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<span class="articleHeader__specialIssue_tag">特殊的问题</年代p一个n> <h2 class="articleHeader__specialIssue_title">基于状态的科学:生物风险评估模型</h2> <a href="//www.newsama.com/journals/jt/si/894904/" class="articleHeader__specialIssue_url" target="_blank" rel="noreferrer">把这个特殊的问题</一个> </div> <strong>研究文章|开放获取</年代trong> <div class="articleHeader__meta"> <span>体积2012年|</年代p一个n> <span>文章的ID791431年|</年代p一个n> <span class="articleHeader__meta_doiLink"><a href="https://doi.org/10.1155/2012/791431" aria-label="Doi-link" target="_blank" rel="noreferrer">https://doi.org/10.1155/2012/791431</一个></span> </div> <div class="simpleShowMore"> <button class="simpleShowMore__button">显示引用</button> </div> <h1 class="articleHeader__title">更新在Pharmacokinetic-Centric替代第二层项目MMT-Part II:基于生理药代动力学建模和锰的风险评估</h1> <div class="articleHeader__authors"> <span class="articleHeader__authors_author"><strong>Michael d .泰勒</年代trong><a href="//www.newsama.com/cdn-cgi/l/email-protection" aria-label="Mail Option"><span role="img" 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</svg></span></a>,<年代up>1</年代up></span> <span class="articleHeader__authors_author">哈维·j . Clewell,<年代up>2</年代up></span> <span class="articleHeader__authors_author">梅尔文·e·安徒生,<年代up>2</年代up></span> <span class="articleHeader__authors_author">Jeffry d Schroeter,<年代up>2</年代up></span> <span class="articleHeader__authors_author">Miyoung Yoon,<年代up>2</年代up></span> <span class="articleHeader__authors_author">雅典娜m·基恩,<年代up>1</年代up></span> <span class="articleHeader__authors_author">和大卫·c·多尔曼<年代up>3</年代up></span> </div> <div class="simpleShowMore"> <button class="simpleShowMore__button">显示更多</button> </div> <div class="articleHeader__academicEditor"> <strong>学术编辑器:</年代trong> <span>Kannan克里希南</年代p一个n> </div> <div class="articleHeader__timeline"> <div class="articleHeader__timeline_item "> <strong>收到了</年代trong> <span>2011年10月22日</年代p一个n> </div> <div class="articleHeader__timeline_item "> <strong>接受</年代trong> <span>2012年1月25日</年代p一个n> </div> <div class="articleHeader__timeline_item articleHeader__timeline_item_sticky"> <strong>发表</年代trong> <span>2012年5月07</年代p一个n> </div> </div> </div> <div class="articleBody"> <div class="xml-content"> <h4 class="header" id="abstract">文摘</h4> <p>最近,各种各样的生理基础药代动力学(PBPK)模型已经开发了锰的基本元素。本文综述PBPK模型的开发(如成人,怀孕、哺乳期和新生儿老鼠,非人灵长类动物,和成人,怀孕,哺乳期,和新生儿人类)和相关的风险评估程序。每个PBPK模型包含了关键特性包括饱和组织能力存在剂量依赖的相关性和不对称扩散通量的锰在大脑和其他组织。不同的流入和流出扩散率和绑定常量不同大脑区域占微分在大脑区域增加锰浓度观察实验。我们还展示了小说PBPK模拟预测锰在胎儿组织浓度,新生儿,怀孕,或年龄的个人以及个人与肝脏疾病或慢性吸入锰。这些模拟的结果可以帮助指导风险评估应用程序的不确定性因素,建立接触公众指南或工人。</p> <span class="end-abs"></span> <h4 id="introduction">1。介绍</h4> <p>作为一个重要元素,锰(Mn)是正常功能所需的中枢神经系统(CNS)和其他组织(<一个href="#B1">1</一个>]。与所有其他金属一样,锰毒性可能发生过度暴露。各种各样的临床疗效与锰毒性相关联,包括锰中毒,帕金森运动障碍,主要影响多巴胺能和<我>γ</我>酸氨基丁酸(GABA)包含中脑结构,控制电动机的功能(<一个href="#B2">2</一个>]。更微妙的影响也会发生。例如,工人长期接触锰可以开发视觉反应时间的变化,稳定,和手眼协调能力<一个href="#B3">3</一个>]。这些神经毒性症状发展当锰摄入过多(如后高剂量口服、吸入或注射用药物的锰暴露)或者当肝胆管的间隙的金属受损。这个观察表明,锰交付到目标区域的剂量在中枢神经系统内的主要决定因素是锰神经毒性。</p> <p>美国环境保护署(构成)的有害空气污染物包括锰化合物。美国环境保护部和卫生机构在其他国家担心,长期吸入锰低水平的环境空气可能对公众健康构成风险由于锰的可能积累在目标组织(<一个href="#B4">4</一个>]。这些问题促使美国环境保护部要求一系列的药代动力学研究,以及基于生理药代动力学的发展(PBPK)模型对锰作为测试的一部分,要求有机金属燃料添加剂methylcyclopentadienyl锰tricarbonyl (MMT)<年代up>®</年代up>的注册商标Afton化学公司)<一个href="#B5">5</一个>]。这两部分系列的第一部分讨论了开发构成替代第二层的测试程序对MMT收集重要的药代动力学数据,锰在啮齿动物和非人灵长类动物(<一个href="#B5">5</一个>]。所有测试报告和相关通信可以找到替代二级测试MMT在联邦诉讼事件表管理系统(fdm)<一个href="http://www.regulations.gov/" target="_blank">http://www.regulations.gov/</一个>通过摘要识别号码epa -总部-桨- 2004 - 0074。</p> <p>MMT替代二级计划的一个目的是生成数据支持锰(PBPK模型的开发<一个href="#B5">5</一个>,<一个href="#B6">6</一个>]。这些模型的发展代表了一个努力跨越超过十年之久。主要药代动力学数据需要支持PBPK模型开发和范式为锰tissue-dose-based健康风险评估最初被安徒生和同事(<一个href="#B7">7</一个>1999年),并帮助指导未来的研究。大量动物实验随后解决许多安徒生和同事提出的数据差距(<一个href="#B7">7</一个>)(审核(<一个href="#B5">5</一个>,<一个href="#B6">6</一个>,<一个href="#B8">8</一个>])。这手稿描述了一系列的发展为锰PBPK模型。此外,我们为他们提供了一个框架应用程序风险评估。</p> <h4 id="manganese-pbpk-models:-development-and-status">2。锰PBPK模型:发展和地位</h4> <p>PBPK模型的发展进行的步进式,迭代的方式增加模型的复杂性被添加在每一步。表<一个href="//www.newsama.com/journals/jt/2012/791431/tab1/" target="_blank">1</一个>概述了最初的“第一代”模型为本研究开发的项目。最早的剂量学模型都是改编自药代动力学模型开发的锌、铜、和其他基本金属,关注饮食摄入量不足。这些模型的特点,被认为重要的锰包括这些模型的特点,被认为重要的锰包括必不可少的元素的能力描述稳态控制在正常饮食条件不足,汇率和区划的和线性的使用分配到组织和细胞间的基本元素。最早的锰定量模型被用来测试的假设关于锰的啮齿动物胃肠道的运动(GIT)和肝脏<一个href="#B9">9</一个>),确定系统的程度和口头锰处理同样在肝脏<一个href="#B10">10</一个>]。由此产生的药代动力学模型准确地描述减少胃肠道(GI)锰吸收和增加肝胆的消除与饮食中锰含量的上升。</p> <div class="floats-partial-section partial-other-wrapper" data-section="tab1"> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">表1</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/tab1/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> 最初的“第一代”的概述为锰开发的药代动力学模型。</d我v> <a class="table-thumb-overlay" href="//www.newsama.com/journals/jt/2012/791431/tab1" target="_blank" aria-label="View full page"></a> </div> </div> <p>早期的努力也开发了一个初始框架multicompartment PBPK模型。这些模型的动力学行为评估大脑中的锰,肝脏和呼吸道吸入锰(期间和之后<一个href="#B11">12</一个>,<一个href="#B12">13</一个>]。几个模型结构被认为是在这个发展阶段(表<一个href="//www.newsama.com/journals/jt/2012/791431/tab1/" target="_blank">1</一个>)。最终,锰动力学是最好的用一个模型来描述,包括饱和组织约束力存在剂量依赖的相关性以及自由和束缚锰(<一个href="#B12">13</一个>]。在这种背景下,结合锰仅限于组织和反映基底锰浓度。自由锰循环血液中浓度和增加了在吸入锰。自由锰暴露后迅速清除,从而组织锰浓度恢复原有的基础水平。描述了这个免费的崛起的大脑锰浓度与扩散速率常数(<年代vg height="14.475" id="M7" style="vertical-align:-3.13504pt;width:17.725px;" version="1.1" viewbox="0 0 17.725 14.475" width="17.725" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.475)"> <g transform="translate(72,-60.42)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="2.4330561" y="0"> n</t年代p一个n> </text> </g> </g> </svg>和<年代vg height="14.5875" id="M8" style="vertical-align:-3.22281pt;width:23.200001px;" version="1.1" viewbox="0 0 23.200001 14.5875" width="23.200001" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5875)"> <g transform="translate(72,-60.33)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> o</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.3759999" y="0"> u</t年代p一个n> <tspan style="font-size: 8.75px; " x="8.7519999" y="0"> t</t年代p一个n> </text> </g> </g> </svg>)。组织锰浓度峰值被组织约束最大结合容量(<年代vg height="14.35" id="M9" style="vertical-align:-3.22282pt;width:34.112499px;" version="1.1" viewbox="0 0 34.112499 14.35" width="34.112499" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.35)"> <g transform="translate(72,-60.52)"> <text transform="matrix(1,0,0,-1,-71.95,63.79)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-63.25,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> 米</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> 一个</t年代p一个n> <tspan style="font-size: 8.75px; " x="10.694944" y="0"> x</t年代p一个n> </text> </g> </g> </svg>)。重要的是,剂量依赖性侬模型预测的(<一个href="#B12">13</一个>)符合总锰组织水平测量大鼠吸入锰。快速增长的模型还复制组织锰浓度在吸入锰浓度最高,以及停止接触后迅速恢复到基线。侬和同事开发的模型(<一个href="#B12">13</一个>成年鼠事务局这些和其他特性,用于所有后续的基础“第二代”动物PBPK模型(表<一个href="//www.newsama.com/journals/jt/2012/791431/tab2/" target="_blank">2</一个>)。</p> <div class="floats-partial-section partial-other-wrapper" data-section="tab2"> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">表2</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/tab2/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> 概述“第二代”PBPK模型开发锰。</d我v> <a class="table-thumb-overlay" href="//www.newsama.com/journals/jt/2012/791431/tab2" target="_blank" aria-label="View full page"></a> </div> </div> <p>从2009年开始,建模工作的焦点开始转向更完整的发展PBPK模型动物(表<一个href="//www.newsama.com/journals/jt/2012/791431/tab2/" target="_blank">2</一个>)。这些模型保留了许多特性侬模型(<一个href="#B12">13</一个>),包括饱和组织能力存在剂量依赖的相关性和不对称扩散通量锰成各种组织的隔间。第二代基于颗粒动力学模型也用气道沉积模型来描述锰交付呼吸道(<一个href="#B13">17</一个>]。描述的上呼吸道被扩大到包括描述的鼻腔和嗅觉上皮Schroeter发布的使用数据等。<一个href="#B14">18</一个>]。关于中枢神经系统,为嗅球单独的隔间,纹状体,脑垂体,小脑发达。特定的流入和流出扩散速率常数(<年代vg height="14.475" id="M11" style="vertical-align:-3.13504pt;width:17.725px;" version="1.1" viewbox="0 0 17.725 14.475" width="17.725" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.475)"> <g transform="translate(72,-60.42)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="2.4330561" y="0"> n</t年代p一个n> </text> </g> </g> </svg>,<年代vg height="14.5875" id="M12" style="vertical-align:-3.22281pt;width:23.200001px;" version="1.1" viewbox="0 0 23.200001 14.5875" width="23.200001" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5875)"> <g transform="translate(72,-60.33)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> o</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.3759999" y="0"> u</t年代p一个n> <tspan style="font-size: 8.75px; " x="8.7519999" y="0"> t</t年代p一个n> </text> </g> </g> </svg>)和绑定常量(<年代vg height="14.35" id="M13" style="vertical-align:-3.22282pt;width:34.112499px;" version="1.1" viewbox="0 0 34.112499 14.35" width="34.112499" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.35)"> <g transform="translate(72,-60.52)"> <text transform="matrix(1,0,0,-1,-71.95,63.79)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-63.25,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> 米</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> 一个</t年代p一个n> <tspan style="font-size: 8.75px; " x="10.694944" y="0"> x</t年代p一个n> </text> </g> </g> </svg>,<年代vg height="14.5875" id="M14" style="vertical-align:-3.22282pt;width:14.7125px;" version="1.1" viewbox="0 0 14.7125 14.5875" width="14.7125" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5875)"> <g transform="translate(72,-60.33)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>,<年代vg height="14.6" id="M15" style="vertical-align:-3.24037pt;width:15.7px;" version="1.1" viewbox="0 0 15.7 14.6" width="15.7" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.6)"> <g transform="translate(72,-60.32)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>)对于不同的大脑区域被用来解释微分在大脑区域增加锰浓度在各种实验条件下。这些修改发布了修订后的成年老鼠模型中描述图<一个href="//www.newsama.com/journals/jt/2012/791431/fig1/" target="_blank">1</一个>(<一个href="#B15">14</一个>]。额外的模型随后被用来描述授乳的(<一个href="#B16">15</一个>)和妊娠期(<一个href="#B17">16</一个>锰在老鼠身上转移。在所有情况下,模型输出与吸入获得的数据在这个测试程序,从可用的文学。</p> <div class="partial-carousel-wrapper"> <div class="floats-partial-section"> <div class="floats-partial-content"> <div class="partial-carousel--full-image partial-carousel-0e5104bd757ba1f5ee4c23ff3a611396"> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.001a.jpg"> <br> <strong>(一)</年代trong> </div> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.001b.jpg"> <br> <strong>(b)</年代trong> </div> </div> </div> <div class="floats-partial-middle"> <div class="floats-partial-middle--thumbs"> <div class="partial-carousel-dots-0e5104bd757ba1f5ee4c23ff3a611396 partial-carousel-thumbnail"> <button aria-label="Slide to (a) " class="partial-carousel-dot"><img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.001a_th.jpg"><br><strong>(一)</年代trong></button> <button aria-label="Slide to (b) " class="partial-carousel-dot"><img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.001b_th.jpg"><br><strong>(b)</年代trong></button> </div> </div> <div class="floats-partial-middle--nav"> <div class="partial-carousel-next-prev-0e5104bd757ba1f5ee4c23ff3a611396 partial-carousel-next-prev"> <button aria-label="Previous" class="carousel-prev"></button> <button aria-label="Next" class="carousel-next"></button> </div> </div> </div> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">图1</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/fig1/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> <table> <tbody> <tr> <td>侬和同事开发的PBPK模型结构(<一个href="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431/">14</一个>)描述组织锰在成年老鼠动力学。整个PBPK模型结构所示(一个);呼吸道的扩展视图建模(b)所示。吸入锰吸收通过沉积粒子的鼻和肺上皮细胞。大部分的锰沉积在鼻腔吸收进入全身血液虽然经历了一小部分直接交付嗅球。每一个组织都有约束力的能力,<年代vg height="14.35" id="M16" style="vertical-align:-3.22282pt" version="1.1" viewbox="0 0 34.112499 14.35" width="34.112499" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.35)"> <g transform="translate(72,-60.52)"> <text transform="matrix(1,0,0,-1,-71.95,63.79)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-63.25,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> 米</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> 一个</t年代p一个n> <tspan style="font-size: 8.75px; " x="10.694944" y="0"> x</t年代p一个n> </text> </g> </g> </svg>,协会定义的亲和力和离解速率常数(<年代vg height="14.5875" id="M17" style="vertical-align:-3.22282pt" version="1.1" viewbox="0 0 14.7125 14.5875" width="14.7125" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5875)"> <g transform="translate(72,-60.33)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>,<年代vg height="14.6" id="M18" style="vertical-align:-3.24037pt" version="1.1" viewbox="0 0 15.7 14.6" width="15.7" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.6)"> <g transform="translate(72,-60.32)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>)。自由移动全身血液中锰和锰存储在每个组织。流入和流出扩散速率常数(<年代vg height="14.475" id="M19" style="vertical-align:-3.13504pt" version="1.1" viewbox="0 0 17.725 14.475" width="17.725" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.475)"> <g transform="translate(72,-60.42)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="2.4330561" y="0"> n</t年代p一个n> </text> </g> </g> </svg>,<年代vg height="14.5875" id="M20" style="vertical-align:-3.22281pt" version="1.1" viewbox="0 0 23.200001 14.5875" width="23.200001" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5875)"> <g transform="translate(72,-60.33)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> o</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.3759999" y="0"> u</t年代p一个n> <tspan style="font-size: 8.75px; " x="8.7519999" y="0"> t</t年代p一个n> </text> </g> </g> </svg>)允许差增加锰水平对不同组织。<年代vg height="16.4625" id="M21" style="vertical-align:-4.74141pt" version="1.1" viewbox="0 0 18.299999 16.4625" width="18.299999" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,16.4625)"> <g transform="translate(72,-58.83)"> <text transform="matrix(1,0,0,-1,-71.95,63.61)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-62.19,60.48)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>,<年代vg height="14.575" id="M22" style="vertical-align:-3.2316pt" version="1.1" viewbox="0 0 18.0375 14.575" width="18.0375" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.575)"> <g transform="translate(72,-60.34)"> <text transform="matrix(1,0,0,-1,-71.95,63.61)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-62.19,60.48)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>,<年代vg height="14.5625" id="M23" style="vertical-align:-3.22281pt" version="1.1" viewbox="0 0 37.875 14.5625" width="37.875" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5625)"> <g transform="translate(72,-60.35)"> <text transform="matrix(1,0,0,-1,-71.95,63.61)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-62.19,60.48)"> <tspan style="font-size: 8.75px; " x="0" y="0"> t</t年代p一个n> <tspan style="font-size: 8.75px; " x="2.4330561" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.8661122" y="0"> 年代</t年代p一个n> <tspan style="font-size: 8.75px; " x="8.2706404" y="0"> 年代</t年代p一个n> <tspan style="font-size: 8.75px; " x="11.675168" y="0"> u</t年代p一个n> <tspan style="font-size: 8.75px; " x="16.051168" y="0"> e</t年代p一个n> </text> </g> </g> </svg>是指肺通气、心输出量和组织血液流动。从[转载<一个href="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431/">14</一个>)(同意)。</td> </tr> </tbody> </table> </div> </div> </div> </div> <p>2009年,侬和同事还描述了非人灵长类动物的PBPK模型的发展从修改后的成年大鼠模型(<一个href="#B15">14</一个>]。猴子PBPK模型被视为一个关键的步骤,适当的人类的进化模型(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig2/" target="_blank">2</一个>)。建模工作的目标之一是保持尽可能多的鼠模型中包含的功能。体重、组织卷嗅觉和呼吸道组织表面区域,通风率、血液流动、和某些其他模型参数调整来描述猴子生理学而其他人(胆汁间隙和脑扩散通量)allometrically基于体重的比例。组织绑定能力扩展各自组织卷而tissue-binding速率常数(<年代vg height="14.5875" id="M24" style="vertical-align:-3.22282pt;width:14.7125px;" version="1.1" viewbox="0 0 14.7125 14.5875" width="14.7125" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5875)"> <g transform="translate(72,-60.33)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>和<年代vg height="14.6" id="M25" style="vertical-align:-3.24037pt;width:15.7px;" version="1.1" viewbox="0 0 15.7 14.6" width="15.7" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.6)"> <g transform="translate(72,-60.32)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>从老鼠到猴子)几乎是常数。膳食摄入和基底胆汁排泄率也被调整以适应测量背景组织锰浓度。</p> <div class="partial-carousel-wrapper"> <div class="floats-partial-section"> <div class="floats-partial-content"> <div class="partial-carousel--full-image partial-carousel-35e54413bafc6637d1708ddbe6fa3dab"> <div class="partial-carousel--single-image"> <img loading="lazy" alt="" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.002.jpg"> <br> <strong></strong> </div> </div> </div> <div class="floats-partial-middle"> <div class="floats-partial-middle--thumbs"> <div class="partial-carousel-dots-35e54413bafc6637d1708ddbe6fa3dab partial-carousel-thumbnail"> <button aria-label="Slide to " class="partial-carousel-dot"><img loading="lazy" alt="" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.002_th.jpg"><br><strong></strong></button> </div> </div> <div class="floats-partial-middle--nav"> <div class="partial-carousel-next-prev-35e54413bafc6637d1708ddbe6fa3dab partial-carousel-next-prev"> <button aria-label="Previous" class="carousel-prev"></button> <button aria-label="Next" class="carousel-next"></button> </div> </div> </div> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">图2</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/fig2/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> <table> <tbody> <tr> <td>平行四边形方法发展中Mn PBPK模型对于成年人,以及妊娠和哺乳期。</td> </tr> </tbody> </table> </div> </div> </div> </div> <p>建模程序的最后步骤是对人类开发PBPK模型(表<一个href="//www.newsama.com/journals/jt/2012/791431/tab3/" target="_blank">3</一个>)。这一努力的起点是猴子PBPK模型由侬et al。<一个href="#B15">14</一个>)以适当的生理变化描述、异速生长的缩放胆道间隙和大脑扩散通量体重,和小的变化组织绑定速率常数(<年代vg height="14.5875" id="M26" style="vertical-align:-3.22282pt;width:14.7125px;" version="1.1" viewbox="0 0 14.7125 14.5875" width="14.7125" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.5875)"> <g transform="translate(72,-60.33)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>和<年代vg height="14.6" id="M27" style="vertical-align:-3.24037pt;width:15.7px;" version="1.1" viewbox="0 0 15.7 14.6" width="15.7" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.6)"> <g transform="translate(72,-60.32)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>)。显著改变模型中涉及的使用更多的生理描述GIT解决一个明显的延迟在胃肠道吸收明显的示踪Mn研究灵长类动物(<一个href="#B18">19</一个>)和微分在lifestages肠上皮细胞流动率(<一个href="#B19">20.</一个>]。Schroeter和同事(<一个href="#B18">19</一个>)包括一系列肠道隔间(例如,胃肠道腔和上皮)更好地描述摄入锰的吸收和储存的金属。上皮衬里的小型和大型肠细胞高营业额,包含快速增殖细胞(肠上皮细胞),取代那些流腔。肠上皮细胞是一个重要的网站最终金属吸收和排泄,通过这些细胞的脱落。在我们的模型中,从GIT上皮转移到低锰GIT引起肠上皮细胞脱落的上皮细胞层。流中的锰肠上皮细胞最终汇聚成粪便没有进入体循环。这使得微分率的肠上皮细胞脱落发现在不同的生命阶段(占<一个href="#B18">19</一个>,<一个href="#B19">20.</一个>]。锰吸收的GIT的分数(<年代vg height="16.612499" id="M28" style="vertical-align:-5.03984pt;width:37.662498px;" version="1.1" viewbox="0 0 37.662498 16.612499" width="37.662498" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,16.6125)"> <g transform="translate(72,-58.71)"> <text transform="matrix(1,0,0,-1,-71.95,63.79)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-64.22,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> d</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.3759999" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> e</t年代p一个n> <tspan style="font-size: 8.75px; " x="10.616176" y="0"> t</t年代p一个n> <tspan style="font-size: 8.75px; " x="13.049232" y="0"> u</t年代p一个n> <tspan style="font-size: 8.75px; " x="17.425232" y="0"> p</t年代p一个n> </text> </g> </g> </svg>)和胆汁排泄速率常数(<年代vg height="14.6" id="M29" style="vertical-align:-3.24037pt;width:33.849998px;" version="1.1" viewbox="0 0 33.849998 14.6" width="33.849998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.6)"> <g transform="translate(72,-60.32)"> <text transform="matrix(1,0,0,-1,-71.95,63.6)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-65.17,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> b</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.3759999" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> l</t年代p一个n> <tspan style="font-size: 8.75px; " x="9.2421122" y="0"> e</t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-52.05,60.47)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>)是基于稳态组织浓度和校准<年代up>54</年代up>Mn示踪研究。诱导胆消除锰也包括在模型中。这些模型结构的变化足以捕捉观察到的变化存在剂量依赖的相关性锰吸收的GIT和胆汁排泄的肝胆的系统。Schroeter和同事(<一个href="#B18">19</一个>)使用步进式模型开发方法首先开发一个修改后的猴子PBPK模型,其次是一个成年人的模型,验证了人类Mn示踪剂可用数据(<一个href="#B18">19</一个>]。建模工作的最后一步达到发展的一个模型,描述人类锰的妊娠和哺乳的转移(<一个href="#B19">20.</一个>]。</p> <div class="floats-partial-section partial-other-wrapper" data-section="tab3"> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">表3</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/tab3/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> 锰人力PBPK模型开发的概述。</d我v> <a class="table-thumb-overlay" href="//www.newsama.com/journals/jt/2012/791431/tab3" target="_blank" aria-label="View full page"></a> </div> </div> <h4 id="pbpk-models-in-manganese-risk-assessment:-why-tissue-dose-matters">3所示。锰PBPK模型风险评估:为什么组织剂量问题</h4> <p>作为基本金属锰是所有哺乳动物组织中发现的。几种自我平衡的机制已经进化到严格控制这些组织锰浓度在正常范围值。对大多数组织来说,正常的人类锰浓度范围从0.15到4<我><i>μ</我></i>g Mn / g湿组织(<一个href="#B1">1</一个>]。如前所述,锰神经毒性发生在锰摄入量超过消除,导致锰的积累在大脑区域包括苍白球、中锰的积累尤为敏感过度。尽管锰神经毒性敏感的照射剂量,相对不敏感的接触途径,类似神经反应与长期大剂量吸入锰,饮用水摄入,长期全肠外营养(TPN),或受损的锰间隙由于肝胆的功能障碍(<一个href="#B20">24</一个>]。由于锰的无处不在的性质和膳食锰的作用建立稳态组织浓度,风险评估的吸入锰应该考虑锰从饮食的重要性建立的组织浓度改变水平增加的吸入或摄入锰。因此,了解人类和过量的锰暴露风险,重要的是要确定接触条件,导致大脑中锰浓度与大脑锰浓度显著增加而引起的正常饮食摄入量(<一个href="#B7">7</一个>]。药代动力学模型可以用来帮助建立安全的曝光水平预测曝光条件导致锰毒理学地显著的组织。</p> <h4 id="application-of-pbpk-models-in-human-health-risk-assessment">4所示。PBPK模型应用于人类健康风险评估</h4> <p>第一个尝试应用PBPK模型场景相关的人类健康风险评估是由Schroeter和他的同事们(<一个href="#B18">19</一个>]。这些调查人员使用他们的大脑PBPK模型来预测锰浓度在猴子和人subchronic吸入锰(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig3/" target="_blank">3</一个>)。预测的苍白球锰浓度的猴子(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig3/" target="_blank">3(一个)</一个>与多尔曼观察到)优于et al。<一个href="#B21">21</一个>在猴子subchronically接触硫酸锰(MnSO<年代ub>4</年代ub>),增加了信心,PBPK模型设计和适当的参数化。人类的模拟由Schroeter模仿一个8小时/天,5天/周职业暴露。更大的大小变化预测相比,猴子与人类吸入暴露浓度可能是由于在较高饱和度的锰结合位点在猴子饮食中锰浓度越高。人类饮食通常是低锰含量相比,饮食在实验室动物食物,通常补充高得多(<我>~</我>100 ppm)的水平。最低的人类接触浓度用于我们的模拟(0.001 mg Mn / m<年代up>3</年代up>),模型预测没有可观增长从基底浓度(< 1%)在人类苍白球锰浓度高于背景水平与正常的膳食暴露(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig3/" target="_blank">3 (b)</一个>)。暴露浓度为0.01毫克Mn / m<年代up>3</年代up>轻微的增加(<我>~</我>在背景苍白球锰浓度超过5%)水平预测吸入暴露期间。更重要(> 30%)增加苍白球锰浓度预测更高的暴露浓度(> 0.1毫克Mn / m<年代up>3</年代up>)。这些数据符合派生的基准浓度浓度的亚临床神经从职业影响研究0.2毫克Mn / m<年代up>3</年代up>(<一个href="#B22">25</一个>),表明显著增加组织锰浓度高于正常背景变化所需的亚临床效果体现。</p> <div class="partial-carousel-wrapper"> <div class="floats-partial-section"> <div class="floats-partial-content"> <div class="partial-carousel--full-image partial-carousel-7b06d90723b4bfab2b6df658d2ed92ba"> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.003a.jpg"> <br> <strong>(一)</年代trong> </div> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.003b.jpg"> <br> <strong>(b)</年代trong> </div> </div> </div> <div class="floats-partial-middle"> <div class="floats-partial-middle--thumbs"> <div class="partial-carousel-dots-7b06d90723b4bfab2b6df658d2ed92ba partial-carousel-thumbnail"> <button aria-label="Slide to (a) " class="partial-carousel-dot"><img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.003a_th.jpg"><br><strong>(一)</年代trong></button> <button aria-label="Slide to (b) " class="partial-carousel-dot"><img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.003b_th.jpg"><br><strong>(b)</年代trong></button> </div> </div> <div class="floats-partial-middle--nav"> <div class="partial-carousel-next-prev-7b06d90723b4bfab2b6df658d2ed92ba partial-carousel-next-prev"> <button aria-label="Previous" class="carousel-prev"></button> <button aria-label="Next" class="carousel-next"></button> </div> </div> </div> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">图3</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/fig3/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> <table> <tbody> <tr> <td>曲线显示模拟end-of-exposure脑组织锰浓度在猴子(a)和(b)的函数吸入暴露浓度(毫克Mn / m<年代up>3</年代up>)。模拟风险敞口为90天(5天/周)6小时/天(猴子)或8小时/天(人类)。猴子仿真结果为1.5毫克/米<年代up>3</年代up>(a)与数据从多尔曼et al。<一个href="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431/">21</一个>)描述符号显示方式和标准误差(SEs)从4到6个猴子每个时间点。更大的大小变化预测相比,猴子与人类吸入暴露浓度可能是由于在较高的饱和锰结合位点的猴子来自高锰浓度在猴子的饮食。修改从[<一个href="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431/">19</一个>]。</td> </tr> </tbody> </table> </div> </div> </div> </div> <p>根据我们的成功在描述老鼠和猴子组织数据和一致性与人类的反应和特定的曝光,我们进行了额外的模拟使用可用的PBPK锰模型中确定表<一个href="//www.newsama.com/journals/jt/2012/791431/tab2/" target="_blank">2</一个>和<一个href="//www.newsama.com/journals/jt/2012/791431/tab3/" target="_blank">3</一个>解决其他暴露场景毒理学家和风险评估人员的关注。我们的目标是预测组织浓度与生理学改变由于个人发展的人生阶段(方案1)或疾病(场景2)。第二个目标是使用大脑PBPK模型预测锰浓度长时间吸入暴露和变量膳食摄入锰(场景3)。这些模拟的结果可以帮助指导风险评估应用程序的内部或跨物种的不确定性因素(UFs)建立公众接触准则时(例如,一个吸入参考浓度或RfC)或工人(如阈限值或电磁阀)。在大多数的风险评估,UFs应用于较低的可接受的空气浓度保护物种或潜在的易感人群占反应的差异。例如,当前美国环保署锰RfC 1000年推导了复合超滤,其中包括UFs 10来保护敏感的个体,使用LOAEL 10,和10个数据库的局限性,如不到慢性暴露时期,信息不充分发育和生殖毒性,毒性的不确定性和各种形式的锰(<一个href="#B23">26</一个>]。</p> <p>替代PBPK模型方法,我们目前的结果在这个手稿的药代动力学的发展chemical-specific调整因素(CSAFs)(或数据外推因素(DDEFs)),可用于代替默认UFs使用在大多数风险评估(<一个href="#B24">27</一个>,<一个href="#B25">28</一个>]。药代动力学CSAF是比人类或动物的可测量的指标内部接触活性化合物如曲线下的面积(AUC) (AUC是每日的代理和/或锰累积剂量受到个体),<年代vg height="14.4375" id="M31" style="vertical-align:-3.22282pt;width:33.724998px;" version="1.1" viewbox="0 0 33.724998 14.4375" width="33.724998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.4375)"> <g transform="translate(72,-60.45)"> <text transform="matrix(1,0,0,-1,-71.95,63.71)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-63.56,60.58)"> <tspan style="font-size: 8.75px; " x="0" y="0"> 米</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> 一个</t年代p一个n> <tspan style="font-size: 8.75px; " x="10.694944" y="0"> x</t年代p一个n> </text> </g> </g> </svg>,或者一个基线之间的间隙和潜在的易感分组人口(<一个href="#B24">27</一个>]。UFs尽管用途相同,这些推断的因素是基于化学感兴趣的数据直接相关,而不是让他们依据默认假设国米,种内的变化(<一个href="#B25">28</一个>]。这种方法导致更高的信心计算调整因素和导致监管流程和决策的一致性<一个href="#B25">28</一个>]。除非另外注明,所有模拟在这些场景中提供的结果总组织锰浓度。</p> <p><span class="statement" id="head1"><span class="statement-title"><i class="statement-title">场景1。基于考虑潜在的易感人群Lifestage和怀孕状态</我></span><br>与年龄相关的生理学变化可以影响药物动力学的外源性物质,和一些实验数据表明,老年人神经系统可能是由于接触锰的风险增加。例如,manganese-induced纹状体谷胱甘肽的耗竭是更严重的年龄(20个月大)大鼠相比,年轻的(三)后大鼠重复(7天)高剂量Mn(15 - 100毫克/公斤/天)口腔接触氯化锰(<一个href="#B26">29日</一个>]。职业和环境暴露的研究表明,年龄的增加可能是一个风险因素manganese-induced神经行为赤字(<一个href="#B27">30.</一个>]。探索这个问题更多的定量,我们使用啮齿动物PBPK模型,作为数据在文献中关于肺功能随年龄增长而下降的程度。<br>老龄大鼠模型模拟(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig4/" target="_blank">4</一个>)降低25%用于分钟通气量与报道一致减少肺功能在老年大鼠(<一个href="#B28">22</一个>,<一个href="#B29">23</一个>]。老老鼠目标脑组织锰浓度低于中年动物在同一曝光。这种差异可能是由于老年动物的呼吸频率和肺容量减少(<一个href="#B30">31日</一个>]。自组织锰浓度小于潜在的易感群在成年男性,一个药代动力学CSAF人生阶段应该< 1岁。这个模拟从老鼠延伸到人类需要一些变化在当前使用的生理参数模型。例如,肝脏体积的变化和肝血流量显著影响异型生物质新陈代谢和间隙发生在老年人类患者(<一个href="#B31">32</一个>]。同样,人类改变了胆汁(岁<一个href="#B32">33</一个>)、肺(<一个href="#B33">34</一个>),和胃肠道(<一个href="#B34">35</一个>)函数可能改变锰药物动力学。这些复杂性需要一个人类模型模拟的场景,是目前的焦点之外的手稿。然而,我们提供的模板生成一个药代动力学CSAF岁人。初步分析表明,大调整因素可能没有必要从成年男性推断,这通常是职业流行病学研究的主题,确定锰风险评估的出发点,老年生活阶段。<br>评估其他生命阶段也很重要,因为他们也从职业研究推断UFs覆盖。儿童流行病学研究报道高膳食锰暴露与神经行为和神经认知赤字(<一个href="#B35">36</一个>]。关注潜在的脆弱性在胎儿和新生儿发展锰神经毒性已被监管机构提出(<一个href="#B36">37</一个>]。PBPK模型为这个项目开发的可用于定量估计的作用更高的肠道吸收摄入锰和较低的基底的孩子(见[胆汁排泄率<一个href="#B1">1</一个>在吸入锰]审查)影响dose-to-target-tissue。为此,Yoon和同事(<一个href="#B19">20.</一个>]使用人类PBPK模型估计的平均预期每日auc苍白球在不同生命阶段(妊娠、怀孕和哺乳期妇女、胎儿、婴儿护理,和3岁的孩子)三个不同的曝光条件,即0,0.001和0.01毫克Mn / m<年代up>3</年代up>24小时/ 7天/周(见[<一个href="#B19">20.</一个>),图<一个href="//www.newsama.com/journals/jt/2012/791431/fig7/" target="_blank">7</一个>)。曝光时间在不同的模拟不同人生阶段(~ 9月怀孕妇女和胎儿;护理4个月的婴儿,他们的母亲和儿童出生后3年)。平均每日AUC苍白球是计算在每个仿真运行后模型适合选择的生命阶段的持续时间。怀孕和哺乳期没有极大地影响模拟大脑的内部剂量的锰。平均每日auc是男性比女性高剂量Mn的环境暴露,也就是说,暴露在大脑锰浓度从基础水平开始上升。平均每日苍白球AUC的变化造成大剂量吸入锰在护理婴儿比其他更大的生命阶段由于(略微不足)基础水平较低的组织锰在这个年龄(<一个href="#B19">20.</一个>]。例如,估计平均AUC高度暴露婴儿大约是11.5<我>μ</我>g Mn<我>·</我>人力资源/相比大约7.9克/天<我>μ</我>g Mn<我>·</我>人力资源/ g /天未曝光的婴儿,而成年男性的AUC增加从9.3<我>μ</我>g Mn<我>·</我>人力资源/ 11.5 g /天<我>μ</我>g Mn<我>·</我>人力资源/ g /天。这个明显的敏感性增加对提高组织浓度是由于新生儿的基底组织水平较低,可能代表了在这段时期的增强对锰的需求(<一个href="#B19">20.</一个>,<一个href="#B37">38</一个>]。在成人和儿童在断奶后,吸入的相对贡献(0.01毫克/米<年代up>3</年代up>)小于正常饮食摄入量在这些吸入暴露。因为没有生活阶段取得了AUC高于成年男性,PK模拟支持胎儿的药代动力学CSAF 1,新生儿,怀孕和妊娠女性生命阶段。</年代p一个n></p> <div class="partial-carousel-wrapper"> <div class="floats-partial-section"> <div class="floats-partial-content"> <div class="partial-carousel--full-image partial-carousel-5dde930820bb686eeba8507604bc7e39"> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.004a.jpg"> <br> <strong>(一)</年代trong> </div> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.004b.jpg"> <br> <strong>(b)</年代trong> </div> </div> </div> <div class="floats-partial-middle"> <div class="floats-partial-middle--thumbs"> <div class="partial-carousel-dots-5dde930820bb686eeba8507604bc7e39 partial-carousel-thumbnail"> <button aria-label="Slide to (a) " class="partial-carousel-dot"><img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.004a_th.jpg"><br><strong>(一)</年代trong></button> <button aria-label="Slide to (b) " class="partial-carousel-dot"><img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.004b_th.jpg"><br><strong>(b)</年代trong></button> </div> </div> <div class="floats-partial-middle--nav"> <div class="partial-carousel-next-prev-5dde930820bb686eeba8507604bc7e39 partial-carousel-next-prev"> <button aria-label="Previous" class="carousel-prev"></button> <button aria-label="Next" class="carousel-next"></button> </div> </div> </div> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">图4</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/fig4/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> <table> <tbody> <tr> <td>模拟嗅球(左)和纹状体(R)锰浓度在成年和老年(16个月)6小时/ d吸入MnSO后雄性老鼠<年代ub>4</年代ub>暴露在0.5毫克Mn / m<年代up>3</年代up>为90天。老龄大鼠模型模拟分钟通气量下降25%与报道一致减少肺功能(<一个href="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431/">22</一个>,<一个href="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431/">23</一个>]。</td> </tr> </tbody> </table> </div> </div> </div> </div> <p><span class="statement" id="head2"><span class="statement-title"><i class="statement-title">场景2。考虑患者严重肝胆的功能障碍</我></span><br>患有严重的肝胆的疾病经常开发大脑锰浓度升高与正常相比个人(<一个href="#B38">39</一个>]。例如,罗斯和同事(<一个href="#B38">39</一个>]报道大脑锰浓度尸检样本肝硬化患者。年龄组相比,肝硬化患者大脑锰浓度显著升高。苍白球这些增加最为明显,在严重的肝硬化患者指(±SEM) pallidal锰的浓度<年代vg height="12.2375" id="M32" style="vertical-align:-1.09097pt;width:72.474998px;" version="1.1" viewbox="0 0 72.474998 12.2375" width="72.474998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.2375)"> <g transform="translate(72,-62.21)"> <text transform="matrix(1,0,0,-1,-71.95,63.35)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="9.3772497" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="24.655916" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="35.996136" y="0"> 1</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="45.373386" y="0"> 5</t年代p一个n> <tspan style="font-size: 12.50px; " x="51.624886" y="0"> 4</t年代p一个n> </text> </g> </g> </svg><i>μ</我>g / g和<年代vg height="12.05" id="M33" style="vertical-align:-1.09097pt;width:72.474998px;" version="1.1" viewbox="0 0 72.474998 12.05" width="72.474998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.05)"> <g transform="translate(72,-62.36)"> <text transform="matrix(1,0,0,-1,-71.95,63.5)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 1</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="9.3772497" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 1</t年代p一个n> <tspan style="font-size: 12.50px; " x="24.655916" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="35.996136" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="45.373386" y="0"> 9</t年代p一个n> <tspan style="font-size: 12.50px; " x="51.624886" y="0"> 1</t年代p一个n> </text> </g> </g> </svg><i>μ</我>在控制g / g。罗斯和同事(<一个href="#B38">39</一个>]也检验了鼠模型是否使用一个end-to-side portacaval吻合或intracholedochal注射福尔马林和伴随的结扎胆管创建一个实验模型的胆汁性肝硬化可以模仿这些发现。正如所料,大鼠胆汁性肝硬化或portacaval-shunt pallidal增加(增加27%到57%)和尾状核/壳(增加了57 67%)相比锰浓度与虚假的操作或正常对照组。重要的是要注意,人类和动物研究上升有重要临床肝脏疾病。例如,肝硬化患者研究玫瑰等。<一个href="#B38">39</一个>)死于肝性脑病(即的极端形式。、肝昏迷)。<br>肝脏或胆汁性肝硬化患者肝血流量还可以开发重大变化可能影响锰药物动力学。Annet和同事(<一个href="#B39">40</一个>)报道,各种等级的慢性肝病患者(即。,Child-Pugh classes A, B, and C) had mean (±SD) apparent liver perfusion rates of<年代vg height="12.175" id="M34" style="vertical-align:-1.09097pt;width:88.112503px;" version="1.1" viewbox="0 0 88.112503 12.175" width="88.112503" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.175)"> <g transform="translate(72,-62.26)"> <text transform="matrix(1,0,0,-1,-71.95,63.4)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 3</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 6</t年代p一个n> <tspan style="font-size: 12.50px; " x="12.503" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="21.880251" y="0"> 9</t年代p一个n> <tspan style="font-size: 12.50px; " x="30.907415" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 1</t年代p一个n> <tspan style="font-size: 12.50px; " x="48.499138" y="0"> 7</t年代p一个n> <tspan style="font-size: 12.50px; " x="54.750637" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="57.876389" y="0"> 9</t年代p一个n> <tspan style="font-size: 12.50px; " x="64.127884" y="0"> 6</t年代p一个n> </text> </g> </g> </svg>毫升/分钟/ 100毫升肝脏体积与<年代vg height="12.2375" id="M35" style="vertical-align:-1.09097pt;width:88.112503px;" version="1.1" viewbox="0 0 88.112503 12.2375" width="88.112503" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.2375)"> <g transform="translate(72,-62.21)"> <text transform="matrix(1,0,0,-1,-71.95,63.35)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 6</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 5</t年代p一个n> <tspan style="font-size: 12.50px; " x="12.503" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="21.880251" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="30.907415" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="48.499138" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="54.750637" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="57.876389" y="0"> 7</t年代p一个n> <tspan style="font-size: 12.50px; " x="64.127884" y="0"> 3</t年代p一个n> </text> </g> </g> </svg>毫升/分钟/ 100毫升非肝硬化患者的肝脏体积(使用磁共振成像来衡量)。肝血流量减少约50%总出现在狗左右或者end-to-side portacaval吻合(<一个href="#B40">41</一个>]。其他调查人员报告重要的(<我>~</我>50%)减少肝血流量与胆总管结扎大鼠(<一个href="#B41">42</一个>]。类似的观察也出现在肝硬化患者(<一个href="#B42">43</一个>]。这些研究表明,应该有一个肝血流量减少50% PBPK模型参数的一致性的观察实验诱导肝胆的功能障碍。<br>受损的分泌胆汁酸、胆红素和其他有机阴离子,符合减少胆道功能,也观察到在肝脏疾病(<一个href="#B43">44</一个>]。例如,有轻度肝狭窄的老鼠有一个近似基底胆汁流量减少15%与对照组相比(<一个href="#B44">45</一个>]。一个动物模型胆汁的功能已经定量检查肝功能异常subchronic诱导的慢性管理TPN,静脉饮食在严重的胃肠道疾病。Das et al。<一个href="#B45">46</一个>)报道,兔子接收TPN将开发定性类似的减少胆汁流(减少了60%),胆汁酸分泌(52%),和sulfobromophthalein (BSP)排泄(38%)与对照组相比。这些动物还开发了肝细胞变性和门户呼吸道炎症。因此,可用的数据支持使用减少50%胆汁流PBPK模型模拟。<br>在这项研究中,我们使用了Schroeter et al。<一个href="#B18">19</一个>)模型来模拟苍白球锰浓度在人类吸入MnSO一年<年代ub>4</年代ub>暴露于0.00005(美国环境保护部RfC)或0.2毫克(当前工作者电磁阀)Mn / m<年代up>3</年代up>8小时/天,5 d /周。模型模拟的人肝胆管的损伤肝脏血流量下降50%和胆汁排泄减少伴随的50% (<年代vg height="14.375" id="M36" style="vertical-align:-3.24037pt;width:37.287498px;" version="1.1" viewbox="0 0 37.287498 14.375" width="37.287498" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.375)"> <g transform="translate(72,-60.5)"> <text transform="matrix(1,0,0,-1,-71.95,63.79)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-62.42,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> b</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.3759999" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> l</t年代p一个n> <tspan style="font-size: 8.75px; " x="9.2421122" y="0"> e</t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-49.29,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>)符合更改报告在人或动物肝脏疾病,正如上面所讨论的。不管吸入浓度,模拟显示,该模型预测更高pallidal大脑锰浓度由于肝脏功能障碍(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig5/" target="_blank">5</一个>),预计基于可用的数据。吸入的RfC pallidal浓度没有显著影响,不管肝胆的功能(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig5/" target="_blank">5(一个)</一个>)。吸入浓度的增加产生的电磁阀end-of-exposure pallidal锰浓度,除了增加(约从肝胆的疾病。0.85<我>μ</我>g / g和0.68<我>μ</我>g / g在控制图<一个href="//www.newsama.com/journals/jt/2012/791431/fig5/" target="_blank">5 (b)</一个>)。~ 1.25(0.85/0.68)的CSAF PBPK模型支持的极度敏感的子群。因为这个CSAF值是确定在职业暴露水平,没有观察到变化RfC,这疾病CSAF可能是保守的环境因素不会引起组织积累。</年代p一个n></p> <div class="partial-carousel-wrapper"> <div class="floats-partial-section"> <div class="floats-partial-content"> <div class="partial-carousel--full-image partial-carousel-b07dede8c95f82e12c6eb2af9e1bdb73"> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.005a.jpg"> <br> <strong>(一)</年代trong> </div> <div class="partial-carousel--single-image"> <img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.005b.jpg"> <br> <strong>(b)</年代trong> </div> </div> </div> <div class="floats-partial-middle"> <div class="floats-partial-middle--thumbs"> <div class="partial-carousel-dots-b07dede8c95f82e12c6eb2af9e1bdb73 partial-carousel-thumbnail"> <button aria-label="Slide to (a) " class="partial-carousel-dot"><img loading="lazy" alt="(一)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.005a_th.jpg"><br><strong>(一)</年代trong></button> <button aria-label="Slide to (b) " class="partial-carousel-dot"><img loading="lazy" alt="(b)" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.005b_th.jpg"><br><strong>(b)</年代trong></button> </div> </div> <div class="floats-partial-middle--nav"> <div class="partial-carousel-next-prev-b07dede8c95f82e12c6eb2af9e1bdb73 partial-carousel-next-prev"> <button aria-label="Previous" class="carousel-prev"></button> <button aria-label="Next" class="carousel-next"></button> </div> </div> </div> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">图5</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/fig5/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> <table> <tbody> <tr> <td>模拟苍白球锰浓度在人类吸入MnSO<年代ub>4</年代ub>0.00005 (a) (b)或0.2毫克Mn / m<年代up>3</年代up>8小时/天,5 d /周,一年。模拟进行使用人体模型由Schroeter et al。<一个href="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431/">19</一个>]有以下例外:与肝胆管的损伤模型模拟人类肝脏血流量下降了50%和50%的减少胆汁排泄(<年代vg height="14.375" id="M37" style="vertical-align:-3.24037pt" version="1.1" viewbox="0 0 37.287498 14.375" width="37.287498" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,14.375)"> <g transform="translate(72,-60.5)"> <text transform="matrix(1,0,0,-1,-71.95,63.79)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-62.42,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> b</t年代p一个n> <tspan style="font-size: 8.75px; " x="4.3759999" y="0"> 我</t年代p一个n> <tspan style="font-size: 8.75px; " x="6.8090558" y="0"> l</t年代p一个n> <tspan style="font-size: 8.75px; " x="9.2421122" y="0"> e</t年代p一个n> </text> <text transform="matrix(1,0,0,-1,-49.29,60.66)"> <tspan style="font-size: 8.75px; " x="0" y="0"> </t年代p一个n> </text> </g> </g> </svg>)来模拟温和肝胆的疾病(见文本更多细节)。</td> </tr> </tbody> </table> </div> </div> </div> </div> <p><span class="statement" id="head3"><span class="statement-title"><i class="statement-title">场景3。考虑饮食Mn可变性和慢性吸入锰</我></span><br>使用PBPK模型在风险评估的优势包括能够使用模型检查饮食和吸入摄入和支持从高到低剂量推断,在路线,对不同的动物物种,和接触时间长比研究中使用的模型是基于[<一个href="#B46">47</一个>]。迄今为止,最完整的药代动力学数据集对吸入锰可供PBPK模型开发和验证是老鼠和猴子使用接触暴露持续时间90天(通常6小时/天,5天/周,综述(<一个href="#B5">5</一个>])。锰PBPK模型描述在这个手稿可以用来推断除了这些曝光条件。这个场景演示了这种能力通过预测苍白球锰浓度在人后连续(24小时/天)慢性锰暴露(图(1年)<一个href="//www.newsama.com/journals/jt/2012/791431/fig6/" target="_blank">6</一个>)。<br>猴子PBPK模型由侬et al。<一个href="#B15">14</一个>)扩展到人类是用来模拟苍白球锰浓度在人们改变饮食摄入量。正常变异苍白球由于锰浓度的波动在日常膳食暴露模拟10000年成人人口使用蒙特卡罗技术。这些模拟不同的日常饮食摄入量锰使用公布的数据(意味着(±SD):<年代vg height="12.05" id="M38" style="vertical-align:-1.09097pt;width:64.662498px;" version="1.1" viewbox="0 0 64.662498 12.05" width="64.662498" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.05)"> <g transform="translate(72,-62.36)"> <text transform="matrix(1,0,0,-1,-71.95,63.5)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="9.3772497" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 3</t年代p一个n> <tspan style="font-size: 12.50px; " x="24.655916" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="35.996136" y="0"> 1</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="45.373386" y="0"> 8</t年代p一个n> </text> </g> </g> </svg>毫克/天;范围0.07 - -6.2毫克/天)(<一个href="#B47">48</一个>]。发表分布值(平均)被用于体重(70公斤),组织量体重(%)(8%)、血骨(12%),脑(2%),肝(3%)、肺(1%),和身体的其余部分(0.74%)<一个href="#B48">49</一个>,<一个href="#B49">50</一个>]。分配值(平均)组织血流量(%心输出量)对骨(4%),脑(11%),肝(23%),和鼻子(1%)也被<一个href="#B48">49</一个>,<一个href="#B49">50</一个>]。变异系数用于体重,组织体积,和血流量参数为0.30。平均值为心输出量和肺通气量设置在13 L /人力资源/公斤,20 L /人力资源/公斤,分别。用于这些参数的变异系数为0.50。所有被两个标准差截断参数分布和统计相关性的参数并没有包括在我们的分析中。空气中锰浓度范围从当前构成RfC(0.00005毫克Mn / m<年代up>3</年代up>)0.5毫克Mn / m<年代up>3</年代up>,集中代表了潜在的职业暴露水平,尽管连续暴露在这种情况下。<br>第二个问题,我们想探讨的是曝光时间的影响在苍白球锰浓度变化的速度吸入锰。这里,我们比较了end-of-exposure组织浓度subchronic(90天)与2年非人灵长类动物模型(图的曝光时间<一个href="//www.newsama.com/journals/jt/2012/791431/fig7/" target="_blank">7</一个>)。苍白球锰浓度迅速达到pseudosteady状态水平在高剂量的锰暴露。这些模拟符合观测报告的多尔曼和同事(<一个href="#B21">21</一个>)报道,恒河猴暴露(5 d /周)15,33岁或65天MnSO的敞口<年代ub>4</年代ub>在1.5毫克Mn / m<年代up>3</年代up>发达的意思(±SEM)苍白球锰的浓度<年代vg height="12.05" id="M39" style="vertical-align:-1.09097pt;width:72.474998px;" version="1.1" viewbox="0 0 72.474998 12.05" width="72.474998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.05)"> <g transform="translate(72,-62.36)"> <text transform="matrix(1,0,0,-1,-71.95,63.5)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 1</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="9.3772497" y="0"> 9</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="24.655916" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="35.996136" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="45.373386" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="51.624886" y="0"> 0</t年代p一个n> </text> </g> </g> </svg>,<年代vg height="12.05" id="M40" style="vertical-align:-1.09097pt;width:72.474998px;" version="1.1" viewbox="0 0 72.474998 12.05" width="72.474998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.05)"> <g transform="translate(72,-62.36)"> <text transform="matrix(1,0,0,-1,-71.95,63.5)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="9.3772497" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 1</t年代p一个n> <tspan style="font-size: 12.50px; " x="24.655916" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="35.996136" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="45.373386" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="51.624886" y="0"> 9</t年代p一个n> </text> </g> </g> </svg>,<年代vg height="12.05" id="M41" style="vertical-align:-1.09097pt;width:72.474998px;" version="1.1" viewbox="0 0 72.474998 12.05" width="72.474998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.05)"> <g transform="translate(72,-62.36)"> <text transform="matrix(1,0,0,-1,-71.95,63.5)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="9.3772497" y="0"> 9</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="24.655916" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="35.996136" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="45.373386" y="0"> 2</t年代p一个n> <tspan style="font-size: 12.50px; " x="51.624886" y="0"> 3</t年代p一个n> </text> </g> </g> </svg><i>μ</我>g Mn / g组织湿重,分别是明显不同(<年代vg height="11.25" id="M42" style="vertical-align:-0.30096pt;width:56.150002px;" version="1.1" viewbox="0 0 56.150002 11.25" width="56.150002" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,11.25)"> <g transform="translate(72,-63)"> <text transform="matrix(1,0,0,-1,-71.95,63.35)"> <tspan style="font-size: 12.50px; " x="0" y="0"> </t年代p一个n> <tspan style="font-size: 12.50px; " x="10.890113" y="0"> <</t年代p一个n> <tspan style="font-size: 12.50px; " x="22.930502" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="29.182001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="32.307751" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="38.559254" y="0"> 5</t年代p一个n> </text> </g> </g> </svg>)比背景组织的水平<年代vg height="12.05" id="M43" style="vertical-align:-1.09097pt;width:72.474998px;" version="1.1" viewbox="0 0 72.474998 12.05" width="72.474998" xmlns="http://www.w3.org/2000/svg"> <g transform="matrix(1.25,0,0,-1.25,0,12.05)"> <g transform="translate(72,-62.36)"> <text transform="matrix(1,0,0,-1,-71.95,63.5)"> <tspan style="font-size: 12.50px; " x="0" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="6.2515001" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="9.3772497" y="0"> 4</t年代p一个n> <tspan style="font-size: 12.50px; " x="15.62875" y="0"> 8</t年代p一个n> <tspan style="font-size: 12.50px; " x="24.655916" y="0"> ±</t年代p一个n> <tspan style="font-size: 12.50px; " x="35.996136" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="42.247639" y="0"> 。</t年代p一个n> <tspan style="font-size: 12.50px; " x="45.373386" y="0"> 0</t年代p一个n> <tspan style="font-size: 12.50px; " x="51.624886" y="0"> 4</t年代p一个n> </text> </g> </g> </svg><i>μ</我>g Mn / g组织湿重。延长2年模拟产生了一种非常轻微的左方exposure-accumulation曲线的改变,但这并没有改变组织积累的门槛。例如,在0.2毫克MnSO<年代ub>4</年代ub>/ m<年代up>3</年代up>当前工作者(电磁阀),药代动力学CSAF subchronic慢性持续时间是1.06。一旦暴露通过组织积累的门槛,PK CSAF暴露持续时间的最大1.1。<br>这些模拟显示几个重要发现的结果。大脑锰浓度控制在一个广泛的中度以上暴露条件下典型的环境因素。由于自我平衡的控制,从曝光globus pallidal锰浓度的变化,由几个数量级甚至超过当前RfC (0.05 mg Mn / m<年代up>3</年代up>)是小相比,那些被视为正常的结果变化的膳食摄入锰的蒙特卡罗分析证明了饮食变化(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig6/" target="_blank">6</一个>)。然而,一旦这些体内平衡机制(s)是不知所措,pallidal锰浓度迅速上升。这个响应的门槛似乎发生在大约0.001 - -0.01毫克Mn / m<年代up>3</年代up>(图<一个href="//www.newsama.com/journals/jt/2012/791431/fig7/" target="_blank">7</一个>)。</年代p一个n></p> <div class="partial-carousel-wrapper"> <div class="floats-partial-section"> <div class="floats-partial-content"> <div class="partial-carousel--full-image partial-carousel-7709d0626a4a5bb47e2252bff71f1a3d"> <div class="partial-carousel--single-image"> <img loading="lazy" alt="" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.006.jpg"> <br> <strong></strong> </div> </div> </div> <div class="floats-partial-middle"> <div class="floats-partial-middle--thumbs"> <div class="partial-carousel-dots-7709d0626a4a5bb47e2252bff71f1a3d partial-carousel-thumbnail"> <button aria-label="Slide to " class="partial-carousel-dot"><img loading="lazy" alt="" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.006_th.jpg"><br><strong></strong></button> </div> </div> <div class="floats-partial-middle--nav"> <div class="partial-carousel-next-prev-7709d0626a4a5bb47e2252bff71f1a3d partial-carousel-next-prev"> <button aria-label="Previous" class="carousel-prev"></button> <button aria-label="Next" class="carousel-next"></button> </div> </div> </div> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">图6</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/fig6/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> <table> <tbody> <tr> <td>分布(min, 5日地中海,95和max)的苍白球浓度模拟人口与场景3中描述的输入分布(见文本更多细节)。比较稳态大脑锰浓度后365天的连续曝光(24小时/ 7天)。有一个重叠的组织Mn含量吸入接触与饮食之间的变化。globus pallidal锰浓度的变化从曝光< 0.05毫克Mn / m<年代up>3</年代up>很小的影响相比,正常的饮食变化。</td> </tr> </tbody> </table> </div> </div> </div> </div> <div class="partial-carousel-wrapper"> <div class="floats-partial-section"> <div class="floats-partial-content"> <div class="partial-carousel--full-image partial-carousel-64d0526f7d4008fd727c4595d42813ea"> <div class="partial-carousel--single-image"> <img loading="lazy" alt="" src="https://static.hindawi.com/articles/jt/volume-2012/791431/figures/791431.fig.007.jpg"> <br> <strong></strong> </div> </div> </div> <div class="floats-partial-middle"> <div class="floats-partial-middle--thumbs"> <div class="partial-carousel-dots-64d0526f7d4008fd727c4595d42813ea partial-carousel-thumbnail"> <button aria-label="Slide to " class="partial-carousel-dot"><img loading="lazy" alt="" src="https://static.hindawi.com/articles/jt/volume-2012/791431/thumbnails/791431.fig.007_th.jpg"><br><strong></strong></button> </div> </div> <div class="floats-partial-middle--nav"> <div class="partial-carousel-next-prev-64d0526f7d4008fd727c4595d42813ea partial-carousel-next-prev"> <button aria-label="Previous" class="carousel-prev"></button> <button aria-label="Next" class="carousel-next"></button> </div> </div> </div> <div class="floats-partial-footer"> <div class="floats-partial-caption"> <span class="caption-text">图7</年代p一个n> <a aria-label="View full page" class="caption-partial-url" href="//www.newsama.com/journals/jt/2012/791431/fig7/" title="" target="_blank"></a> </div> <div class="floats-partial-caption-text"> <table> <tbody> <tr> <td>模拟end-of-exposure非人灵长类动物苍白球锰浓度后24 h / d, d / 7周吸入90天(subchronic)或2年(慢性)接触MnSO<年代ub>4</年代ub>。这些模拟表明,苍白球锰浓度预计将迅速达到pseudosteady-state水平在高剂量的锰暴露,暴露的持续时间的影响最小。只发生一次曝光的贡献达到阈值导致组织积累。</td> </tr> </tbody> </table> </div> </div> </div> </div> <h4 id="future-applications-of-pbpk-models">5。未来的应用PBPK模型</h4> <p>这里有探索的场景可以很容易地扩大到解决其他问题与锰的人类健康风险评估。另一个场景中,可能有用的风险评估是一个考虑改变铁稳态在锰药物动力学的影响,因为缺铁和缺铁贫血存在全球(<一个href="#B50">51</一个>]。组织铁状态不足造成饮食缺铁或贫血会导致大脑改变锰沉积在动物<一个href="#B51">52</一个>- - - - - -<一个href="#B53">54</一个>]。还不知道铁和锰之间的相互作用对于二价金属转运蛋白1 (DMT1)和其他共享细胞膜金属转运蛋白占这一效应(<一个href="#B54">55</一个>,<一个href="#B55">56</一个>]。一旦这些途径和交互更充分阐明,尤其是定量测量,这些特性可以被纳入现有的PBPK模型。</p> <p>尽管最初创建PBPK模型支持燃烧产品的风险评估的燃料添加剂MMT(见[<一个href="#B5">5</一个>),他们有更广泛的应用毒理学家和风险评估。PBPK模型可以考虑粒度和溶解度的影响锰剂量测定法,特别是当它涉及到纳米材料。锰纳米粒子暴露期间可能发生职业暴露场景,可能包括焊接。纳米颗粒显示几个好奇的吸入药代动力学行为,可能是独立的化学形式(<一个href="#B56">57</一个>]。例如,吸入鼻腔中广泛沉积纳米材料(<一个href="#B57">58</一个>];此外,很大一部分(~ 75%)的纳米材料到达肺泡地区仍然在那个网站,有不到5%的吸入纳米颗粒把肺部的<一个href="#B58">59</一个>];带电纳米颗粒更容易前往大脑通过在嗅觉神经轴突运输比中性的纳米颗粒(<一个href="#B59">60</一个>];和纳米颗粒大小也会影响器官分布和肾排泄(<一个href="#B60">61年</一个>,<一个href="#B61">62年</一个>]。几个PBPK模型已经开发了纳米颗粒(<一个href="#B63">11</一个>,<一个href="#B61">62年</一个>- - - - - -<一个href="#B64">64年</一个>]。这些模型参数化和验证使用药代动力学实验数据对不同纳米材料(如铱、银、或technetium-labeled碳纳米颗粒)使用数据从老鼠和人类。只有稀疏manganese-based纳米颗粒的药物动力学数据。一些工作研究了锰氧化物(MnO易位<年代ub>2</年代ub>)纳米粒子从鼻腔到大脑<一个href="#B65">65年</一个>];然而,这些调查人员依赖于鼻腔滴注法的使用而不是吸入。长辈和同事(<一个href="#B66">66年</一个>暴露大鼠MnO<年代ub>2</年代ub>纳米粒子与个人空气动力学直径3 - 8海里(注意这些粒子的形式<我>~</我>30纳米团聚体接触系统)6小时/天,5天/周,总数为12个吸入暴露天。在这项研究中,嗅球显示最大的促炎基因表达的变化与中脑相比,纹状体和其他大脑区域。这个发现支持这样的结论:吸入锰纳米颗粒较大的颗粒,可以进行嗅觉运输从鼻腔嗅球。然而,PBPK模型在啮齿动物和灵长类动物核磁共振分析表明嗅觉通路似乎并不显著影响锰交付组织以外的嗅觉通路(<一个href="#B67">67年</一个>,<一个href="#B68">68年</一个>]。尽管锰纳米粒子的研究仍然是有限的,有证据表明,可溶性锰可能更可利用和导致更多的影响相对于等量的纳米锰。而大部分沉积纳米材料似乎停留在肺部,可溶性锰很容易生物利用率(<一个href="#B15">14</一个>,<一个href="#B58">59</一个>,<一个href="#B69">69年</一个>]。此外,锰纳米颗粒似乎不如同等剂量的有毒的可溶性锰<年代up>2 +</年代up>。每日气管内的可溶性MnCl滴注法<年代ub>2</年代ub>老鼠3 - 6周导致增加大脑中锰的水平,减少身体体重增加,并减少户外运动相比,控制,而MnO的等效剂量<年代ub>2</年代ub>纳米颗粒没有明显的影响(<一个href="#B65">65年</一个>]。此外,MnO<年代ub>2</年代ub>纳米颗粒的毒性更低PC-12细胞<我>在体外</我>通过MTT测定比同等剂量(ug /毫升)的可溶性醋酸锰(<一个href="#B70">70年</一个>]。因此,当前PBPK模型、基于可溶性锰(MnSO<年代ub>4</年代ub>),可能代表了最糟糕的情况相对于nano-manganese后占肺沉积差异。这个预期将进一步澄清更多的数据变得可用比较纳米的药代学和药效学和可溶性锰。</p> <p>锰PBPK模型的另一个潜在的应用风险评估是评价文学的锰暴露在灵长类动物的神经系统的结果,从而识别组织浓度,导致负面影响。这个评估将允许模型探讨锰暴露的药效学方面。模型可以用于选择最合适的剂量指标建立一个起点在未来的风险评估。先前试图评估剂量反应Mn在实验动物的影响<一个href="#B71">71年</一个>]依靠估计累积摄入锰作为唯一衡量比较研究不同剂量、持续时间和路线。替代毒理学地相关剂量指标,包括估计的峰值浓度、平均浓度和累积剂量(即。,AUC) during the Mn exposure period could be estimated using a PBPK model known to accurately account for dose dependencies of Mn distribution in the monkey for combined inhalation and dietary exposures. A large nonhuman primate response literature exists for analysis, including exposures by inhalation, oral, intraperitoneal, and subcutaneous dose routes, and spanned durations up to 2 years [<一个href="#B71">71年</一个>]。这种类型的分析使用PBPK模型正在进行中,将有可能提供一个一致的描述的剂量反应关系的影响锰接触独立路线。</p> <p>最后,PBPK模型可用于替代dosimetric-based风险评估基本要素战略考虑饮食摄入量,自然组织背景水平,和饮食和人口的变化。上层安全暴露值可能是基于空气浓度改变脑组织水平不超过正常的变化在一个健康的人口的一部分(<一个href="#B7">7</一个>,<一个href="#B72">72年</一个>]。暴露水平和靶组织水平之间的关系将由PBPK模型的使用,这将占的存在剂量依赖性转变(即。阈值水平)的积累。这种方法本质上是保守的对神经系统的结果,随着空气指南只会被设置为防止组织积累。潜在的敏感种群中描述的场景在这里可以定量考虑PBPK模型代替UFs场景中描述的应用程序。药代动力学的方法对风险评估的另一个主要优势是,它不依赖现有的职业研究,限制对暴露评估,评估的不利影响,并建立因果关系(了<一个href="#B27">30.</一个>建立起点[]),<一个href="#B72">72年</一个>]。类似PBPK模型剂量学方法也应该考虑风险评估与其他基本金属,如铜和锌。然而,任何要素的综合PBPK模型发展取决于足够多样的可用性和健壮的数据集,使模型建设和验证。现在这些数据存在Mn,很大程度上归因于MMT的替代二级测试项目(<一个href="#B5">5</一个>]。</p> <h4 id="conclusions">6。结论</h4> <p>PBPK模型的开发促进了更严格的定量分析可用的药代动力学数据,并允许剂量的比较和考虑目标组织风险评估决策。虽然PBPK模型对于许多外源性化合物已成为常规,有更多的挑战在理解生物因素的全套控制吸收,分布,间隙的锰和其他必需营养素,施加在高剂量毒性。建模工作的总体目标是评估的情况下,可能会导致大脑积累增加由于锰调节改变在健康和潜在的易感人群。这些亚种群,认定为部分替代MMT项目二级测试,包括成年男性、女性、老人、胎儿、新生儿、孕妇,以及那些有高或低膳食摄入锰。药代动力学计算CSAFs成年男性的推断,这是典型的学科评估在职业锰的研究中,这些其他生命阶段。这些值都是≤1,表明不需要药代动力学调整占这些人群。关于时间的曝光,CSAF 1到1.1计算根据吸入浓度一旦暴露水平增加组织积累的门槛(即以上。,0.001 - -0.01 ug / m<年代up>3</年代up>)。此外,而患病的人通常不包括在推断在典型的环境暴露的健康风险评估,我们已经延长了模拟包括那些中度到重度的肝胆的不足来表示人口风险更高的锰效果。模拟表明,受损的个人可能大脑不管吸入锰锰浓度水平升高,和典型的环境水平不增加这个负担。在更高的暴露水平,1.25是派生的CSAF极其敏感的子群。总的来说,这里开发的药代动力学CSAFs小于10的药代动力学部分典型的超滤对人类变化纳入目前环境锰暴露的风险评估。未来的努力可以细化场景呈现在人类,检查铁稳态的影响,并评估粒子大小和溶解度的影响,包括锰纳米颗粒。</p> <p>第二个这些努力的结果是增加了定量预测的信心锰水平升高,可能作为dosimetry-based风险评估的基础。一个潜在的假设这个风险评估方法是提高大脑锰浓度锰神经毒性的发展的先决条件。从风险评估员的角度来看,上层安全暴露值可能是基于空气浓度改变脑组织水平不超过正常的变化在一个人口的一部分(<一个href="#B7">7</一个>,<一个href="#B72">72年</一个>]。虽然有些数据差距依然存在有关锰生物学的运输和存储,这手稿描述的模型捕获锰性格的主要特征存在剂量依赖的相关性。使用蒙特卡罗分析模拟人口变化对靶组织锰水平,模型模拟表明,空气中锰浓度0.001 - -0.01毫克/米<年代up>3</年代up>需要开始影响自然背景组织浓度在成年男性中,这是最敏感的小组关于锰组织积累目前检查。与猴子的即将到来的评估使用模型来评估锰毒性剂量测定法的研究和应用对人类数据集,目前PBPK模型应该是未来的一个重要组成部分tissue-dose-based Mn的风险评估方法。</p> <p>总之,与替代二级测试相关数据收集工作计划MMT在过去10至15年在组织Mn吸入暴露在不同的饮食水平和相关PBPK模型的理解有了很大的提高多个流程的集成,共同控制锰浓度在不同的组织。这些努力产生了使用路线,multispecies PBPK模型概括摄入量有关大脑积累过度曝光。所需的主要生物学特性的拟合模型鼠和猴子组织时间进程数据有限的能力组织绑定,绑定离解缓慢Mn,消除存在剂量依赖的相关性从肝脏和从饮食摄入存在剂量依赖的相关性。如预期和控制过程与政策必不可少的金属毒性、生理过程保持身体商店Mn在低摄入量加速排泄,减少口服吸收摄入更高。这些过程存在剂量依赖的相关性是众所周知的一般方式,但不是每一个生化细节。生物因素组织约束力、膜运输、Mn保留在肠上皮细胞,这些细胞脱落到肠道流明正在接受调查。更多细节关于这些步骤将细化具体参数在当前PBPK模型。下一代PBPK模型中包含的一个领域是增加知识的金属转运蛋白(<一个href="#B73">73年</一个>- - - - - -<一个href="#B75">75年</一个>]。更详细的dose-dependencies这些转运蛋白将精心制作的不对称,吸收过程为大脑在当前模型存在剂量依赖的相关性(<一个href="#B76">76年</一个>]。然而,从当前的相对速率常数不能显著改变自模拟与当前模式显示很好与所有可用的组织时间进程数据通信。因此,尽管一些差距在理解基础生物学,显然与Mn PBPK模型显示类似的过程如何工作控制基底Mn含量非常常见的跨物种浓度以及它们如何实现控制的组织Mn面对广泛的不同的饮食摄入量。控制吸入后Mn包括增强消除但缺乏限制的能力通过提供的肺上皮细胞吸收肠道上皮口服摄入的金属。显然,当前人类PBPK模型随时准备帮助进一步整合新兴知识转化为更为量化和生物体内调节Mn的完整描述。未来的工作,可能包括不确定性和敏感性分析,将分析建模和缩放的固有局限性,以帮助确定精确的信心水平,可以归结于当前人类苍白球锰浓度的预测。然而,在其目前的形式,人类Mn PBPK模型已经提供了一个坚实的基础为提高风险评估基本金属,它同样会引起神经毒性与高剂量暴露在人类身上。</p> <h4 id="acknowledgments">确认</h4> <p>安迪侬博士的宝贵贡献的发展锰PBPK模型和图的生成<一个href="//www.newsama.com/journals/jt/2012/791431/fig6/" target="_blank">6</一个>感激地承认。作者要感谢建模技术咨询小组的成员,包括Drs。丹尼尔Krewski(椅子),杰夫•费舍尔和米歇尔Medinsky有用的贡献和对锰PBPK模型。这份出版物和工作是基于研究赞助和由Afton下产生的注册要求的化学公司的满意度,第211条(a)和(b)的《清洁空气法》和相应的法规在40 CFR 79.50节的物质。</p> </div> </div> <div class="ArticleReferences_xmlContent__p_40j"> <h4 class="ArticleReferences_references__GH2t_" id="references">引用</h4> <ol class="ArticleReferences_orderedReferences__mJr9M"> <li class="ArticleReferences_articleReference__ouEuh" id="B1"> <div class="referenceContent"> <p class="referenceText">m . 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Lu和d .傅“锌运输车YiiP结构”<我>科学</我>,卷317,不。5845年,第1748 - 1746页,2007年。</p>视图: <a href="https://doi.org/10.1126/science.1143748" target="_blank" rel="noreferrer">出版商的网站</一个> <span class="sep">|</年代p一个n> <a href="https://scholar.google.com/scholar_lookup?title=Structure%20of%20the%20zinc%20transporter%20YiiP&author=M.%20Lu&author=D.%20Fu&publication_year=2007" target="_blank" rel="noreferrer">谷歌学术搜索</一个> </div></li> <li class="ArticleReferences_articleReference__ouEuh" id="B74"> <div class="referenceContent"> <p class="referenceText">b·r·钱德拉·m·Yogavel,沙玛,“ABC-family周质锌结合蛋白的结构分析提供了新的见解的配体吸收和释放机制、“<我>分子生物学杂志</我>,卷367,不。4、970 - 982年,2007页。</p>视图: <a href="https://doi.org/10.1016/j.jmb.2007.01.041" target="_blank" rel="noreferrer">出版商的网站</一个> <span class="sep">|</年代p一个n> <a href="https://scholar.google.com/scholar_lookup?title=Structural%20analysis%20of%20ABC-family%20periplasmic%20zinc%20binding%20protein%20provides%20new%20insights%20into%20mechanism%20of%20ligand%20uptake%20and%20release&author=B.%20R.%20Chandra&author=M.%20Yogavel&author=A.%20Sharma&publication_year=2007" target="_blank" rel="noreferrer">谷歌学术搜索</一个> </div></li> <li class="ArticleReferences_articleReference__ouEuh" id="B75"> <div class="referenceContent"> <p class="referenceText">r·j·麦克马洪和r . j .表兄弟“哺乳动物锌转运蛋白,”<我>营养学杂志》</我>,卷128,不。4、667 - 670年,1998页。</p>视图: <a href="https://scholar.google.com/scholar_lookup?title=Mammalian%20zinc%20transporters&author=R.%20J.%20McMahon&author=R.%20J.%20Cousins&publication_year=1998" target="_blank" rel="noreferrer">谷歌学术搜索</一个> </div></li> <li class="ArticleReferences_articleReference__ouEuh" id="B76"> <div class="referenceContent"> <p class="referenceText">d·h·Nies“细胞如何控制锌体内平衡,”<我>科学</我>,卷317,不。5845年,第1696 - 1695页,2007年。</p>视图: <a href="https://doi.org/10.1126/science.1149048" target="_blank" rel="noreferrer">出版商的网站</一个> <span class="sep">|</年代p一个n> <a href="https://scholar.google.com/scholar_lookup?title=How%20cells%20control%20zinc%20homeostasis&author=D.%20H.%20Nies&publication_year=2007" target="_blank" rel="noreferrer">谷歌学术搜索</一个> </div></li> </ol> </div> <h4 class="copyright-title" id="copyright">版权</h4> <div class="copyright-body"> 版权©2012年迈克尔·d·泰勒等。这是一个开放的分布式下文章<一个rel="license" href="http://creativecommons.org/licenses/by/3.0/">知识共享归属许可</一个>,它允许无限制的使用、分配和复制在任何媒介,提供最初的工作是正确引用。</d我v> <div id="related-articles"></div> </div> </div> <div class="ant-col ThreeColumnLayout_rightColumn__b_MuL"> <div> <div> <div class="ArticleRightSection_articleRightSection__rG8Zh"> <div class="ArticleToolbar_articleToolbar__8fsAH"> <a href="https://downloads.hindawi.com/journals/jt/2012/791431.pdf" class="ButtonGroup_buttonGroupWrapper__Rqhy0" role="button" type="primary" aria-label="PDF" tabindex="0" unselectable="on" 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fill="currentColor"></path> </svg></span><span>PDF</年代p一个n></span><span role="img" class="anticon ButtonGroup_buttonGroupWrapperIcon__CFikg"> <svg width="1em" height="1em" viewbox="0 0 20 22"> <defs> <clippath> <path fill-rule="evenodd" clip-rule="evenodd" d="M3,22a3,3,0,0,1-3-3V16a1,1,0,0,1,2,0v3a1,1,0,0,0,1,1H17a1,1,0,0,0,1-1V16a1,1,0,1,1,2,0v3a3,3,0,0,1-3,3Zm6.288-6.3-4-4a1,1,0,0,1,1.414-1.414L9,12.586V1a1,1,0,0,1,2,0V12.586l2.293-2.293a1,1,0,0,1,1.414,1.414l-4,4a1,1,0,0,1-1.423,0Z" fill="currentColor"></path> </clippath> </defs> <g> <path fill-rule="evenodd" clip-rule="evenodd" d="M3,22a3,3,0,0,1-3-3V16a1,1,0,0,1,2,0v3a1,1,0,0,0,1,1H17a1,1,0,0,0,1-1V16a1,1,0,1,1,2,0v3a3,3,0,0,1-3,3Zm6.288-6.3-4-4a1,1,0,0,1,1.414-1.414L9,12.586V1a1,1,0,0,1,2,0V12.586l2.293-2.293a1,1,0,0,1,1.414,1.414l-4,4a1,1,0,0,1-1.423,0Z" fill="currentColor"></path> </g> </svg></span></a> <a href="//www.newsama.com/journals/jt/2012/791431.ris" class="ButtonGroup_buttonGroupWrapper__Rqhy0" role="button" type="ghost" aria-label="Download Citation" tabindex="0" unselectable="on" data-testid="download-citation"><span class="ButtonGroup_leftGroup__FJAmS"><span role="img" class="anticon ButtonGroup_buttonGroupWrapperIcon__CFikg"> <svg width="1em" height="1em" viewbox="0 0 24 24" fill="none" xmlns="http://www.w3.org/2000/svg"> <path d="M16 12H8C7.44772 12 7 12.4477 7 13C7 13.5523 7.44772 14 8 14H16C16.5523 14 17 13.5523 17 13C17 12.4477 16.5523 12 16 12Z" fill="currentColor"></path> <path d="M16 16H8C7.44772 16 7 16.4477 7 17C7 17.5523 7.44772 18 8 18H16C16.5523 18 17 17.5523 17 17C17 16.4477 16.5523 16 16 16Z" fill="currentColor"></path> <path d="M10 8H8C7.44772 8 7 8.44772 7 9C7 9.55228 7.44772 10 8 10H10C10.5523 10 11 9.55228 11 9C11 8.44772 10.5523 8 10 8Z" fill="currentColor"></path> <path d="M15 2C15 1.44772 14.5523 1 14 1C13.4477 1 13 1.44772 13 2V8C13 8.55228 13.4477 9 14 9H20C20.5523 9 21 8.55228 21 8C21 7.44772 20.5523 7 20 7H15V2Z" fill="currentColor"></path> <path fill-rule="evenodd" clip-rule="evenodd" d="M14.7071 1.29289C14.5196 1.10536 14.2652 1 14 1H6C4.34315 1 3 2.34315 3 4V20C3 21.6569 4.34315 23 6 23H18C19.6569 23 21 21.6569 21 20V8C21 7.73478 20.8946 7.48043 20.7071 7.29289L14.7071 1.29289ZM6 3H13.5858L19 8.41421V20C19 20.5523 18.5523 21 18 21H6C5.44772 21 5 20.5523 5 20V4C5 3.44772 5.44772 3 6 3Z" fill="currentColor"></path> </svg></span><span>下载引用</年代p一个n></span><span role="img" class="anticon ButtonGroup_buttonGroupWrapperIcon__CFikg"> <svg width="1em" height="1em" viewbox="0 0 20 22"> <defs> <clippath> <path fill-rule="evenodd" clip-rule="evenodd" d="M3,22a3,3,0,0,1-3-3V16a1,1,0,0,1,2,0v3a1,1,0,0,0,1,1H17a1,1,0,0,0,1-1V16a1,1,0,1,1,2,0v3a3,3,0,0,1-3,3Zm6.288-6.3-4-4a1,1,0,0,1,1.414-1.414L9,12.586V1a1,1,0,0,1,2,0V12.586l2.293-2.293a1,1,0,0,1,1.414,1.414l-4,4a1,1,0,0,1-1.423,0Z" fill="currentColor"></path> </clippath> </defs> <g> <path fill-rule="evenodd" clip-rule="evenodd" d="M3,22a3,3,0,0,1-3-3V16a1,1,0,0,1,2,0v3a1,1,0,0,0,1,1H17a1,1,0,0,0,1-1V16a1,1,0,1,1,2,0v3a3,3,0,0,1-3,3Zm6.288-6.3-4-4a1,1,0,0,1,1.414-1.414L9,12.586V1a1,1,0,0,1,2,0V12.586l2.293-2.293a1,1,0,0,1,1.414,1.414l-4,4a1,1,0,0,1-1.423,0Z" fill="currentColor"></path> </g> </svg></span></a> <div class="ant-collapse ant-collapse-icon-position-end articleToolbarOtherFormats_otherFormatsCollapse__VHaOL"> <div class="ant-collapse-item"> <div class="ant-collapse-header" aria-expanded="false" aria-disabled="false" role="button" tabindex="0"> <div class="ant-collapse-expand-icon"> <span role="img" class="anticon ant-collapse-arrow"> <svg width="1em" height="1em" viewbox="0 0 32 32" fill="none"> <path fill-rule="evenodd" clip-rule="evenodd" d="M17.773 23.453l11.2-11.265a1.918 1.918 0 000-2.641 1.75 1.75 0 00-2.542 0l-9.929 10.101-9.933-10.1a1.75 1.75 0 00-2.542 0 1.919 1.919 0 000 2.64L15.23 23.453c.352.365.811.547 1.271.547.46 0 .92-.182 1.271-.547z" fill="currentColor"></path> </svg></span> </div> <span class="ant-collapse-header-text"><span><span role="img" class="anticon articleToolbarOtherFormats_atofDownloadIcon__YRM5T"> <svg width="1em" height="1em" viewbox="0 0 20 22"> <defs> <clippath> <path fill-rule="evenodd" clip-rule="evenodd" d="M3,22a3,3,0,0,1-3-3V16a1,1,0,0,1,2,0v3a1,1,0,0,0,1,1H17a1,1,0,0,0,1-1V16a1,1,0,1,1,2,0v3a3,3,0,0,1-3,3Zm6.288-6.3-4-4a1,1,0,0,1,1.414-1.414L9,12.586V1a1,1,0,0,1,2,0V12.586l2.293-2.293a1,1,0,0,1,1.414,1.414l-4,4a1,1,0,0,1-1.423,0Z" fill="currentColor"></path> </clippath> </defs> <g> <path fill-rule="evenodd" clip-rule="evenodd" d="M3,22a3,3,0,0,1-3-3V16a1,1,0,0,1,2,0v3a1,1,0,0,0,1,1H17a1,1,0,0,0,1-1V16a1,1,0,1,1,2,0v3a3,3,0,0,1-3,3Zm6.288-6.3-4-4a1,1,0,0,1,1.414-1.414L9,12.586V1a1,1,0,0,1,2,0V12.586l2.293-2.293a1,1,0,0,1,1.414,1.414l-4,4a1,1,0,0,1-1.423,0Z" fill="currentColor"></path> </g> </svg></span><span>下载其他格式</年代p一个n></span></span> </div> </div> </div> <a href="//www.newsama.com/reprints/791431/confirm" class="ButtonGroup_buttonGroupWrapper__Rqhy0" role="button" type="ghost" aria-label="Order printed copies" tabindex="0" unselectable="on" target="_blank"><span class="ButtonGroup_leftGroup__FJAmS"><span role="img" class="anticon ButtonGroup_buttonGroupWrapperIcon__CFikg"> <svg width="1em" height="1em" viewbox="0 0 24 24" fill="none" xmlns="http://www.w3.org/2000/svg"> <path fill-rule="evenodd" clip-rule="evenodd" d="M7.41667 1H18.6667C19.1269 1 19.5 1.44772 19.5 2V22C19.5 22.5523 19.1269 23 18.6667 23H7.41667C5.80584 23 4.5 21.433 4.5 19.5V4.5C4.5 2.567 5.80584 1 7.41667 1ZM6.16667 16.3368V4.5C6.16667 3.67157 6.72631 3 7.41667 3H17.8333V16H7.41667C6.96933 16 6.54552 16.1208 6.16667 16.3368ZM17.8333 18H7.41667C6.72631 18 6.16667 18.6716 6.16667 19.5C6.16667 20.3284 6.72631 21 7.41667 21H17.8333V18Z" fill="currentColor"></path> </svg></span><span>订单打印副本</年代p一个n></span><span role="img" class="anticon ButtonGroup_buttonGroupWrapperIcon__CFikg"> <svg width="1em" height="1em" viewbox="0 0 18 14"> <defs> <clippath id="a"> <path d="M10.293,13.707a1,1,0,0,1,0-1.414L14.586,8H1A1,1,0,0,1,1,6H14.586L10.293,1.707A1,1,0,0,1,11.707.293l6,6a1,1,0,0,1,.172.231h0l.01.019,0,.005.007.014.006.012,0,.008.008.018v0a1,1,0,0,1-.009.817l0,0L17.9,7.44l0,.009-.005.011-.007.013,0,.008-.008.015,0,.005-.01.016,0,0-.011.017,0,0-.012.018,0,0-.012.017,0,0L17.8,7.6l0,0-.011.014,0,.006-.01.012-.009.011-.006.007-.015.017h0l-.04.042-6,6a1,1,0,0,1-1.414,0Z" transform="translate(3 5)"></path> </clippath> </defs> <g transform="translate(-3 -5)"> <path d="M10.293,13.707a1,1,0,0,1,0-1.414L14.586,8H1A1,1,0,0,1,1,6H14.586L10.293,1.707A1,1,0,0,1,11.707.293l6,6a1,1,0,0,1,.172.231h0l.01.019,0,.005.007.014.006.012,0,.008.008.018v0a1,1,0,0,1-.009.817l0,0L17.9,7.44l0,.009-.005.011-.007.013,0,.008-.008.015,0,.005-.01.016,0,0-.011.017,0,0-.012.018,0,0-.012.017,0,0L17.8,7.6l0,0-.011.014,0,.006-.01.012-.009.011-.006.007-.015.017h0l-.04.042-6,6a1,1,0,0,1-1.414,0Z" transform="translate(3 5)" fill="currentColor"></path> </g> </svg></span></a> <div class="articleToolbarStatistics_articleToolbarStatistics__8_woN"> <div class="articleToolbarStatistics_column__R2GqD"> <div> <div> <span>的观点</年代p一个n> <div class="articleToolbarStatistics_amount__vJIDp"> 1743年</d我v> </div> <div> <span>下载</年代p一个n> <div class="articleToolbarStatistics_amount__vJIDp"> 1186年</d我v> </div> </div> </div> <div class="articleToolbarStatistics_column__R2GqD articleToolbarStatistics_dimensions__pe7pO"> <div> 引用</d我v> <span class="__dimensions_badge_embed__ articleToolbarStatistics_circle__p2dSc" data-doi="10.1155/2012/791431" data-style="small_circle"></span> </div> </div> <ul class="articleToolbarSocials_articleToolbarSocials__g02HH"> <li><a href="https://twitter.com/share?url=https://doi.org/10.1155/2012/791431&via=Hindawi" unselectable="on" title="" rel="noopener noreferrer" target="_blank"><span role="img" class="anticon"> <svg xmlns="http://www.w3.org/2000/svg" width="1em" height="1em" viewbox="126.444 2.281 589 589"> <circle 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