2-fonsyI-~-~ethylpyridinium chloride oxime, pralidoxime), reactivation with this compound occurs in one millionth the time of that with hydroxylamine (19). Some bisquaternary oxides were later shown to be even more potent as reactivatore; an example is obitoxime chloride (Figure 3)- 1~1~-(oxydimethylene)o Lis(4-fonmy~pyridiniu~), dichloride dioxide (20~. 0 ~,c - ~~ D.oc~ "canoed 1~, 1 Cal CHe ~d~b8~. c~P~(~-J Ho~cH x" 0~.~ Chase Fig. 3: Cholinesterase Deactivators. Reproduced from Roelle, G.B. In:The Pharmacologic Basis of Therapeutics (Goodman, L.S. and Gilman, A., eds.), 5th ed. Macmillan Publo CO.. 1975, pg. 458. The mechanism of reactivation is sketched in Figure 4. When the quaternary ammonium group of pralitoxime is attracted electrostatically to the anionic site of the enzyme, the oxime group of the former is oriented optimally to exert nucleophillc attack on the electrophilic phosphorus atom of the phosphorylatet esteratic site; the oxime-phospho~ate is then split off, leaving the enzyme (21,22~. Although the oximes reactivate phoaphorylatet cholinestereae in vitro and increase recovery from intoxication produced in vivo by some organophosphates, they are not panaceas for the treatment of pig by anti-ChEs. Pralidoxime and obidoxime are Quarternary ammonium compounds, and their capacity to reactivate brain enzymes is inhibited by the blood-brain barrier. In is also debatable whether pralitoxime and related agents can effectively antagonize the manifestations of intoxication by neostig~ine and other carbamyl ester inhibitors. Moreover, coat phosphorylated AChEs undergo a fairly rapid process termed aging and within the course of Pollutes or hours, thereby become completely resistant to reactivatora.

OCR for page 5
Hox so H.C~O =.1~? :~J IC - ~I - - o ~tC3O j =3~' Kl -of Pock +~0. QC=NOH CL7I .NOF' ~=9_ Come Ontme phospl~ot~o - ~CH~bJOted CH, HACK Amp. _~_ InI~ Fig. 4. Reactivation of alkylphoaphorylated acetylcholinesterase (AChE). After alkylphosphorylation of AChE by DFP (left), spontaneous hydrolytic reactivation occurs at an insignificant rate (upper reaction), as indicated by the dashes arrow. -4 1ng. is the loss of one of the isopropoxy residues that occurs more rapidly than spontaneous hydrolysis; the product is very realatant to regeneration by pralldoxlme. Pralidoxlme (lower reaction) combines with the anionic site by electrostatic attraction of ita qua ternary nitrogen atom, Which orients the nucleophlllc oxide group to react with the electrophilic phosphorus atom; the oxime-phoaphonate is split off, leaving the regenerated enzyme. Reproduced from Koelle, G.B.: In The Pharmacologic Basis of Therapeutles (Goodman, L.S. and Gilman, A., ads.), 5th ed. Macmillan Publ. Co., 1975, pg. 457. AGING OF I~IBI~ ACHE Aging causes Inhibited enzymes to become refractory to reactivation. The phenomenon was first reported In 1955 by Bobblger (23) and later observed with OE-inblbited AChEs (26,25) ant with an OP-lahibited atropinesterase (26). An extensive discussion of aging Way be found in Berend's thesis (27). The process determines the time during which reactivatore can be expected to be beneficial for those exposed to OF anti-ChEa. In the case of OF anti-ChEs, an Inhibited (e.g., phoaphorylated) 11

OCR for page 5
enzyme, which initially can be reactivated by oxides, is changed to a form that cannot be reactivated by these compounds (19). The term aging has been applied because the amount of inhibited enzyme refractory to reactivation increases with time. For example, Berry et al. (28) observed that, although pretreatment of animals with a combination of pralltoxime (2-PAM) and atroplne increased the LD,o values of several compounds (cog., TEPP and DFP), it hat little effect on the lethality of satin and none on the lethality of soman; they concluded that this was the result of the rapid aging of the ChEs inhibited by satin ant aortas. More direct evidence of in viva aging was obtained by Harris et al. (29), who injected 32P-labeled saris and aoman into rats and observed that the rate of aging of the inhibited rat-brain AChE was the same in viva as in parallel in vitro experiments. Aging is probably due to the aplitting-off of one alkyl or alkoxy group from the inhibited enzyme, leaving a more stable monoalkyl- or monoalkoxy-phosphoryl AChE (30,31). Wilson (32) pointed out that the difference in reactivatability may be associated with the relative reactivity of secondary and tertiary phosphate esters. Whereas the original inhibited enzyme is a tertiary phosphate ester, the dealkoxylated derivative is a secondary phosphate ester. Thus-, the rate of aging depends on the phosphoryl group (33) and not on the group hydrolyzed from the OP by cholinesterase (ChE). Berry and Davies (28) observed, as have many others, that soman yields the most rapidly aged-inhibited ChE obtained from any available anti-ChE; the half-life of the pinacolyl phosphonylatet enzyme was determined to be less than 1.5 min. The next most rapidly aged-inhibited enzyme also contained a branched-chain secondary group; (CH3)2-CH-CH(CX3)-0~-) Some straight-chain secondary groups, such as CH3-CH2-CH(CH3)-OH-, were also associated with relatively rapidly aged-inhibited enzymes, the phosphonylated enzyme half-life being about 0.5 h. Berry and Davies (28) noted that aging 'is slow when the alkyl group is a primary alcohol, whether or not the carbon chain is branched, but is much more rapid if the alkyl group is a secondary or cyclic alcohols CHOLINERGIC RECEPTOR AND ACH CHANNEL . In addition to reacting with ChEa, OPs ant other anti-ChEa also can react with other critical molecules in nerves or in effector organs. OP drugs may exert direct effects on the cholinergic receptor or on its phospholipid environment, at both CNS and ENS synapses (34-38~. OPa also react with other neural ant metabolic enzymes, ant some of them are capable of alkylating DNA. The biologic consequences of these reactions are not as well understood as are those inhibiting ChE. White and Stedman (39) Suggester that, in addition to inhibiting AChE, OP compounds have an effect on the aite where the ACh molecule reacts at the neuromuscular Junction. Riker and Wescoe (40) showed a direct agonist action of neostlgmlne at the neuromuscular junction, ant many others have found that neoatigmine and some other anti-ChE agents have anticurare effects not apparently related to inhibition of ChE (41). Additional observations indicated that preparations that had been denervated for over 20 d responded with a contracture when exposes to satin, 12

OCR for page 5
and findings described below indicate that anti-ChE agents like neostigmine cause marked destruction of denervated muscle (42,43~; this phenomenon is most likely correlated with the partial agonist effect of neostigmine. Similarly' Mique] (44) suggested that OP compounds react with other sites on the muscle, in addition to the enzyme itself. Studies by Xavier ant Valle (45) disclosed that Phos~rinR, an OP insecticide, was able to affect both the ACh receptor and the ion channel associated with it, but without affecting AChE itself. They also found, using two different methods, that physostig~ine and neostigmine, in addition to producing blockade of AChE, potentiated the muscle response to ACh when applied in the presence of complete AChE blockade. Albuquerque's studies with OP compound. (46) have suggested an additional effect on the ionic channel that is unrelated to the sites of reaction of ACh on AChE or on the ACh receptor. The simple presence of OP compounds makes the reaction of many agonists, particularly ACh and anatoxin (AnTX),, more intensive and speed ~ the ef feet s of some compounds that block the ion channel. Several agents that react both with the ACh receptor and the channel appear to antagonize the action of the OP compounds in this manner. Conversely, the binding rate of OPs is increased when increasing concentrations of the agonist are present (46), and the rate of binding induced by the presence of large quantities of agonist can occur whether ACh is the agonist or other agents--such as AnTX, subaryldicholine, and succiny~choline--are used in place of ACh. PRESY.NAPTIC ACTION Anti-a~E agents have presynaptic effects that are related mostly to a reaction with the presynaptic nerve seminal (47-55~. A number of workers reported that compounds such as neostigmine and physostig~ine augment and prolong - spontaneous release of ACh (miniature endplate potentials or MEPPs) ant increase the size of endplate potentials (EPPs) (48,56-59~. Boy d and H - rtin (48) reported a biphasic effect of ChE inhibitors: an increase at low concentrations and a decrease at high concentrations. In a detailed study of the action of neostigmine, ambenonium, edrophonium, and methoxyambenonium on cat tenuissimus muscle, Blaber and Christ (60) reported that MEPP frequency was increased by several ChE inhibitors, and concluded that the effect is probably not related to ChE inhibition but might be related to excitation-secretion coupling, the process by which an action potential releases ACh. The only published study on presynaptic effects of the more potent ChE inhibitors is that of Abraham and Edery (49), who examined the effect of soman on synaptic transmission in rat diaphragm. In vitro soman increased the frequency of MEPPs (an effect blocked by Mgl'), caused muscle depolarization that reversed spontaneously, ant increased quantal content. It was suggested that the observed changes in transmitter release resulted from an effect on the action potential invadlag the nerve terminal, although no direct evidence was offered. 13

OCR for page 5
In addition, several ChE inhibitors generate an.tidromic action potentials in motor nerves; these may occur spontaneously (57,619 62) or after an orthodromic nerve volley (47,50,62-64~. The potentials are apparently not caused by action potentials originating in muscle, inasmuch as the antidromic repetitive firing has been observed in nerves from muscle incapable of twitching (62)0 Riker en al. (50) and Werner (5l,52) concluded that the antidromic discharges were produced by direct actions on the motor nerve terminal. Although ChE inhibitions smith later accumulation of ACh and an increase in extracellular potassium concentration, may be the cause of the observed effects, these posalbilittes are unlikely. NERVE MEMBRANE _ ~ .. Another example of an effect apparently unrelated to ChE inhibition is found in studies of the actions of ChE inhibitors on ionic conductances of electrically excitable membranes. When single frog nerve fibers were used, physostigmine (~-10 - ) attenuated action potential and current, markedly prolonged the duration of the current, and slowed conduction. This mechanism might be involved in functional sensory deficit aad--$f selective for inhibitory fibers, as is the case with local anesthetics (65)o~might play a role in generation of facilitation before depression. CENTRAL NERVOUS SYSTEM The situation is still more complex in the CNS. Even if the action of anti-ChEs were limited to the inhibition of postsynaptic AChE, the complex circuitry of the brain provides ample opportunity for effects at other sites. Because brain cholinergic pathways are diffuse ant connect with many other systems, overactivity or blockade of cholinergic synapses can lead to aboonmal activity in many other neurons. Apparently, there is no end to the lint of transmitters and bioactive substances that can be affected indirectly or directly by cholinergic agonists (66~. Among the effects in question are those on the Y -aminobutyric acid (GABA) system which are important in brain excitability and epileptogenesis (67), as well as those involving peptide transmitters and bioactive peptides (68)0 It it unknown whether these effects are brief or long-lasting. For example, it is unlikely that a perturbation in GABA content would be long-lived after the initial effect of the ant i-ChE on the GABA system. However, the circuit ~ are complex, and even a temporary perturbation: might lead to reverberations that persist for a long time. The CIIS has only a limited capacity to regenerate, and recovery after tissue damage might be slow or incomplete. It is also known that a brief presence of excess transmitter in a synapse can lead to compensatory changes in the number of postsynaptic receptors. "NECtROTOXIC" ESTERASE (NTE) Some OPs react with a poorly cnaracterizet enzyme--"neurotoxic esterase" (NTE)--of unknown function resident in CNS, ENS, and some o ther tissues and precipitate a delayed CHS-PtIS distal axonal degeneration, which is expressed clinically as a sensorimotor

OCR for page 5
The aubJectIve manifeatatio4e of brain dysfunction usually disappear shortly after cessatlo4 of exposure; in most 14atances, BEG abnontallties reportedly dleappear vlthin 2 Ok of acute exposure or termination of chronic exposure (90~92). ACUTE TOXIC EFFECTS Toxicity of particular OF compounds does not vary greatly ~IBODg mammals. Slgna and y'rptoole differ eal41y to sequence and 14 indivltual prominence (93-96). Rapidity of appearance, 14te4~1ty, and timecouree depend 04 close and route of adel4istratlo4. The effects of acute latoslcatlo4 with antl-ChZ agents are manifest by o~uscarinic and 4icotl41c ig4e and "ptoes and, except for compounds of extremely low colubllity 14 lipids, 1gns referable to the CNS. Effects may be local or general. Local effects are due to the action of vapors or aerosols at their elte of contact filth the eye a or respiratory tract or to the local absorptlo4 after liquid contamluatIon of the skin or oucoua membranes, 14clutlDg those of the geatrointestl~l tract. Genere1 effects rapidly follow systemic absorption by any route; they appear moat Tepidly after inhalation of vapors or aerosols, In which case severe effects any appear within a few minutes. In contrast, the onset of Captor after gastrointestinal and percutaneous abeorptlo4 1e delayed. The duration of effects is determined largely by the nature of the compound; it may vary from minutes, as after an overtone of edrophonlum, to several days or even veeka after lrreverelble alkylphoaphorylation of AChE, as by DFP or sable. After exposure to vapors or aerosols or after lchalatlo4, ocular and respiratory effects generally appear first. Ocular effects include marked miosia, con junctival congestion, clliary spasm, and brovache, along with watery nasal dlecharge; respiratory effects consist of tightnesa" to the cheat and-'rheezing due to the combination of bronchoconatriction and increased bronchial secretion. After ingestion, geatrointestinal effects appear first, including anorexia, nausea and vomiting, abdominal cramps, and diarrhea. After percutaneous absorption of liquid, localized sweating and muscular faaciculatlon in the immediate vicinity are generally the earliest olanifeatations. Severe intoxication la manifest by extreme salivation, Involuntary defecatlo4 and urination, sweating, lacri~atlon, bradycardia, and hypote4eIo4. .Nlcotinic actions at the neuromuscular junctlo4e of Iceleeal mnacle usually consist of fatigability and generalized weakness, involuntary trltchi~, scattered faaciculatlo4, and eventually severe weakness and paralysis. The most erloua co4eequence of the neuromuacular actions la paralyala of the respiratory muscles. The effects 04 the CNS include co~uaio4, atasla, slurred speech, lose of reflexes, coca, and central respiratory paralysis. Actions on the vasomotor and other cardiovascular centers add to the peripheral actions to complicate the hemodynamic patted. Afeer large doses or lchalation of high coocentratlo4s, the Dime course may be telescoped into a few minutes and "my of the above 1gns overshadowed by dyspnea, apnea, and collapse. ~ case of severe accidental poisoning in man is illustrative (97). Development of signs after smaller doses has been described by Grob (98,99) and others (100-104). 21

OCR for page 5
16. Burgen, A.S.V. and Hobbiger, F., 1951: The inhibition of cholinesterses by alky~phosphates and slky~phenolphosphates BrO J. Pharmac . Chemother. 6. 593~605. 17. Wilson, I.B., 1951: Acetylchollnestersse. XI Reversibility of te tree thyl pyrophosphate inhibition. J. Biol . Chem. 190. Ill-~17. 18. Wilson, I.B. and Ginsburg, S., L95S: A powerful reactivator of al ly lpho sphat e-inhi bited acetylcholines terase . Biochem. Biophys. Acta 18 :168-170. 19. Heilbronn-Wikstrom, E., 1965: Phosphorylatet cholinesterases, their formation, reactions ant intucet hydrolysis. Svensk Kem. Tits Kr. ~ 17 :11-43. 20. Hobbiger, F., and Vo~vodic, V., 1966: The ractlvating and antidotal actions of ~B4 and Toxogonin and with particular reference to ~cheir effect on phosphorylated acety~cholinesterase in ~che brain. Blochem. PharmacolO 1501677-1690. 21. WiLson, I.B., 1959: Molecular complementarily and antidotes for alkylphosphate poisoning. Fed. Proc. Am. Soc. Exp. Biol. 18o 752-758. 22. Froede, H. and Wilson, J.B. 1971: Acetylchol~nesterase, In: The Enzyme s, Vol . 5 . ~ Boyer, F.13 . ed ~ Acad . Press Inc O N . Y. pp 87-114. 23. Hobbiger, F., 1955: Effect of nicotinhydroxamic acid methlodide on human plasma cholinesterase inhibited by organophosphates containing a dialkylphosphato group. Bri t. J. Pharmac. 10 :356-362 . 24. Michel, HoO., 1958 Development of resistance to alkyl phosphorylatet cholinesterase to reactivation by oximes (Abstract) Fed. Proc. 17:275. 25. Rozengard, V.~. and Balashova, E.K., 1965: Russian Title Doklady Akad. Nauk. SSSR 164:937~940. 26. Adie, P.A., 1967: Proceetings of the conference on structure and reactions of DFP sensitive enzymes (Heibronn, E. ea.) Stockholm, pp. 167-172. 27. Berends, F., 1964: 'Veroutering van Esterasen Geremd met Organische Fosforverbindengen, Thesis. University of Leiden. 28. Berry, W.K. and Davies, D.R., 1966: Factors influencing the rate of "Aging of a series of alky1 methylphosphonyl- acety~cholinesterases. Biochem. J. 100:572-576. /. ~

OCR for page 5
29. Elarris, L.W., Fleisher, J.H., Clark, J. ant Cliff, W.J., 1966: Dealkylation and 108s of capacity for reactivation of cholinesterase lohibited by sarin. Science 154:404-407. 30. Berents, F., Posthumua, C.H., Van ter Sloys I. and Deierkauf, F.A., 1959: The chemical basis of the aging process of DFF-inhibited pseutocholinesterase. Blochim. Biophys. Acta 34: 57 6-578. 31. Fleisher, J.H. and Harris, L.W., 1965: Dealkylatlon as a mechanism for aglag of cholinesterase after poisoning with pinacolyl methylphosphonofluoritate, Biochem. Pharmacology 14: 641~650. 32. Wilson, I.B., 1967: Confoneation changes in acetylcholinesterase . Ann. N.Y. Acat. Science 144: 664O674 . 33. Lamb, JoC ~ and Steinberg, G.M., 1964 : Gompari sons of reactivation ant ageing rates of eel acety~cholinesterase inhibltet by GB and 4PPAM. Biochim. Biophys. Acta. 89:171-1730 X~rczmar , A.G., 1967 : Neuromuscular Pharmacology . Ann. Rev. of Pharmacology (Elliott ed. ~ 7:241-276. 35. Van Heter, W.G., Karesmar, A.G., and Fiscus, R.R., 1978: CNS effects of anticholinesterase-s in the presence of inhibited cholinesterases. Arch. Int. Pharmacodyn. Ther. 23:249-260. 36. Kuba, K., ALbuquerque, E.X., Daly, J. and Barnart, E.A., 1974: A study of the irreversible cholinesterase inhibitor, tiisop~opyl-fluorophosphate, on t ime course of entplate currents in frog sartorius muscle. J. Pharmacol. Exp. Ther. 189:499-512. 37. Gage, P.W. ~ 1976. Re~r. 56 :17 7-24 7 . Generation of endplate potentials. Phys. 38. Baron, L.R., 1981: Delayed neurotoxicity and other consequences of organophosphate esters. Ann. Rev. Eneomol. 26 :29-48. 39. White, A.C. and Sted~an, E., 1931: On physos~igmine-like action of certain synthetic urethanes. J. Pharmacol Exp. Therap. 41: 259-288. 40. Riker, W.K., Jr. and Wescoe, W.C., 1946: The tirect action of prostigmine on skeletal muscle; lts relationship to the choline esters. J. Pharmacol. Exp. Ther. 88: 58-66. 41. Walker, M.B., 1934: Lancet 1:1200-1201. 42. Tiedt, T.N., Albuquerque, E.X., Hudson, C.S., and Rash, J.E., 1978: Neostigmine-induced alterations at the mammalion neuromuscular Junction. I. Muscle contraction and electrophysiology. J. Phar~acol. Exp. Ther. 205:326-339. 41

OCR for page 5
43. Hudson, C.S., Rash, J.E., Tiett, T.N., and Albuquerque, E.Xr, 978: Neostigmine-induced alterations at the ca~alian neuromuscular Junction Il. Ultrastructure. J. Pharm. Expo Therap. 205: 340-356 44. Miquel, 0., 1946: The effect of chloroform ant ether on the activity of cholinest-erase. J. Phamacol. 880190~193. 45. Xavier, E. and Valle, J.R., 1963: Synergism of cholineaterase inhibitors with acetylcholine on toad rectus abdominis mnacle. Ac ta Physiol. Lat . Amer. 13: 282-289. 46. Albuquerge, Edson (1982) Unpublished studies, University of Maryland School of Medicine, Baltimore ~ HD. Blaber, L.C. and Bowman, WOC., 19636: Studies on the repetitive discharges evoked in motor nerve and skeletal muscle after in jection of anticholinesterase drugs. Brit. J. Phar~aeol. 20:326 344. 48. Boyd, IoA. and Martin, A.R., 1956a: Spontaneous subthreshold activity at mammalian neuromnacular junctions. J. Phyalol. (London) 132:61-73. 49. Abraham, S. and Edery, H. (1977) Presynaptic effect of soman in the rat isolated diaphragm. Israel J. of Medical Sciences 13.1142~11430 50e Riker, WoFe ~ Jr. Roberta, J., Standaert, F.G., and Fu jimori, H., 1957: The motor nerve terminal as the primary focus for drug-laduced facilitation of neuromuscular transmission. J. Phame Exp. Therapeut. 121:286-312. 51. Werner, G., 1960a: Neuromuscular facilitation and antidromic discharges i:~ motor nerves: Their relation to activity in motor terminals. J. Neurophysiol. 23 :171-187. 52. Werner, G., 1960b: Generation of antidromic activity in motor nerves O J. Neurophysiol. 23: 453-461. 53. Hubbard, J. and Schmidt, ReF. ' 1961: Stimulation of motor nerve terminals. Na ture 191: 1103-1104. 54. Laskowski, M.B., and Dettbarn, W.D., 1975: Presynap tic effects of neuromuscular cholineaterase inhibition. J. Pharm. Exp. Ther. 194:351-361. 55. Laskowski, M.B., Olson, W.ll., and Dettbarn, W.D., 1977: Initial ul tras truce trual abnonealitlea at the motor endplate produced by a cholinesterase inh! bitor. Exp. Neurol. 57 :13-3 3. 56. Feng, T.P., 1940: Studies on the neuromuscular junction. Chin. J. Physiol. 15 :367-404. 42

OCR for page 5
57. Feng, T.P., ant Li, T.H., 1941: Studies OR the neuromusclar Junction. Chin. J. Physiol. 16: 37-56. 58. Eccles, J.C. and MacFarlane, As., 1949: Actions of Anticholinesterases on endplate potential of frog muscle J. Ndurophysiol . 12:5 9~0. 59. Fatt, P. and Katz, 8., 1951: An analyata of the end plate potential recorded with an intra-cellular electrode, J. Physiol. (London) 115: 320~3 70. 60. Blaber, L. C. and Christ, D.D., 1967: The action of facilitatory drugs on the isolated tenuissimus muscle of the cat. Int. J. Neuropharm. 6: 473-484. 61. Midland, R.L. and Wigton, R.S., 1940: Nerve activity accompanying fasciculation produced by prostig~in. J. Neurophysiol. 3: 269-2 75. 62. Barstad, J.A.B., 1962: Presynaptic effect of the neuro-musclular transmitter. Experientla 18: 579-580. 63. Blaber, L.C. ant Bowman, W.C., 1963a : The effect a of Some drugs on the repetitive discharges produced in nerve and muscle by anti cholinesterase s. Int . J. Neuropha=. 2 :~-16. 64. Standaert, F.G., 1964: The mechanisms of post tetanic potentiation in cat soleus and gastrocnemius muscle. J. Gen. Physiol. 47: 987-1001 . 65. Frank, G.B. and Sanders, H.D., 1963: A proposed mechanist of action for general and local anesthetics in the central nervous system. Bri t . J. Phar~acol. 21 :1-9 . 66. 67. Glisson, S.N., Karczmar, A.G. and Barnes, L., 1972. Cholinergic effects on adrenergic transmitters in rabbit brain pert e. Neurophamaco}. 11:456~477. Bowery, N.G., Collins, J.F. and Hill, R.G., 1976: Bicyclic pho sphorus esters that are potent convulsants and GABA antagonists. Nature 261: 601-603 . 68. O'Neill, J.J., 1981: Non-cholinesterase effects of antichollne~terases. Eland. and Appl. Toxicol. 1:154-160. 6 9. Johnson, H.K., 1982: The target for initiation of delayed neuro toxicity by organophosphorua esters: Biochemical studies and toxicological applications. Reviews in Biocheme Toxicol. ~ (Hodgson, E. ~ Band Ee and Philpot, R.M. ~ eds. ) Sol. 4, Elsevier, N. Holland, flew York. 43

OCR for page 5
70. Boultin, T.W. and Cavanaugh, J.B., 1979: Organophoaphorus neuropathy: 1. A tessed-flber atuty of the spatio-temporal spread of atonal degeneration. Am. J. Phar~acol. 94:241. 71. Cavanaugh, J.B., 1979: Tri-orthocresylphosphate poisoni:~8. In: Bandbook of Clinical Neurology. Vol. 37: Intoxications of the Nervous System Part IT. (Vinken,- Pal. and Bruyn, G.W. eds) North Holland P~blo Cc~o ~ Am~te~da~, 1979 e Karczmar' A.G. and Van Heter, W.G., 1963: Reports, Subcontract no. SU-630505-63, Mbipar, Inc., 1963. Preusaman, R., Schneider, H., and Epple, R., 1969: Untersuchuengen zum Nachweis Alkylierender Argentien. Azzueimittelforachun~g 19.1059~1073. 74. Bedf ord , C.T. and Robluson, J., 1972 : The allqlating properties of organophosphates. Xenobiotica 2: 307-337. 75. Derache, R., 1977: orgsaophosphate peaticidea. Criteria (dose/effect relatiotlship) for organophosphate pesticides. Pergaman Prese, N.Y. Decloitre, F., 1978: Evaluation of the rat-liver DNA tamage by parathion in relation with its non~mutagenicity. Mutation Res. 53:175. 77. Klmura, H., McGeer, P.L., Peng, J.H., and McGeer, E.G., 1981, Central cholinergic system atudied by choline acetyltranaferase i~unohistochemistry in the cat . J. Comp . Neurol. 200 :151-201 . 78. Hobson, J.A., 1974, The cellular basis of aleep cycle control IQ: Ad~rances in Sleep Research et. by EeDe Weitzman, pp. 217-270, Spectrum, ~w York. 79. Singh, M.M. and Lal, H., 1978, Dy~functions of cholinergic process in schizophrenia 1~: Developments in Psychiatry, Proceetings of 2nd World Cbugress Blological Psychiatry, Barcelona pp. 438~439, VOle IIae 80e Karczmar, AeGe and Richardson, DeLe ~ 1982, Cholinergic mechanisms, schizophrenia and neuropsychiatric adaptive dyofunctions in: Cholinergic mechanisme and adaptive dyofunctions ede by Helle Singh, DeMe Warburton, and H. Lal. Plenum Press, New York. 81. Gershon, S. and Shaw, F., 1961: Psychiatric sequellae of chronic exposure to organophosphorus insecticides. I.ar~cet 13711:13714. 82. Metcalf, D.R. and Holmes, J.H., 1969: EEG, psychological and neurological alterations in h~ans with organophosphate exposure. Ann. N.Y. Acad. Sci., 160:3S7-365. 44

OCR for page 5
83. Duffy, F.A. ant Burchflel, J.L., 1980, Long term effects of the organophosphate sarin on BEG in monkeys ant humans. Neurotoxicology ~ :66 7-689. 84. Freeman, A.G. and Ohta, Y., 1981, Neuromyophar~aacology as related to ~anticholinesterase action. Fundamental and Applied Toxicology ~ :13 5-142. 85. Koelle, G.B., 1975: Anticholinesterase agents. In: The pharmacological Basis of Therapeutics. 5th Ed. (~:ood~nan, I`.S. and Gilman, A. eds) pp 445~466. Alan Co., New York. 86. Wadia, R.S., Sadagopan, C., Amin, R.B., and Sardesai, H.Y., 19 74: J. Neurol. Neuro~urg . Psychiat ~ 37: 841-847. 87. Burchfiel, J.L., Duffy, F.H. and Sim, V.M., 1976: Persistent effects of satin and dieldrin upon the primate elec troncephalogram. Toxico}. Appl. Pharm. 35 0 365-379. 88. Grob, D., and Harvey, J.C., 1958: Effects in man of the anti cholinest erase compound satin ~ $sopropy~me thy~phosphonon- fluoridate) . J. Clin. Tamest . 37: 350O368. 89. Bowers, M.B., Goodman, E. and Sin, V.N., 1964: Some behavioral changes in man following antlcholinesterase administration. Journ. Nervous and Mental Disease 138: 383-389. 90. Grob, D., Harvey, A.M., Langworthy, O.R. and Lilienthal, 3.L., Jr., 1947: The administration of ditsopropy] fluorophosphate (DFP) to man: III Effect on the central nervous system with special reference to the elec trical activity of the brain. Bull . Johns Hopkins Hosp ., 81: 257-266. 91. Holme s, 3. H. and Goon, M.D . 1956: Observations an acute and multiple exposure to anticholinesterase agents. Trans. of American Clinical and Climatological Assn. 69th Ann. Mtg. Nov. I,2~3, pp. 86-103, Sky 'rOp Lodge, Sky Top, PA. Wa~rerly Press. 92. Santolucito, J.A. and Morrison, G., 1971: BEG of Rhesus monkeys following prolonged low-level feeding of pesticides. 'row. Appl. Pha maco ~ . 19 :14 7-154 . 93. Grob, D., 1963: Adticholinesterase intoxication in man and its treatment. In: Cholinesterases and anticholinesterase agents., ~ G. B. Koelle ed . ~ Handbook Exp. Phaneacol. 15: 989-1027. Springer-Veriag, Berlin. 94. *Prop, S. , Green, R.E., ~escoe, W.C. , and Kunkel, A.~. , 1951: The pharmacology of GA and GB. Observations on respiratory, circulatory and intestinal actions. HDRR39, Edgewood, MD. *Found only at the Edgewood library. 45

OCR for page 5
95. Modell, W.E. ant Krop, S., 1946 Antitotes to poisoning by "i-isopropyl fluorophosphate ln cata. J. Pharm. Expr TherapO 88 34-38. 96. DeCandolle, C.A., Douglaa, W.W., Evana, C.I~., Holmea, R., Spencer, K.E.V., Torrance, R.W., and Wilaon, R.M., 1953 The failure of reapiration ln death by anticholineat:ereae potoo~ n~g . Brit . Journ. Phamaco3. 0 ~ 466-475 ~ 97. *Ward, J.R., Goaselin, R., Comatock, J., Stagg, ~JO' and Blanton, 8.R., 1952 Case report of a aevere human poisoning by G8. ~RR 151, Edgewood' - . 98. *Grob, D. and Harvey, A.~., 1951 Final Summary Contract DA-18-108-C~-416, Edgawood ~ - . 99. *Grob, D. and Harvey, A.M., 1953 The effects and treatment of nerve gas poisoning. MLCR 18, Edgewood, ~. 100. *Kimura, K.K., McNamara, B.P., and S1m, V.M., 1960: Intravenous ad~iniatratior~ of VX in mesa. C8DLR 3017, Edgewood, MD. 101. *Gaon, M.D., 1959 Report of medical experience on acute and repeated exposure a in humane with nerve gsa (GB) at RHA. Proceedings of the 1959 Army Science Conference, U.S. Mllitary Academy ~ ~Jest Point, NY, June 24-26, 1959. e 102. *Sim, V.M. and Stubbs, J.~., 1960 VX Percutaneoua stuties in man. CRDLR 3015' Edgewood, MD. 103. *Brown, E.C., 1948 Effecta of G-agenta on man: Clinical obeervations. M'R 158, Edgewood, ~). 104. *Sitell, F.R., 1967 Bu~an reaponaea to intravenous VX. EATk 4082 ~ Edgewood ~ MD. 105. *Marzulli, F.N., Wilea, J.S., Weimer, J'oT.. Van te Wal, A., Thomea, W.V., ant Atkinaon, J.C., 1959 Intramuacular toxicit' and signe of poisoning with VX: with reco~ended estimatea for humane beaed on animal data. CWL Special Pub. 2-23, Edgewood, MD. 106. *Neitlich, H.W., 1965 Effect of percutaneoua GO on huo~ar subJects. CRDL TM 2-51~ Edgewood, }21). 107. *~mford, S.A., l9SO: Physiologicalaasesament of the nerve gases. Porton ~morandum 39, Great Britain. 108. *McNamara, B.P., 1960: Preacnt status of knowledge and aome required toxicity infor~ation on VX. CWL TM 24-46, Edgewood, MD *Found only at the Edgewood Ilbrary. 46 4

OCR for page 5
109. *Creathull, P., Coon, W.S., t2cGrath, F.P., and Oberat, F.W., ~957: Inhalation effects incapacitation and mortality) for monkeys exposed to GA, GB and GE Capote (U). CWLR 2179. 110. *Lubash, G.D., Grlbetz, I., and Johnson, R.P., 1960: Pulmonary and cardiovascular effect o of satin in treated dabs. CHAR 2389, Edgewood, MD. 111. *Cresthull, P., Christensen, M.K., and Oberot, FeWe ~ 1961: Estimated Speed of action of GB vapor for death and various degrees of incapacitation tn man. CRDI*R 3050, Edgewood, tID. 112. *Silver, S.D., 1953: The estimation of the toxicity of GB to man MLSR 23, Edgewood, MD. 113. *Punts, C.L. and Atkinson, 1960: Ichalatlon toxicity and speed of action of VX with suggested estimates for man based on animal data ~ U) . Edgewood, HD . 114. S~inivasan, R. ,~ Karczmar, AoGe ~ and Bershon, J., 1976: Rat brain acety~cholinesterase and its isoenzymes after intracere brat administration of DFP . Biochem. Pharmacol 25: 2739-2745. 115. Russel, R.W., Carson, V.G., Booth, R.A., and Jeuden, D.~., 1981: Neuropha ntaco l . 20 :1197 . 116. I`orot, C., 1899: I`es combinations de la creosote dans le traitmant de la tuberculose pulmonaire, Thesis, Paris. Cited by lIuntter, D. In: Industrial Toxicology, Clarenden Press, Oxford, 1944. 117. Burley, B.T., 1932: Polyneuritia from tricresylphosphate. J. Am. Hed. Assoc. 98 :298-304. 118. Smith, H. ant Spalting, J.~.K., 1959: Outbreak of paralysis in Morocco due to orthocresyl phosphate poisoning. Liancet 277 :1019-1021. ~ 119. Xintaras, C. and Burg, J.R., 1980: Screening and prevention of human neurotoxic outbreaks: Issues and Problems In: Experimental and Clinical Neurotoxicology ~ Spencer, P. S . and Schaumberg, B.~. ede. ~ pp. 663-674. Williams and Wilkins Co., Baltimore, MD. 120. Morgan' J.P. and Penovlch, P., 1978: Jamaica ginger paralysis. Forty-seven-year follow~up. Arch. Neurol. 35:530-532. *Found only at the Edgewood library. 47

OCR for page 5
121. Abou-Donla, M.D., Grahaot, D.G. and Komcil, A.A., 1979: Delayet neurotoxlci ty of 0~( 2, 4-dichlorophenyl) -O~e thy 1 phoaphonothiate. Effect of a aingle oral tose on hena. Tox. Appl. Pharmacol. 49:293. 122. Airing, C.D., 1942. The aystemic nervous affinity of trtorthocresylphoaphate (Jamaice Gi DgeF Palay). Brain 65:45-47 123. Spencer, P.S. and SchauD'burg, H.H., 1980: Claasification of neurotoxic disease. ~ morphological approach. In: Experio~ental and Clinical Neurotoxicology, (Spencer, P.S. ant Schaumburg, H.H., eda. ) pp. 92-99, Williao~e ant Wilkins Co., Baltimore . 124. Davies, D.R., Holland, P. and Rumens, H.J., 1960: The relationship between the chemical structure and aeurotoxicity of allyl organophosphorus compounde. Brit. J. phar~acol. 15 o2 71-2713 0 125. Tabershaw. I.R. and Cooper, W.C., 1966: Sequellae of ac~ate organic pho sphate poisoning ~ JO Occup ~ Med ~ 8 0 5-10 ~ 126. Rowntree, D.W., Nevin, S., ant Wilaon, A., 1950: The effects of disopropylfluorophosphonate in schi20phrenia ant manic tepreaslve paychosis. J. Neurology, Neurosurgery and Paychiatry 13:47~62. 127. Duffy, F.~., Burchfiel, J.I`., Bartela, P.~., Gaon, M. and Sim, V. 1979: 1.ong-tene effects of an organophoaphate upon the human electroencephalogram. Toxicol. Appl. Phar~acol. 47 :161-176. 128. Petrea, J.M., 1981: Soman Neurotoxicity. Funt. and Applo Toxicol. ~ :242 ~ 1290 Fenichel, G.M., Ribler, W.B., Olson, M.D. and Dettbarn, W.D., 1972: Chronic inhibition of cholinesterase as a cause of myopathy, Neurology 22:1026~33. 130. Engle, A.G., Iambert, F.~. and Santa' T., 1973: Study of long-ter~ anticholinesterase therapy: Effects on neuro~uscular transmission and on motor end-plate structure. Neurology 23:12 73-1281. 131. Glazer, E.J., Balcer, T. and Riker, Si.F., Jr., 1978: The neuropathology of DFP at cat soleus neuromuscular Junction. J. Neurocytol. 7: 741-758. 132. Laskowski, M.B., 0180n, W.Il., and Dettbarn, W.~., 1975: Ultrsatructural ehangea at the motor end-plate produced by an irreversible cholinesterase inhi bitor. E5cp. Neurol. 47: 290~3 06. 48

OCR for page 5
133. Fenlchel, G.M., ICibler, W.B. ant Dettbarn, lI.D., 1974: l~he effect of immobilization and exerclae on acetylcholine~etiated myopathic 8 ~ ~urology 24:1086-1090. 134. Wecker, Id. ant Dettharn, W.D., 1976: Paraoxon-intuced myopathy: ^acle specifict~cy and acety~choline tnvolvement. Exp. Neurol. 51:281-291. 135. Lowntes, H.E., Bal~er, T., and Riker, W.F., Jr., 1974: Motor nerve dy~function in telayet DFP neuropathy. European J. Phamacol. 29:66-73. 136. Wecker, L. and Dettbarn, W.D., 1976: Paraoxon-inducet myopathy: Mbscle specificity ant acetylcholine in~olvement. Exp. Neurol. 51:281-291. 137. Wecker, I.., Mrak' R.E., and Dettbarn' W.D., 1981: J. Environ Pathol. Toxicol. 13 8. Laskowski, M. B. , Olson, W.H. ant Dettbarn, W.D. , 1976: Motor end-plate degeneration coincident with cholinesterase (ChE) i~nhibition and increased miniature end-plate potential frequency. (Abetract) Fed. Proceed. 35:800. 139. Sylianco, C.Y.~., 1978: Some interac~tions affecting the mutagenicity potential of dipyrone, hexachiorophene, thiodan and malathion. Mutation Res. S3:271-272. 140. Wild, D., 1975: ~tagenicity seudies on organophosphon~s in~ecticide~. Hutation Res. 32:133-150. 141. Simmon, V.F., Poole, D.C., and Newell, G.W., 1976: In vitro mutagenic studies of twenty pesticides. (Abetract) Tox. Appl. Pharmacol. 37:109. 142. Griesemer, R.A. and Cueto, C. Jr., 1980: Toward a classification acheme for degrees of experi~ental evidence for the carcinogenicity of che~cals for animale. Molecular and cellualr aspects of carcinogen acreening teste. (Moncoano, R., Bart ach, H. a" Tomatis, ~ . ede) lARC Scientif ic Pu blications, No. 27, Z.yon, France. 143. Krause, W. an Homola, S., 1972: Beeinflusaung der Spermiogenese diurch DI)VP (Dichlonro 8)e Arch. Dermstol. Forech. 244:439-441. 144. Bateman, A.~., 1976: The mutagenic action of urethane. MOtation Re s. 39 :7 5-96 . 145. Tomatis, L., Agthe, C., Bartsch, II., Huff, J., Montesano, R. Saracci, R., Walker, E., and Wilbourn, J., 1978: Evaluation of the carcinogenicity of chemicala: a re~riew of the monograph programe of the International Agency for Research on Cancer. Cancer Research 38: 877-~85. 49

OCR for page 5
146. Kimbrough, R.D., and Gaines, T.B. 1968: Effect of organic phosphorus compounds and all~ylating agents on the rat fetus O Arch. Environ. Health 16:805008. 147. Dobbins, P.K., 1967: Organic Phosphate ~aecticides as Teratogens in the rat. J. Fla. Hied. Assoc. 54:452-456. 148. Altelason, U. and Hol~berg, As' 1966: The frequency of cataract after Biotic therapy. Acta..Ophthal. 44.421-429. 16~9. Shafer, R.N. and Hetherington, JO, Jr., 1966. Anticholinesterase druge.and cataracts. AD. J. Ophthal. 62:613-618. 150. Latiea, Add., 1969: Localization in cornea and lens of topically-applied irreversible cholineatereae inhibitors. Am. J. Ophthal. 68.848-857. 151. Kaufman, POD. ant Axelason, V., 1975: Induction of aubcapsular cataracts tn aniridio velvet monkeys by echothiophateO InvestO OphthalO 140863-8660 -. 1520 Chamberlain, W., 1975: Anticholinestease miotles in the management of accommodative eso tropia O J. Pedia trio Ophthal . 12: 151-1S6. 153. Van ICaulla, K. and Holmes, J.~.: Changes in blood coagulation following exposure to antlchollnestersse agents (parathion and sari n) Semi-sanual progre so report . Contract DA-18-108 6~05~CML-264. October 1958-March 1959, Supplement 20 1540 Von Kaulla, K. and Hole, J.H., 1961: Changes following anticholinesterase exposures. Arch Environ. Health 2:82-168. 155. Holmes, Jut., Starr, H., Hacisch, R.C. and van Kanalla9 Ko' 1974: Short-term toxlelty of mevInphos. Arch. Environ. Health 29: 84-89. 156. *Sidell, F.R., Groff, W.A., and Vocci, F., 1965: Effects of EA 3148 ado~intstered intravenously to humane (U). CRDL TM 2-31, Etgewood, ha). 157. Research News; 1981: 2lalathlon threat tebunlcet. Science 213: 526-52 7 ~ *Fount only at the Edgewood library. 50