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Systematic review of potential health risks posed by pharmaceutical occupational and consumer exposures to metallic and nanoscale aluminum aluminum oxides aluminum hydroxide and its soluble salts

机译：对药物职业和消费者暴露于金属和纳米级铝氧化铝氢氧化铝及其可溶性盐类所构成的潜在健康风险的系统评价

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摘要

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by .Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al” assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold.The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+2 and Al(H2O)6+3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2•− and OH•. Thus, it is the Al+3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates.Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer’s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants.The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances.
机译：铝是一种普遍存在的物质，自然地（作为第三种最丰富的元素）和有意地（用于水，食品，药品和疫苗中）都遇到；它也存在于环境和职业空气传播颗粒中。现有数据强调了铝的物理和化学形式对于其吸收，积累和全身生物利用度的重要性。本次审查代表了对有关铝材料的不良健康影响的同行评审文献的系统检查，因为该文献是由先前的关键性评估汇编而成。在进行本次审查时所遇到的挑战反映了不同物理和化学形式的铝的实验使用，不同的给药途径，以及与暴露程度，频率和持续时间有关的不同靶器官。饮食差异很大可能导致铝的摄入量通常高于世界卫生组织基于柠檬酸铝的研究得出的暂定每周耐受摄入量（PTWI）。在“总铝”的基础上比较每日饮食中的铝暴露量，假设所有膳食铝形式的胃肠道生物利用度均与柠檬酸铝相当，这种方法需要验证。相同Al物质的当前职业暴露极限（OEL）差异高达15倍。不同Al形式的毒性在很大程度上取决于其物理行为和在水中的相对溶解度。可溶性Al形式的毒性取决于Al +3 向靶组织的递送剂量。三价Al与水反应生成与O2络合后的双齿超氧化物配位球[Al（O2）（H2O4） +2 和Al（H2O）6 +3 ] sup>•-，生成Al超氧化物[Al（O2 •）]（H2O5）] +2 。半还原的AlO2 •自由基会消耗线粒体铁并促进H2O2，O2 •-和OH •的生成。因此，Al +3 诱导的氧自由基形成是导致固有凋亡的氧化损伤的原因。相比之下，不溶性氧化铝的毒性主要取决于其作为颗粒的行为。铝一直被认为是人类发病率和死亡率的原因，但是没有一致和令人信服的证据表明以一定剂量将食物和饮用水中的铝结合在一起以及目前生活在北美和西欧的人们所食用的化学形式以及罹患阿尔茨海默氏病（AD）的风险增加。没有明确的证据显示使用含铝的腋下止汗剂或化妆品会增加罹患AD或乳腺癌的风险。金属铝，其氧化物和常见的铝盐尚未显示出遗传毒性或致癌性。新生儿和小儿肠胃外营养（PN）期间的铝暴露可损害骨骼矿化并延迟神经系统发育。含铝佐剂的疫苗已出现不良反应；然而，最近的对照试验发现，对某些含铝佐剂的疫苗的免疫应答没有增加，在某些情况下也比不含铝佐剂的相同疫苗接种后的免疫应答低。关于铝的不良健康影响的科学文献广泛。 Al的健康风险评估必须考虑各个辅助因素（例如年龄，肾功能，饮食，胃酸碱度）。从当前的审查得出的结论表明，需要完善PTWI，减少PN溶液中的Al污染，为疫苗中常规添加Al的合理性，以及协调Al物质的OEL的必要性。

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