Report on Carcinogens 致癌物报告

U.S. Department of Health and Human Services 美国健康与人类服务部

Public Health Service  National Toxicology Program

Introduction

The probability that a resident of the United States will develop cancer at some point in his or her lifetime is 1 in 2 for men and 1 in 3 for women (ACS 2010). Nearly everyone’s life has been directly or indirectly affected by cancer. Most scientists involved in cancer research believe that the environment in which we live and work may be a major contributor to the development of cancer (Lichtenstein et al. 2000). In this context, the “environment” is anything that people interact with, including exposures resulting from lifestyle choices, such as what we eat, drink, or smoke; natural and medical radiation, including exposure to sunlight; workplace exposures; drugs; socio-economic factors that affect exposures and susceptibility; and substances in air, water, and soil (OTA 1981, IOM 2001). Other factors that play a major role in cancer development are infectious diseases, aging, and individual susceptibility, such as genetic predisposition (Montesano and Hall 2001). We rarely know what environmental factors and conditions are responsible for the onset and development of cancer; however, we have some understanding of how some types of cancer develop, especially cancer related to certain occupational exposures or the use of specific drugs. Many experts firmly believe that much of the cancer associated with the environment may be avoided (Tomatis et al. 1997).

介绍

美国居民在一生某时段罹患癌症的几率，男性为每两人中一位，女性为每三人中一位(ACS2010)。几乎每个人的生活都已直接或间接地受到癌症的影响。大多数从事癌症研究的科学家相信，我们生活和工作的环境可能是癌症发病的主要帮凶。此处，“环境”是指与人们互动的所有一切，包括生活方式的选择，吃、喝、抽烟，自然或医学辐射，如日光辐射；工作场所有害接触；药物；外加左右各类有害接触及受害程度的社会-经济因素；以及周围空气、水体和土壤中的有害物质。其它影响癌症发病的重要因素还包括感染性疾病，老龄，以及个体易感性，比如基因偏差等。我们很少知道何种环境因素条件直接造成癌症发病和发展，但对某些种类的癌症，尤其是那些与职业接触、使用药物有关的癌症，的发展有所了解。很多专家相信，大部分与环境相关的癌症是可以避免的。

The people of the United States, concerned about the relationship between their environment and cancer, have asked, through the U.S. Congress, for information about substances that are known or appear likely to cause cancer (i.e., to be carcinogenic). Section 301(b)(4) of the Public Health Service Act, as amended, provides that the Secretary of the Department of Health and Human Services shall publish a biennial report that contains the following information:

• A list of all substances (1) which either are known to be human carcinogens or may reasonably be anticipated to be human carcinogens and (2) to which a significant number of persons residing in the United States are exposed

• Information concerning the nature of such exposure and the estimated number of persons exposed to such substances.

• A statement identifying (1) each substance contained in this list for which no effluent, ambient, or exposure standard has been established by a Federal agency and (2) for each effluent, ambient, or exposure standard established by a Federal agency with respect to a substance contained in this list, the extent to which such standard decreases the risk to public health from exposure to the substance.

• A description of (1) each request received during the year to conduct research into, or testing for, the carcinogenicity of a substance and (2) how the Secretary and other responsible entities responded to each request.

美国公众深度关切环境与癌症的关系，通过美国国会要求了解已知或可能诱发癌症(亦即致癌性)的物质的相关信息。公共健康服务法案301(b)(4)节，修正版，要求卫生与公众服务部部长必须出版双年报告，提供下列信息：

• 物质清单，其为 1) 已知及相当预期人类致癌物 2) 相当数量居住美国的人员会接触到的

• 有关此类接触的信息以及接触此类物质的人员数量的估算

• 公告申明 1) 此清单中每一未由任何联邦机构设定排放、环境、接触标准的物质；2) 此清单中有关每一物质已由联邦机构设定的排放、环境、接触标准对有接触的公众的健康风险可降低的程度。

• 情况说明 1) 当年收到的对某物质致癌性进行研究或测试的申请 2) 部长及其他责任机构如何回应此类申请

The Report on Carcinogens (RoC) is an informational scientific and public health document that identifies and discusses agents, substances, mixtures, or exposure circumstances (hereinafter referred to as “substances”) that may pose a hazard to human health by virtue of their carcinogenicity. For each listed substance, the RoC contains a substance profile which provides information on (1) the listing status, (2) cancer studies in humans and animals, (3) studies of geno-toxicity (ability to damage genes) and biologic mechanisms, (4) the potential for human exposure to these substances, and (5) Federal regulations to limit exposures. The RoC does not present quantitative assessments of the risks of cancer associated with these substances. Thus, the listing of substances in the RoC only indicates a potential hazard and does not establish the exposure conditions that would pose cancer risks to individuals in their daily lives. Such formal risk assessments are the responsibility of the appropriate Federal, state, and local health regulatory and research agencies.

致癌物报告(RoC)是信息性的科学及公共健康文件，识别并探讨因自身致癌性特点对人类健康产生危害的媒剂、物料、混合物、及接触条件(下列通称“物质”)。对每一列名物质，RoC报告附有该物质概述，提供相关信息，包括 1) 列名状态 2) 人类及动物癌症研究 3) 基因毒性(基因致损性)研究及生物学机制 4) 人类接触此物质的潜在可能 5) 限制此类接触的联邦规范。RoC报告不带有与此物质相关的按正风险的定量分析。因此，RoC内的物质清单仅提示潜在危害，而并不设定个人日常生活中由此物质造成癌症风险的接触条件。此种正式风险评估需由适当的联邦、州立和地方健康立法和研究机构进行。

The substances listed in the RoC are either known or reasonably anticipated to cause cancer in humans in certain situations. With many listed substances, cancer may develop only after prolonged exposure. For example, smoking tobacco is known to cause cancer in humans, but not all people who smoke develop smoking-related cancer. With some substances or exposure circumstances, however, cancer may develop after even brief exposure. Examples include certain occupational exposures to asbestos or bis(chloromethyl) ether. The cancer hazard that listed substances pose to any one person depends on many factors. Among these are the intrinsic carcinogenicity of the substance, the amount and duration of exposure, and the individual’s susceptibility to the carcinogenic action of the substance. Because of these considerations, the RoC does not attempt to rank substances according to the relative cancer hazards they pose.

RoC报告所列物质为已知或相当预期在某些条件下诱发人类癌症。有很多物质，癌症可能在较长接触时间后发展。例如，吸烟已知为癌症诱发因素，但并非所有吸烟者会发生吸烟相关的癌症。而有些物质或接触条件，则在相对短暂的接触后，就会发生癌症。比如某些职业性接触石棉或二氯甲基醚。所列物质对任一单个个体的癌症风险取决于若干因素。其中包括物质本身的致癌性，接触量及时长，以及个体对该物质致癌性的敏感程度。基于此些考虑，RoC不对各物质所表现的癌症风险排序。

Identification of Carcinogens

For many years, government research agencies (including the National Toxicology Program), industries, academia, and other research organizations have studied various substances to identify those that may cause cancer. Much of the information on specific chemicals or occupational exposures has been published in the scientific literature or in publicly available and peer-reviewed technical reports. This literature is a primary source of information for identifying and evaluating substances for listing in the RoC. Many of the listed substances also have been reviewed and evaluated by other organizations, including the World Health Organization’s International Agency for Research on Cancer (IARC), in Lyon, France, the Environmental Protection Agency of the State of California, and other U.S. Federal and international agencies.

致癌性识别

多年来政府研究机构(包括国家毒性学项目)，产业界，学术界，及其他研究机构研究了各种物质以识别其中可能诱发癌症的物质。大部分关于特定化学品或职业接触的信息都已发表在科学文献，或面向公众、经同行评审的技术报告中。这部分文献是辨识和评估RoC物质列名的基础信息。很多列名物质经其他机构审定评估，包括在法国里昂的世界卫生组织下属的国际癌症研究所，加州环境保护署，以及其他联邦和国际机构。

Studies in both humans and experimental animals are used to evaluate whether substances are potentially carcinogenic in humans. Other studies that may elucidate possible mechanisms of action of potential carcinogens also are considered in the evaluations. The strongest evidence for establishing a relationship between exposure to any given substance and cancer in humans comes from epidemiological studies — studies of the occurrence of a disease in a defined human population and the factors that affect its occurrence (Hill 1971). Interpretation of epidemiological studies of human exposure and cancer can be difficult (Rothman 1986), as they must rely on natural, not experimental, human exposure and must therefore consider many factors that may affect cancer prevalence in addition to the exposure under study. One such factor is the latency period for cancer development (i.e., the time between first exposure to a carcinogen and development of cancer). The first sign of cancer often appears many years (sometimes 20 to 30 years or more) after exposure to the carcinogen. Epidemiological studies of workers exposed to high levels of chemicals have led to the identification of many carcinogens in the United States (Fontham et al. 2009).

人体研究和实验动物研究并行开展以评估物质对人类的潜在致癌性。其它阐述潜在致癌物可能作用机理的研究也在评估过程中被用以参考。确定给定物质接触史与人类癌症间关系最有力的证据来自流行病学研究 – 即研究限定人群中某疾病的发生情况以及影响其发生的因素。直接解释人类接触与癌症之间流行病学研究比较困难，因为这需要自然的，而非实验性的，人类与对象物质的接触，并要同时在考虑接触条件外，再考虑许多影响癌症胜出的因素。其中一个因素就是癌症生长的时间跨度(即初次接触致癌物到癌症发生之间的时长)。癌症初期症状往往出现在接触致癌物很多年以后(有时达20到30年或更长)。在美国对工人接触高浓度化学品的流行病学研究直接确定了很多致癌物质。

Another valuable method for identifying substances as potential human carcinogens is the long-term bioassay in experimental animals. These studies provide accurate information about dose and duration of exposure, and they are less affected than epidemiological studies by possible interactions of the test substance with other chemicals or modifying factors (Huff 1999). In these studies, the substance is given to one or (usually) two species of laboratory rodents over a range of doses for nearly the animals’ entire lives. Experimental cancer research is based on the scientific assumption that substances causing cancer in animals will have similar effects in humans; however, it is not possible to predict with complete certainty from animal studies alone which substances will be carcinogenic in humans. Known human carcinogens have also been shown to cause cancer in experimental animals when tested adequately (Fung et al. 1995). In many cases, a substance first was found to cause cancer in animals and later confirmed to cause cancer in humans (Huff 1993, 1999). How experimental animals respond to substances, including developing cancer or other illnesses, does not always strictly correspond to how people will respond. Nevertheless, experimental animal studies remain the best tool for detecting potential human health hazards of all kinds, including cancer (OTA 1981, Tomatis et al. 1997).

确定人类潜在致癌物的另一有价值的方法是实验动物中长期的生物鉴定。这些研究提供关于剂量、接触时长的精确数据，且比流行病学方法较少受到被测物质与其它化学品或修正因子可能的交互影响的干扰。此类研究中，受测物质被施于一或两种(通常)实验室啮齿动物，施用不同剂量，贯穿大部分生命周期。实验癌症研究基于这样一种科学假定即诱发动物癌症的物质对人类有相似效应；然而，单从动物试验尚未有绝对把握预测哪一种物质对人类有致癌性。已知人类致癌物在恰当实验条件下也确实显示对实验动物能诱发癌症。在很多情况下，一种物质首先被发现对实验动物引发癌症，然后再确认对人类有致癌性。实验动物对物质的反应，比如生成癌症或其它疾病，并不总是严格对应人类的反应。无论如何，实验动物还是测定各种人类健康危害，包括癌症，最好的工具。

Listing Criteria

The criteria for listing an agent, substance, mixture, or exposure circumstance in the RoC are shown in the box on this page. The listing criteria presented here were first adopted for use in the Eighth Report on Carcinogens, which was published in 1998. The listing criteria were clarified the following year in two Federal Register notices (NTP 1999a,b). Listing criteria for substances listed in earlier editions of the RoC are outlined in the introductions to those editions.

列名标准

RoC对媒剂、物质、混合物或接触条件列名的标准，可见下表。此处列举的列名标准最初是由1998年颁布的第八版RoC报告采纳的。列名标准于次年由两个联邦注册通告予以澄清。RoC报告早期版本中的列名物质的列名标准在该些版本的介绍部分做了说明。

Known To Be Human Carcinogen:

There is sufficient evidence of carcinogenicity from studies in humans,* which indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer.

已知人类致癌物

根据人类研究有致癌性的充足证据显示接触该媒剂、物质、或混合物，与人类癌症之间的因果关系。

Reasonably Anticipated To Be Human Carcinogen:

There is limited evidence of carcinogenicity from studies in humans,* which indicates that causal interpretation is credible, but that alternative explanations, such as chance, bias, or

confounding factors, could not adequately be excluded,

or

there is sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors (1) in multiple species or at multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual degree with regard to incidence, site, or type of tumor, or age at onset,

or

there is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance, or mixture belongs to a well-defined, structurally related class of substances whose members are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcinogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans.

充分推断人类致癌物

人类研究中致癌性有一定证据，显示因果关系的解释是可信的，也有替代解释，比如，偶因、偏向，或复合因素，尚未能恰当排除；

或

根据实验动物研究有充足证据显示不断增加的恶性和/或恶性良性混合肿瘤的病例，且 1) 在多个物种或在多个组织部位，或 2) 通过多种接触途径，或 3) 病例、部位、或肿瘤类型、或初发年龄，达到某种反常的程度。

或

人类研究或实验动物研究的致癌性证据尚未充足，但该液剂、物质、或混合物属于已经充分界定、结构相关的组群的物质，其同构物在前版RoC中已列名为确认人类致癌物或充分推断人类致癌物，或有可信的相关信息表明该媒剂可通过可能诱发人类癌症的机理发生作用。

Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgment, with consideration given to all relevant information. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive sub-populations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance. For example, there may be substances for which there is evidence of carcinogenicity in laboratory animals, but there are compelling data indicating that the agent acts through mechanisms which do not operate in humans and would therefore not reasonably be anticipated to cause cancer in humans.

有关人类或实验动物的致癌性的结论是基于科学判断的，充分考虑了所有相关信息。相关信息包括，但不仅限于，剂量反应、接触途径、化学结构、新陈代谢、药物动力学、敏感亚群体、基因影响或与作用机理相关的数据、特定物质独有因素等。比如，有些物质其实验动物显示有致癌性，但有充足证据显示该媒剂的作用机理并不发生于人类，因而不能作为充分推断人类致癌物。

*This evidence can include traditional cancer epidemiology studies, data from clinical studies, and/or data derived from the study of tissues or cells from humans exposed to the substance in question, which can be useful for evaluating whether a relevant cancer mechanism is operating in humans.

此类证据也包括传统的癌症流行病学研究、临床研究数据、和/或人类接触存疑物质的组织或细胞研究数据，其也被用于评估某癌症发病机理是否作用于人类。