<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'>SUMMARY</title>The objective of this review is to support tobacco scientists when evaluating information published on smoking machines, and on cigarette mainstream smoke (<italic>in vivo</italic> and <italic>in vitro</italic>) exposure systems and collection devices.The intriguing development of smoking machines (mainly for cigarettes) is followed for more than 170 years - from the first simple set-ups in the 1840s to the sophisticated and fully automated analytical smoking machines available today. Systems for the large-scale production of smoke (condensate) for preparative work are equally considered. The standardization of machine smoking methods and test pieces has solved several technical problems and produced sensible rules but, at the same time, given rise to new controversies like the compatibility of artificial and human smoking, and the implementation of more intense machine smoking regimes.Adequate space is allotted for the discussion of configurations for <italic>in vivo</italic> smoke exposure of rodent and non-rodent species and the machines generating the required smoke (condensate). Covered as well is the field of <italic>in vitro</italic> toxicity testing, including the increasingly informative new techniques of air-liquid interface exposure, which are becoming more and more refined with the use of organotypic cultures and genetic analyses.The review is completed by the examination of the considerable variety of mainstream smoke collection devices (filters and traps) developed over time - some for very specific purposes - and refers to the perpetual problem of artifact formation by aging.</abstract>

Beiträge zur Tabakforschung International, Chausseestraße 51A, 10115 Berlin,

Cigarette Mainstream Smoke: The Evolution of Methods and Devices for Generation, Exposure and Collection

<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'>Summary</title>A new safe and sensitive method to determine hydrogen cyanide (HCN) in cigarette smoke using continuous flow analyser (CFA) has been developed and validated. The use of highly toxic potassium cyanide (KCN) as a standard necessitates the development of a safer method for the determination of HCN in cigarette smoke. In this described method KCN is replaced by less toxic potassium tetracyanozincate (Lethal Dose LD50 oral is 7.49 mg/kg for KCN and 2000 mg/kg for potassium tetracyanozincate). Furthermore, the new method uses isonicotinic acid-barbituric acid (coupling reagent) instead of pyridine-pyrazolone as a reagent for the determination of HCN, and hence eliminates the use of pyridine. In this method HCN is trapped on both the Cambridge Filter Pad, then extracted with aqueous sodium hydroxide solution, and in an impinger containing the same solution. The solution thus extracted is oxidised to cyanogen chloride by Chloramine-T and treated with coupling reagent, the resulting stable chromophore was measured colorimetrically at 600 nm. The regression equation was linear in the range of 1 to 25 μg/mL for cyanide with a correlation coefficient (R2) &gt; 0.9998. The limit of detection (LOD) was 0.76 μg/cig and the overall relative standard deviation (RSD) of the method was less than 10%. Excellent recoveries of cyanide were obtained in the range from 92% to 112% and the HCN yields from the Kentucky Reference Cigarette 3R4F obtained from the newly developed method are in good agreement with those from the conventional KCN method. The proposed method is robust, reliable, selective and safer than any of the existing methods for determination of hydrogen cyanide in mainstream as well as in sidestream cigarette smoke.</abstract>

Determination of Hydrogen Cyanide in Cigarette Smoke by Continuous Flow Analysis Method Using Safer Chemistry

<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

Dr. J. Michael Moore, Recipient of the 2023 Tobacco Science Research Conference Lifetime Achievement Award

<abstract>
<title style='display:none'>SUMMARY</title>
The airtightness of heated tobacco product (HTP) packs is a very important indicator for the product quality and is also of great importance during the conditioning process. A method for evaluation of the airtightness was developed based on the air pressure difference in a constant pumping configuration. The essential feature of this method is that the pressure difference between the inside and the outside of the HTP packs during the deflation process is used to characterize the sealing quality of HTP packs. The detailed setup, the principle as well as the determination procedure are described. The accuracy and the repeatability of the method were assessed, and the effect of airtightness on the conditioning process was also investigated. The developed method is proven to be reliable with a standard deviation less than 0.09 kPa and repeatability less than 0.30 kPa. In addition, it was found that, although the transmission of moisture between HTPs and atmosphere could not be entirely prevented by the packs, airtightness still plays a significant role during the conditioning process, especially if the airtightness was at a relatively low level (e.g., lower than 1.5 kPa under a pumping flow rate of 200 mL/min). The method provides a promising way to assess and monitor the sealing quality of HTP packs, and it is suggested that the airtightness of the pack should not be lower than 2 kPa under a pumping flow rate of 200 mL/min. [Contrib. Tob. Nicotine Res. 32 (2023) 140–145]
</abstract>

A Pumping Method for Assessing Airtightness of Packs - Application to Heated Tobacco Products *

<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 *

<abstract>
<title style='display:none'>SUMMARY</title>
Heated tobacco products (HTPs) are a recent category of tobacco products, with their relative safety compared to cigarette smoking and potential to help smokers to quit being two reasons why regulators may consider their market approval. Designed to heat tobacco rather than to burn in order to produce aerosol, different heating techniques are applied to commercial HTPs, which may result in differing aerosol formation. Therefore, each product requires separate assessment. This work focuses on a closed-end HTP (coded as HTP-A), which is electrically heated and designed to allow puffing air flow to bypass its tobacco section, resulting in reduced oxygen concentration within the tobacco section during heating and aerosol forming. To provide a preliminary aerosol chemistry and <italic>in vitro</italic> toxicological screening, this study assessed HTP-A against a commercial electrically heated HTP (IQOSTM, coded as HTP-B) and a 3R4F reference cigarette. Under Health Canada Intense (HCI) smoking regime, the levels of 9 regulatory priority toxicants in the aerosol of HTP-A were either reduced or comparable to those in HTP-B on a per-stick basis. Additionally, both HTPs showed significant reduction (greater than 90%) in comparison to those measured in mainstream smoke of 3R4F cigarette for these toxicants. Using a set of standard <italic>in vitro</italic> toxicological assays (Ames, Micronucleus and Neutral Red Uptake), the two HTPs showed no observable responses while significant toxicity responses were recorded for 3R4F’s total particulate matter. Based on these preliminary results, the novel closed-end HTP-A design may provide similar toxicological profiles to the comparator HTP-B. Further toxicological and clinical assessments are warranted to evaluate HTP-A’s potential for exposure or disease risk reduction. [Contrib. Tob. Nicotine Res. 32 (2023) 146–156]
</abstract>

A Comparative <italic>In Vitro</italic> Toxicological Screening of a Closed-End Heated Tobacco Product *

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

<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

Guidelines for Reviewers

Instruction for Authors

Publication Ethics Statement

Review Process

Complete Contents