肌电图检查在有机磷中毒后迟发性神经病诊断中的应用

目的探讨有机磷中毒后迟发性神经病的肌电图特点及诊断价值。方法对22例有机磷中毒后迟发性神经病的患者进行神经传导速度测定与同心圆针肌电图检测。结果神经传导速度测定显示广泛性周围神经脱髓鞘及轴索的损害，同心圆针肌电图提示神经源性损害，分析发现运动神经损害重于感觉神经，下肢神经损害重于上肢。结论肌电图检查对有机磷农药中毒后迟发性神经病有重要的诊断意义。有机磷农药中毒患者应及时进行肌电图检查．以助于迟发性神经病的早期诊断与治疗。     

急性有机磷农药中毒致迟发性多发性神经病30例分析

目的探讨急性有机磷农药中毒后迟发性神经病的临床特点,以提高早期诊断及治疗效果。方法回顾30例迟发性多发性神经病发生的时间、症状及体症,结合辅助检查,进行系统分析。结果 30例迟发性多发性神经病患者均为口服中毒,潜伏期为10～32d,平均18d。主要表现为肢体末端开始的感觉和运动障碍,表现为疼痛、麻木、无力、肌肉萎缩、腱反射减弱或消失,肌电图示神经源性损害。用糖皮质激素、B族维生素等综合治疗,大部分预后良好。结论迟发性多发性神经病经早期诊断,积极治疗,预后一般良好,激素治疗可加速神经功能恢复。     

有机磷中毒迟发性神经病42例临床与电生理检查

目的：探讨有机磷中毒迟发性神经病的临床与电生理检查的价值。方法：对2005年7月-2009年2月42例有机磷中毒迟发性神经病（OPIDP）患者的临床表现和神经电生理检查资料进行总结分析。结果：MCV表现为减慢共39例，3例未引出波型；SCV表现为减慢5例，其余37例正常。经临床随访观寨，分别于3～12个月症状、体征消失，肌力恢复正常，肌电图复查正常。结论：神经电生理检查有助于及早发现病变，值得临床医生予以重视。     

黄芪注射液治疗有机磷杀虫剂中毒致迟发性神经病

目的:观察黄芪注射液对急性有机磷杀虫剂中毒所致的迟发性神经病的治疗作用.方法:采用Doll法将有机磷杀虫剂中毒患者34例随机分为两组.对照组18例,采用常规方法治疗(维生素B12 500 μg,im,每周2次;维生素B6、维生素B1、三磷腺苷各20 mg,复方丹参片3片,均口服,tid;并给予对症、支持治疗等).治疗组16例,则在常规方法基础上加用黄芪注射液30 mL加入0.9%氯化钠注射液200 mL中静脉滴注,bid,用6 d,停1 d,3个月为1个疗程.观察其迟发性神经病患者肌力恢复的情况,并采用肌电图测试正中神经和腓总神经的传导速度.结果:治疗组显效率43.7%,对照组显效率5.6%(P＜0.01);治疗组肌力及神经传导速度恢复情况明显优于对照组,差异有极显著性(P＜0.01).结论:黄芪注射液对急性有机磷杀虫剂中毒所致的迟发性神经病有较好的治疗作用.     

法舒地尔治疗急性有机磷农药中毒迟发性周围神经病变的临床观察

目的探讨法舒地尔对急性有机磷农药中毒迟发性周围神经病变的疗效。方法采用前瞻性随机对照研究方法,对我院2009年2月至2011年12月收治的36例重度有机磷农药中毒患者,随机分为对照组(n=16)和治疗组(n=20),两组均给予阿托品、氯解磷定及血液灌流等常规治疗,治疗组在此基础上给予法舒地尔静脉滴注,对两组患者的临床症状、迟发性周围神经病变的发病率进行分析,观察两组患者临床症状及神经电生理变化,判断其疗效。结果法舒地尔治疗组患者迟发性神经病变发生率明显低于对照组(P<0.05);法舒地尔能显著改善神经传导速度。结论法舒地尔治疗急性有机磷农药中毒能降低迟发性周围神经病变的发病率。     

法舒地尔治疗有机磷农药中毒的临床观察

目的 探讨法舒地尔(Fasudil,Rho激酶抑制剂)对有机磷农药中毒迟发性神经病发病率的影响,以及对其治疗作用.方法 对80例重度有机磷农药中毒患者,随机分为对照组和治疗组,两组均给予阿托品、盐酸戊乙奎醚及氯解磷定等综合治疗,治疗组在此基础上给予应用Fasudil静脉滴注,对两组患者的临床表现、发病率进行分析,观察两组患者临床表现、神经电生理变化,判断临床疗效.结果 Fasudil治疗组患者迟发性神经病发生率低于对照组(P<0.05);Fasudil能改善患者的神经功能.结论 临床应用法舒地尔治疗有机磷农药中毒能降低迟发性神经病的发生率,并能有效治疗该病.     

改良型鼻肠管和鼻胃管联用于血液净化对预防和治疗重症有机磷农药中毒患者诱导迟发性多发神经病的疗效比较

目的:比较改良型鼻肠管和鼻胃管联用于血液净化对预防和治疗重症有机磷农药中毒患者诱导迟发性多发神经病的疗效。方法:选取2014年6月—2015年10月间收治的急性重度有机磷中毒(ASOP)患者80例,将其随机分为观察组和对照组,每组40例;两组患者均给予自动洗胃机清水洗胃、快速建立静脉通道,以及给予硫酸阿托品注射液、氯解磷定注射液及对症支持治疗;对照组患者则在此基础上给予单纯洗胃等治疗以及给予硫酸阿托品注射液、氯解磷定注射液及对症支持治疗;观察组患者均给予自动洗胃机清水洗胃、快速建立静脉通道,以及给予硫酸阿托品注射液、氯解磷定注射液及对症支持治疗,同时置入鼻肠管和鼻胃管洗胃等治疗,比较两组患者洗胃等治疗后昏迷复醒时间、机械通气时间、胆碱酯酶(ChE)活性复常时间、住院时间和药物用量,以及迟发性多发神经病的发生情况等。结果:观察组患者治疗后昏迷复醒时间、机械通气时间、胆碱酯酶(ChE)活性复常时间、住院时间均短于对照组(P<0.05),中间综合征的发生率和病死率低于对照组(P<0.05);阿托品、氯解磷定用量小于对照组(P<0.05),提示观察组患者治疗效果优于对照组(P<0.05);随访患者结果发现,观察组患者迟发性神经病的发生率低于对照组(P<0.05),运动传导速度(MCV)、感觉传导速度(SCV)优于对照组(P<0.05),提示改良型鼻肠管和鼻胃管联用于血液净化可有效预防重症有机磷农药中毒患者诱导迟发性多发神经病的发生,并有益于患者运动功能的恢复。结论:改良型鼻肠管和鼻胃管联用于血液净化可有效预防和治疗重症有机磷农药中毒患者诱导迟发性多发神经病的发生,可改善患者预后的康复。     

乐果诱导的大鼠迟发性神经病电生理变化的研究

目的通过建立乐果诱导的迟发性神经毒性的大鼠模型,探讨乐果所致迟发性神经病的电生理变化特点,为疾病的早期诊断提供理论依据。方法健康雄性SD大鼠60只,随机分成3组。观察染毒后中毒症状。电子显微镜下观察周围神经的病理变化。测定大鼠摆尾温度阈值(tailflick threshold temperature,TTT);检测胫神经、腓肠神经的运动神经传导速度(motor nerve conduct velocity,MNCV)、感觉神经传导速度(sense nerve conduct velocity,SNCV)、潜伏期(latency,LAT)、波幅(amlitude,AMP)和肌电图等电生理变化。结果神经病理改变:透射电子显微镜下可见,髓鞘普遍疏楹,可见部分髓鞘缺失。神经传导速度和肌电图的变化;第2周时染毒组波幅明显降低,与对照组相比差异有统计学意义。染毒后第4周时,高、低剂量组胫神经运动神经传导速度下降了,波幅的变化与运动传导速度一致。潜伏期增加差异有统计学意义。与对照组比腓肠神经与胫神经变化一致,但幅度较胫神经变化大。肌电图检查结果在实验2周时,高剂量组和低剂量组的大鼠小腿肌肌电图上观察到了纤颤电位,而到4周时,纤颤电位、正锐波更加频繁。结论用大鼠建立乐果迟发性神经病的动物模型是可行的;电生理检查可以作为早期诊断迟发性多发神经病的一个重要指标。     

有机磷农药中毒致迟发性神经病康复治疗1例报告

有机磷农药是目前使用最广泛的杀虫剂之一。有机磷农药中毒在发展中国家较为常见。迟发性神经病是有机磷农药中毒的临床表现之一。本文报告1例表现为双下肢痉挛性瘫痪的有机磷农药中毒迟发性神经病患者的发病情况与康复治疗过程。     

有机磷引起的迟发性神经病的临床与电生理研究

目的：依据迟发性神经病（ＯＰＩＤＮ）电生理异常特性，神经髓鞘与轴索共同受累现象，探讨ＯＰＩＤＮ发病机制学说。方法：对２８例有机磷引起的ＯＰＩＤＮ行运动神经传导速、速神经传导速度和肌电图检测。结果：６９．４％的被检肌肉出现失神经电位（正锐波及纤颤电位），运动神经传导速度与正常对照组比较显著减慢（Ｐ〈０．０１），感觉神经传导速度与正常对照组比较无显著差异（Ｐ〉０．０１）。     

Organophosphate-induced delayed polyneuropathy

Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness and paraesthesiae occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the aetiological attribution of OP-induced peripheral neuropathy. In fact, pre-marketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates that were not used as insecticides but as hydraulic fluids, lubricants and plasticisers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article, we mainly discuss OP pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos and by certain carbamates. We also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent and unexplained changes of unclear significance in peripheral nerves are briefly discussed.     

Triphenylphosphite neuropathy in hens

Single doses of triphenyl phosphite (TPP), a triester of trivalent phosphorus, cause ataxia and paralysis in hens. Characteristics of neurotoxicity were described as somewhat different from organophosphate induced delayed polyneuropathy (OPIDP), which is caused by triesters of pentavalent phosphorus. The onset of TPP neuropathy was reported to occur earlier than that of OPIDP (5–10 versus 7–14 days after dosing, respectively), and chromatolysis, neuronal necrosis and lesions in certain areas of the brain were found in TPP neuropathy only. Pretreatment with phenylmethanesulfonyl fluoride (PMSF) protects from OPIDP, but it either partially protected from effects of low doses or exacerbated those of higher doses of TPP. In order to account for these differences with OPIDP, it was suggested that TPP neuropathy results from the combination of two independent mechanisms of toxicity: typical OPIDP due to inhibition of neuropathy target esterase (NTE) plus a second neurotoxicity related with other target(s). We explored TPP neuropathy in the hen with attention to the phenomena of promotion and protection which are both caused by PMSF when given in combination with typical neuropathic OPs. When PMSF is given before neuropathic OPs it protects from OPIDP; when given afterwards it exaggerates OPIDP. The former effect is due to interactions with NTE, the latter to interactions with an unknown site. The time course of NTE reappearance after TPP (60 or 90 mg/kg i.v.) inhibition showed a longer half-life when compared to that after PMSF (30 mg/kg s.c.) (10–15 versus 4–6 days, respectively). The clinical signs of TPP neuropathy (60 or 90 mg/kg i.v.) were similar to those observed in OPIDP, appeared 7–12 days after treatment, correlated with more than 70% NTE inhibition/aging and were preceded by a reduction of retrograde axonal transport in sciatic nerve of hens. TPP (60 mg/kg i.v.) neuropathy was promoted by PMSF (120 mg/kg s.c.) given up to 12 days afterwards and was partially protected by PMSF (10–120 mg/kg s.c.) when given 24 h before TPP (60 or 90 mg/kg i.v.). The previously reported early onset of TPP neuropathy might be related to the higher dose used in those experiments and to the resulting more severe neuropathy. The lack of full protection might be explained by the slow kinetics of TPP, which would cause substantial NTE inhibition when PMSF effects on NTE had subsided. Since PMSF also affects the promotion site when given before initiation of neuropathy, the resulting neuropathy would then be due to both protection from and promotion of TPP effects by PMSF. No promotion by PMSF (120 mg/kg s.c.) was observed in TPP neuropathy (90 mg/kg i.v.) partially protected by PMSF (10–30 mg/kg s.c.) This might also be explained by the concurrent effects on NTE and on the promotion site obtained with PMSF pretreatment. We conclude that TPP neuropathy in the hen is likely to be the same as typical OPIDP. The unusual effects of combined treatment to hens with TPP and PMSF are explained by the prolonged pharmacokinetics of TPP and by the dual effect of PMSF i.e. protection from and promotion of OPIDP.     

Two cases of organophosphate poisoning with development of intermediate syndrome

Two cases of intermediate syndrome caused by organophosphorus poisoning are reported. Trichlorfon, propoxur (a carbamate pesticide) and fenthion were ingested in both attempts at suicide. After successful conventional therapy during the cholinergic phase, but before the time when the onset of delayed neuropathy might be expected, an intermediate syndrome developed. It affected the proximal limb muscles, neck flexors and respiratory muscles 2 d after pesticide ingestion. The two patients needed respiratory support. Recovery from the intermediate syndrome was complete in both patients, although one subsequently developed delayed neuropathy.     

Organophosphate induced delayed polyneuropathy

This review discusses the current understanding of organophosphate induced delayed polyneuropathy (OPIDP) with emphasis on molecular mechanisms, pathogenesis and possibilities for prevention/therapy. OPIDP is a rare toxicity caused by certain organophosphorus compounds (OP) characterized by degeneration of some long axons in the central and peripheral nervous system that appear about 2-3 weeks after exposure. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). NTE can be inhibited by two types of inhibitors: a) phosphates, phosphonates, and phosphoramidates, which cause OPIDP when >70% of the enzyme is inhibited, and b) phosphinates, carbamates, and sulfonyl halides which inhibit NTE and cause either protection from, or promotion, of OPIDP when given before or after a neuropathic OP, respectively. The ability of a NTE inhibitor to cause OPIDP, besides its affinity for the enzyme, is related to its chemical structure and the residue left attached to the NTE. If such residues undergo the aging reaction i.e. the loss of an alkyl group bound to the enzyme, those OPs usually have a high likelihood of causing OPIDP. Protection from neuropathic doses of OP inhibitors is obtained when NTE is inhibited with nonageable inhibitors. Promotion of OPIDP involves another site besides NTE because it can occur when all NTE is affected. It is now known that this other site is similar to NTE in that it is also sensitive to mipafox but at much higher concentrations. Promotion affects either the progression or expression of OPIDP after the initial biochemical effect on NTE. Some recent observations suggest that development of OPIDP in hens can be influenced by atropine, oximes and methylprednisolone when they are given before or soon after neuropathic OPs.     

Phenylmethanesulfonyl fluoride elicits and intensifies the clinical expression of neuropathic insults

It has been recently reported that phenyl-methanesulfonyl fluoride (PMSF) when given to hens after a neuropathic organophosphate (OP) promotes organophosphate-induced delayed polyneuropathy (OPIDP). Chicks are resistant to OPIDP despite high inhibition/aging of neuropathy target esterase (NTE), the putative target of OPIDP initiation. However, when PMSF (300 mg/kg s.c.) is given to chicks after di-butyl 2,2-dichlorovinyl phosphate (DBDCVP, 1 or 5 mg/kg s.c.), OPIDP is promoted. Inhibition/aging of at least 30% of NTE was thought to be an essential prerequisite for promotion to be elicited in adult hens. However, we observed in hens that when NTE is maximally affected (>90%) by phenyl N-methyl N-benzyl carbamate (40 mg/kg i.V.), a non-ageable inhibitor of NTE, and then PMSF is given (120 mg/kg/day s.c. × 3 days) clinical signs of neuropathy become evident. Methamidophos (50 mg/kg p. o. to hens), which produces in vivo a reactivatable form of inhibited NTE, was shown either to protect from or promote OPIDP caused by DBDCVP (0.45 mg/kg s. c), depending on the sequence of dosing. Because very high doses of methamidophos cause OPIDP, we considered this effect to be a “self-promoted” OPIDP. We concluded that NTE inhibitors might have different intrinsic activities for producing OPIDP once NTE is affected. Aging might differentiate highly neuropathic OPs, like DBDCVP, from less neuropathic OPs, like methamidophos, or from the least neuropathic carbamates, which require promotion in order for neuropathy to be expressed. Retrograde axonal transport in motor fibers was measured as the accumulation of¹²⁵ I-tetanus toxin in spinal cord after injection in the gastrocnemius muscle of chicks treated either with DBDCVP (5 mg/kg s.c.) or with DBDCVP followed by PMSF (300 mg/kg s.c). Retrograde axonal transport was reduced in both groups (to about 50%, 10 days after dosing) and returned to normal 27 days after dosing. However, DBDCVP-treated chicks had a mild neuropathy which recovered relatively quickly, whereas chicks to which PMSF was also given had more severe signs which did not recover by day 27. We concluded that promotion affects a site other than NTE and that it acts at a point downstream from initiation. PMSF was also shown to promote 2,5-hexanedione (2,5-HD) neuropathy. 2,5-HD was given to hens at doses (200 mg/kg/day i.p. × 8 days) which caused mild and reversible neuropathy. When PMSF (120 mg/kg/day × 2 days at the end of 2,5-HD treatment) was given, more severe and irreversible signs of neuropathy were observed. We conclude that promotion might be a common feature in neuropathies of different origin. Part of this work was presented at the 30th Annual Meeting of the Society of Toxicology held in Dallas, TX, USA, February – March 1991     

有机磷中毒迟发性神经损害35例随访研究

目的研究有机磷农药中毒迟发性神经病（OPIDN）的治疗和预后。方法对OPIDN患者给予能量合剂、胞苷三磷酸（CTP）治疗,改善能量供应,给予活血药物改善循环,给予神经营养剂治疗,肌张力增高患者加服降肌张力药。随访1～4年。结果在30例周围性神经损害患者中,29例恢复良好,1例四肢肌肉中度萎缩,生活不能自理。5例中枢性神经损害患者,均遗留肢体肌张力增高,活动笨拙,智力轻度减退;1例年轻女性伴内分泌功能障碍,断经、不孕4年。5例均能生活自理。结论及时纠正缺氧、改善血液循环是早期防治的关键,能量合剂、胞苷三磷酸配合活血和营养神经药物对OPIDN的治疗有效。     

The influence of chirality on the delayed neuropathic potential of some organophosphorus esters: neuropathic and prophylactic effects of stereoisomeric esters of ethyl phenylphosphonic acid (EPN oxon and EPN) correlate with quantities of aged and unaged neuropathy target esterase in vivo

Organophosphate-induced delayed polyneuropathy (OPIDP) is thought to result from organophosphorylation of neuropathy target esterase (NTE), followed by an "aging" of the phosphorylated NTE. Prophylactic against OPIDP should thus be achieved by production of an inhibited but "nonaging" NTE. Resolved stereoisomers of ethyl phenylphosphonic acid esters produce two forms of inhibited NTE; in vitro one form ages rapidly and the other only negligibly. The present study examined the in vivo effects of two preparations of incompletely resolved isomers of EPN oxon (ethyl 4-nitrophenyl phenylphosphonate) and its thionate on adult hen brain and spinal cord NTE and the relationship of inhibition and aging to the development of OPIDP. Single doses of the L-(-)-isomers (Preparation A, 7:3 proportion of isomers, or Preparation B, 9:1) caused severe neuropathy after doses which produced 70% aged inhibited NTE and mild effects after 50-60%. Single doses of the D-(+)-isomers produced either equal amounts of aged and unaged inhibited NTE (Preparation A) or predominantly unaged (Preparation B): the amount of aged was never more than 50% and no clinical OPIDP occurred. Doses of D-(+) which produced 50% unaged inhibited NTE were protective: challenge with the highly neuropathic phenyl saligenin cyclic phosphate did not cause OPIDP. All effects are consistent with the two-stage initiation process which requires both inhibition of NTE and subsequent modification of the protein by an "aging" process. Previously reported neuropathic effects of D-(+)-EPN probably reflect a substantial proportion of L-(-)-isomer present in the test material. Neuropathic studies with chiral OP esters should consider the possibility of production of protective unaged inhibited NTE in test animals.     

Low non-neuropathic tri-o-cresyl phosphate (TOCP) doses inhibit neuropathy target esterase near the neuropathic threshold in n-hexane pretreated hens

Simultaneous intoxication with hexacarbon solvents and organophosphorus compounds has been considered a possible critical factor in some occupational neuropathies and their interactions proved to cause potentiation effects in hens [1-3]. A high degree of inhibition of neuropathy target esterase (NTE) is needed to develop organophosphorus induced polyneuropathy (OPIDP). In this work, the inhibition of NTE, BuChE and AChE by TOCP on control and n-hexane pretreated (7-15 days, 300 mg/kg per day) hens is studied. Using a single TOCP dose of 200 mg/kg, n-hexane pretreated hens showed synergistic effects, but no significant differences were observed in the inhibition of cholinesterases and NTE in brain or spinal cord. With lower TOCP dose (20 mg/kg) statistically significant differences were observed, which were not drastic but could be important because they involved an increase of inhibition up to critical threshold values (from 40-50% to 60-70% inhibition). However, no clinical effects were observed in these animals. Possible mechanisms of neurotoxic interaction are discussed.     

Effects of S-ethyl hexahydro-1H-azepine-1-carbothioate (molinate) on di-n-butyl dichlorovinyl phosphate (DBDCVP) neuropathy.

Certain esterase inhibitors protect from organophosphate-induced delayed polyneuropathy (OPIDP) when given before a neuropathic organophosphate by inhibiting neuropathy target esterase (NTE). In contrast, they can exaggerate OPIDP when given afterwards and this effect (promotion) is associated with inhibition of another esterase (M200). In vitro sensitivities of hen, rat, and human NTE and M200 to the active metabolites of molinate, sulfone, and sulfoxide, were similar. NTE and M200 were irreversibly inhibited (> 78%) in brain and peripheral nerve of hens and rats given molinate (100-180 mg/kg, sc). No clinical or morphological signs of neuropathy developed in these animals. Hens and rats were protected from di-n-butyl dichlorovinyl phosphate neuropathy (DBDCVP, 1 and 5 mg/kg, sc, respectively) by molinate (180 or 100 mg/kg, sc, 24 h earlier, respectively) whereas 45 mg/kg, sc molinate causing about 34% NTE inhibition offered partial protection to hens. Hens treated with DBDCVP (0.4 mg/kg, sc) developed a mild OPIDP; molinate (180 mg/kg, 24 h later) increased the severity of clinical effects and of histopathology in spinal cord and in peripheral nerves. Lower doses of molinate (45 mg/kg, sc), causing about 47% M200 inhibition, did not promote OPIDP whereas the effect of 90 mg/kg, sc (corresponding to about 50-60% inhibition) was mild and not statistically significant. OPIDP induced by DBDCVP (5 mg/kg, sc) in rats was promoted by molinate (100 mg/kg, sc). In conclusion, protection from DBDCVP neuropathy by molinate is correlated with inhibition of NTE whereas promotion of DBDCVP neuropathy is associated with > 50% M200 inhibition.     

Toxicological assessment of isomeric pesticides: a strategy for testing of chiral organophosphorus (OP) compounds for delayed polyneuropathy in a regulatory setting.

Many compounds, including some pesticides, contain structural centres of asymmetry, which convey the property of a type of stereoisomerism known as chirality. Such compounds can exist in two or more forms, depending on the number of chiral atoms and are termed stereoisomers or enantiomers. Stereoisomers of a particular compound can have different biological properties; one such of particular importance for toxicological evaluation, is the potential for differences in metabolic disposal of and binding of stereoisomers to molecular targets in the cell. The combination of differential metabolism of chiral organophosphorus (OP) pesticides and opposing stereoselectivity of inhibition of neuropathy target esterase (NTE) and acetylcholinesterase (AChE) can affect the value of the hen test, performed to OECD guidelines, in predicting the potential to cause organophosphate-induced delayed polyneuropathy (OPIDP) in humans. This is a mixed central and sensory and motor neuropathy. The experimental data on structural analogues of the pesticide methamidophos and the evidence for stereoselective OPIDP are reviewed and a model is given demonstrating how the properties of a chiral OP can result in the neuropathic potential not being detected by the standard hen test. A strategy for the assessment of a racemic mixture comprised of two OP enantiomers for the potential to induce OPIDP is outlined. The strategy uses information from structure activity relationships (SAR), in vitro tests and in vivo tests to allow risk assessment decisions to be made. It is suggested that the potential for stereoselective toxicity of pesticides should be routinely considered in regulatory assessments.