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      The Toxic Effects of Cigarette Additives. Philip Morris' Project Mix Reconsidered: An Analysis of Documents Released through Litigation

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          Abstract

          Stanton Glantz and colleagues analyzed previously secret tobacco industry documents and peer-reviewed published results of Philip Morris' Project MIX about research on cigarette additives, and show that this research on the use of cigarette additives cannot be taken at face value.

          Abstract

          Background

          In 2009, the promulgation of US Food and Drug Administration (FDA) tobacco regulation focused attention on cigarette flavor additives. The tobacco industry had prepared for this eventuality by initiating a research program focusing on additive toxicity. The objective of this study was to analyze Philip Morris' Project MIX as a case study of tobacco industry scientific research being positioned strategically to prevent anticipated tobacco control regulations.

          Methods and Findings

          We analyzed previously secret tobacco industry documents to identify internal strategies for research on cigarette additives and reanalyzed tobacco industry peer-reviewed published results of this research. We focused on the key group of studies conducted by Phillip Morris in a coordinated effort known as “Project MIX.” Documents showed that Project MIX subsumed the study of various combinations of 333 cigarette additives. In addition to multiple internal reports, this work also led to four peer-reviewed publications (published in 2001). These papers concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied. Internal documents revealed post hoc changes in analytical protocols after initial statistical findings indicated an additive-associated increase in cigarette toxicity as well as increased total particulate matter (TPM) concentrations in additive-modified cigarette smoke. By expressing the data adjusted by TPM concentration, the published papers obscured this underlying toxicity and particulate increase. The animal toxicology results were based on a small number of rats in each experiment, raising the possibility that the failure to detect statistically significant changes in the end points was due to underpowering the experiments rather than lack of a real effect.

          Conclusion

          The case study of Project MIX shows tobacco industry scientific research on the use of cigarette additives cannot be taken at face value. The results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes, including the level of TPM. In particular, regulatory authorities, including the FDA and similar agencies elsewhere, could use the Project MIX data to eliminate the use of these 333 additives (including menthol) from cigarettes.

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          The tobacco industry in the United States has recognized that regulation of its products was inevitable as early as 1963 and devoted increasing attention to the likelihood of regulation by the US Food and Drug Administration in the mid-1990s, which finally became law in 2009. In addition, the World Health Organization (WHO) Framework Convention on Tobacco Control (WHO FCTC), which came into force in June 2003, includes provisions addressing the regulation of the contents of tobacco products and the regulation of tobacco product disclosures. Although these steps represent progress in tobacco control, the events of the past few decades show the determination of the tobacco industry to avoid regulation, including the regulation of additives. In the United States, executives of the tobacco company Philip Morris (PM) recognized the inevitability of regulation and responded by initiating efforts to shape legislation and regulation by reorganizing its internal scientific activities and conducting scientific research that could be used to shape any proposed regulations. For example, the company conducted “Project MIX,” a study of chemical constituents in and toxicity of smoke produced by burning cigarettes containing three different combinations of 333 cigarette additives that “were constructed to resemble typical commercial blended cigarettes.” The resulting four papers published in Food and Chemical Toxicology in January 2002 concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied.

          Why Was This Study Done?

          The use of cigarette additives is an important concern of the WHO, FDA, and similar national regulatory bodies around the world. Philip Morris has used the published Project MIX papers to assert the safety of individual additives and other cigarette companies have done similar studies that reached similar conclusions. In this study, the researchers used documents made public as a result of litigation against the tobacco industry to investigate the origins and design of Project MIX and to conduct their own analyses of the results to assess the reliability of the conclusions in the papers published in Food and Chemical Toxicology.

          What Did the Researchers Do and Find?

          The researchers systematically examined tobacco industry documents in the University of California San Francisco Legacy Tobacco Documents Library (then about 60 million pages made publicly available as a result of litigation) and used an iterative process of searching, analyzing, and refining to identify and review in detail 500 relevant documents.

          The researchers found that in the original Project MIX analysis, the published papers obscured findings of toxicity by adjusting the data by total particulate matter (TPM) concentration. When the researchers conducted their own analysis by studying additives per cigarette (as was specified in the original Project MIX protocol), they found that 15 carcinogenic chemicals increased by 20%. The researchers also reported that, for unexplained reasons, Philip Morris deemphasized 19 of the 51 chemicals tested in the presentation of results, including nine that were substantially increased in smoke on a per cigarette basis of additive-added cigarettes, compared to smoke of control cigarettes.

          The researchers explored the possibility that the failure of Project MIX to detect statistically significant changes in the toxicity of the smoke from cigarettes containing the additives was due to underpowered experiments rather than lack of a real effect by conducting their own statistical analysis. This analysis suggests that a better powered study would have detected a much broader range of biological effects associated with the additives than was identified in Philip Morris' published paper, suggesting that it substantially underestimated the toxic potential of cigarette smoke and additives.

          The researchers also found that Food and Chemical Toxicology, the journal in which the four Project MIX papers were published, had an editor and 11 of its International Editorial Board with documented links to the tobacco industry. The scientist and leader of Project MIX Edward Carmines described the process of publication as “an inside job.”

          What Do These Findings Mean?

          These findings show that the tobacco industry scientific research on the use of cigarette additives cannot be taken at face value: the results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes. In addition, better powered studies would probably have detected a much broader range of adverse biological effects associated with the additives than identified to those identified in PM's published papers suggesting that the published papers substantially underestimate the toxic potential combination of cigarette smoke and additives.

          Regulatory authorities, including the FDA and similar agencies elsewhere who are implementing WHO FCTC, should conduct their own independent analysis of Project MIX data, which, analyzed correctly, could provide a strong evidence base for the elimination of the use of the studied additives (including menthol) in cigarettes on public health grounds.

          Additional Information

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001145.

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          Most cited references 64

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          Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: shape of the exposure-response relationship.

          Fine particulate matter exposure from both ambient air pollution and secondhand cigarette smoke has been associated with larger risks of cardiovascular mortality than would be expected on the basis of linear extrapolations of the relative risks from active smoking. This study directly assessed the shape of the exposure-response relationship between cardiovascular mortality and fine particulates from cigarette smoke and ambient air pollution. Prospective cohort data for >1 million adults were collected by the American Cancer Society as part of the Cancer Prevention Study II in 1982. Cox proportional hazards regression models that included variables for increments of cigarette smoking and variables to control for education, marital status, body mass, alcohol consumption, occupational exposures, and diet were used to describe the mortality experience of the cohort. Adjusted relative risks of mortality were plotted against estimated average daily dose of fine particulate matter from cigarette smoke along with comparison estimates for secondhand cigarette smoke and air pollution. There were substantially increased cardiovascular mortality risks at very low levels of active cigarette smoking and smaller but significant excess risks even at the much lower exposure levels associated with secondhand cigarette smoke and ambient air pollution. Relatively low levels of fine particulate exposure from either air pollution or secondhand cigarette smoke are sufficient to induce adverse biological responses increasing the risk of cardiovascular disease mortality. The exposure-response relationship between cardiovascular disease mortality and fine particulate matter is relatively steep at low levels of exposure and flattens out at higher exposures.
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            Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke.

             J V Fowles,  E Dybing (2003)
            To provide a hazard prioritisation for reported chemical constituents of cigarette smoke using toxicological risk assessment principles and assumptions. The purpose is to inform prevention efforts using harm reduction. International Agency for Research on Cancer Monographs; California and US Environmental Protection Agency cancer potency factors (CPFs) and reference exposure levels; scientific journals and government reports from the USA, Canada, and New Zealand. This was an inclusive review of studies reporting yields of cigarette smoke constituents using standard ISO methods. Where possible, the midpoint of reported ranges of yields was used. Data on 158 compounds in cigarette smoke were found. Of these, 45 were known or suspected human carcinogens. Cancer potency factors were available for 40 of these compounds and reference exposure levels (RELs) for non-cancer effects were found for 17. A cancer risk index (CRI) was calculated by multiplying yield levels with CPFs. A non-cancer risk index (NCRI) was calculated by dividing yield levels with RELs. Gas phase constituents dominate both CRI and NCRI for cigarette smoke. The contribution of 1,3-butadiene (BDE) to CRI was more than twice that of the next highest contributing carcinogen (acrylonitrile) using potencies from the State of California EPA. Using those potencies from the USEPA, BDE ranked third behind arsenic and acetaldehyde. A comparison of CRI estimates with estimates of smoking related cancer deaths in the USA showed that the CRI underestimates the observed cancer rates by about fivefold using ISO yields in the exposure estimate. The application of toxicological risk assessment methods to cigarette smoke provides a plausible and objective framework for the prioritisation of carcinogens and other toxicant hazards in cigarette smoke. However, this framework does not enable the prediction of actual cancer risk for a number of reasons that are discussed. Further, the lack of toxicology data on cardiovascular end points for specific chemicals makes the use of this framework less useful for cardiovascular toxicity. The bases for these priorities need to be constantly re-evaluated as new toxicology information emerges.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                December 2011
                December 2011
                20 December 2011
                : 8
                : 12
                Affiliations
                [1 ]Center for Tobacco Control Research and Education, University of California San Francisco, San Francisco, California, United States of America
                [2 ]Department of Social and Behavioral Sciences, School of Nursing, University of California San Francisco San Francisco, California, United States of America
                [3 ]Thoracic Surgery, Schillerhoehe Hospital, Gerlingen, Germany
                [4 ]Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
                London School of Hygiene & Tropical Medicine, United Kingdom
                Author notes

                Conceived and designed the experiments: SAG. Analyzed the data: MSW TK SP SAG. Contributed reagents/materials/analysis tools: SAG. Wrote the first draft of the manuscript: MSW SP. Contributed to the writing of the manuscript: MSW TK SP SAG. ICMJE criteria for authorship read and met: MSW TK SP SAG. Agree with manuscript results and conclusions: MSW TK SP SAG.

                Article
                PMEDICINE-D-10-00854
                10.1371/journal.pmed.1001145
                3243707
                22205885
                Wertz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 15
                Categories
                Research Article
                Medicine
                Public Health
                Tobacco Control
                Toxicology
                Toxic Agents
                Science Policy
                Research Integrity
                Technology Regulations

                Medicine

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