国际癌症研究机构-二氧化钛-致癌.doc

资料来源：国际癌症研究机构网址：http:/monographs.iarc.fr/ http:/monographs.iarc.fr/ENG/Monographs/vol93/index.php 二氧化钛（TiO2）可致肺癌和一系列病变（国际癌症研究机构（IARC）专题论文第93篇 第五节）5.1 Exposure data“接触暴露”数据Titanium dioxide was first produced commercially in 1923, primarily for pigment production. Relatively small quantities of titanium dioxide are used for non-pigmentary purposes. In 2004, worldwide production of titanium dioxide was 4.4 million tonnes.1923年，工业生产中第一次生产二氧化钛。二氧化钛主要被用于生产“钛白粉”，相对而言，其它行业使用二氧化钛的量非常小。2004年，二氧化钛在全世界的总产量达440万公吨。Titanium dioxide is obtained from a variety of ores that contain ilmenite, rutile,anatase and leucoxene, which are mined from deposits located throughout the world. Most titanium dioxide pigment is produced from titanium mineral concentrates by the chloride or sulfate process, either as the rutile or the anatase form. The primary particles are typically between 0.2 and 0.3 m in diameter, although larger aggregates and agglomerates are formed. Ultrafine grades of titanium dioxide have a primary particle size of 1050 nm and are used predominantly as ultraviolet blockers in sunscreens and plastics, and in catalysts. Most commercial titanium dioxide products are coated with inorganic (e.g. alumina, zirconia, silica) and organic (e.g. polyols, esters, siloxanes, silanes) compounds to control and improve surface properties.二氧化钛可以从“钛铁矿”、“金红石”、“锐铁矿”和“白钛石”等矿石中采集，而这些矿石又遍布全世界各地。大多数的“钛白粉”都是从“金红石”或“锐钛矿”等钛矿中采集，再经过“氯化”或“硫化”过程提炼而来。尽管会产生一些聚合物和团聚体，但是最初的二氧化钛主要是直径为0.2到0.3微米的微粒。“超细二氧化钛”主要指直径为10-50纳米的微粒，作为紫外线吸收剂，常被添加到“防晒霜”中；二氧化钛还被广泛用于生产塑料和催化剂。大多数商业二氧化钛产品都都经过了“无机表面处理”（例如：氧化铝、氧化锆、二氧化硅）和“有机表面处理”（例如：多元醇、脂类、硅氧烷、硅烷）。Levels of occupational exposure to titanium dioxide during its manufacture have been reported from the USA and Europe between 1970 and 2000. The highest levels of exposure were observed during packing and milling, although high peak exposure also occurred in occupations such as site cleaning and maintenance. Average levels of exposure to respirable dust in these occupations up to 6 mg/m3 (geometric mean) were reported, but have declined over time. No data were available that would allow the characterization or quantification of exposure to ultrafine primary particles. Workers in the titanium dioxide manufacturing industry may also be exposed to ore and other dusts, strong acids and asbestos.美国和欧洲分别于1970年和2000年报道了在生产二氧化钛过程中，职业暴露在二氧化钛粉尘环境下的级别。尽管“场地清理”和“维护”相关职业的暴露级别很高，但是最高的还是二氧化钛的“包装”和“碾磨”过程。据报道，职业暴露在“可吸入粉尘”中的平均级别达6 mg/m3（几何平均数），但是后来这一标准被忽略了。现在还没有现成的数据来规定或量化职业暴露在“超细二氧化钛”粉尘下的标准。不过，二氧化钛生产工厂的工人们不仅暴露在二氧化钛粉尘里，还直接接触到矿石粉末、尘土、强酸和石棉纤维等微粒。5.2 Human carcinogenicity data导致人类致癌的数据调查Three epidemiological cohort studies and one population-based casecontrol study from North America and western Europe were available for evaluation.北美和西欧国家进行了三组“流行病学队列研究”和一组“基于人群的病例对照研究”来评价二氧化钛是否会导致人类致癌这一话题。The largest of the cohort studies was among white male production workers in the titanium dioxide industry in six European countries. The study indicated a slightly increased risk for lung cancer compared with the general population. However, there was no evidence of an exposureresponse relationship within the cohort. No increase in the mortality rates for kidney cancer was found when the cohort was compared with the general population, but there was a suggestion of an exposureresponse relationship in internal analyses. The other cohort studies, both of which were conducted in the USA, did not report an increased risk for lung cancer or cancer at any other site; no results for kidney cancer were reported, presumably because there were few cases.规模最大的一组“流行病学队列研究”是针对二氧化钛行业生产工人的调查，这些工人来自六个欧洲国家，均为白人男性。这项调查显示，与普通人群相比，这些工人患肺癌的风险有所增加；然而，在该调查中，却没有找到“暴露反应关系”的证据。这些工人与普通人相比，虽然因肾癌导致的死亡率并没有增加，但是却显示出轻微的“暴露反应关系”。另外两组调查是在美国执行的，这两组调查都没有报道称是否有肺癌或者其它癌症发病率升高的情况，也没有肾癌发病率的相关报道，大概是因为这种案例比较少。One population-based casecontrol study conducted in Montral did not indicate an increased risk for lung or kidney cancer.“基于人群的病例对照研究”调查是在蒙特利尔进行的，在这项调查中，没有肺癌或肾癌发病率升高的报道。In summary, the studies do not suggest an association between occupational exposure to titanium dioxide as it occurred in recent decades in western Europe and North America and risk for cancer.总之，正如最近几十年发生在西欧国家和北美国家的情况一样，调查研究并没有发现职业暴露在二氧化钛环境下与增加患癌症风险之间的直接关系。All the studies had methodological limitations; misclassification of exposure could not be ruled out. None of the studies was designed to assess the impact of particle size (fine or ultrafine) or the potential effect of the coating compounds on the risk for lung cancer.以上所有调查研究方式都有它的局限性，将暴露属性错误分类的情况也不能被完全排除。没有哪一项研究是针对二氧化钛粒子大小（极细和超细）不同而设计的，也没有考虑过涂层化合物是否会增加患肺癌的风险或带来潜在的影响。5.3 Animal carcinogenicity data导致动物致癌的实验数据分析Pigmentary and ultrafine titanium dioxide were tested for carcinogenicity by oral administration in mice and rats, by inhalation exposure in rats and female mice, by intratracheal administration in hamsters and female rats and mice, by subcutaneous injection in rats and by intraperitoneal administration in male mice and female rats.实验室采用“钛白粉”和“超细二氧化钛”通过以下方式来测试二氧化钛对老鼠的致癌性：给小白鼠和大老鼠采用“灌胃多次给药法”；使大老鼠和雌性小白鼠“吸入暴露”；给仓鼠、雌性大老鼠和小白鼠“气管内给药”；给大老鼠“皮下注射”；给雄性小白鼠和雌性大老鼠“腹腔内注射”。In one inhalation study, the incidence of benign and malignant lung tumours was increased in female rats. In another inhalation study, the incidence of benign lung tumours was increased in the high-dose groups of male and female rats. Cystic keratinizing lesions that were diagnosed as squamous-cell carcinomas but re-evaluated as non-neoplastic pulmonary keratinizing cysts were also observed in the high-dose groups of female rats. Two inhalation studies in rats and one in female mice gave negative results.在一组“吸入暴露实验”中，雌性大老鼠患“肺肿瘤”（良性和恶性）的发病率升高；在另一组“高剂量吸入暴露实验”中，雄性大老鼠和雌性大老鼠患“良性肺肿瘤”的发病率均增长。在这组“高剂量吸入暴露实验”中，雌性大老鼠由于“鳞状细胞癌”，被诊断为“囊性角质化病变”，但是后来又被复诊为“非肺肿瘤角质化囊肿”。两组大老鼠和雌性小白鼠“吸入暴露实验”都证明了负面结果。 Intratracheally instilled female rats showed an increased incidence of both benign and malignant lung tumours following treatment with two types of titanium dioxide. Tumour incidence was not increased in intratracheally instilled hamsters and female mice.给老鼠“气管内用药”的那组实验在使用两种二氧化钛之后，表现为雌性大老鼠患良性肺肿瘤和恶性肺肿瘤的发病率同时增加，而仓鼠和雌性小白鼠患肺肿瘤的发病率没有上升。 Oral, subcutaneous and intraperitoneal administration did not produce a significant increase in the frequency of any type of tumour in mice or rats.给大老鼠和小白鼠“灌胃给药”、“皮下注射”和“腹腔内注射”的几组实验均没有发现任何肿瘤发病率明显升高的情况。5.4 Mechanistic considerations and other relevant data机械性因素和其它相关数据Humans can be exposed to titanium dioxide via inhalation, ingestion or dermalcontact. In human lungs, the clearance kinetics of titanium dioxide is poorly characterized relative to that in experimental animals. (General particle characteristics and host factors that are considered to affect deposition and retention patterns of inhaled, poorly soluble particles such as titanium dioxide are summarized in the monograph on carbon black.) With regard to inhaled titanium dioxide, human data are mainly available from case reports that showed deposits of titanium dioxide in lung tissue as well as in lymph nodes.人类可能会通过吸入、吞食或皮肤接触的方式暴露在二氧化钛中。人的肺部对吸入二氧化钛后产生的“间隙动力学”和实验室动物不太一样。（一般来讲，“微粒特性”和“宿主因素”都会影响二氧化钛被吸入后的沉积模式；难溶于水的粒子，例如二氧化钛相关的专题论文被归类在炭黑一类）。人吸入二氧化钛的调查研究数据主要来源于案例报道。这些数据显示，二氧化钛主要沉积在“肺泡组织”以及“淋巴组织”内。A single clinical study of oral ingestion of fine titanium dioxide showed particle size-dependent absorption by the gastrointestinal tract and large inter-individual variations in blood levels of titanium dioxide. Studies on the application of sunscreens containing ultrafine titanium dioxide to the healthy skin of human volunteers revealed that titanium dioxide particles only penetrate into the outermost layers of the stratum corneum, suggesting that healthy skin is an effective barrier to titanium dioxide. No studies on thepenetration of titanium dioxide in compromised skin were available.一项口服二氧化钛的临床调查研究显示，不仅胃肠道会根据二氧化钛粒子大小而选择性吸收，而且血液中的二氧化钛含量也与粒子大小有关。调查研究还显示，“防晒霜”中使用的“超细二氧化钛”对人的皮肤是安全的，二氧化钛只能渗透到皮肤的最表层细胞，即“角质层”。因此，健康的皮肤能有效阻止二氧化钛渗入身体。目前还没有研究数据证明受损的皮肤是否也可以有效防止二氧化钛渗入。Respiratory effects that have been observed among groups of titanium dioxide-exposed workers include a decline in lung function, pleural disease with plaques and pleural thickening, and mild fibrotic changes. However, the workers in these studies were also exposed to asbestos and/or silica.根据几组研究调查显示，暴露在二氧化钛粉尘下的工人，直接吸入二氧化钛后导致身体机能发生一系列病变，包括“肺功能衰竭”、“胸膜长斑和胸膜增厚”、轻微的“肺泡组织纤维化”等。当然，在这些调查中，工人们同时还直接接触了“石棉”和“二氧化硅”。No data were available on the genotoxic effects in titanium dioxide-exposed humans.还没有数据可以直接证明人暴露在二氧化钛环境下是否会有“遗传毒性”的情况发生。Titanium dioxide causes varying degrees of inflammation and associated pulmonary effects including lung epithelial cell injury, cholesterol granulomas and fibrosis. Rodents experience stronger pulmonary effects after exposure to ultrafine titanium dioxide particles compared with fine particles on a mass basis. These differences are related to lung burden in terms of particle surface area, and are considered to result from impaired phagocytosis and sequestration of ultrafine particles into the interstitium.二氧化钛会导致不同程度的“炎症”以及跟肺部相关的疾病，包括“肺部上皮细胞受损”、“胆固醇肉芽肿”和“纤维化”。在动物实验中，把啮齿动物暴露在“超细二氧化钛”中，肺部发生病变的概率比在“极细二氧化钛”环境下更大。造成这一区别的原因在于微粒表面积对动物肺部造成的压力不同，也被认为是隔离吞噬“超细二氧化钛”的介质受损的结果。 Fine titanium dioxide particles show minimal cytotoxicity and inflammatory/ profibrotic mediator release from primary human alveolar macrophages invitro compared with other particles. Ultrafine titanium dioxide particles inhibitphagocytosis of alveolar macrophages in vitro at mass dose concentrations at which this effect does not occur with fine titanium dioxide.与其它粒子相比，“极细二氧化钛”表现为极低的毒性。高浓度时，“超细二氧化钛”微粒可以阻断“肺泡巨噬细胞”的吞噬作用；但是，如果换成“极细二氧化钛