Bioaccumulation of lead (Pb) and its effects on human: A review
铅 (Pb) 的生物累积及其对人体的影响:综述

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Highlights 亮点

  • This review article discusses in detail the health effects in humans due to long-term exposure to lead.
    这篇评论文章详细讨论了长期接触铅对人类健康的影响。

  • The article also illustrates the complications when the blood lead level in both men and women is more.
    文章还说明了男性和女性血铅水平较高时的并发症。

  • The oxidative stress that occurs in the human cells causing severe cell damage has also been discussed.
    人体细胞中发生的氧化应激会导致严重的细胞损伤,这一点也得到了讨论。

  • Finally, the preventive measures and the treatment for lead toxicity and lead accumulation have been discussed along with chelation therapy.
    最后,讨论了铅中毒和铅蓄积的预防措施和治疗以及螯合疗法

Abstract 抽象的

Lead is a prevalent heavy metal that pollutes the environment and accumulates in the human body via absorption, bioavailability, bioconcentration, and biomagnification disrupts the neurological, skeletal, reproductive, hematopoietic, renal, and cardiovascular systems. Lead's distinctive physical and chemical characteristics make it ideal for a variety of uses. It has been linked to human activities for ages and is harmful to health. This review article examines the long-term health consequences of lead exposure in humans. Acute and chronic symptoms of lead poisoning include kidney, brain, reproductive organ, and CNS/PNS damage. Toxic metals have a long half-life in the bone matrix and brain (2–3 years), causing neurological problems and bone loss. The article also shows the problems of high BPb in both men and women during pregnancy. Renal system blood lead levels of 30–60 g/dL may cause kidney failure in severe circumstances. The oxidative stress that occurs in human cells has also been explored. Finally, lead poisoning and lead buildup prevention and therapy have been reviewed. The use of micronutrients and antioxidants has demonstrated a reduction in harmful effects. Adults with BPb >45 g/dL should have chelation, whereas children should receive succimer.
铅是一种普遍存在的重金属,它会污染环境,并通过吸收、生物利用度、生物浓缩和生物放大作用在人体内积累,破坏神经、骨骼、生殖、造血、肾脏和心血管系统。铅独特的物理和化学特性使其成为多种用途的理想选择。长期以来,它一直与人类活动联系在一起,并且对健康有害。这篇综述文章探讨了人类铅暴露的长期健康后果。铅中毒的急性和慢性症状包括肾脏、大脑、生殖器官和中枢神经系统/三七总皂甙损伤。有毒金属在骨基质和大脑中的半衰期很长(2-3年),会导致神经问题和骨质流失。文章还展示了男性和女性在怀孕期间的高血压问题。肾脏系统血铅水平达到 30-60 g/dL 严重时可能会导致肾衰竭。人类细胞中发生的氧化应激也已被探索。最后,对铅中毒和铅蓄积的预防和治疗进行了回顾。微量营养素和抗氧化剂的使用已证明可以减少有害影响。 BPb > 45 g/dL 的成人应接受螯合治疗,而儿童则应接受琥珀酸治疗。

Keywords 关键词

Heavy Metals
Lead
Pollutant
Lead Toxicity
Lead Accumulation
Lead in Plants

重金属
带领
污染物
铅毒性
铅积累
植物中的铅

1. Introduction 一、简介

The term heavy metal (HM) refers to a group of metals or metalloids having toxic effects even at lower concentrations (part per billion level) and possess higher density (Sharma and Agrawal, 2005) and have poisonous nature at lower concentrations. HMs include essential metals (Cu, Zn, Co, Cr, Mn, and Fe), non-essential metals (Ba, Al, Li and Zr), less toxic metals (Sn and As), and highly toxic metals (Hg, Cd, and Pb) (Duffus, 2002). HMs enter into the food chain and relates to the accumulation in biological tissues. When the rate of intake of these HMs by biological systems exceeds the rate of excretion, then we call that bioaccumulation of HMs and this occurs in biological systems (Singh and Kalamdhad, 2011; Khan et al., 2015).
术语重金属(HM)是指即使在较低浓度(十亿分之一的水平)下也具有毒性作用且具有较高密度 Sharma和Agrawal,2005 )并且在较低浓度下具有毒性的一组金属或准金属。 HMs 包括必需金属(Cu、Zn、Co、Cr、Mn 和 Fe)、非必需金属(Ba、Al、Li 和 Zr)、毒性较小的金属(Sn 和 As)和剧毒金属(Hg、Cd)和 Pb)( Duffus,2002 )。 HMs进入食物链并与生物组织中的积累相关。当生物系统摄入这些HMs的速率超过排泄速率时,我们称之为HMs的生物累积,这发生在生物系统中( Singh和Kalamdhad,2011Khan等,2015 )。

The incidence of heavy metals (HM) in the human body causes toxicity resulting in Alzheimer's, multiple sclerosis, Parkinson's disease, muscular dystrophy (Neeti & Prakash; K. 2013). HM poisoning can either cause chronic effects like neurological disorders, physical abnormalities, muscular effects, genetic and hereditary problems, or acute effects like vomiting, dehydration, drowsiness, nausea, renal failure, and abdominal pain (Markich et al., 2001; Sun et al.,  2018). The excess usage of HMs to satisfy human needs has heavily polluted the environment. Accumulation in living beings occurs when these metals are taken up and stored at a higher rate which thereafter is metabolized and excreted (Nędzarek et al., 2013). Lead toxicity in human's dates back to at least 5000 years ago when humans started to process lead (Gidlow, 2015).
重金属(HM)在人体内的发生会引起毒性,导致阿尔茨海默病、多发性硬化症帕金森病肌肉萎缩症(Neeti & Prakash; K. 2013 )。 HM 中毒可引起慢性影响,如神经系统疾病、身体异常、肌肉影响、遗传和遗传问题,或急性影响,如呕吐、脱水、嗜睡、恶心、肾功能衰竭和腹痛( Markich 等,2001Sun 等)等,2018 )。为了满足人类需求而过度使用HMs已经严重污染了环境。当这些金属以较高的速率被吸收和储存时,就会在生物体中积累,然后代谢并排出体外( Nędzarek 等,2013 )。人类的铅毒性至少可以追溯到 5000 年前,当时人类开始加工铅( Gidlow,2015 )。

Lead (Pb) is a naturally occurring metal and generally form lead compounds by combining with two or more elements. Lead reacts with air and water to form lead sulfate, lead carbonates or lead oxide. These compounds act as a protective barrier to prevent corrosion. Lead can also interact with both acid as well as base. It has a low melting point and located above hydrogen in the electromotive series. Although the existence of lead is indicated in nature but human activities has been found as the main reason for increasing lead content in the environment (Shahid et al., 2015). Lead is released in air from mining of lead, factories utilizing lead compounds, alloys, vehicle exhaust and burning of fossil fuels (Violante et al., 2010). The lead is removed from atmosphere by rain and transferred to soil or comes in contact with surface water. Moreover, lead is used as pesticide during vegetable and fruit cultivation (Gall et al., 2015). Disposal of lead containing waste products, removal of lead based paints from bridges, buildings and damaged battery from industries further results into the accumulation of lead in municipal landfills. Lead combines very strongly with the soil particles and present in the top layer of soil (Gupta et al., 2008). Lead enters water bodies or lakes when these soil particles are washed away by rain water. Thus, lead is transferred to animals and plants from air, water, soil and this cycle continues (Abadin et al., 2007).
铅 (Pb) 是一种天然存在的金属,通常通过与两种或多种元素结合形成铅化合物。铅与空气和水反应生成硫酸铅、碳酸铅或氧化铅。这些化合物充当防止腐蚀的保护屏障。铅还可以与酸和碱相互作用。它的熔点较低,在电动系列中位于氢之上。尽管自然界中已表明铅的存在,但人类活动已被发现是环境中铅含量增加的主要原因( Shahid等,2015 )。铅开采、使用铅化合物、合金的工厂、汽车尾气和化石燃料的燃烧都会释放到空气中( Violante 等,2010 )。铅通过雨水从大气中去除并转移到土壤中或与地表水接触。此外,铅在蔬菜和水果种植过程中被用作农药( Gall et al., 2015 )。含铅废物的处理、桥梁、建筑物中含铅油漆的去除以及工业中受损电池的清除进一步导致市政垃圾填埋场中铅的积累。铅与土壤颗粒的结合非常牢固,并存在于土壤的表层( Gupta 等人,2008 年)。当这些土壤颗粒被雨水冲走时,铅就会进入水体或湖泊。 因此,铅从空气、水、土壤转移到动物和植物中,并且这个循环持续下去( Abadin 等,2007 )。

Lead is not a foreign material to the human body as it is distributed to the brain, liver, kidney, and bones and is stored in bones and teeth, However, this is only 10 μg/dL in adults and 1.4 μg/dL in children (Jusko et al., 2008; Singh and Kalamdhad, 2011). The guideline value of lead indicated by world health organization is 0.01 mg/L (Edition, 2011). The Nervous system is mainly affected by lead. The normal functioning of nervous system is influenced if an individual is exposed to lead for a long time. Moreover, longer exposure also causes severe effects on kidney as well as brain (Abadin et al., 2007). Lead is easily absorbed by the body. Children absorb higher amounts of lead than adults which is highly dangerous as they are developing (Lidsky and Schneider, 2003). In children lead is not absorbed by the bones like in the case of adults therefore they are at a higher risk of poisoning as the other soft tissues absorb the excess lead. Lead acts as a calcium analog, thus it is easily absorbed in people with calcium, zinc, and iron deficiencies. Lead affects the reproductive systems of both males and females (Flora et al., 2006). In the case of males, there is a reduction in sperm count and volume, the motility and the morphology of the sperm are also affected (Wu et al., 2012). In females who have high exposure to this metal, miscarriage, premature birth, low birth weight, and developmental problems are seen. When toxicity of lead has reached higher amounts, spontaneous abortion of the fetus occurs (D. C, 2005). Lead can damage cell structure, cell membrane and most importantly it interferes with DNA transcription (Yedjou et al., 2010). At developmental stages, lead passes through the placenta into the body of the fetus. At developmental stages, lead passes through the placenta into the body of the fetus (Mason et al., 2014).
铅对人体来说不是异物,因为它分布在大脑、肝脏、肾脏和骨骼中,并储存在骨骼和牙齿中,但成人仅为 10 μg/dL,儿童为 1.4 μg/dL ( Jusko 等人,2008 年Singh 和 Kalamdhad,2011 年)。世界卫生组织规定的铅指导值为0.01mg/L( 2011年版)。神经系统主要受铅的影响。如果一个人长期接触铅,神经系统的正常功能就会受到影响。此外,长时间暴露还会对肾脏和大脑造成严重影响( Abadin 等,2007 )。铅很容易被人体吸收。儿童比成人吸收更多的铅,这在他们的发育过程中是非常危险的( Lidsky 和 ​​Schneider,2003 )。儿童的铅不像成人那样被骨骼吸收,因此他们中毒的风险更高,因为其他软组织会吸收多余的铅。铅是钙的类似物,因此钙、锌和铁缺乏的人很容易吸收。铅会影响男性和女性的生殖系统( Flora 等,2006 )。就男性而言,精子数量和体积减少,精子的活力和形态也会受到影响( Wu等,2017)。,2012)。大量接触这种金属的女性会出现流产、早产、低出生体重和发育问题。当铅的毒性达到较高水平时,胎儿会发生自然流产( D.C,2005 )。铅会损害细胞结构、细胞膜,最重要的是它会干扰 DNA 转录( Yedjou 等,2010 )。在发育阶段,铅通过胎盘进入胎儿体内。在发育阶段,铅通过胎盘进入胎儿体内( Mason et al., 2014 )。

When Pb exposed to atmosphere they form sulphates, oxides and carbonates (Sharma and Agrawal, 2005). Lead concentrations on the earth surface are product of a variety of natural and anthropogenic sources. Natural pathways include Geological process controlling Pb composition of silicates contributes to the natural Pb concentration and it is reported that Pb occurs < 50 mg/kg in earth's crust and (Duffus, 2002). Pb mimics ca by binding to the same receptors in cell activities and its uptake by plants exhibits serious effects on humans when consumed, Ronnie Levin et al. reported that the natural pathway for lead accumulation in humans and plants also depends on the seasonality (Edition, 2011). The Pb concentration where found to be lower in spring and higher concentrations were observed when soil pH and salinity decreases. Temperature, humidity, bioavailability, Mobility, Environmental acidification, solar radiation also contributes to the increased Pb concentration. (Khan et al., 2015).
当铅暴露在大气中时,它们会形成硫酸盐、氧化物和碳酸盐( Sharma 和 Agrawal,2005 )。地球表面的铅浓度是多种自然和人为来源的产物。自然途径包括地质过程控制硅酸盐的铅成分,从而影响天然铅浓度,据报道,地壳中的铅含量< 50 mg/kg( Duffus,2002 )。 Ronnie Levin 等人指出,Pb 通过与细胞活动中的相同受体结合来模仿 ca,植物吸收 Pb 后会对人类产生严重影响。据报道,人类和植物体内铅积累的自然途径也取决于季节性( 2011 年版)。春季 Pb 浓度较低,而当土壤 pH 值和盐度降低时,Pb 浓度较高。温度、湿度、生物利用度、流动性、环境酸化、太阳辐射也导致铅浓度增加。 (汗等人,2015 )。

The anthropogenic influence on the environment has resulted in Pb impacting soils, waters, and the atmosphere. Since these medias are used for food, drinking water, and air, any contaminants can enter the biosphere and can potentially affect human health (Ismail et al., 2005). It is found that anthropogenic pathways contribute more in most cases of human Pb exposure, Common anthropogenic contributions are Gasoline, car batteries, sewage sludge, fertilizers and other anthropogenic exposure of Pb includes Mining, Pb bearing sulfide deposits, Pb additives in petrol, Pb water pipes, Pb added in paints (Singh and Kalamdhad, 2011). Pb in drinking water is the major pathway of accumulation into human body which arises mainly due to the use of lead piping, still Pb piping are used in some places and records almost 29 mg L through such piping (K. Neeti and Prakash, 2013). Other sources of increased Pb concentration in water are Landfills, electroplating, Au-Ag-Pb-Zn mining etc. (Z. Sun et al., 2018, Zeng et al., 2007). Geochemical and anthropogenic Pb cycles showed changes in Pb's functions and forms for human needs, Jian-su MAO et al. traced these changes and it is found that Lead ore and scrap are two influencing anthropogenic sources of Pb. The major changes in forms of lead are the conversion of PbS Ore in to metal Pb, PbO2, and PbSO4 (MAO et al., 2014). It should be noted that Small Pb particles potentially show trans boundary movement supported by evidences, whereas large particles tend to deposit and this anthropogenic pathway leads to the accumulation of Pb in human lungs resulting in serious health effects (Markich, 2001).
人为对环境的影响导致铅对土壤、水和大气产生影响。由于这些介质用于食品、饮用水和空气,任何污染物都可能进入生物圈并可能影响人类健康( Ismail 等,2005 )。研究发现,在大多数人类铅暴露情况下,人为途径贡献更大,常见的人为贡献有汽油、汽车电池、污水污泥、化肥,其他人为暴露的铅包括采矿、含铅硫化物沉积物、汽油中的铅添加剂、含铅水中管道、涂料中添加的铅( Singh 和 Kalamdhad,2011 年)。饮用水中的铅是累积到人体的主要途径,这主要是由于铅管道的使用而产生的,但仍有一些地方使用铅管道,并记录通过此类管道的铅含量接近29毫克/升( K. Neeti和Prakash,2013 ) 。水中铅浓度增加的其他来源包括垃圾填埋场、电镀、金银铅锌矿开采等( Z. Sun 等,2018Zeng 等,2007 )。地球化学和人为铅循环显示铅的功能和形态发生变化以满足人类需求,Jian-su MAO 等人。追踪这些变化发现铅矿石和废铅是影响铅的两个人为来源。 铅形态的主要变化是PbS矿石转化为金属Pb、PbO 2和PbSO 4 ( MAO等,2014 )。应该指出的是,小铅颗粒可能表现出有证据支持的跨界运动,而大颗粒则倾向于沉积,这种人为途径导致铅在人肺中积聚,从而造成严重的健康影响(Markich,2001)。

Both natural and Anthropogenic pathways of Pb can be traced effectively by Isotopic (Pb) fingerprinting technique, here isotopic ratios (208Pb, 207Pb, and 206Pb) are analyzed by TIMS, ICP-QMS, and ICP-SFMS techniques. This proves to be a better alternative to traditional statistical analysis of large databases (Ali et al., 2019). Anthropogenic sources of Pb were analyzed by GIS-based data, and the metal distributions were analyzed by principal component analysis (PCA) and cluster analysis (CA). With supported data Harley T. Davis et al. experimentally determined that increased Pb Concentration in both urban and rural are due to anthropogenic sources (Balkhair and Ashraf, 2016). This review addresses various morphological, physiological, and biochemical effects of Lead toxicity in humans and also strategies adopted by humans for Pb detoxification and developing tolerance to Pb.
通过同位素 (Pb) 指纹技术可以有效追踪 Pb 的自然和人为途径,这里通过 TIMS、ICP-QMS 和 ICP-SFMS 技术分析同位素比率( 208 Pb、 207 Pb 和206 Pb)。事实证明,这是对大型数据库的传统统计分析的更好替代方案( Ali et al., 2019 )。通过基于GIS的数据分析Pb的人为来源,并通过主成分分析(PCA)和聚类分析(CA)分析金属分布。根据 Harley T. Davis 等人的支持数据。实验确定城市和农村的铅浓度增加是由于人为来源造成的( Balkhair 和 Ashraf,2016 )。这篇综述讨论了铅毒性对人类的各种形态、生理和生化影响,以及人类为铅解毒和发展铅耐受性所采取的策略。

2. Lead intake by humans
2.人类的铅摄入量

Pb is an environmental pollutant. Despite the low amounts absorbed, prolonged exposure to Pb can accumulate in the human body system, resulting in lead poisoning or toxicity. Lead has a half-life of around 30 days in the blood, after which it diffuses into soft tissues such as the kidneys, brain, and liver and then distributed to bones, teeth and hair as lead phosphate (Engwa et al., 2019). ROS (Reactive oxygen species) such as hydroperoxide, hydrogen peroxide, and singlet oxygen are produced as a result of lead poisoning. Pb generates these free radicals which leads to oxidative stress causing cellular damage to the body cells. The body suffers oxidative stress when there is an imbalance of ROS and antioxidant defences. Oxidative stress causes cell and tissue destruction, which increases the likelihood of adverse health outcomes like cardiovascular disease and cancer (Flora, 2011). The Fig. 1 shows the effect of Pb accumulation in the human body. Increased oxidative stress causes lipid peroxidation, which damages cell membranes resulting in cell damage. Lead inhibits the activity of 5-aminolevulinic acid dehydratase, resulting in hemoglobin oxidation and lipid peroxidation, which can cause red cell hemolysis (Pourrut et al., 2011). Fig. 2 displays that when there is increase in concentration of Pb, the equilibrium between the ROS and antioxidants is altered. The rise in ROS production causes depletion of antioxidant defense causing oxidative stress which eventually leads to cell damage. Lead also interferes with the activity of other antioxidant enzymes including superoxide dismutase and catalase (Violante et al., 2010). Glutathione in the body helps to maintain ROS in balance. Ninety percent of glutathione in the cell is reduced, while ten percent is oxidized, and it serves as an antioxidant defense mechanism. Glutathione stabilizes ROS and is reduced back to GSH by glutathione reductase after being oxidized to glutathione disulfide (Sardar et al., 2013). By attaching to the sulfhydryl group of glutathione, Pb inactivates it, making GSH replenishment ineffective and increasing oxidative stress (Batool et al., 2017). The deposition of a small amount of Pb in the human body causes cellular malfunction and has a negative impact on an individual's health
铅是一种环境污染物。尽管吸收量很少,但长期接触铅会在人体系统中积累,导致铅中毒或中毒。铅在血液中的半衰期约为 30 天,此后它会扩散到肾脏、大脑和肝脏等软组织中,然后以磷酸铅的形式分布到骨骼、牙齿和头发中( Engwa 等,2019 ) 。铅中毒会产生氢过氧化物、过氧化氢和单线态氧等 ROS(活性氧)。铅会产生这些自由基,从而导致氧化应激,从而对身体细胞造成细胞损伤。当活性氧和抗氧化防御失衡时,身体就会遭受氧化应激。氧化应激会导致细胞和组织破坏,从而增加心血管疾病和癌症等不良健康结果的可能性( Flora,2011 )。图1显示了Pb在人体内积累的影响。氧化应激增加会导致脂质过氧化,从而损害细胞膜,导致细胞损伤。铅抑制5-氨基乙酰丙酸脱水酶的活性,导致血红蛋白氧化和脂质过氧化,从而引起红细胞溶血( Pourrut等,2011 )。如图。图2显示当Pb浓度增加时,ROS和抗氧化剂之间的平衡被改变。 ROS 产生的增加导致抗氧化防御的耗竭,从而引起氧化应激,最终导致细胞损伤。铅还会干扰其他抗氧化酶的活性,包括超氧化物歧化酶过氧化氢酶 Violante et al., 2010 )。体内的谷胱甘肽有助于维持活性氧的平衡。细胞中百分之九十的谷胱甘肽被还原,百分之十被氧化,它作为一种抗氧化防御机制。谷胱甘肽可稳定 ROS,并在被氧化为谷胱甘肽二硫化物后被谷胱甘肽还原酶还原回 GSH Sardar 等,2013 )。通过附着在谷胱甘肽的巯基上,铅使其失活,使 GSH 补充无效并增加氧化应激( Batool 等,2017 )。少量的铅在人体内沉积会导致细胞功能障碍,对个人的健康产生负面影响

Fig 1
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Fig. 1. Effects of heavy metal accumulation in human body.
图1 .重金属在人体内蓄积的影响。

Fig 2
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Fig. 2. The mechanism underlying the development of oxidative stress in a cell on lead exposure.
图2 .铅暴露导致细胞氧化应激发展的机制。

3. Physiological and biochemical effects of lead accumulation in human beings
3.铅在人体中积累的生理生化效应

Lead (Pb) is one of the ancient heavy metals used by human beings. From time immemorial, Pb has huge applications in the manufacturing of instruments and tools due to its splendid physical and chemical properties. Lead is used in the manufacture of boats, bearings, buildings, paints, lead batteries, automobiles, gasoline, pipes, ceramics, plastics, and in smelting, mining processes, and the arms industry. Studies have revealed that both adults and children are affected by lead toxicity. In the case of children, both internal and external tissues are soft, hence making them more susceptible (Ara and Usmani, 2015). Its malleability, ductility, corrosion resistance, low melting point, and abundant availability are the reasons lead is used till today, even though its accumulation is hazardous (Wani & Usmani, 2015). Being non-biodegradable in nature, the removal of lead from the environment is inevitable. Lead toxicity and lead accumulation in humans is one of the major health concerns. While occupational causes like dermal contact and inhalation contribute to the indirect intake of lead in humans, consumption of Pb contaminated food and water are direct sources of accumulation. Acute Pb toxicity leads to dysfunction of the kidney, reproductive system, and brain while chronic damages are caused to the CNS and PNS.
铅(Pb)是人类古老的重金属之一。自古以来,铅因其优异的物理和化学性质,在仪器和工具的制造中有着巨大的应用。铅用于制造船舶、轴承、建筑、油漆、铅电池、汽车、汽油、管道、陶瓷、塑料,以及冶炼、采矿过程和军火工业。研究表明,成人和儿童都会受到铅中毒的影响。就儿童而言,内部和外部组织都很柔软,因此使他们更容易受到影响( Ara 和 Usmani,2015 )。尽管铅的积累是危险的,但其延展性、延展性、耐腐蚀性、低熔点和丰富的可用性是铅至今仍被使用的原因( Wani & Usmani,2015 )。由于铅本质上不可生物降解,因此从环境中去除铅是不可避免的。铅毒性和人体铅积累是主要的健康问题之一。虽然皮肤接触和吸入等职业原因会导致人类间接摄入铅,但食用受铅污染的食物和水是铅积累的直接来源。急性铅中毒会导致肾脏、生殖系统和大脑功能障碍,而慢性损伤则会导致中枢神经系统和三七总皂苷。

Lead also inhibits the synthesis of hemoglobin. Pregnant women with low calcium, iron or zinc levels are prone to the effects of lead accumulation (Kwong et al., 2004). Lead is a poisonous metal and disturbs the functions of almost every organ in the human body as depicted in Fig. 3. Common symptoms observed are behavioral changes, lowered IQ, slow learning in children, diarrhea, anemia, skin allergies, kidney malfunctioning and many more (Cerazy and Cottingham, 2010). Also the Pb interacts with mechanisms and functions of the male reproductive system and affects the sperm count (B. Quintanilla-Vega et al., 2000). Even low levels of Pb in the kidney cause chronic renal malfunctioning (Barbier et al., 2005). It is found that Pb interferes with the activities of several enzymes, delta-aminolevulinicacid dehydratase (ALAD), ferrochetase catalase, superoxide dismutase (SOD) and many more (Onalaja, A. O., & Claudio, L.,A.O. 2000). Lead-induced oxidative stress increases radical production damaging the cell membranes, cell functions and DNA (Hsu and Guo, 2002; Ahamed and Siddiqui, 2007).
铅还会抑制血红蛋白的合成。钙、铁或锌含量低的孕妇容易受到铅蓄积的影响( Kwong等,2004 )。铅是一种有毒金属,会干扰人体几乎每个器官的功能,如图3所示。观察到的常见症状是行为改变、智商降低、儿童学习缓慢、腹泻、贫血皮肤过敏、肾功能障碍等等( Cerazy 和 Cottingham,2010 )。此外,Pb 还与男性生殖系统的机制和功能相互作用,并影响精子数量( B. Quintanilla-Vega 等,2000 )。即使肾脏中的铅含量很低,也会导致慢性肾功能障碍( Barbier 等,2005 )。研究发现,Pb 会干扰多种酶的活性,包括 δ-氨基乙酰丙酸脱水酶(ALAD)、亚铁酶过氧化氢酶超氧化物歧化酶(SOD) 等(Onalaja, AO 和 Claudio, L., AO 2000 )。铅诱导的氧化应激会增加自由基的产生,从而损害细胞膜、细胞功能和DNA( Hsu和Guo,2002Ahamed和Siddiqui,2007 )。

Fig 3
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Fig. 3. Diagrammatic representation of lead accumulation in the major organs.
图3 .主要器官中铅积累的图示。

3.1. Effect of lead on the nervous system
3.1.铅对神经系统的影响

Lead toxicity affects the nervous system drastically when compared to the other organ systems in the human body. Symptoms worsen and give rise to paralysis, coma, or even death (Gilani et al., 2015). Lead is considered to be a neurotoxin. The half-life of Pb in the brain is 2 to 3 years whereas in the blood it is 30 days. Encephalopathy is a condition where there is a progressive deterioration in the parts of the human brain, major manifestations of encephalopathy including headache, dullness, poor attention span, memory loss, and hallucinations within a few weeks of exposure (Karri et al., 2008; Arora et al., 2015).
与人体其他器官系统相比,铅毒性对神经系统的影响极大。症状恶化并导致瘫痪、昏迷甚至死亡( Gilani et al., 2015 )。铅被认为是一种神经毒素。铅在大脑中的半衰期为 2 至 3 年,而在血液中的半衰期为 30 天。脑病是人类大脑部分进行性恶化的病症,脑病的主要表现包括头痛、迟钝、注意力不集中、记忆力减退以及在接触病毒后几周内出现幻觉( Karri et al., 2008阿罗拉等人,2015 )。

Children are more likely to get affected by Pb toxicity in their developing stages than adults (Needleman, 2004). Pb toxicity in children is mostly asymptomatic, while children below 5years show some symptoms like lethargy, abdominal cramps, vomiting, irritability, and loss of appetite. Epidemiological studies reveal that children with Blood Lead Level BPb (BPb -‘Biomarker’ is a term used to measure the interactions between the biological system and an external environmental agent) less than 10 µg/dL are affected severely (Garza et al., 2006 ; Sander et al., 2009). Astrocytes, a type of glial cells in the brain, along with neurons and the extracellular matrix contain the physical Blood-Brain Barrier (BBB). As Pb2+ions easily substitute Ca2+ions, it crosses the BBB swiftly and accumulates in the brain cells (Florea et al., 2013). Joint F. A. O et al. performed experiments on the children's IQ. As Pb2+ions easily substitute Ca2+ions, it crosses the Blood-Brain-Barrier (BBB) swiftly and accumulates in the brain cells. Pb2+replaces Ca2+ in Protein Kinase C(PKC) Enzyme assay, a calcium-dependent process, changes the behavior of endothelial brain cells and disrupts the functions of BBB (Joint F. A. O., & WHO Expert Committee on Food Additives, F.A.O. 2002). On testing the intelligence, it was found that IQ dropped by 3 points when BPb level increased from 10 µg/dL to 20 µg/dL and WHO concluded that for every 10 µg/dL increase in BPb levels, IQ decreases by 1–5 points (Bellinger et al.,  2005, Reuben et al., 2017). Lanphear et al. examined 4853 children of NHANES(III) (National Health and Nutrition Examination Survey – it is a program that is designed to assess the health and nutrition of adults and children in the US) and conducted psychometric tests for them (Lanphear et al., 2000). He disclosed that the mean BPb level was 1.8–1.9 µg/dL and also found that children had neural development, linguistic and processing problems, decrement in the memory power, and difficulty in comprehension of visuospatial skills (Rogan et al., 2001). Stokes et al. in their research studies stated that occupational exposure is a major source of Pb accumulation in adults and affects the PNS.
儿童在发育阶段比成人更容易受到铅中毒的影响( Needleman,2004 )。儿童铅中毒大多无症状,而5岁以下儿童则表现出嗜睡、腹部绞痛、呕吐、烦躁、食欲不振等症状。流行病学研究表明,血铅水平BPb(BPb -“生物标志物”是一个用于测量生物系统与外部环境因素之间相互作用的术语)低于 10 µg/dL 的儿童会受到严重影响( Garza 等人,2006 年)桑德等人,2009 )。星形胶质细胞是大脑中的一种神经胶质细胞,与神经元和细胞外基质一起构成了物理血脑屏障 (BBB)。由于Pb 2+离子很容易取代Ca 2+离子,因此它能迅速穿过血脑屏障并在脑细胞中积聚( Florea et al., 2013 )。联合 FA O 等人。对孩子们的智商进行了实验。由于Pb 2+离子很容易取代Ca 2+离子,因此它能迅速穿过血脑屏障(BBB)并在脑细胞中积聚。 Pb 2+在蛋白激酶 C (PKC) 酶测定中取代 Ca 2+ ,这是一种钙依赖性过程,会改变内皮脑细胞的行为并破坏 BBB 的功能(FAO 和 WHO食品添加剂联合专家委员会, FAO)2002)。在智力测试中,发现当 BPb 水平从 10 µg/dL 增加到 20 µg/dL 时,智商下降 3 分,世界卫生组织得出结论,BPb 水平每增加 10 µg/dL,智商下降 1-5 分( Bellinger 等人,2005 年Reuben 等人,2017 年)。兰菲尔等人。对 NHANES(III)(国家健康和营养检查调查 - 这是一项旨在评估美国成人和儿童的健康和营养的计划)的 4853 名儿童进行了检查,并对他们进行了心理测试( Lanphear 等人,2000 年) )。他透露,平均 BPb 水平为 1.8–1.9 µg/dL,并发现儿童存在神经发育、语言和处理问题、记忆力下降以及视觉空间技能理解困难( Rogan 等,2001 )。斯托克斯等人。在他们的研究中指出,职业暴露是成人铅积累的主要来源,并影响三七总皂甙。

Silbergeld et al. proposed that there can be two types of neurotoxicity:
西尔伯格德等人。提出可能有两种类型的神经毒性

  • (1)

    Neurodevelopmental Pb that disturbs the functions of CNS.
    神经发育铅会干扰中枢神经系统的功能。

  • (2)

    Neuropharmacological Pb intrudes and alters the ionic mechanisms of the neurotransmitters.
    神经药理学 铅侵入并改变神经递质的离子机制。

Observations state that high BPb concentrations >4 µM result in acute Encephalopathy, Apoptosis, dysfunction of the Blood-Brain Barrier (BBB), and severe conditions leading to hemorrhage and schizophrenia (Ishaq et al., 2021). Tetraethyl lead (TEL) is a powerful neurotoxin and an additive in motor fuel and 25 workers died in 1925 due to longtime exposure to Pb. Pb2+also can replace Ca2+ ions, thus increasing the Pb2+ concentration in the cells. Even nanomolar concentrations of Pb2+ disturb the mitochondrial functions and kill brain cells via apoptosis (Yang et al., 2014). This state is initiated when the mitochondria dysfunctions. Mitochondrial dysfunction is caused by the increase in intercellular Ca2+ ions or by the accumulation of Pb2+ions. Pb2+ ions disrupt Ca2+ homeostasis leading to higher Ca2+ ions in cells.
观察表明,高 BPb 浓度 >4 µM 会导致急性脑病、细胞凋亡、血脑屏障 (BBB) 功能障碍,以及导致出血和精神分裂症的严重病症( Ishaq 等人,2021 )。四乙基铅(TEL) 是一种强效神经毒素,也是汽车燃料的添加剂,1925 年有 25 名工人因长期接触铅而死亡。 Pb 2+还可以取代Ca 2+离子,从而增加细胞内Pb 2+ 的浓度。即使是纳摩尔浓度的 Pb 2+也会扰乱线粒体功能并通过细胞凋亡杀死脑细胞( Yang et al., 2014 )。当线粒体功能障碍时,就会启动这种状态。线粒体功能障碍是由细胞间Ca 2+离子增加或Pb 2+离子积累引起的。 Pb 2+离子破坏Ca 2+稳态,导致细胞内Ca 2+离子增多。

3.2. Effect of lead on the skeletal system-Bone
3.2.铅对骨骼系统——骨的影响

Lead exposure from both occupational and environmental sources causes an increase in levels of lead in the bone matrix throughout childhood and most of adulthood. The major Pb2+ concentration is detected in the bone tissues of human beings which can be seen in Fig. 4. In a case study, it has been reported that a woman with acute lead toxicity was diagnosed with abdominal and knee pain, neurological symptoms, hypertension, chronic kidney disease, and anemia with basophilic stippling. It was observed that, compared to her previous pregnancy, lead levels in her body tripled in her subsequent one. This increase in blood lead concentration was likely due to the skeletal mobilization without any new lead exposure. This acute lead toxicity traced is due to mobilization and redistribution of lead from the bone by pathophysiological and physiological conditions. The subject had a serious failure in her neurologic, renal, orthopedic, hematologic, and gastrointestinal systems and her reproductive system (Riess & Halm,Matthias 2007). It was reported that occupational exposure to lead decreased the calcitriol formation resulting in lowered absorption of phosphorous and calcium at the renal and intestinal tracts. It was observed that the total serum calcium levels and serum ionized calcium levels decreased by 14–21% in all the study groups and similarly the serum phosphorous levels were also decreased by 14–19%. It was also reported that this increased lead exposure showed a slight elevation in systolic (7–13%) and diastolic (5–17%) pressure (Dongre et al.,NN 2013; Rodríguez & Mandalunis,J. 2018). It is reported that lead affects osteoblasts, osteoclasts, and chondrocytes, and increases the risk of osteoporosis. Women undergoing menopause are at a higher risk of experiencing osteoporosis. Moreover, Pb exposed individuals suffer a serious fracture and recover at a very slow rate in comparison with non-exposed individuals (Carmouche et al.,  2005).
职业和环境来源的铅暴露会导致整个儿童期和成年期大部分时间骨基质中的铅含量增加。主要的Pb2+浓度是在人类的骨组织中检测到的,如图4所示。在一项案例研究中,据报道,一名患有急性铅中毒的女性被诊断出患有腹部和膝盖疼痛、神经系统症状、高血压、慢性肾病和嗜碱性点画贫血。据观察,与前一次怀孕相比,她体内的铅含量在接下来的怀孕中增加了两倍。血铅浓度的增加可能是由于骨骼动员而没有任何新的铅暴露所致。所追踪的这种急性铅毒性是由于病理生理和生理条件下铅从骨中的动员和重新分布造成的。该受试者的神经、肾脏、骨科、血液、胃肠系统以及生殖系统出现严重衰竭(Riess & Halm, Matthias 2007 )。据报道,职业接触铅会减少骨化三醇的形成,导致肾脏和肠道对磷和钙的吸收减少。据观察,所有研究组的血清总钙水平和血清离子钙水平下降了 14-21%,同样,血清磷水平也下降了 14-19%。另据报道,铅暴露的增加表明收缩压(7-13%)和舒张压(5-17%)略有升高(Dongre 等,2017)。, NN 2013 ;罗德里格斯和曼达鲁尼斯, J. 2018 )。据报道,铅会影响成骨细胞、破骨细胞和软骨细胞,并增加骨质疏松症的风险。经历更年期的女性患骨质疏松症的风险较高。此外,与未接触铅的个体相比,接触铅的个体会遭受严重骨折,并且恢复速度非常慢( Carmouche等,2005 )。

Fig 4
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Fig. 4. The half-life of lead in bones.
图4 .铅在骨骼中的半衰期。

3.3. Effect of lead on the reproductive system
3.3.铅对生殖系统的影响

The reproductive system of both males and females are affected by increased BPb levels. Studies reveal that pregnant women tend to have greater complications due lead accumulations (Vigeh et al.,M. 2010). Men with BPb levels greater than 25 µg/dL experience reduced sperm mobility, fertility, sperm count, and abnormal sperm morphology. On the other hand, women with 10 µg/dL BPb level face complications like preterm birth, low birth weight, infertility, miscarriage, neural defects in early childhood, and maternal hypertension (van Straaten, 2000). BPb level in the range 10–15 µg/dL in women of childbearing age directly affects the developing fetus. Generally, women who give birth after 30–35 years are more vulnerable to having Pb in their breast milk (Bellinger, D.C. 2005; Shannon,M. 2003). Assent et al. studied the sperm count of lead workers. His-studies reported Teratospermia (genetic damage to sperm), Hypospermia (low sperm count), and chromosomal aberrations (Telišman et al., 2007). Protamine (HP2) is a Zn protein that protects the sperm DNA. Pb tends to replace this Zn and causes sperm DNA damage (Quintanilla-Vega et al.,  2000). It has also been observed that the fetus has 19% more BPb level than the mother at the time of birth (Cleveland et al., 2008). At 12 weeks of the gestation period, the lead easily crosses the placenta (Hatzidaki et al., 2005). A fetus accumulates about 30 g of calcium into the fetal skeleton during the gestation period. During the bone resorption, a bone lead that has been accumulated for years is transferred to the fetal circulations through the placenta. (Téllez-Rojo, M.M. 2004)
男性和女性的生殖系统都会受到 BPb 水平升高的影响。研究表明,孕妇往往会因铅积累而出现更大的并发症(Vigeh 等人, M. 2010 )。 BPb 水平高于 25 µg/dL 的男性精子活动能力、生育能力、精子数量和精子形态异常都会降低。另一方面,BPb水平为10 µg/dL的女性面临早产、低出生体重、不孕、流产、幼儿期神经缺陷和产妇高血压等并发症( van Straaten,2000 )。育龄妇女的 BPb 水平在 10–15 µg/dL 范围内会直接影响发育中的胎儿。一般来说,30-35 岁后分娩的女性更容易受到母乳中铅的影响(Bellinger, DC 2005 ;Shannon, M. 2003 )。同意等人。研究了领头工人的精子数量。他的研究报告了畸形精子症(精子的遗传损伤)、精子减少症(精子数量低)和染色体畸变 Telišman 等,2007 )。鱼精蛋白(HP2) 是一种保护精子 DNA 的锌蛋白。 Pb 往往会取代 Zn 并导致精子 DNA 损伤( Quintanilla-Vega 等,2000 )。 据观察,胎儿出生时的 BPb 水平比母亲高 19%( Cleveland 等,2008 )。在妊娠期 12 周时,导线很容易穿过胎盘(Hatzidaki 等,2005)。胎儿在​​妊娠期间会在胎儿骨骼中积累约30克钙。在骨吸收过程中,多年积累的骨铅通过胎盘转移到胎儿循环中。 (特莱斯-罗霍, MM2004年)

3.4. Effect of lead on the hematopoietic system
3.4.铅对造血系统的影响

Lead directly affects the hematological system at very low BPb levels-10 µg/dL. It restrains the synthesis of hemoglobin by the inhibition of important enzymes involved in heme synthesis and reduces the life span of erythrocytes by the destabilization and increasing fragility of its cell membrane. This directly results in anemia and high blood Pb levels lead to Frank's anemia (iron deficiency anemia) (Ameen et al.,2009). Acute lead exposure leads to hemolytic anemia, where the red blood cells are destroyed as fast as they are made (Guidotti et al.,2008). A key enzyme for the synthesis of heme is δ-aminolevulinic acid dehydratase (ALAD). δ-ALAD, a cytoplasmic enzyme rich in SH groups, is the enzyme that catalyzes the formation of porphobilinogen from δ-aminolevulinic acid (ALA). Nikkanen et al. in their studies demonstrated that δ-ALAD is inhibited when the BPb levels are as low as 5 µg/dL and leads to behavioral changes and childhood lead encephalopathy. The inhibition of δ-ALAD results in the accumulation of δ-ALA in the plasma and excess of δ-ALA leads to severe neurological effects (Dehari-Zeka et al., 2020). δ- ALA in urine is also used as an indicator for lead exposure among industrial workers. Ferrochelatase is another mitochondrial enzyme that catalyzes the incorporation of iron (Fe2+) into the porphyrin ring. Lead toxicity inhibits this enzyme and in case of low availability Fe2+, Zn2+ is substituted and also interferes with the trans-mitochondrial transport of iron (Jangid et al.,  2012). More than 90% of Pb in the blood is bound to the RBC keeping plasma lead concentrations constant at 2–3 µg/dL even when BPb concentration is 10–150 µg/dL (Mrugesh et al., 2011; Patrick, 2006). These lead to decrease in hemoglobin in human beings, followed by anemia, weight loss, complications during pregnancy, kidney malfunctioning, and cancer in severe cases are some direct effects.
铅在 BPb 水平极低(10 µg/dL)时直接影响血液系统。它通过抑制参与血红素合成的重要酶来抑制血红蛋白的合成,并通过破坏细胞膜的稳定性和增加其脆性来缩短红细胞的寿命。这直接导致贫血,而高血铅水平导致弗兰克氏贫血(缺铁性贫血)(Ameen et al.,2009)。急性铅暴露会导致溶血性贫血,红细胞在产生的同时就被破坏(Guidotti 等, 2008 )。合成血红素的关键酶是δ-氨基乙酰丙酸脱水酶(ALAD)。 δ-ALAD 是一种富含 SH 基团的细胞质酶,是催化 δ-氨基乙酰丙酸 (ALA) 形成胆色素原的酶。尼卡宁等人。他们的研究表明,当 BPb 水平低至 5 µg/dL 时,δ-ALAD 会受到抑制,并导致行为改变和儿童铅脑病。抑制 δ-ALAD 会导致血浆中 δ-ALA 的积累,过量的 δ-ALA 会导致严重的神经系统影响 ( Dehari-Zeka et al., 2020 )。尿液中的δ-ALA也被用作产业工人铅暴露的指标。铁螯合酶是另一种线粒体酶,可催化铁 (Fe2+) 掺入卟啉环。铅毒性会抑制这种酶,在 Fe2+ 可用性较低的情况下,Zn2+ 会被取代,并且还会干扰铁的跨线粒体转运( Jangid 等,2012 )。 血液中超过 90% 的铅与红细胞结合,即使 BPb 浓度为 10–150 µg/dL,血浆铅浓度也能恒定在 2–3 µg/dL( Mrugesh 等,2011Patrick,2006 )。这些会导致人类血红蛋白减少,随之而来的是贫血、体重减轻、怀孕期间的并发症、肾功能障碍,严重时甚至会引发癌症。

3.5. Effect of lead on the renal system
3.5.铅对肾脏系统的影响

The mechanism of lead nephrotoxicity, renal cancer-role of the lead binding protein, adverse effect of low level environmental and chronic lead exposure in neurotoxicity, renal toxicity, renal cancer, renal dysfunction, and other complications were reported (Assi et al., 2016). Jia, et al. reported the mechanism of lead nephrotoxicity and formation of inclusion bodies such as lead-protein complex due to accumulation of lead in proximal renal tubular lining cells with cause proximal tubular dysfunction (Jia et al.,Q. 2012). The effect of lead in nephrotoxicity was reported to be occurring in three stages, primarily reversible or acute nephropathy, next stage is chronic nephropathy and the final stage is the renal tubular cell neoplasia or adenocarcinoma (Flora et al., 2012). Clinical manifestation includes a decrease in energy-dependent transport functions, including glycosuria, aminoaciduria, and changes in specific ion transport (Niemann and Serkova, 2007). Reduced glomerular filtration rate, decreased inulin clearance, and decreased maximal reabsorption of glucose are also observed in chronic nephropathy (Wang et al., 2002). Lead can bind with proteins and creates the risk of renal cancer. Kidney-specific proteins act as receptors and facilitate interactions with DNA in renal proximal tubular cells, the altered gene results in cancer (Silbergeld et al., 2000). Lead exposure also influenced renal plasma excretion and plasma renin activity. Lead poisoning in mitochondria creates deficiency of ATP, this reduces the reabsorption of sodium, an important process of kidney and increased renal excretion of sodium is observed (Marsden,P.A. 2003). Patients with acute and chronic renal injury were observed with excretion of more than 600 μg of lead over 72 h after an EDTA-mobilization test (Fontanellas et al.,A 2002). Almost 99% of blood lead bounded to zinc-dependent delta-aminolaevulinic acid dehydratase (ALAD) are stored in erythrocytes, since ALAD is inhibited this reflects in suppression of the heme synthesis (Siddarth et al.,M 2018).
肾毒性的机制、肾癌-铅结合蛋白的作用、低水平环境和慢性铅暴露对神经毒性、肾毒性、肾癌、肾功能障碍和其他并发症的不利影响 Assi等,2016) )。贾,等。报道了铅肾毒性的机制以及由于铅在近端肾小管衬里细胞中积累导致近端肾小管功能障碍而形成包涵体(例如铅-蛋白复合物)(Jia等人, Q.2012 )。据报道,铅的肾毒性作用分三个阶段发生,首先是可逆性或急性肾病,下一阶段是慢性肾病,最后阶段是肾小管细胞瘤或腺癌 Flora等,2012 )。临床表现包括能量依赖性转运功能下降,包括糖尿氨基酸尿和特定离子转运的变化( Niemann 和 Serkova,2007 )。在慢性肾病中还观察到肾小球滤过率降低、菊粉清除率降低和葡萄糖最大重吸收降低( Wang et al., 2002 )。铅可以与蛋白质结合并产生患肾癌的风险。 肾脏特异性蛋白质充当受体并促进与肾近端肾小管细胞中的 DNA 相互作用,改变的基因会导致癌症( Silbergeld 等,2000 )。铅暴露还影响肾血浆排泄和血浆肾素活性。线粒体中的铅中毒导致 ATP 缺乏,这减少了钠的重吸收,这是肾脏的一个重要过程,并且观察到钠的肾脏排泄增加(Marsden, PA 2003 )。观察到患有急性和慢性肾损伤的患者在 EDTA 动员试验后 72 小时内排泄了超过 600 μg 的铅(Fontanellas 等人, A 2002 )。几乎 99% 与锌依赖性 δ-氨基乙酰丙酸脱水酶 (ALAD) 结合的血铅储存在红细胞中,因为 ALAD 受到抑制,这反映了血红素合成的抑制 (Siddarth et al., M 2018 )。

A study collected workers' renal biopsies and analyzed for various parameters like inclusion bodies glomeruli filtrate rate, the plasma concentration of urinary excretion of ALA, renal excretion of lead, and lead-induced nephropathy. The samples with acute exposure showed the presence of nuclear inclusion bodies in the proximal tubular lining and greater urinary excretion of lead and the biopsy samples with chronic exposure showed peritubular fibrosis (Karimooy et al.,H.N. 2010).
一项研究收集了工人的肾活检并分析了各种参数,如包涵体肾小球滤过率、尿排泄 ALA 的血浆浓度、肾排泄铅和铅诱发的肾病。急性暴露的样本显示近端肾小管内壁存在核包涵体,并且尿中铅排泄较多,而慢性暴露的活检样本显示肾小管周围纤维化(Karimooy 等人, HN 2010 )。

3.6. Effect of lead on the cardiovascular system
3.6.铅对心血管系统的影响

Lead also affects the cardiovascular system and has a significant impact on the human heart. Besides inducing increased blood pressure and hypertension, it has been observed that exposure to high levels of lead is also associated with increased risks of stroke, peripheral arterial disease, coronary heart disease, and cardiovascular functional abnormalities such as left ventricular hypertrophy and alterations in the cardiac rhythm (Lustberg & Silbergeld,M. 2002; Menke et al.,2006; Navas-Acien et al.,A. 2004; Schober et al.,2006).Another study demonstrated the positive association between blood lead levels and total peripheral resistance, reduced cardiac output, and reduced stroke volume in response to acute stress in children (9 to 11 years) when the blood lead level was below 10 µg/dL (Gump et al., 2011). At the blood lead level >5 µg/dL, the percentage of adults above the threshold of systolic blood pressure elevates as the age group increases. A report on steel factory workers in Poland revealed a significantly higher left ventricle mass and lower ejection fraction when the results were compared to the administrative workers of the same factory (Kasperczyk et al., 2005). The workers who were in contact with higher concentrations of lead had developed weakened diastolic functions when compared with the workers who were not exposed to lead (Beck & Steinmetz, B. 2005). Lead can also escalate the release of pro-inflammatory cytokines by stimulating the endothelial and peripheral mononuclear cells in humans (Nawrot et al., 2002). Inflammatory cytokines cause an increase in endothelial inflammation along with cardiovascular damage (Cao et al., 2015). Lead has the potential to play a role in arterial stiffness and the mechanism of involvement of metals in cardiovascular pathology has been studied. Pre-school children who are exposed to e-waste show a positive response to future cardiovascular diseases, as the elevated blood lead level is associated with the heightened vascular endothelial inflammation (Zheng et al.,  2019). Thus the effect of lead on the cardiovascular systems is first noticed when there is an increase in blood pressure. However, this becomes apparent when the blood lead level crosses the threshold level of 5 µg/dL (Navas-Acien et al., 2007).
铅还会影响心血管系统,对人的心脏有重大影响。除了引起血压升高和高血压外,据观察,接触高浓度的铅还会增加中风、外周动脉疾病冠心病和心血管功能异常(如左心室肥大和心脏功能改变)的风险。 (Lustberg & Silbergeld, M. 2002 ; Menke et al.,2006 ; Navas-Acien et al., A. 2004 ; Schober et al., 2006 )。另一项研究表明血铅水平与总外周阻力之间呈正相关当血铅水平低于 10 µg/dL 时,儿童(9 至 11 岁)因急性应激而导致心输出量减少和每搏输出量减少( Gump 等人,2011 年)。当血铅水平 >5 µg/dL 时,超过收缩压阈值的成年人比例随着年龄组的增加而升高。一份关于波兰钢铁厂工人的报告显示,与同一工厂的管理人员相比,其左心室质量明显较高,射血分数较低( Kasperczyk 等,2005 )。 与未接触铅的工人相比,接触较高浓度铅的工人的舒张功能较弱(Beck & Steinmetz, B. 2005 )。铅还可以通过刺激人类的内皮细胞和外周单核细胞来增加促炎细胞因子的释放( Nawrot 等,2002 )。炎症细胞因子导致内皮炎症增加以及心血管损伤( Cao et al., 2015 )。铅有可能在动脉硬化中发挥作用,并且金属参与心血管病理学的机制已被研究。接触电子垃圾的学龄前儿童对未来的心血管疾病表现出积极的反应,因为血铅水平升高与血管内皮炎症加剧有关( Zheng et al., 2019 )。因此,当血压升高时,首先会注意到铅对心血管系统的影响。然而,当血铅水平超过 5 µg/dL 的阈值水平时,这一点就会变得明显( Navas-Acien 等人,2007 年)。

3.7. Effect of lead on the saliva, hair, nail, and tooth
3.7.铅对唾液、头发、指甲和牙齿的影响

3.7.1. Lead in saliva 3.7.1.唾液中的铅

Some reports indicate the presence of lead in the salivary glands which can be seen in the saliva at high concentrations (Thaweboon et al.,  2005). In a study conducted by Thaweboon et al. on a population residing in a highly lead-contaminated area, he noticed that the salivary lead levels were higher in the affected population than in the reference population. However, the lead levels in the saliva were much lower than the ones present in the blood. This may be because the lead levels in the saliva are proportional to the diffusible lead present in the blood rather than the lead present in the whole of the blood.
一些报告表明唾液腺中存在铅,在唾液中可以看到高浓度的铅( Thaweboon 等,2005 )。 Thaweboon 等人进行的一项研究中。针对居住在铅高度污染地区的人口,他注意到受影响人口的唾液铅水平高于参考人口。然而,唾液中的铅含量远低于血液中的铅含量。这可能是因为唾液中的铅含量与血液中存在的可扩散铅成正比,而不是与整个血液中存在的铅成正比。

3.7.2. Lead in hair 3.7.2.头发中的铅

Correlation between blood lead levels and hair has been previously reported in occupationally exposed workers (Ahmad et al., 2018). Concentrations of lead in hair cannot be used to monitor the environmental exposure of lead, this makes hair an ineffective biological indicator (Mehra et al., 2011)
此前曾报道过职业暴露工人的血铅水平与头发之间的相关性( Ahmad 等,2018 )。头发中的铅浓度不能用于监测铅的环境暴露量,这使得头发成为无效的生物指标( Mehra et al., 2011

3.7.3. Lead in nail 3.7.3.钉子里含铅

Nail is also a point of excretion of lead. The concentration of lead found in the nail is higher than that found in the hair in occupationally exposed workers and the concentration of lead in nails depends on the age of the subject (Mehra and Juneja, 2004; Nowak & Chmielnicka, B. 2000). However, it does not depend on the sex of the subject (Rodushkin & Axelsson,I. 2000).
指甲也是铅的排泄点。在职业接触工人中,指甲中的铅浓度高于头发中的铅浓度,并且指甲中的铅浓度取决于受试者的年龄( Mehra 和 Juneja,2004 年;Nowak 和 Chmielnicka, B. 2000 年)。然而,它并不取决于受试者的性别(Rodushkin & Axelsson, I. 2000 )。

3.7.4. Lead in tooth 3.7.4.牙齿中的铅

Teeth tend to accumulate lead over a long period. The accumulation of lead in children in their teeth occurs even before the tooth eruption (Asaduzzaman et al., 2017). The lead concentration in the carious teeth is 33% higher than the non-carious teeth. Hence the carious molar is an efficient pathway for the contamination of lead. Also, it has been recorded that the carious and molar teeth of boys are a better contamination path for lead. This shows an increased tooth lead concentration in boys than in girls (Arruda-Neto et al., 2009).
牙齿往往会在很长一段时间内积累铅。儿童牙齿中的铅甚至在牙齿萌出之前就已积聚( Asaduzzaman 等,2017 )。龋齿中的铅浓度比非龋齿高33%。因此,龋齿是铅污染的有效途径。此外,据记录,男孩的龋齿和臼齿是铅更好的污染途径。这表明男孩的牙齿铅浓度高于女孩( Arruda-Neto 等,2009 )。

4. Prevention and treatment of lead accumulation in human beings
4、人体铅蓄积的防治

The most successful and vital treatment is chelation therapy. It is a clinical intervention where chelating agents are administered, which in turn binds Pb2+ and removes it from the tissues via urine in case of acute exposure (Hao et al.,  2013). Calcium disodium ethylene diamine tetraacetic acid (CaNa2EDTA) is one of the best chelators. Succimer (2,3 meso‑dimercaptosuccinic acid or DMSA), an oral chelating agent, is preferred for mild and asymptomatic cases (Cao et al., 2015). They forms stable water-soluble complexes and reduces lead levels in blood, brain, and kidney immediately. They are dosed at 350 mg/m2 and given thrice a day for five days (Batool et al., 2017). Then it is reduced to twice per day for 14 days. DMSA being an antioxidant significantly depletes Pb-induced oxidative stress and apoptosis (Obeng-Gyasi,  2019). The most common sources of lead exposure in children and adults illustrated by Taina Litwak have been depicted in Fig. 5 that can be highly avoided. The best treatment available to quickly reduce the blood lead level is chelation therapy (Kumar et al., 2017). Since Pb2+ is toxic and finds no application in the human body, it has to be completely eliminated. This is possible only by replacing the existing Pb2+ ions by Ca2+ ions which are useful. This is because Pb2+ ions replace Ca2+ ions in important sites and causes severe damages that have been discussed above. Only chelation therapy fits this condition. Brought into clinical use in 1950 as antidote for lead toxicity, much research has been done since the early chelating agent that is, EDTA. Chelation therapy is sought out as it can drastically clean out the blood lead levels and Pb2+ ions can be easily removed from the body by urine. (Aaseth et al., 2015). Never the less, since the chelating agents cause side effects, their usage is limited to severe cases of over exposure of heavy metals (Kushwaha et al., 2018).
最成功和最重要的治疗方法是螯合疗法。这是一种临床干预措施,其中使用螯合剂,螯合剂反过来结合 Pb 2+并在急性暴露时通过尿液将其从组织中去除( Hao 等,2013 )。乙二胺四乙酸二钠钙(CaNa 2 EDTA)是最好的螯合剂之一。琥珀聚体(2,3内消旋二巯基丁二酸或DMSA)是一种口服螯合剂,对于轻度和无症状病例是首选( Cao等,2015 )。它们形成稳定的水溶性复合物,并立即降低血液、大脑和肾脏中的铅含量。它们的剂量为 350 mg/m 2 ,每天给药三次,持续五天( Batool 等,2017 )。然后减少到每天两次,持续 14 天。 DMSA 作为一种抗氧化剂,可显着减少 Pb 诱导的氧化应激和细胞凋亡( Oben-Gyasi,2019 )。 Taina Litwak 举例说明了儿童和成人最常见的铅暴露来源,如图 5所示,这些来源是可以高度避免的。快速降低血铅水平的最佳治疗方法是螯合疗法( Kumar et al., 2017 )。由于Pb 2+有毒并且在人体中没有应用,因此必须将其完全消除。 这只有通过用有用的Ca 2+离子替换现有的Pb 2+离子才有可能。这是因为Pb 2+离子在重要部位取代了Ca 2+离子并造成了上面已经讨论的严重损害。只有螯合疗法适合这种情况。 1950年作为铅中毒的解毒剂进入临床,自早期的螯合剂EDTA以来,人们已经进行了大量的研究。人们寻求螯合疗法,因为它可以彻底清除血铅水平,并且 Pb 2+离子可以很容易地通过尿液从体内去除。 ( Aaseth 等人,2015 )。尽管如此,由于螯合剂会产生副作用,因此其使用仅限于重金属过度暴露的严重情况( Kushwaha et al., 2018 )。

Fig 5:
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Fig. 5. The most common sources of Lead exposure in children can be found in their homes.
图5 。儿童最常见的铅暴露来源可以在他们的家中找到。

5. Conclusion 5. 结论

Lead poisoning affects most organs in both children and adults. So knowing the therapy is really important. Preventing exposure to lead is the primary therapy. Keeping in mind that once lead enters the body, it cannot be totally removed, dietary supplements and medical therapies may help lower the quantity of Pb stored in various organs and help eliminate Pb from organ tissues. Also, lead buildup in bones does not directly cause difficulties, but the immobile bone deposits cause major pregnancy issues. They produce renal tubular cell destruction, nephropathy, and renal inefficiency. Low BPb (5 g/dL) causes hypertension and vascular endothelial inflammation. The effects of lead in nails, hair, teeth, and saliva are unknown since they are much lower than in blood. Lead disrupts ionic processes and causes oxidative stress, causing enzyme and protein malfunction. While micronutrients like Ca, Zn, and Fe cannot entirely eliminate lead from the body, they may lower its level. Natural antioxidants, vitamins (flavonoids) scavenge ROS. Early detection of lead poisoning and continuous monitoring of BPb levels may prevent significant consequences. Preventing direct exposure and keeping sufficient diet prevents Pb2+ buildup in tissues.
铅中毒影响儿童和成人的大多数器官。所以了解治疗方法非常重要。防止接触铅是主要治疗方法。请记住,铅一旦进入体内,就无法完全清除,膳食补充剂和药物治疗可能有助于降低各器官中储存的铅含量,并有助于消除器官组织中的铅。此外,骨骼中的铅积聚不会直接导致困难,但固定的骨沉积物会导致严重的怀孕问题。它们会造成肾小管细胞破坏、肾病和肾功能低下。低血压 (5 g/dL) 会导致高血压和血管内皮炎症。指甲、头发、牙齿和唾液中铅的影响尚不清楚,因为它们的含量比血液中低得多。铅会破坏离子过程并引起氧化应激,导致酶和蛋白质功能障碍。虽然钙、锌和铁等微量营养素不能完全消除体内的铅,但它们可能会降低铅的水平。天然抗氧化剂、维生素(类黄酮)可清除活性氧。及早发现铅中毒并持续监测 BPb 水平可以防止出现严重后果。防止直接接触并保持充足的饮食可防止 Pb 2+在组织中积聚。

Funding information 资金信息

The authors gratefully acknowledge the financial support from the European Union’s Horizon 2020 research and innovation program under the grant agreement No. 857287.
作者衷心感谢欧盟 Horizo​​n 2020 研究和创新计划根据第 857287 号拨款协议提供的财政支持。

Declaration of Competing Interest
竞争利益声明

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
作者声明,他们没有已知的可能影响本文报告工作的相互竞争的经济利益或个人关系。

References