模拟溶出法研究胶基型嚼烟烟碱在口腔中的释放行为

为研究胶基型无烟气烟草制品中烟碱的口腔溶出规律,开发了一种新型口腔模拟溶出装置,并建立了烟碱体外模拟溶出研究方法。以市售胶基型嚼烟中烟碱的体内溶出量为参照,确定了该装置的咀嚼力度、咀嚼频率和唾液量等模拟溶出参数,考察了不同配方设计和制作工艺的典型胶基型嚼烟产品中烟碱的体外溶出规律。结果表明:(1)该装置可较好地模拟胶基型嚼烟中烟碱的体内溶出行为。(2)胶基型嚼烟中烟碱的溶出呈先快后慢的趋势。咀嚼15 min时,烟碱的溶出率在80%左右。(3)在溶出的初始阶段,胶基型嚼烟的包衣对其烟碱的体外溶出有明显延缓作用。(4)酒石酸-烟碱复合盐形式烟碱的溶出率在8 min内明显低于烟草超微粉末形式,且复合盐中烟碱的总体溶出率低于超微烟草粉末,表明复合盐具有明显的烟碱缓释效果。该方法为胶基型嚼烟的加工制作及质量控制提供了技术支撑。     

袋装口含型无烟气烟草制品烟碱体外释放分析

研制了一套能够模拟口含型无烟气烟草制品烟碱在口腔释放的体外释放装置,并采用该装置对袋装口含型无烟气烟草制品烟碱及游离烟碱的释放进行分析.该装置主要包括溶媒存储瓶、恒流泵、恒温槽、预热线圈、保温管、恒温溶出池和释放液收集装置,其中恒温溶出池用来模拟人体口腔,通过恒流泵、恒温槽、预热线圈、保温管、恒温溶出池使烟碱在模拟条件下释放.该装置操作方便,稳定性好,能够有效地模拟口含型无烟气烟草制品在口腔的释放行为,区分不同产品间的烟碱释放差异,对口含型无烟气烟草制品的质量评价、烟碱调控以及烟碱生物利用度评价具有一定的实用价值.     

应用人造口腔模拟挤压装置研究口含烟烟碱释放的影响因素

为研究含水率、烟粉粒径和pH对口含烟烟碱释放率的影响,开发了一套模拟口含烟烟碱在口腔中释放的分析系统,并建立了口含烟烟碱体外释放的分析方法。参照Swedish Match GothiaTek~?标准制备口含烟样品,考察了不同含水率、烟粉粒径和pH条件下烟碱的体外溶出规律。结果表明:①含水率30%样品与10%样品相比,2 min内烟碱释放率提升40%;含水率超过30%时,样品的烟碱释放率变化不明显。②初始2 min内,烟粉粒径180μm样品的烟碱释放率是烟粉粒径1 700μm样品的3倍。③在6.7、7.4和8.5三个pH条件下,样品中的烟碱均可有效释放。④口含烟烟碱释放的3个影响因素模型符合指数函数,拟合系数R~2大于0.95。该研究结果可为口含烟的质量评价、烟碱释放调控提供参考。     

口含烟对人口腔致病菌的影响

  目的  研究口含烟对人口腔卫生的影响。  方法  将3种不同类型口含烟（胶基型、袋装型、含片型）提取物和传统卷烟烟气总粒相物（TPM）基于烟碱含量配成不同浓度,研究其对变形链球菌和牙龈卟啉单胞菌的抑菌效应。选取20名志愿者吸食3种口含烟和传统卷烟,以吐取法采集吸食前5 min和吸食后0~2min,2~5 min,5~10 min,10~15min,90~95 min共6个时间段的唾液,提取唾液中细菌DNA,通过实时荧光定量PCR（探针法）检测各时间节点总细菌、变形链球菌和牙龈卟啉单胞菌水平。  结果  （1）3种口含烟在体外对2种细菌无抑菌作用,普通卷烟TPM有一定抑菌作用。（2）吸食袋装型、含片型口含烟和传统卷烟后,唾液中细菌总量短期有所降低,但1 h后均恢复至使用前水平。牙龈卟啉单胞菌与变形链球菌量变化趋势与总细菌基本一致。  结论  口含烟及传统卷烟在吸食后短期内对口腔微生物有抑制作用。      

基于猪口腔黏膜模型的口含烟烟碱渗透速率的影响因素

为考察口含型无烟气烟草制品烟碱在口腔黏膜中的渗透行为,设计了透皮扩散池与猪口腔黏膜配套装置,结合高效液相色谱(HPLC)法,研究了口含烟所受压力、口含烟pH及含水率对其所含烟碱渗透速率的影响。结果表明:(1)在0.70~44.65μg/m L质量浓度范围内烟碱标准曲线的线性良好(R~2=1.000),回收率为96.45%~98.96%;(2)口含烟中烟碱透过猪口腔黏膜为直线规律,属于膜-贮库型;(3)在0.5~12.0 h内,施加6.65×10~(-2)N/cm~2的压力可显著提高烟碱的渗透速率;(4)含水率处于30%~50%之间时,pH=7.4~8.4的口含烟的烟碱渗透速率明显高于pH=5.3~5.4的口含烟。因此,可主要通过改变压力和口含烟pH来调控口含烟烟碱在口腔黏膜中的渗透行为。     

口用型无烟气烟草制品中烟碱的测定

为准确测定口用型无烟气烟草制品中烟碱的含量(质量分数),通过对样品前处理和检测条件进行优化,建立了测定口用型无烟气烟草制品(袋装口含烟、胶基烟、含化烟)中烟碱的气相色谱-氢火焰离子化法(GC-FID),并测定了23个袋装口含烟、20个胶基烟和2个含化烟样品。结果表明:(1)该方法的检出限0.01 mg/g,定量限0.05 mg/g;回收率90.2%~106.2%,日内和日间精密度分别为0.80%~3.27%和0.92%~4.81%。(2)所测定的袋装口含烟样品中有2个不含烟碱,其余21个样品中烟碱的含量为6.19~17.08 mg/g;胶基烟样品中烟碱的含量为1.20~3.95 mg/g,2个含化烟烟碱含量分别为0.85、1.62 mg/g。该方法灵敏度和准确度高,适合于口用型无烟气烟草制品中烟碱的定量检测。     

国外袋装型口含烟产品调研分析

为给国内相关产品研发设计提供技术思路和依据,对国外某公司76款袋装型口含烟产品的品牌信息、类型、小袋及盒装规格、理化品质特征和产品强度等指标进行了分析和数据挖掘。结果显示:(1)76款口含烟产品共分为15个品牌、3种类型、4种袋形,产品强度定义为5级;白色型目前是其主流产品,产品设计最为多样化;4种袋形分为大袋形、细长袋形、超细长形和迷你袋形,且不同袋形的尺寸、小袋质量不同;产品强度与总烟碱量、游离烟碱量、每袋烟碱量和pH显著正相关,与含水率负相关。(2)为满足不同地域消费群体多样化的需求,国外公司通过对不同参数的组合设计,实现了不同品质特点的系列化袋装型口含烟产品。     

胶基型无烟气烟草制品中烟碱的释放行为研究

研制了一种用于体外评价胶基型无烟气烟草制品烟碱释放行为的模拟咀嚼机,并利用该设备结合高效液相色谱仪测试了4种市售胶基型无烟气烟草制品的体外烟碱释放率.该设备主要包括溶媒存储瓶、蠕动泵、恒温槽、循环水箱、载物台、空气压缩机、气缸、电机、气动夹子和释放液收集装置.其中循环水箱和载物台形成的测试腔用来模拟人体口腔,以人工唾液为溶媒,空气压缩机带动气动夹子反复挤压被测样品以模拟人体咀嚼状态.体内、体外烟碱释放测试结果表明:利用该模拟咀嚼机评价胶基型无烟气烟草制品烟碱释放行为的方法简便可靠,测试结果与人体使用该类产品时的烟碱释放情况接近.该技术对胶基型无烟气烟草制品的质量控制、烟碱生物利用度评价以及烟碱调控具有一定的应用价值.     

行业标准方法测试口含烟化学指标的适用性

为研究现行的行业标准方法对口含烟样品化学指标的适用性,以企业自制口含烟为样本,在行业内7家实验室开展了烟碱、含水率、pH、甘油、1,2-丙二醇、重金属、TSNAs等指标的共同实验。结果表明:①针对烟碱、含水率、pH、甘油、1,2-丙二醇、重金属、TSNAs等指标,现行行业标准检测方法的重复性标准偏差与均值的比值范围为0.20%~7.20%,再现性标准偏差与均值的比值范围为1.56%~32.28%。②现行的行业标准检测方法的前处理技术以及色谱检测条件均适用于口含烟样品。但称量袋装口含烟时,需先用剪刀将样品从中间剪开,无需过筛,小袋计入样品总质量。③袋装口含烟含水率普遍较高,因此可以根据样品情况适当调节称取质量和萃取溶剂体积。     

模拟口腔加工对馒头体外淀粉消化特性的影响

为探究不同口腔加工方法对体外淀粉消化特性的影响,以青稞馒头和小麦馒头为实验材料,研究了5种模拟口腔加工方法(切块、切块加涡旋、切块加研磨、切块加涡旋并与人工唾液混合、切块加研磨并与人工唾液混合)对淀粉消化特性的影响,并以体内口腔加工为对照,以期优化馒头类产品的体外模拟淀粉消化方法。结果表明:体外模拟口腔加工后的食团粒径(155~350μm)和含水量(62%~64%)均高于体内口腔咀嚼(110~300μm、57%~59%);而模拟口腔加工的食团硬度(0.73~3.77N)低于体内口腔咀嚼(2.44~4.39N)。与未添加人工唾液组相比,添加人工唾液后得到的模拟口腔加工食团在物理特性和消化特性方面均更接近于体内口腔咀嚼。所有的体外方法中,切块加涡旋并与人工唾液混合的方法最能够模拟体内咀嚼,可作为馒头类制品体外模拟淀粉消化过程中的前处理方法。机械破坏的方式和水平以及固体颗粒与唾液混合的方式都会影响团块的形成,进而影响馒头的消化动力学。相关性分析结果显示,馒头类制品在消化后期的最终水解率与粒径呈显著负相关(r=-0.93494,P＜0.05)。考量各指标,切块加涡旋并与人工唾液混合的体外模拟口腔处理方式最适合馒头类制品的体外模拟淀粉消化。     

国内口用型无烟气烟草制品专利分析

为使我国烟草行业相关科技人员准确把握口用型无烟气烟草制品的研发现状,预测今后的发展趋势,对国家知识产权局1985-2018年公开公告的有关口用型无烟气烟草制品的专利进行了检索和统计分析。结果表明:(1)1985-2018年口用型无烟气烟草制品中国专利共计270件,其中发明233件、实用新型28件、外观设计9件。其中袋装口含型专利占50%以上,是目前口用型无烟气烟草制品专利的主流技术。(2)2008年以来,口用型无烟气烟草制品中国专利申请经历了活跃期和高峰期,国内烟草行业专利申请总量于2013年超过国外烟草公司,专利申请量以云南中烟工业有限责任公司和中国烟草总公司郑州烟草研究院领先。国外烟草公司申请的口用型无烟气烟草制品中国专利中,雷诺士烟草公司的申请量最多,其次是菲利浦·莫里斯烟草公司和美国无烟烟草公司,且均为发明专利。(3)袋装口含烟关键技术是产品配方、制备技术、包装技术等,含化烟关键技术是制备工艺、产品形态、产品配方等;袋装口含烟专利在包装方式、缓释技术、熟化技术等领域涉及较少,含化烟专利在缓释技术、成型技术等领域涉及较少。     

国外口含型无烟气烟草制品总烟碱、游离烟碱和烟草特有亚硝胺含量分析

采用CORESTA推荐方法测定了65种国外口含型无烟气烟草制品样品的含水率、烟碱、pH、游离烟碱和4种烟草特有亚硝胺(TSNAs).结果表明,口含型无烟气烟草制品的各项化学指标差异显著:含水率为12.07％ ～55.58％;pH为5.55～8.98;以湿重计,烟碱含量为5.41 ～27.68 mg/g,释放游离烟碱含量为0.63 ～ 10.46 mg/g,游离烟碱释放率为7.8％～72.3％;N-亚硝基降烟碱(NNN)为0.31～17.00 μg/g,4-(N-亚硝基甲胺基)-1-(3-吡啶基)-1-丁酮(NNK)为0.07～6.00μg,/g,N-亚硝基新烟草碱(NAT)为0.11 ～6.51 μg/g,N-亚硝基假木贼碱(NAB)为0.01 ～2.54μg/g,同一样品中4种TSNAs总含量为0.54～31.91μg/g.     

LC-MS/MS法测定口含烟中的4种亚硝基氨基酸

建立了液相色谱-四级杆串接质谱（LC-MS/MS）测定口含烟中N-亚硝基肌氨酸（NSAR）、3-（N-甲基亚硝基氨基）丙酸（MNPA）、4-（N-甲基亚硝基氨基）丁酸（MNBA）、亚硝基氮杂环丁烷-2-羧酸（NAzCA）的分析方法。样品经水萃取,硅藻土液液萃取柱净化后浓缩,进LC-MS-MS分析。结果表明:① NSAR、NAzCA、MNPA、MNBA的检出限分别为5.0 ng/g、2.4 ng/g、5.7 ng/g、1.4 ng/g,日内精密度小于6.5%,日间精密度小于9.4%,回收率在77.7%~111%之间。②分析了国内外14种口含烟,胶基型和含化型制品未检出4种亚硝基氨基酸;口含型样品中部分检出NSAR、NAzCA,均检出MNPA及MNBA,含量范围分别为ND~128.3 ng/g、ND~141.6 ng/g、1687.1~2424.1 ng/g、65.0~199.5 ng/g。该方法简单、准确,适用于口含烟中4种亚硝基氨基酸的分析。      

Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge

Objective

To compare nicotine pharmacokinetics and subjective effects of three new smokeless tobacco potential reduced exposure products (PREPs; Ariva, Revel and Stonewall) with moist snuff (Copenhagen) and medicinal nicotine (Commit lozenge).

Methods

10 subjects completed a randomised, within‐subject, crossover study. Subjects used one product for 30 min at each of the five laboratory sessions. Maximal nicotine concentration (C_max) was determined and area under the concentration time curve (AUC) was calculated for a 90‐min period (during use and 60 min after use). Nicotine craving, withdrawal symptoms and ratings of product effects and liking were measured during product use.

Results

Nicotine AUC and C_max were higher for Copenhagen than for any other product (p<0.002) and higher for Commit than for either Ariva or Revel (p<0.001). C_max for Commit was also higher than for Stonewall (p = 0.03). Craving was lowest during use of Copenhagen (p<0.03). Craving during use of Stonewall, Ariva and Commit was lower than during use of Revel (p<0.05). Withdrawal symptom score during use of Copenhagen was lower than during use of Revel (p = 0.009). Copenhagen scores were higher (p<0.005) than all other products in several measures of drug effects and liking (feel good effects, satisfaction, liking and desire for product, and strength of product).

Conclusion

The new smokeless tobacco PREPs result in lower nicotine concentrations and equivalent or lower reductions in subjective measures compared with medicinal nicotine. Since health effects of PREPs are largely unknown, medicinal nicotine should be preferentially encouraged for smokers or smokeless tobacco users wishing to switch to lower‐risk products.Over the past several years, a number of new tobacco products have been introduced, some of which are being marketed, either implicitly or explicitly, as having reduced toxicant exposure or decreased health risks. To assist in evaluating these potential reduced exposure products (PREPs), the United States Food and Drug Administration in 1999 asked the Institute of Medicine to formulate methods and standards by which PREPs could be assessed.¹ More recently, an expert panel was convened to develop guidelines for the evaluation of PREPs on both individual and population levels. Among the topics addressed was human clinical testing, which included recommendations on methods and biomarkers to assess PREPs.^2,3 The recommended evaluation of PREPs included conducting studies on the pharmacokinetic properties of the products and assessing misuse liability by measuring subjective responses to the products and ability of the products to suppress withdrawal.³The use of smokeless tobacco products, in lieu of cigarettes, has been suggested as a promising method by which to reduce tobacco‐related health consequences.⁴ Currently, tobacco companies including major cigarette‐manufacturing companies are test marketing smokeless and spitless tobacco products (eg, Camel Snus by Reynolds American, Taboka by Philip Morris) as a substitute for smoking. Although overall morbidity and mortality associated with the use of moist snuff or chewing tobacco is lower than the risks associated with cigarette smoking, health consequences such as increased rates of oral and pancreatic cancers remain.^5,6 Furthermore, health effects of all forms of smokeless tobacco are not equivalent. For example, an evaluation of the content of tobacco‐specific nitrosamines found large differences between the various forms and brands of smokeless tobacco.⁷ In a human study, a significant decrease in the uptake of tobacco carcinogens has been observed when users of conventional brands of smokeless tobacco switch to Swedish snus.⁸ A comparison of several brands of moist snuff products found significant differences between brands in the amount of unionised (free) nicotine^9,10,11 and in exposure to nicotine and heart rate response after use of a single dose of each product.¹² To accurately assess the potential health effects of a product and the factors associated with consumer use, it is therefore necessary to test each smokeless tobacco product individually, including evaluating the nicotine pharmacokinetics.The purposes of this study were to assess the pharmacokinetics and subjective responses of smokeless tobacco users when using three new PREPs and to compare them with a commonly used brand of moist snuff (Copenhagen) and the medicinal nicotine lozenge (4 mg Commit). The new smokeless tobacco products studied were (1) Ariva, a compressed powdered tobacco lozenge manufactured to contain low tobacco‐specific nitrosamines by Star Scientific marketed for use by smokers when they cannot or choose not to smoke; (2) Stonewall, another compressed powdered low tobacco‐specific nitrosamine tobacco lozenge from Star Scientific marketed as a spit‐free alternative for users of traditional moist snuff smokeless tobacco products; and (3) Revel, a spit‐free smokeless tobacco packet marketed by US Smokeless Tobacco for smokers seeking a discrete alternative to smoking.     

Review of the evidence that pH is a determinant of nicotine dosage from oral use of smokeless tobacco

OBJECTIVE: To determine whether manipulation of the pH of moist-snuff products by manufacturers could control the delivery of nicotine. DATA SOURCES: Medline database 1966-97 using the following subject headings and keywords: nicotine, absorption, mouth mucosa, skin, hydrogen-ion concentration, smokeless tobacco, biological transport, and membranes; computer database of the tobacco bibliography maintained by the US Centers for Disease Control and Prevention's Office on Smoking and Health; bibliographies of pertinent journal articles, books, and governmental reports; personal communications with experts in nicotine pharmacology and addiction; and Brown & Williamson Tobacco Corporation documents in the Tobacco Control Archives of the University of California, San Francisco. STUDY SELECTION: Included all relevant animal studies, in-vitro studies, nicotine replacement therapy trials, and human observational studies. DATA SYNTHESIS: We found that the effects of pH on drug absorption have been well established in animal models for nicotine and many other acidic or basic compounds. Increased alkalinity promotes the absorption of nicotine and increases its physiological effects. Human studies, which are more limited, confirm these processes. For example, nicotine absorption is directly related to the pH when nicotine is delivered in either tobacco smoke or nicotine polacrilex gum. CONCLUSIONS: Although other factors could influence the rate of nicotine absorption from oral tobacco, manipulating tobacco pH appears to be the primary means by which the speed of nicotine absorption is determined in moist-snuff products.


     

Rauchlose Tabakprodukte und die Folgen ihres Gebrauchs für die Gesundheit

Smokeless tobacco products include chewing tobacco, oral tobacco and snuff for inhalation. These products are consumed without burning the tobacco. Smokeless tobacco products contain tobacco specific nitrosamines and several other carcinogenic substances and additives. Epidemiologic studies from North America, Europe, Asia and Africa provide sufficient evidence that smokeless tobacco causes oral cancer and cancer of the pancreas. The evidence for an association of smokeless tobacco with cardiovascular disease and diabetes is limited. Furthermore, there is some evidence for adverse pregnancy outcomes in pregnant women who use smokeless tobacco. The health consequences of smokeless tobacco products are discussed critically against the background of the international debate about a proposed strategy of harm reduction, which involves offering smokeless tobacco as a smoking cessation aid.     

无烟气烟草制品技术发展现状及趋势研究

为把握国外无烟气烟草制品研发的技术特点和发展趋势,借助Thomson Innovation 专利分析工具对1985 ～ 2014 年间无烟气烟草制品技术专利进行分析,系统揭示近30 年来无烟气烟草制品的研发现状与态势、研发热点以及技术分布。分析结果表明:专利申请变化趋势受政策影响较大;中国和美国是无烟气烟草制品技术专利申请的主要国家;3 类无烟气烟草制品技术研发热点各有不同;以跨国烟草公司为代表的企业通过收购与并购成为无烟气烟草制品技术研发的主导力量。      

Pharmacokinetics and pharmacodynamics of moist snuff in humans

INTERVENTION: Four brands of moist snuff and a non-tobacco mint snuff were tested. Subjects reported to the laboratory for five experimental sessions. After baseline measurement of dependent variables, each subject placed 2 g of one of the brands of snuff (or one Skoal Bandits pouch) between the cheek and gum for 30 minutes. The subjects remained in the experimental laboratory for an additional 60 minutes. SUBJECTS: Ten volunteers who were daily users of smokeless tobacco. MAIN OUTCOME MEASURES: Plasma nicotine concentration, cardiovascular effects, and subjective effects. RESULTS: Large amounts of nicotine were delivered rapidly to the bloodstream. The amount of nicotine absorbed and the rate of absorption were related to the pH of the snuff product in aqueous suspension. Cardiovascular and subjective effects were related to the amount of nicotine absorbed. CONCLUSIONS: Snuff products are capable of rapidly delivering high doses of nicotine, which can lead to dependence. Long-term use of snuff can lead to a number of adverse health effects including oral cancers, cardiovascular diseases, and gingival diseases. For these reasons, it is important that the public health community considers oral snuff use as a burden on public health in the same way that cigarette smoking is recognised.     

Tobacco-specific nitrosamines in new tobacco products.

New tobacco products, designed to attract consumers who are concerned about the health effects of tobacco, have been appearing on the market. Objective evaluation of these products requires, as a first step, data on their potentially toxic constituents. Tobacco-specific nitrosamines (TSNAs) are an important class of carcinogens in tobacco products, but virtually no data were available on their levels in these products. In the present study, we analyzed several new products-Ariva, Stonewall, Exalt, Revel, Smokey Mountain, and Quest-for TSNAs and compared their TSNA levels with those in nicotine replacement products and conventional smokeless tobacco and cigarette brands. TSNAs were not detected in Smokey Mountain, which is a tobacco-free snuff product. The lowest levels among the new products containing tobacco were in Ariva and Stonewall (0.26-0.28 microg/g wet weight of product). The highest levels in the new products were found in Exalt (3.3 microg/g tobacco), whereas Revel and Quest had intermediate amounts. Only trace amounts were found in nicotine replacement products, and conventional brands had levels consistent with those reported in the literature. These results demonstrate that TSNA levels in new tobacco products range from relatively low to comparable with those found in some conventional brands.     

European Union policy on smokeless tobacco: a statement in favour of evidence based regulation for public health

Rationale: This statement is an updated version of one released by the same authors in February 2003. The statement was produced to follow up the Royal College of Physicians (RCP) Tobacco Advisory Group report "Protecting smokers, saving lives: the case for a tobacco and nicotine regulatory authority",¹ which argued for an evidence based regulatory approach to smokeless tobacco and harm reduction and posed a series of questions that regulators must address in relation to smokeless tobacco.

The purpose of this statement is to provide arguments of fact and principle to follow the RCP's report and to outline the public health case for changing existing European Union (EU) regulation in this area. A review of regulation in relation to harm reduction and regulation of tobacco products other than cigarettes is required in Article 11 of EU directive 2001/37/EC,² and this is a contribution towards forming a consensus in the European public health community about what policy the EU should adopt in the light of this review, or following ongoing legal action that may potentially strike out the existing regulation altogether.

Public health case: We believe that the partial ban applied to some forms of smokeless tobacco in the EU should be replaced by regulation of the toxicity of all smokeless tobacco. We hold this view for public health reasons: smokeless tobacco is substantially less harmful than smoking and evidence from Sweden suggests it is used as a substitute for smoking and for smoking cessation. To the extent there is a "gateway" it appears not to lead to smoking, but away from it and is an important reason why Sweden has the lowest rates of tobacco related disease in Europe. We think it is wrong to deny other Europeans this option for risk reduction and that the current ban violates rights of smokers to control their own risks. For smokers that are addicted to nicotine and cannot or will not stop, it is important that they can take advantage of much less hazardous forms of nicotine and tobacco—the alternative being to "quit or die"... and many die. While nicotine replacement therapies (NRT) may have a role in harm reduction, tobacco based harm reduction options may reach more smokers and in a different, market based, way. Chewing tobacco is not banned or regulated in the EU but is often highly toxic, and our proposal could remove more products from the market than it permitted.

Regulatory options: We believe that the EU policy on smokeless tobacco should adapt to new scientific knowledge and that the European Commission should bring forward proposals to amend or replace Article 8 of directive 2001/37/EC with a new regulatory framework. Canada has developed testing regimens for tobacco constituents and these could be readily adapted to the European situation. A review of EU policy in this area is required no later than December 2004, and we believe the Commission should expedite the part of its review that deals with harm reduction and regulation of tobacco products other than cigarettes so as to reconsider its policy on smokeless tobacco. We held this view before Swedish Match brought its legal proceedings to challenge EU legislation and we will continue to hold these views if its action fails.