Department of General Surgery, Tripler Army Medical Center, Honolulu, HI 96859, USA.
Toxicol Appl Pharmacol. 2012 Feb 15;259(1):74-86. doi: 10.1016/j.taap.2011.12.008. Epub 2011 Dec 16.
Significant controversy over the environmental and public health impact of depleted uranium use in the Gulf War and the war in the Balkans has prompted the investigation and use of other materials including heavy metal tungsten alloys (HMTAs) as nontoxic alternatives. Interest in the health effects of HMTAs has peaked since the recent discovery that rats intramuscularly implanted with pellets containing 91.1% tungsten/6% nickel/2.9% cobalt rapidly developed aggressive metastatic tumors at the implantation site. Very little is known, however, regarding the cellular and molecular mechanisms associated with the effects of inhalation exposure to HMTAs despite the recognized risk of this route of exposure to military personnel. In the current study military-relevant metal powder mixtures consisting of 92% tungsten/5% nickel/3% cobalt (WNiCo) and 92% tungsten/5% nickel/3% iron (WNiFe), pure metals, or vehicle (saline) were instilled intratracheally in rats. Pulmonary toxicity was assessed by cytologic analysis, lactate dehydrogenase activity, albumin content, and inflammatory cytokine levels in bronchoalveolar lavage fluid 24h after instillation. The expression of 84 stress and toxicity-related genes was profiled in lung tissue and bronchoalveolar lavage cells using real-time quantitative PCR arrays, and in vitro assays were performed to measure the oxidative burst response and phagocytosis by lung macrophages. Results from this study determined that exposure to WNiCo and WNiFe induces pulmonary inflammation and altered expression of genes associated with oxidative and metabolic stress and toxicity. Inhalation exposure to both HMTAs likely causes lung injury by inducing macrophage activation, neutrophilia, and the generation of toxic oxygen radicals.
海湾战争和巴尔干战争中贫铀使用对环境和公共健康的影响引起了重大争议，促使人们研究和使用其他材料，包括重金属钨合金（HMTAs）作为无毒替代品。最近发现，肌肉内植入含有 91.1%钨/6%镍/2.9%钴的丸剂的大鼠在植入部位迅速发展出侵袭性转移性肿瘤，这使得人们对 HMTAs 的健康影响产生了浓厚兴趣。然而，尽管人们认识到这种暴露途径对军事人员存在风险，但对于吸入 HMTAs 暴露相关的细胞和分子机制却知之甚少。在目前的研究中，含有 92%钨/5%镍/3%钴（WNiCo）和 92%钨/5%镍/3%铁（WNiFe）的军事相关金属粉末混合物、纯金属或载体（盐水）被气管内滴注到大鼠体内。通过细胞学分析、乳酸脱氢酶活性、白蛋白含量和支气管肺泡灌洗液中的炎症细胞因子水平来评估肺部毒性在滴注后 24 小时。使用实时定量 PCR 阵列对肺组织和支气管肺泡灌洗细胞中的 84 个应激和毒性相关基因的表达进行了分析，并进行了体外测定以测量肺巨噬细胞的氧化爆发反应和吞噬作用。这项研究的结果表明，暴露于 WNiCo 和 WNiFe 会引起肺部炎症和与氧化和代谢应激和毒性相关的基因表达改变。吸入 HMTAs 可能会通过诱导巨噬细胞激活、嗜中性粒细胞增多和产生有毒氧自由基来引起肺部损伤。
