What is Neurotoxicity?

Neurotoxicity occurs when the exposure to natural or manmade toxic substances (neurotoxicants) alters the normal activity of the nervous system. This can eventually disrupt or even kill neurons, key cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies, and organ transplants, as well as exposure to heavy metals such as lead and mercury, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness; loss of memory, vision, and/or intellect; headache; cognitive and behavioral problems; and sexual dysfunction. Individuals with certain disorders may be especially vulnerable to neurotoxicants.

接触天然或人造的毒性物质(神经毒素)、造成神经系统正常活动受扰，即发生了神经毒性。其结果可以干扰甚或杀死神经元，亦即那些脑内和神经其它部位传输处理信号的关键细胞。神经毒性可源于接触特定物质，比如用于化疗、放疗、药物治疗、器官移植的，或接触重金属，比如铅和汞，或某些食物及食物添加剂、杀虫剂、工业溶剂、化妆品、以及某些天然物质。其症状可以即时或延时出现。症状包括四肢瘫软麻痹、失忆、失明、失智、头痛、认知或行为障碍；性功能障碍。有某些缺陷的个体特别易受神经毒素侵害。

Is there any treatment?

Treatment involves eliminating or reducing exposure to the toxic substance, followed by symptomatic and supportive therapy.

对神经毒素中毒的治疗方法包括隔绝或减少接触毒性物质，随后根据症状进行针对性辅助治疗。

What is the prognosis?

The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxicants can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment.

神经毒素中毒的后遗症取决于接触时长和程度，还有神经伤害的严重性。某些情况下，接触神经毒素可致命。也有情况下患者可存活但无法完全康复。其它一些情况，很多个体在治疗后可完全康复。

What research is being done?

Scientists are investigating the role occupational or environmental toxicants have on progressive neurodegenerative disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Also being studied are the mechanisms that trigger neuroimmune responses in the central nervous system and the possibility that some brain disorders in children may occur when environmental triggers interact with genes.

科学家在研究职业性和环境性毒物对进行性神经退化病变的作用，包括帕金森病、肌萎缩症、多发性硬化症、以及老年痴呆症等。中枢神经系统的神经免疫反应的出发机制、环境刺激物与基因交互作用导致儿童大脑病变的可能性等也在研究之中。

Solvent neurotoxicity 溶剂神经毒性

Organic solvents are widely employed in industry and are used in large quantities across the world. A solvent can be defined as “a liquid that has the ability to dissolve, suspend or extract other materials, without chemical change to the material or solvent”. Organic solvents are so widely used in the modern world as to be ubiquitous and are employed in paints, pharmaceuticals, degreasants, adhesives, printing inks, pesticides, cosmetics, and household cleaners. Commonly used solvents include, isopropanol, toluene, xylene, solvent mixtures such as white spirits and the chlorinated solvents, methylene chloride, trichloroethylene, and perchloroethylene. In Europe alone, approximately 300 000 metric tonnes of chlorinated solvents are sold each year. The United Kingdom's Health and Safety Executive estimate that 8% of the working population regularly use organic solvents. The largest end user is the coatings industry where solvents play an important role in the quality and durability of paints and varnishes. The volumes of organic solvents used in some industries, for example dry cleaning, are declining, largely due to equipment and process improvements. Increasingly solvents are recovered and recycled, partly in response to environmental controls on volatile organic compound (VOC) discharges. In addition, environmental legislation has led to a growth in the use of water based paints both in North America and in Europe at the expense of more traditional, solvent based coatings. The Montreal Protocol of 1987 was a landmark in environmental regulation and led to the production of a number of ozone depleting solvents being restricted or phased out. The protocol arose from concerns about the adverse impact of some solvents, including chlorofluorocarbons, on tropospheric ozone. Recently, 1‐bromopropane, a solvent introduced to replace ozone depleting agents such as 1,1,1‐trichloroethane (methylchloroform), has been shown to be neurotoxic in humans.

有机溶剂在工业量广泛使用，在世界范围也用量巨大。溶剂可以定义为“有能力溶解、悬着、或萃取其它物质，且对该物质及自身不产生化学变化的液体”。有机溶剂在现代世界应用如此广泛几乎无处不在，其用于油漆、制药、脱脂剂、黏胶剂、油墨、杀虫剂、化妆品、以及家具清洁剂等。常用溶剂包括，异丙醇、甲苯、二甲苯、混合溶剂如溶剂油和氯代物溶剂，氯甲烷、三氯乙烷、和四氯乙烷等。仅在欧洲，每年销售大约30万吨氯代物溶剂。英国健康与安全局估计工作群体中8%经常接触有机溶剂。有机溶剂的最大应用是涂料行业，其中溶剂对油漆和上光剂的质量和耐久性起到重要作用。在有些行业中有机溶剂的使用量在下降，比如，干洗业，主要是因为设备和工艺的改进。溶剂也越来越多地被回收和再生，部分是为了响应对挥发性有机化合物VOC排放的环保减排要求。此外，欧洲和北美的环保立法还引导了水性涂料使用量的增长，以取代传统的溶剂型涂料。1987年蒙特利尔公约是环保立法的里程碑，产生了对若干臭氧耗蚀性溶剂生产的限制或淘汰。公约是由对某些溶剂负面效应的担忧而缘起的，其中包括氯氟碳CFC对对流层臭氧的负面影响。近来，1-溴代丙烷   1-bromopropane，一种被引入取代臭氧耗蚀性物质三氯乙烷1,1,1‐trichloroethane (甲基氯仿) 的溶剂，却被发现对人类有神经毒性。

Solvents are volatile agents and, in general, occupational exposures occur by inhalation of solvent vapour. However, dermal exposure is important in some industries such as painting and industrial degreasing. Dermal uptake may contribute a significant fraction of the total body burden of solvents in workers employed in these sectors; the example of a worker whose dermal exposure to the solvent xylene would contribute more than 50% of their total body burden is reported.

溶剂是挥发性物质，因而，通常而言，职业接触是由吸入溶剂挥发物而造成。然而，皮肤接触在某些行业中也占很大比重，比如在油漆和工业脱脂行业。皮肤吸收对这些行业中工人体内总的溶剂残留占比很大；有报道举例，工人皮肤接触二甲苯溶剂可占到其体内残留的50%以上。

 

Acute health effects

The acute health effects of organic solvents reflect their central nervous system effects and include headache, dizziness, and light‐headedness progressing to unconsciousness, seizures, and death. Eye, nose, and throat irritation may also occur with exposure to solvent mixtures. Abuse of organic solvents remains a problem, especially among deprived youngsters who use lighter fuel, glues, and household chemicals to obtain a “high”. While the abuse of adhesives has declined over time, other agents of abuse, such as butane lighter fuel, have increased as a proportion of all volatile substance abuse deaths. Every year in the United Kingdom around 65 children die following such abuse. From an occupational perspective workplace solvent exposure may progress to abuse in some workers.

有机溶剂的急性健康危害反映在中枢神经系统，其包括头痛、晕眩、轻度头痛恶化至丧失意识、晕厥乃至死亡。接触混合溶剂也可随发对眼、鼻、喉的刺激。滥用有机溶剂一直是社会问题，特别是在涉世未深的年轻人中，他们使用轻质燃油、黏胶剂、和日用化学品来玩“嗨”虽然滥用黏胶剂随时间推移有下降趋势，滥用其它介质，比如丁烷燃气，在所有因挥发性有机化合物VOC滥用致死事件中的占比有所上升。每年在英国，有大约65个未成年人死于此类滥用行为。从职业健康角度讲，工作场所溶剂接触可能导致工人成瘾性滥用。

The hazards of acute exposure are well recognised but fatalities still occur where poor working practices create the conditions for intense exposure in confined spaces. In the United Kingdom six people died between 1985 and 1996 in incidents involving solvent degreasing tanks (see fig 2). A failure to appreciate the volatile nature of solvents and to take appropriate precautions can lead to a risk of fire and explosion. A number of tragedies have occurred where an ignition source has been used in a confined space in close proximity to solvent vapour with predictable, and sometimes fatal, results.

急性接触危害早已被充分认识，但死亡事件仍时有发生尤其是不当操作流程促成限闭空间高强度接触的条件。在英国，1985至1996年间，有六人死于储罐溶剂除脂事故。未加认识溶剂挥发特性并采取适当的措施还会导致火灾和爆炸风险。发生过一系列悲剧都是点燃源在限闭空间过于接近溶剂挥发物蒸气，从而造成可想而知，甚或伤亡结果。

Figure 2 An industrial degreasing tank containing methylene chloride. This tank is fitted with a roller cover to reduce solvent vapour release into the work environment during operation. A number of workers have died when safe systems of work ...

Long term health effects

A number of long term adverse effects of solvents have been described including leukaemia in benzene exposed workers, scleroderma (mixed solvents), and renal cancer in those exposed to chlorinated hydrocarbons. While the association between benzene and leukaemia is well established, other solvent effects, such as those on the nervous system, are more controversial. Early studies in Scandinavia suggested that long term, high level, solvent exposure might be associated with a syndrome of personality change, memory impairment, and neurological deficits variously termed chronic toxic encephalopathy (CTE), the psycho‐organic syndrome or solvent neurotoxicity. Some termed this “Danish painter's syndrome” although there was little evidence that the syndrome was so restricted, either by geography or occupation. Several early studies had methodological flaws and have since been heavily criticized. Weaknesses of these studies included poor quality exposure surrogates such as ever/never exposed and a failure to adjust for confounders such as age or pre‐morbid IQ. It seems likely that some studies had significant biases and early attempts to reproduce these findings out with Scandinavia were unsuccessful, casting doubt on the existence of this syndrome.

对溶剂长期负面效应已有很多报道，包括苯接触工人间的白血病、氯代溶剂接触者的肾癌和s。虽然苯与白血病之间关系已明确，其它溶剂影响，比如对神经系统的，还存在争议。

One of the many difficulties with early research into solvent neurotoxicity was the lack of an agreed definition of the syndrome. The Nordic Council of Ministers and the World Health Organisation sponsored a conference in 1985 in Denmark that produced a definition of solvent neurotoxicity, which was subsequently revised at a meeting in North Carolina later that year (see table 2). These criteria are important not only for researchers but also for clinicians for several reasons. If a diagnosis of solvent neurotoxicity is established then withdrawal from exposure can prevent further harm to the individual worker. Secondly, these criteria indicate likely prognosis and so are helpful in advising both the worker and their primary care physician. Thirdly, such a diagnosis can alert the employer to the need for improved workplace hygiene measures and so protect other workers.

早期溶剂神经毒性研究的众多困难之一是对综合症缺乏公认的定义。1985年北欧部长你会议与世界卫生组织资助在丹麦召开了一次会议，制定了溶剂神经毒性的定义，当年在北卡罗莱纳的另一会议上对其又做了相应的修订。在很多方面这些指征不仅对研究者，也对临床工作者都很重要。如果诊断确认发生溶剂神经中毒，脱离接触可以阻止对个体工人的 进一步损伤。其次，这些指征揭示了可能的后遗症，因而对工人和初次接诊者有指导作用。第三，此诊断标准可警示雇主需要对需要对工作场所卫生措施予以改进以保护其他工人。

Categorisation of solvent neurobehavioural effects

溶剂毒性-行为效果简表
1类            仅有症状                            记忆力受损、注意力下降、疲劳、活力下降等。接触消除，此类非特定症状可消失。
2A类          持续性人格情绪变化            性格改变伴情绪低落；活力下降；冲动控制力下降；焦虑；易怒。
2B类          智力功能受损                      毒性-心理测试显示认知缺陷，影响注意力、集中度、视觉反应、语言记忆等。
                                                          有轻微神经内科临床症状。接触消除可部分恢复，难以完全恢复。
3类            痴呆                                   认知受损，常伴有神经内科病变。
                                                          神经传导诊断、肌电图、神经放射诊断(CT、核磁共振MRI)可定位病灶。
                                                          接触消除，病变可不恶化。

More recent, well designed studies suggest that in heavily exposed workers, solvents may have subtle effects on cognitive function. The cognitive domains affected by solvent exposures include attention, verbal memory, and visuospatial skills. There is some evidence that solvent neurotoxicity is commoner among those with at least 10 years of occupational exposure to solvents. Whether the important determinant of adverse effects is the lifetime (cumulative) exposure, the intensity of exposure or peaks of exposure remains unclear. An area for further research is the development of better estimates of peak exposures to address this question.

更为近期，精心设计的研究工作提示，与溶剂重度接触的工人其认知功能可能受到深层的影响。受溶剂接触影响的认知能力范围包括注意力、言词记忆、视空能力。另有证据表明溶剂神经毒性在十年以上接触史的工人中较为常见。负面影响的决定因素，是否是生涯(累积)接触、接触浓度、抑或接触峰值，尚未明确。进一步研究的一个领域，就是针对这一问题，推动更详尽地估算接触峰值。

The mechanism by which solvent mixtures exert their adverse effects on the nervous system is uncertain but it is suspected that the metabolism of solvents to toxic intermediates may be important. Attempts to identify the responsible agent are made more difficult as many workers are exposed to industrial grade solvent mixtures of varying composition and purity. The heterogeneous nature of the chemicals classified as solvents poses a problem when comparing the many studies of solvent health effects. There is some evidence that genetic polymorphisms affecting the activity of enzymes that metabolise foreign chemicals may influence the risk of solvent neurotoxicity.

混合溶剂对神经系统发挥负面效应的机制尚不明确，但怀疑其重要因素可能是溶剂代谢产生的有毒中间体。尝试去辨识具体起作用的物质更为困难，因为工人所接触的工业级混合溶剂组分及纯度各异。通称为溶剂的化学品实际具有异质性，比较溶剂健康影响的各类研究时，就会遇到这一困难。比如另有证据显示，负责代谢外源性化学物质的生物酶，因其活动受基因多型性影响，会进而影响神经毒性的风险程度。

Peripheral neuropathy and solvents

There is strong evidence that some solvents may cause peripheral neuropathy. Clinically this presents with symptoms in the feet and lower legs before progressing to involve the hands. Symptoms are those of a sensorimotor neuropathy with altered sensation, loss of vibration perception, impaired proprioception leading to impaired balance, and distal muscle wasting.

有强烈证据显示某些溶剂可引起外周神经疾病。临床可表现为足部及下半肢的症状，进而发展到手部。症状包括运动感觉类神经疾患，感知功能变异、丧失振动敏感度、肌肉运动感受损，导致平衡感受损、末端肌肉失能。

The most researched agent is n‐hexane (the n stands for “normal” hexane to distinguish it from the isoforms of hexane, 3‐methyl pentane, 2‐methyl pentane, and 2,3‐methyl butane) which has been associated with outbreaks of peripheral neuropathy in furniture manufacture, printers, and shoe makers. Methyl n‐butyl ketone was shown to be neurotoxic following an outbreak of peripheral neuropathy in an Ohio textile printing plant. Subsequent animal studies showed that n‐hexane and methyl n‐butyl ketone share a common neurotoxic metabolite, 2,5‐hexanedione. There is some evidence that commonly used ketones (acetone, methyl ethyl ketone, and methyl isobutyl ketone) may potentiate the toxicity of n‐hexane and other solvents, a finding that raises doubts about the widely used method of calculating mixed solvent exposures based on the additivity of exposures. Other solvents have been implicated as peripheral neurotoxins including carbon disulphide, styrene, and 1,1,1‐trichloroethane. The evidence for these latter associations is relatively weak; given the wide usage of some of these substances many more cases of peripheral neuropathy might be anticipated.

最受深入研究的物质为正己烷，其与家具制作工、印刷工、制鞋工等群体中多次爆发的周围神经疾病有关。甲基丁基酮由于在美国俄亥俄州一家纺织印染厂造成周围神经疾病而被列为神经毒物。后续的动物研究表明，正己烷与甲基丁基酮都产生同样的神经毒性代谢物，2,5-己二酮。有证据显示，广泛使用的酮类 (丙酮、甲基乙基酮MEK、甲基异丁基酮MIBK) 可能会增强正己烷和其它溶剂的毒性，此发现从而对广为采用的，基于接触叠加性估算混合溶剂接触量方法的质疑。其它被内定为周围神经毒物的溶剂还有，二硫化碳、苯乙烯、三氯乙烷。后面这几个的相关证据还比较弱，由于这些物质的广泛使用，可以预计今后会出现更多周围神经疾患的例证。

Special senses and solvents

The special senses, taste, sight, and smell may be affected by exposure to solvents. Many, but by no means all, studies have found mild acquired colour vision losses in solvent exposed workers. The impairment is generally subtle, and affected workers are typically unaware of altered colour perception. Unlike congenital colour “blindness”, which is commoner in men and is usually a protan or deutan defect (red–green colour blindness), acquired colour vision losses are frequently tritan, sometimes termed “blue–yellow” loss. These tritan losses may progress to affect red–green colour vision. The practical relevance of such sub‐clinical effects is questionable and at present these findings remain in the realm of research.

专一感官，味觉、视觉、嗅觉，也可受损于溶剂接触。很多，即使不是全部，研究发现在溶剂接触工人中存在轻微的外来性视觉色彩损伤。伤害通常是很深层的，受害工人一般不会感觉色彩感知的变异。先天性色盲，通常会见于男性，多为红色弱或绿色弱，与之不同，外来性视觉色彩损伤普遍为蓝黄色弱，亦有称为蓝-黄盲。此类蓝色弱可进展影响红绿色觉。此类亚临床症候的真实相关性尚存疑问，目前，此类发现还局限于研究圈内。

Key points

• Inhalation is the main exposure route for organic solvents
• Dermal exposure to certain solvents may be an important exposure route in some work settings
• Heavy, long term, exposure to solvents is associated with subtle neuropsychological effects
• Solvents, such as styrene, may cause sub‐clinical colour vision losses
• Solvents affect hearing and may act synergistically with noise exposures

• 吸入，是有机溶剂的主要接触途径
• 皮肤接触在某些工况，也是某些溶剂的主要接触途径
• 重度、长期接触溶剂可产生深层的神经心理影响
• 苯乙烯等溶剂可产生亚临床症状的色彩视觉损伤
• 溶剂可影响听力，可能与噪音产生协同效应