<abstract><title style='display:none'>Summary</title>The objective of this work was to compare the nicotine content and yield of new very low nicotine content cigarettes (VLN™) to the top 100 cigarette brand styles in the United States. Nicotine in tobacco filler and nicotine in smoke were measured. On a dry weight basis, VLN™ cigarettes averaged 0.5 mg of nicotine/g tobacco as compared to 19.4 for the top 100 brand styles in the United States. On a cigarette basis, VLN™ cigarettes contained 0.27 mg of nicotine compared to 12 mg for the top brands. On an ISO smoke yield basis, VLN™ produced 0.03 mg nicotine/cig compared to 0.903 mg nicotine/cig for the leading brands. VLN™ cigarettes contained &gt; 95% less nicotine on a per gram basis of tobacco or per cigarette basis than the top 100 brand styles in the U.S. VLN™ cigarettes yielded &gt; 95% less nicotine in smoke than the top brand styles in the United States.</abstract>

Comparison of the Yield of Very Low Nicotine Content Cigarettes to the Top 100 United States Brand Styles

<abstract><title style='display:none'>Abstract</title> The structures of three types of nicotine salts have been determined. These salts have acid to base ratios of either 1 : 1, 2 : 1, or 3 : 1. Salt formation between organic acids and nicotine is dependent upon the structure of the acids (aliphatic or aromatic) and their functionality. The 1 : 1 salts of nicotine have amino acids or benzoic-type acids bound to the N-methylpyrrolidine nitrogen of nicotine. The 2 : 1 salts are found to bind to one acid group as in the 1 : 1 salts and a second to the nitrogen of the pyridine ring. The 2 : 1 salts of nicotine are formed with formic acid, aliphatic dicarboxylic acids, and/or nitroaromatic acids. Nicotine forms 3 : 1 salts with aliphatic monocarboxylic acids starting with acetic acid. Here one acid is bound as in the 1 : 1 salts while the other two acids dimerize and bind to the nitrogen of the pyridine group. Infra-red (IR), ultra-violet (UV), proton nuclear magnetic resonance (PMR), and carbon nuclear magnetic resonance (CMR) spectroscopy as well as field desorption - mass spectroscopy (FD-MS) were used in this investigation of the structure of nicotine salts. </abstract>

Structural Study of Nicotine Salts

<abstract><title style='display:none'>Summary</title>The present study describes the analysis of several organic acids in tobacco and smokeless tobacco products using a liquid chromatography (LC) method with mass spectrometric (MS) detection (LC-MS). Prior to the application of the LC-MS method, a qualitative analysis for the identification of the organic acids in tobacco and oral tobacco products was performed. The qualitative method used direct silylation of the plant material followed by GC-MS separation and detection. For the acids’ quantitation, a novel LC-MS method has been developed and validated. The acids of interest for quantitation were the following: acetic, citric, fumaric, glyceric, lactic, maleic, malic, oxalic, pyroglutamic, pyruvic, quinic, and trihydroxybutanoic. The LC separation was performed on a Synergy 4u Hydro-RP column 250 × 4.6 mm, with an aqueous mobile phase containing 5% methanol and 0.15% formic acid. The LCMS method has the advantage versus LC methods with other detection types (refractive index, UV absorption at low UV range, or conductivity) of being capable of positive identification of the analytes based on their specific ions, and of having significantly better sensitivity. Unfortunately, the LC-MS method was not generating good results for oxalic acid and acetic acid also expected to be present in some samples of tobacco or tobacco products. The study describes the advantages and disadvantages of the LC-MS method for the analysis of organic acids in tobacco and smokeless tobacco products.</abstract>

An LC-MS Method for the Analysis of Some Organic Acids in Tobacco Leaf, Snus, and Wet Snuff

<abstract><title style='display:none'>Summary</title>Tobacco, <italic>Nicotiana tabacum,</italic> is a high-value crop grown in many temperate and tropical countries of the world. Several insects attack tobacco throughout the season, from transplant production, growth in the field, during storage, and in the marketed product. This review focuses on economically important insects of the seedling tobacco or the growing crop in major tobacco-producing regions of the world. The species covered herein are tobacco aphid, black cutworm, tobacco budworm, tobacco hornworm, tobacco flea beetle, thrips, Japanese beetle, and tobacco wireworm. The occurrence and economic importance of these insects vary from region to region.For each insect discussed, the following information is provided: the scientific name and taxonomic position of the insect; its geographical distribution; the stage that causes the damage and plant hosts; a brief discussion on classification and description of the species; a summary of the biology and ecology; details regarding pest management, which include scouting-/monitoring methods, action threshold, cultural (non-chemical) methods, natural enemies, and chemical control. In addition, a concluding paragraph is presented on insect pest management for tobacco.</abstract>

Principal Insects Affecting Tobacco Plants in the Field

<abstract>
<title style='display:none'>Abstract</title>
This article is a historical review and a vision for the future of tobacco plant research. This is the perspective of an experienced tobacco scientist who devoted his total professional career to tobacco research. From the very beginning, pioneering tobacco research was the foundation of plant science at the dawn of modern development, in such areas as light, nutrition, genetics, growth control, disorders and metabolism. Tobacco research led to current advancements in plant biotechnology. In addition, tobacco plant research contributed significantly to public health research in radioactive elements, mycotoxins, and air pollutants. However, public support for tobacco research has today greatly declined to almost total elimination because of a sense of political correctness. This author points out that tobacco is one of the most valuable research tools, and is a most abundant source of scientific information. Research with tobacco plants will contribute far beyond the frontiers of agricultural science: tobacco can be a source of food supply with nutrition value similar to that of milk; tobacco can be a source of health supplies including medical chemicals and various vaccines; tobacco can be a source of biofuel. All we need is to treat tobacco with respect; the use of tobacco is only in its initial stages.
</abstract>

Tobacco Research and Its Relevance to Science, Medicine and Industry

<abstract>
<title style='display:none'>Abstract</title>
Plants from 64 <italic>Nicotiana</italic> species were sampled in the greenhouse in 1983 and 1984 and from the field in 1985 and 1986 for the purpose of developing a chemical profile of each species. Mature green leaves were harvested at flowering, freeze-dried and ground to pass a 1 mm screen prior to chemical analysis. In this study we report the type and amounts of nicotinoid alkaloids. Alkaloid values were determined by glass-capillary gas chromatography and were averaged over the two years for each environment. Both total alkaloids (mg g-1 dry weight) and the distribution (percentage composition) of nicotine, nornicotine, anabasine, and anatabine were highly correlated between years for greenhouse and field samples. Greenhouse and field data were highly correlated, although total-alkaloid levels were significantly higher from field-grown plants. All of the Nicotiana species tested contained a measurable alkaloid fraction (at least 10 µg g-1). There was a wide range in total-alkaloid levels with nearly a 200-fold difference among greenhouse-grown samples and a 400-fold difference among field-grown species. In general, total-alkaloid levels among the species were found to be relatively low. Eleven species were found to have a different alkaloid composition when green leaf and air-dried samples were compared. Evidence is presented for the association between alkaloid characteristics and the phylogenetic classification of the species in the genus.
</abstract>

Alkaloid Composition of the Nicotiana Species

<abstract>
<title style='display:none'>Summary</title>
The compositions of waterpipe tobaccos available for retail sale on the US market are relatively unknown compared with more popular products such as cigarettes. Indeed, the phrase “waterpipe tobaccos” is used only in some governmental regulations and in journal articles dealing with regulatory aspects of those products. Commercially, the terms “shisha”, “hookah tobaccos”, and “flavored tobaccos” are used. In addition to the differences in commercial terminology, there is also confusion about the composition of such tobaccos, with the term “waterpipe tobacco” also being applied to products on the market that do not contain enough glycerol to prevent combustion during use. Therefore, during the past several years, 40 samples of shisha products on the US market were sent to an ISO 17025 accredited laboratory for the determination of glycerol, propylene glycol, fructose, glucose, and sucrose, in addition to the usual tobacco analytes and water using the Karl Fischer method. Moreover, two surrogate samples of shisha tobacco, one based on flue-cured tobacco and the other based on dark air-cured tobacco, were analyzed by the same laboratory along with samples of the starting tobaccos. The main finding from these analyses was that there were two very different types of shisha tobaccos on the market. One type was based on dark air-cured tobacco and the other type was based on flue-cured tobacco. Among the brand-styles based on flue-cured tobacco, some had higher levels of glycerol and lower levels of added sugars than others that had higher added sugars and lower levels of glycerol. Another important point of differentiation was that the products based on dark air-cured tobacco had much smaller tobacco particle sizes than did those based on flue-cured tobacco. The results of this research as well as other research that will be presented in two subsequent reports showed that waterpipe tobaccos cannot be considered as a single product category. This is particularly true for the determination of emissions using the instrumentation specified in ISO 22486:2019 (Water pipe tobacco smoking machine — Definitions and standard conditions).
</abstract>

Waterpipe Tobaccos, Part I. Composition of Forty Brand-Styles of Contemporary Waterpipe Tobacco Available on the US Market in 2020–2022

<abstract>
<title style='display:none'>Summary</title>
Tobacco smoke consists of over 5000 chemical components, most of them are carcinogenic, respiratory toxicants, cardiovascular toxicants, addictive, etc. In 2006 the Working Group on Tobacco Control identified substances in tobacco smoke, which are harmful and potentially harmful for human health (Priority List) and encouraged the development of methods for the analysis of these components. This review focuses on the different methods of evaluation of harmful and potentially harmful components in tobacco smoke used by the International Agency for Research on Cancer (IARC) and the U.S. Food and Drug Administration (FDA) and furthermore on the official methods proposed by the World Health Organization (WHO) and the Cooperation Center for Scientific Research Relative to Tobacco (CORESTA) for analysing these constituents. The various methods for the determination of the substances in tobacco smoke included in the Priority List are compared. In addition, the different evaluation of components from the Priority List is presented. The authors hope that this review will acquaint readers with the harmful components in tobacco smoke. Also, that it will help accredited or scientific laboratories to compare the different methods and to choose appropriate methods depending on their laboratory equipment and laboratory chemicals available.
</abstract>

Summary of Regulatory Methods and Procedures for Determination of Harmful and Potentially Harmful Components in Tobacco Smoke

<abstract>
<title style='display:none'>Summary</title>
With the improvement of irrigation and transportation infrastructures, single tobacco cultivation has been converted into tobacco–vegetable double cultivation in Yunnan Province. High residual nitrogen (N) levels in soil before tobacco transplanting induced by the excessive N input during the vegetable cultivation season resulted in a reduction of economic income and the quality of flue-cured tobacco. Therefore, the objective of this paper is to describe the optimization of N management and to provide a better understanding of the mechanism of optimal N application rate on the economic benefit and quality of tobacco. A field experiment with six N application rates (0, 45, 60, 75, 90, and 105 kg N ha−1) was carried out with a randomized block design in 2021 and 2022 in Yunnan Province. The economic value and yield, intrinsic chemical and processing quality, leaf growth rate and agronomic characters were determined.
Compared with the currently recommended 105 kg N ha−1 rate, 75 kg N ha−1 significantly increased the total economic value and superior tobacco yields, improved the integrated grade of chemical compounds and resulted in leaf midrib proportions in an appropriate range. The total economic value positively correlated with the superior tobacco leaf yields (R2 = 0.91, p &lt; 0.001), while not with medium and inferior leaf yield. The daily leaf growth rate in prosperous growth stage significantly correlated with the yield of superior tobacco and reached its maximum at a N rate of 75 kg N ha−1. The sum of N application rate and soil residual N before transplanting correlated with the total economic value (R2 = 0.66, p &lt; 0.05) and superior leaf yield (R2 = 0.64, p &lt; 0.05), respectively. Based on the amount of soil residual N before transplanting, the optimal N application rate was 66 kg N ha−1 which was 39 kg N ha−1 lower than the currently recommended N rate (105 kg N ha−1). Our results highlighted that the technical consultants and farmers should adjust the N application rate appropriately according to the residual N amount before transplanting and optimize the water and fertilizer management especially in the prosperous growth stage. An optimized N rate is not only of economic benefit and the improvement of quality of tobacco cultivation, but also environment friendly.
</abstract>

Optimized Nitrogen Application Rate Significantly Increases Total Economic Value and Quality of Flue-Cured Tobacco due to the Improvement of Superior Tobacco Yield

<abstract>
<title style='display:none'>Summary</title>
<sec><title style='display:none'>Background</title>
Next generation of nicotine/tobacco products (NGPs) include electronic cigarettes (ECs), heated tobacco products (HTPs), oral nicotine pouches (NPs) and smokeless tobacco (SLT) products (in particular snus). These products commonly contain nicotine and are intended to replace combustible cigarettes (CCs) and thus can be regarded as tobacco harm reduction products. To fulfill this role, it is essential that nicotine, which has well established addictive properties, is not causally related to health risks upon chronic use.
</sec>
<sec><title style='display:none'>Objectives</title>
The purpose of this review is to evaluate the scientific literature to answer the question, whether nicotine is involved in the development of any diseases or disorders associated with the acute, short, mid- and long-term use of NGPs. Appropriate results from studies with nicotine replacement therapy (NRT) products (gum, patches, inhalers, lozenges) are included as reference basis for inferring the health effects of NGPs. Furthermore, suggestions for filling identified gaps and for avoiding or minimizing limitations and weaknesses in study design are provided.
</sec>
<sec><title style='display:none'>Methods</title>
Literature databases such as MEDLINE, Google Scholar and an in-house ABF library (containing about 180,000 articles) were searched for relevant articles. Furthermore, pertinent monographs (such as the US Surgeon General Reports) and recent reviews were screened for further publications. Inclusion criteria were: all human studies investigating the association between use (preferably chronic use) of the nicotine/tobacco products mentioned above and health effects, including diseases, disorders, changes in biomarkers of biological effect (BOBEs). <italic>In vivo</italic> (animal) and <italic>in vitro</italic> studies were also considered, provided effects of NGPs in the presence and absence of nicotine or in relation to the nicotine exposure dose were reported. Also, reference lists of recent suitable articles were screened. In total, about 500 articles were retrieved by this approach. The role of nicotine was evaluated by considering the article authors’ statements and their cited references as well as by own judgement of reported results. Human studies are presented in a standardized table format.
</sec>
<sec><title style='display:none'>Results</title>
In total, 183 human studies were evaluated, with cardiovascular diseases (CVD) ranking highest (N = 75 studies), followed by respiratory diseases (43), oral health disorders (23), cancer (10), metabolic syndrome (7), reproduction disorders (5) and several other diseases (&lt; 5). The majority of studies do not provide evidence for a participation of nicotine in the pathogenesis. Some (weak) evidence was found that nicotine might be involved in some CVD-related effects and metabolic syndrome. This would be also supported by results from animal and <italic>in vitro</italic> studies.
</sec>
<sec><title style='display:none'>Discussion</title>
Human studies showed some severe limitations and weaknesses with respect to the study design and time of availability of NGPs on the market. A severe flaw is the insufficient consideration of dual use (NGP + CC), particularly in studies on chronic use, which could have led to erroneously increased risks for NGPs with direct consequences also for the role of nicotine. Additionally, prior effects from using CC have an impact. Both circumstances could have led to inaccurate conclusions in terms of elevated risk levels, which require changes in method designs. Suggestions for methodological improvements are provided for future studies.
</sec>
<sec><title style='display:none'>Conclusions</title>
A final evaluation of the role of nicotine in disease development in NGP users is currently not possible because use durations are too short. Chronic studies often suffer from insufficient separation between NGP only and dual use together with CCs, which may falsely increase the observed health risk. There is some limited evidence that nicotine may be involved in CVD-related effects, which, however, has to be verified in well controlled long-term studies. The potential involvement of nicotine in other patho-mechanisms also requires further research.
</sec>
</abstract>

Literature Review on Nicotine’s Role in Human Health

<abstract>
<title style='display:none'>SUMMARY</title>
<sec>
<title style='display:none'>Background</title>
In recent years several nicotine products have been introduced that aim to offer smokers an alternative to cigarettes. As well as having fewer toxicants than combustible cigarettes, such nicotine products must be able to deliver nicotine efficiently. The aim of this study was to determine and compare the pharmacokinetics of nicotine absorption from nine oral tobacco-free smokeless nicotine pouches with varying nicotine content and flavours.
</sec>
<sec>
<title style='display:none'>Methods</title>
In a randomised, open-labelled, controlled, crossover clinical study, nicotine pharmacokinetics and product-liking were compared between nine nicotine pouches (<italic>Velo</italic>, BAT; 4- or 7-mg nicotine per pouch and in eight flavours). During a 10-day confinement period, 42 healthy adult participants, who were current smokers of combustible cigarettes, used a single study product once each day during a 45-min use period following overnight nicotine abstinence.
</sec>
<sec>
<title style='display:none'>Results</title>
Maximum plasma nicotine concentration and area under curve for nicotine concentration <italic>versus</italic> time 180 min after the start of study product use were significantly greater for the 7-mg than for the 4-mg <italic>Velo</italic> pouches <italic>(p</italic> &lt; 0.0001). These values did not differ between flavours among the 7-mg <italic>Velo</italic> nicotine pouches after adjustment for multiple comparisons (both <italic>p</italic> &gt; 0.003). The median time to maximum plasma nicotine concentrations and mean product-liking scores were similar regardless of nicotine content and flavour.
</sec>
<sec>
<title style='display:none'>Conclusions</title>
Regardless of flavour, nicotine pouches with the same nicotine content and formulation produce similar pharmacokinetic parameters and can deliver nicotine efficiently. Nicotine pouches could be a satisfying alternative for smokers switching from conventional cigarettes. [Contrib. Tob. Nicotine Res. 32 (2023) 130–139]
</sec>
</abstract>

Plasma Nicotine Pharmacokinetics of Oral Nicotine Pouches Across Varying Flavours and Nicotine Content *

Editors’ Note

<abstract><title style='display:none'>Abstract</title>A new reference cigarette, the 3R4F, has been developed to replace the depleting supply of the 2R4F cigarette. The present study was designed to compare mainstream smoke chemistry and toxicity of the two reference cigarettes under the International Organization for Standardization (ISO) machine smoking conditions, and to further compare mainstream smoke chemistry and toxicological activity of the 3R4F cigarette by two different smoking regimens, i.e., the machine smoking conditions specified by ISO and the Health Canada intensive (HCI) smoking conditions.The <italic>in vitro</italic> cytotoxicity and mutagenicity was determined in the neutral red uptake assay, the <italic>Salmonella</italic> reverse mutation assay, and the mouse lymphoma thymidine kinase assay. Additionally, a 90-day nose-only inhalation study in rats was conducted to assess the <italic>in vivo</italic> toxicity. The comparison of smoke chemistry between the two reference cigarettes found practically the same yields of total particulate matter (TPM), ‘tar’, nicotine, carbon monoxide, and most other smoke constituents. For both cigarettes, the <italic>in vitro</italic> cytotoxicity, mutagenicity, and <italic>in vivo</italic> toxicity showed the expected smoke-related effects compared to controls without smoke exposure. There were no meaningful differences between the 2R4F and 3R4F regarding these toxicological endpoints. The assessments for the 3R4F cigarette by smoking regimen found as a trivial effect, due to the higher amount of smoke generated per cigarette under HCI conditions, an increased yield of toxicant and higher toxicological activity per cigarette. However, per mg TPM, ‘tar’, or nicotine, the amounts of toxicants and the <italic>in vitro</italic> toxicity were generally lower under HCI conditions, but the <italic>in vivo</italic> activity was not different between the two machine smoking conditions. Overall, as the main result, the present study suggests equivalent smoke chemistry and <italic>in vitro</italic> and <italic>in vivo</italic> toxicity for the 2R4F and 3R4F reference cigarettes.</abstract>

Philip Morris International Operations, Philip Morris Products S.A., Rue des Usines 90, 2000 Neuchâtel, Switzerland

Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Fuggerstr. 3, 51149 Cologne, Germany

Histovia GmbH, SchoeneAussicht 5, 51491 Overath, Germany

Philip Morris International R&D, Philip Morris Research Laboratories bvba, Grauwmeer 14, 3001 Leuven, Belgium

Mainstream Smoke Chemistry and <italic>in Vitro</italic> and <italic>In Vivo</italic> Toxicity of the Reference Cigarettes 3R4F and 2R4F

Letters to the Editor - Tobacco smoke components

<abstract><title style='display:none'>Abstract</title>A new reference cigarette, 2R4F, has been designed to replace the 1R4F Kentucky reference cigarette. This new cigarette has virtually the same blend composition as the 1R4F cigarette. However, the 1R4F cigarette was made in 1983 and the variation in the tobacco from crop year to crop year as well as the difference in the age of the two cigarettes were expected to generate differences in the smoke chemistry. A study done for the quantitation of more than 44 analytes in smoke, including most compounds considered as biologically active, is presented in this report. The analyses were performed by six independent laboratories using a variety of analytical techniques. The smoking was performed using International Standard (ISO) recommendations. The results showed only small differences between the two cigarettes regarding ‘tar', nicotine and carbon monoxide (CO), as well as for aminonaphthalenes, resorcinol, and some aldehydes. Although the two reference cigarettes were made as close as possible, the concentrations of a significant number of analytes in the smoke differed between 10% to 30%. Specific trace compounds in the blend such as metals and tobacco specific nitrosamines (TSNA), which may influence the smoke composition, were also different between the two cigarettes. The level of lead, in particular, was very different in tobacco between 1983 and 2002.</abstract>

Mainstream Smoke Chemical Analyses for 2R4F Kentucky Reference Cigarette

<abstract><title style='display:none'>Abstract</title>Tobacco and tobacco smoke are both complex mixtures. We previously reported 8430 unique chemical components identified in these complex mixtures but two years later our updated number was 8889. Addition of unlisted isomers raised these numbers to 8622 and 9081, respectively. Our previous number of 4994 identified tobacco components is now 5229; our previous number of 5315 identified tobacco smoke components is now 5685. An operational definition of a complex mixture is as follows: A complex mixture is a characterizable substance containing many chemical components (perhaps thousands) in inexact proportions.Detailed knowledge of the amount and type of each component within the substance is uncertain even with today's analytical technology. Although it has been estimated that as many as 100000 components are present in these complex mixtures, their analyses indicate that the vast majority of the mass of each of these complex mixtures accounts for the 8430 compounds reported previously. Over 98.7% of the mass of tobacco has been accounted for in terms of identified components in tobacco. Greater than 99% of the mass of whole smoke has been accounted for based on identified chemical components. Certainly, many more tobacco and tobacco smoke components are present in these complex mixtures but the total mass of these components obviously is quite small.One of the significant challenges we face as a scientific community is addressing the problems of determining the risk potential of complex mixtures. Many issues are associated with toxicological testing of the complex mixture of tobacco smoke. Conducting valid experiments and interpreting the results of those experiments can be quite difficult. Not only is the test agent a complex mixture but also the tests are performed on species that have complicated life-processes. Interpretations of test results are often paradoxical. Significant progress has been made in the toxicological evaluations of complex mixtures in the last 80 years. The challenges we face in terms of testing the biological properties of tobacco smoke are substantial. The statement by DIPPLE et al. in their summary of the research on polycyclic aromatic hydrocarbons from the 1930s through 1980 is equally true today for the cigarette smoke situation:…many important questions remain unanswered…many questions persist despite the considerable progress that has been made.</abstract>

Perfetti and Perfetti, LLC, 2116 New Castle Drive, Winston-Salem, NC 27103-5750, USA

2828 Birchwood Drive, Winston-Salem, NC 27103-3410, USA

The Complexity of Tobacco and Tobacco Smoke

<abstract><title style='display:none'>Abstract</title>These are curious times. The Canadian government has passed legislation that requires cigarette manufacturers to routinely test and publish the amounts of 44 toxic substances in cigarette mainstream smoke (MSS). Following in the footsteps of their northern neighbor, various US legislators and regulators are considering modifications to their cigarette testing and reporting programs that will also list toxicants in MSS. Across the Atlantic Ocean, the European Commission has passed a directive that may also follow the North American lead for public disclosure of MSS toxic chemicals for each brand of cigarette sold in the marketplace. United Kingdom authorities have also expressed their intention to follow this mandate.It is difficult to understand the motivation and value of these existing or potentially forthcoming legislative actions. Although there is nearly total agreement among the world's scientists that cigarette smoking is a health hazard, few are bold enough to say with credibility which smoke chemicals or classes of chemicals are responsible for the adverse effects. Therefore, if the specialists are unable to interpret the smoke toxicant data, how is the general public to use their newfound knowledge?The posting of smoke chemical toxicant data is also problematic for the Tobacco Industry for several reasons. First, no standard analytical methods exist for most suspected toxicants. Second, the listing of smoke toxicant yields may ignite a 21st Century version of the ‘tar’ wars in the USA during the 1960s; we have already seen evidence of such competition beginning in the US. Third, and most important of all, no one knows whether or not reducing the yield of one or more publicized MSS toxicant will result in a ‘less hazardous’ cigarette.Assuming that the current situation is approximately as described above, the authors of this paper critically examined the existing lists of MSS toxicants. They discarded chemicals that are no longer relevant, e.g., DDT, N-nitrosodiethanolamine, added known smoke constituents that are glaringly absent, e.g., dioxins, and replaced the existing 1950-60s era nonfiltered cigarette MSS yields with those more representative of the present-day marketplace. Data for the Kentucky reference 1R4F cigarette smoked under standardized smoking conditions, i.e., those established by the International Organization for Standardization (ISO) and the Federal Trade Commission (FTC), are used as a surrogate for the modern-day cigarette whenever possible.A list of smoke toxicants and their approximate concentrations in today's cigarettes is nearly useless without an appropriate ranking of their relative toxicity. Unfortunately, the toxicological data for ranking importance are available for fewer than 5% of the approximately 4800 reported smoke constituents. Although neither of this paper's authors presumes to be a toxicologist, we cite in our discussion several published attempts at ranking smoke toxicants. Specifically, ranking by US Occupational Safety and Health Administration (OSHA) permissible workplace exposure levels, use of US Environmental Protection Agency (EPA) toxicity criteria supplemented with California EPA criteria, and use of the Human Exposure - Rodent Potential methodology and database developed by AMES et al. when data are available. There appears to be a wide divergence in the permissible exposures allowable in the workplace and those advocated by environmental regulators. Thus, it is expected that rankings such as those presented herein will ultimately form the basis of MSS toxic chemical prioritization for either attempts at reduction by product developers or development of standardized analytical methods.This review of MSS toxicants also explores the limitations of toxicological evaluations. The toxicity data used in the above ranking are derived wholly from studies of pure compounds. It is highly improbable that extrapolation of bioassay results determined on an individual compound to that compound when it is a component of a mixture as complex as cigarette MSS is valid. For example, several decades of research involving numerous investigators reported that the benzo[a]pyrene (BaP) content of cigarette smoke condensate (CSC) accounts for only a few percent of the tumor-bearing animals in the skin-painting bioassay. Subsequently they asserted that the tumorigenic polycyclic aromatic hydrocarbons (PAHs) in CSC could account for no more than 3 to 4% of the tumor-bearing animals. Inclusion of promoters, e.g., phenols, raises the level to about 5%. However, several of the same investigators recently claimed that BaP is one of two smoke components responsible for lung cancer in cigarette smokers.While much is written about the hundred or so toxic components in cigarette smoke, little is published about the numerous nontoxic smoke components that have been shown in various bioassays to counteract the effects of the toxic ones. In some cases the inhibiting components are also listed as toxic, e.g., nicotine inhibits the mutagenicity of N-nitrosodimethylamine; the promoter phenol inhibits the tumorigenicity of BaP; the weakly tumorigenic benz[a]anthracene negates the potent tumorigenicity of BaP. On a one-to-one molar basis, many bicyclic, tricyclic, and tetracyclic nontumorigenic PAHs counteract the tumorigenicity of BaP and dibenz[a,h]anthracene.To further illustrate this murky toxicological situation, the history and current knowledge of the importance of tobacco-specific nitrosamines (TSNAs) to the hazards of smoking is reviewed. In brief, these compounds were discovered in tobacco products and found to transfer to MSS (and sidestream smoke). Toxicological evaluations on the pure compounds demonstrated that they are potent carcinogens. Some public health scientists believed that if the levels of TSNAs could be reduced or lowered in MSS, then this would lead to a ‘less hazardous’ cigarette. Once given this assignment, agronomists discovered that at least for flue-cured tobaccos, the levels of TSNAs can be greatly reduced through the use of indirect heating in the curing barns. This was wonderful news. However, toxicologists soon conducted experiments comparing the toxicity of MSS from flue-cured cigarettes containing high and ultra-low concentrations of TSNAs. It must have been a surprise to these investigators when they could find no significant difference between the toxicities of the two smokes.Some public health scientists have asserted that the reduction of the per cigarette ‘tar’ delivery below 15 mg/cig does not reduce the risk from smoking because of the hazard resulting from the higher levels of additives used to maintain consumer acceptability. Although no data in support of this assertion have ever been offered, much data generated during the past decade contradict the assertion. Ingredient addition at the usual level or at levels several times greater than normal does produce some minor changes in the smoke chemistry, but these changes do not result in any adverse biological response as measured in various bioassays to determine mutagenicity, tumorigenicity, etc.From our review of the literature gathered to prepare this paper, we have come to several conclusions. These include the following:1. It is possible to prepare a list of the known toxicants in MSS and to prioritize some of them based upon existing biological data. However, for more than 95% of the known constituents in MSS, there are no biological data.2. Even if there were biological data for most MSS components, extrapolation of this pure-compound knowledge to the biological properties of a mixture containing them is beyond our scientific ability.3. At our current state of scientific knowledge, no one will ever be able to legitimately claim the development of a ‘less hazardous’ cigarette based solely on the reduction of known toxic chemicals in MSS.4. The approach of reducing ‘tar’ yields of cigarettes appears in retrospect to be the most practical means of producing a ‘less hazardous’ cigarette, because when product developers reduce ‘tar', both the known and unknown toxicants are reduced.5. The ranked toxicants in MSS contain both gas-phase and semi-volatile constituents that appear to be important determinants of toxicity. Some of these constituents, e.g., N-nitrosodimethylamine, phenols, are reduced by triacetin-plasticized cellulose acetate filters. These filters also reduce ‘tar'. Additionally, it is well known that charcoal-containing filters have a high efficiency for removing carbonyl compounds from MSS. Development of more consumer-acceptable products that reduce gas-phase toxicants appears to be another route to a ‘less hazardous’ cigarette.</abstract>

2828 Birchwood Drive, Winston-Salem, North Carolina, 27103-3410, USA

430 Burkeridge Court, Winston-Salem, North Carolina, 27104-2602, USA

Toxic Chemicals in Cigarette Mainstream Smoke - Hazard and Hoopla

Guidelines for Reviewers

Instruction for Authors

Publication Ethics Statement

Review Process

Complete Contents

Contributions to Tobacco & Nicotine Research

Formerly: Beiträge zur Tabakforschung International

Contributions to Tobacco and Nicotine Research (formerly: Beiträge zur Tabakforschung International / Contribution to Tobacco Research International) publishes articles with a focus on tobacco,...

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Contributions to Tobacco and Nicotine Research (formerly: Beiträge zur Tabakforschung International / Contribution to Tobacco Research International)...