香烟烟雾的组成:四种多环芳烃研究的年表

A. Rodgman, T. Perfetti
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Each of these PAHs when tested individually has been shown to possess the following biological properties: 1) Mutagenicity in certain bacterial situations, 2) tumorigenicity in certain animal species, to varying degrees under various administration modes, and 3) a threshold limit below which no tumorigenesis occurs. For more than five decades, it has been known that some of the PAHs, when co-administered in pairs of a potent tumorigen plus a non-tumorigen or weak tumorigen, show inhibitory effects on the tumorigenicity of the most potent, e.g., B[a]A plus DB[a, h]A; B[a]A plus B[a]P; anthracene plus DB[a, h]A. Over the period studied, some regulatory agencies considered these tobacco smoke PAHs to be serious health concerns, others did not. With respect to cigarette MSS, certainly the ‘danger is in the dose’ for any MSS component tested singularly to be tumorigenic. But is the level of any of these MSS PAHs high enough to be of concern to smokers? The information herein presented indicates that over the last five decades the following has occurred: 1) The per cigarette yields of these four PAHs have decreased substantially, 2) compared to CSC or Federal Trade Commission (FTC) ‘tar’, their per cigarette yields have also decreased to a point that they may be below any significance biologically, and 3) the specific tumorigenicity in mouse skin-painting studies of the CSC has decreased. These are the three criteria originally proposed to define the ‘less hazardous’ cigarette. Actually, criterion 1) was first directed only at B[a]P. Previous studies highlighted the concern that some regulatory bodies had in attempting to understand why lung cancer and other forms of cancer seemed more prevalent in smokers. But cigarette smoking alone could not reconcile the evidence. Social, ethnic, environmental, and economic factors are also very important in understanding the entire biological effect. In fact, the level of B[a]P in CSC could only explain about 2% of its specific tumorigenicity observed in skin-painted mice and the combination of the levels of all the known tumorigenic PAHs in CSC could only explain about 3% of its tumorigenicity. Despite an 18-month study in the late 1950s, the search for a ‘supercarcinogen’ in MSS and CSC to explain the observed biological effects was unsuccessful. In addition, the exceptional study on MSS PAHs by United States Department of Agriculture (USDA) personnel in the 1970s indicated no ‘supercarcinogen’ was present. Only recently has the concept of complex mixtures in relation to the understanding of the complexity of carcinogenesis taken hold. Perhaps the reason why MSS is less tumorigenic than expected in humans is because of the presence of other MSS components that inhibit or prevent tumorigenesis. 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引用次数: 5

摘要

多环芳烃(PAHs)是一类主要的香烟主流烟雾(MSS)成分,在实验动物中被证明是致瘤性的,并且可能对人类有致瘤性。迄今为止,在烟草烟雾中已完全或部分鉴定出近540种多环芳烃[roddgman和Perfetti[1]]。详细介绍了烟草烟雾中发现的四种多环芳烃的研究年表,即苯并[A]蒽(B[A]A),其7,12-二甲基衍生物(DMB[A]A),二苯并[A, h]蒽(DB[A, h]A)和苯并[A]芘(B[A]P)。其中,DMB[a] a、DB[a, h] a和B[a]P被认为对小鼠皮肤涂布和皮下注射具有强致瘤性。B[a] a对小鼠皮肤的致瘤性众说纷纭。DMB[a] a常作为引发剂用于致瘤性研究。对这四种多环芳烃与吸烟有关的引用数量的研究表明,自20世纪50年代初以来,人们对B[a]P与其他三种多环芳烃的对比付出了巨大的努力。从1886年至今的注释年表描述了与这四种多环芳烃相关的烟草烟雾相关研究,它们的发现、分离和/或鉴定、定量以及对MSS或香烟烟雾冷凝物(CSC)所观察到的生物活性的贡献。许多关于烟草烟雾中这四种多环芳烃的主要文献都是为了让读者决定目前的证据是否足以将它们归类为吸烟者的健康风险。在过去的几十年里,研究人员确实付出了巨大的努力来了解这些多环芳烃。每一种PAHs在单独测试时都显示出以下生物学特性:1)在某些细菌情况下具有诱变性,2)在不同给药模式下对某些动物物种具有不同程度的致瘤性,以及3)不发生肿瘤的阈值限制。50多年来,人们已经知道,一些多环芳烃,当有效致瘤剂与非致瘤剂或弱致瘤剂成对共同施用时,对最有效的致瘤剂表现出抑制作用,例如,B[a] a加DB[a, h] a;B[a] + B[a]P;蒽加DB[a, h] a。在研究期间,一些监管机构认为这些烟草烟雾中的多环芳烃是严重的健康问题,而另一些机构则不这么认为。关于香烟的MSS,当然,任何单一测试的MSS成分都是致瘤性的,“危险在于剂量”。但是这些MSS多环芳烃的含量是否高到足以引起吸烟者的注意呢?本文提供的信息表明,在过去五十年中发生了以下情况:1)这四种多环芳烃的每支香烟产量大幅下降,2)与CSC或联邦贸易委员会(FTC)的“焦油”相比,它们的每支香烟产量也下降到可能低于任何生物学意义的程度,以及3)CSC小鼠皮肤涂漆研究中的特异性致瘤性已经下降。这是最初提出的定义“低危害”香烟的三个标准。实际上,标准1)最初只是针对B[a]P。先前的研究强调了一些监管机构在试图理解为什么肺癌和其他形式的癌症似乎在吸烟者中更普遍时的担忧。但仅仅是吸烟并不能证明这一点。社会、种族、环境和经济因素在理解整个生物效应方面也非常重要。事实上,CSC中B[a]P的水平只能解释皮肤染色小鼠观察到的约2%的特异性致瘤性,而CSC中所有已知致瘤性多环芳烃水平的综合只能解释约3%的致瘤性。尽管在20世纪50年代末进行了为期18个月的研究,但在MSS和CSC中寻找一种“超级致癌物”来解释观察到的生物效应并没有成功。此外,美国农业部(USDA)人员在20世纪70年代对MSS多环芳烃进行的特殊研究表明,不存在“超级致癌物”。直到最近,复杂混合物的概念才与对致癌性复杂性的理解有关。也许MSS在人类中的致瘤性比预期的要低,是因为存在其他抑制或预防肿瘤发生的MSS成分。例如,众所周知,MSS含有大量的抗癌物质,其含量远远高于所关注的多环芳烃。当人们回顾这四种多环芳烃在MSS或CSC中的历史时,显然仍有许多未解之谜。
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The Composition of Cigarette Smoke: A Chronology of the Studies of Four Polycyclic Aromatic Hydrocarbons
Abstract Among the polycyclic aromatic hydrocarbons (PAHs), a major class of identified cigarette mainstream smoke (MSS) components, are several shown to be tumorigenic in laboratory animals and suspect as possible tumorigens to humans. To date, nearly 540 PAHs have been completely or partially identified in tobacco smoke [Rodgman and Perfetti (1)]. A detailed chronology is presented of studies on four much discussed PAHs identified in tobacco smoke, namely, benz[a]anthracene (B[a]A), its 7,12-dimethyl derivative (DMB[a]A), dibenz[a, h]anthracene (DB[a, h]A), and benzo[a]pyrene (B[a]P). Of the four, DMB[a]A, DB[a, h]A, and B[a]P are considered to be potently tumorigenic on mouse skin painting and subcutaneous injection. Opinions on the tumorigenicity of B[a]A to mouse skin vary. DMB[a]A is frequently used in tumorigenicity studies as an initiator. Examination of the number of tobacco smoke-related citations listed for these four PAHs reveals the enormous effort devoted since the early 1950s to B[a]P vs. the other three. An annotated chronology from 1886 to date describes the tobacco smoke-related research pertinent to these four PAHs, their discovery, isolation and/or identification, quantitation, and contribution to the observed biological activity of MSS or cigarette smoke condensate (CSC). Much of the major literature on these four PAHs in tobacco smoke is presented in order to permit the reader to decide whether the current evidence is sufficient to classify them as a health risk to smokers. There has certainly been a tremendous effort by researchers to learn about these PAHs over the past several decades. Each of these PAHs when tested individually has been shown to possess the following biological properties: 1) Mutagenicity in certain bacterial situations, 2) tumorigenicity in certain animal species, to varying degrees under various administration modes, and 3) a threshold limit below which no tumorigenesis occurs. For more than five decades, it has been known that some of the PAHs, when co-administered in pairs of a potent tumorigen plus a non-tumorigen or weak tumorigen, show inhibitory effects on the tumorigenicity of the most potent, e.g., B[a]A plus DB[a, h]A; B[a]A plus B[a]P; anthracene plus DB[a, h]A. Over the period studied, some regulatory agencies considered these tobacco smoke PAHs to be serious health concerns, others did not. With respect to cigarette MSS, certainly the ‘danger is in the dose’ for any MSS component tested singularly to be tumorigenic. But is the level of any of these MSS PAHs high enough to be of concern to smokers? The information herein presented indicates that over the last five decades the following has occurred: 1) The per cigarette yields of these four PAHs have decreased substantially, 2) compared to CSC or Federal Trade Commission (FTC) ‘tar’, their per cigarette yields have also decreased to a point that they may be below any significance biologically, and 3) the specific tumorigenicity in mouse skin-painting studies of the CSC has decreased. These are the three criteria originally proposed to define the ‘less hazardous’ cigarette. Actually, criterion 1) was first directed only at B[a]P. Previous studies highlighted the concern that some regulatory bodies had in attempting to understand why lung cancer and other forms of cancer seemed more prevalent in smokers. But cigarette smoking alone could not reconcile the evidence. Social, ethnic, environmental, and economic factors are also very important in understanding the entire biological effect. In fact, the level of B[a]P in CSC could only explain about 2% of its specific tumorigenicity observed in skin-painted mice and the combination of the levels of all the known tumorigenic PAHs in CSC could only explain about 3% of its tumorigenicity. Despite an 18-month study in the late 1950s, the search for a ‘supercarcinogen’ in MSS and CSC to explain the observed biological effects was unsuccessful. In addition, the exceptional study on MSS PAHs by United States Department of Agriculture (USDA) personnel in the 1970s indicated no ‘supercarcinogen’ was present. Only recently has the concept of complex mixtures in relation to the understanding of the complexity of carcinogenesis taken hold. Perhaps the reason why MSS is less tumorigenic than expected in humans is because of the presence of other MSS components that inhibit or prevent tumorigenesis. For example, it is well known that MSS contains numerous anticarcinogens present in quantities significantly greater than those of the PAHs of concern. When one reviews the history of these four PAHs in MSS or CSC it is clear that many unanswered questions remain.
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