Tobacco papers and tobacco industry ties in Regulatory Toxicology and Pharmacology

Abstract

We examined the relationship between the tobacco industry and the journal Regulatory Toxicology and Pharmacology (RTP) using the Truth Tobacco Industry Documents Library and internet sources. We determined the funding relationships, and categorised the conclusions of all 52 RTP papers on tobacco or nicotine between January 2013 and June 2015, as “positive”, “negative” or “neutral” for the tobacco industry. RTP’s editor, 57% (4/7) of associate editors and 37% (14/38) of editorial board members had worked or consulted for tobacco companies. Almost all (96%, 50/52) of the papers had authors with tobacco industry ties. Seventy-six percent (38/50) of these papers drew conclusions positive for industry; none drew negative conclusions. The two papers by authors not related to the tobacco industry reached conclusions negative to the industry (p <.001). These results call into question the confidence that members of the scientific community and tobacco product regulators worldwide can have in the conclusions of papers published in RTP.

Introduction

Tobacco companies have a long history of funding and conducting research that supports their political, regulatory and legal positions [1–5]. In 1989, at a time when the movement to create smoke-free indoor environments was accelerating, the tobacco industry assisted in establishing the International Society of the Built Indoor Environment that, in turn, published the journal Indoor and Built Environment. These forces established an editorial board dominated by people who had financial associations with the tobacco industry (67% in 1992 and 66% in 2002) and in which 61% of the papers on tobacco smoke in the environment (that many people call ‘secondhand smoke’) supported industry positions [2]. The journal Regulatory Toxicology and Pharmacology (RTP), published by Elsevier on behalf of the International Society of Regulatory Toxicology and Pharmacology (ISTRP), has been criticised for ties to major industries, including tobacco by academics, public interest groups and journalists [6–9]. Indeed, in June 1999 the ISTRP held its June 1999 council meeting in the Washington, D.C. offices of Keller and Heckman, a major law firm that represents the chemical industry [8].

In 2002, a public interest nutrition policy advocacy organisation, the Center for Science in the Public Interest (CSPI), sent Elsevier a letter in which 43 scientists from around the world expressed concern about the journal’s ties to ISTRP and the composition of the journal’s editorial staff, particularly conflicts of interest, lack of transparency and the absence of editorial independence [6]. Specifically, the letter stated that the journal exhibited a “bias in favor of industries that are subject to governmental health and environmental regulations and that provide support to RTP’s sponsor, ISRTP”. The letter identified the American Chemistry Council, Bristol-Myers Squibb, Dow AgroSciences, Eastman Kodak, Gillette Company, Indspec Chemical Corporation, Merck and Co., Inc., Proctor and Gamble, RJ Reynolds Tobacco Company, The Sapphire Group, Inc., Schering Plough Research Institute and SmithKline Pharmaceuticals as companies or trade associations that had a direct incentive to minimise the regulatory burden on industry. CSPI also identified 16 specific members of the RTP editorial board with ties to industries. The letter requested that Elsevier make three changes at RTP: (1) sever its ties to the industry-sponsored ISRTP, (2) reconstitute its advisory board to dramatically reduce the influence of industry scientists, industry lawyers and academic consultants to industry and (3) adopt an editorial policy of transparency about conflicts of interest [6, 10].

In response to this letter, Elsevier improved disclosure requirements [10], but refused to make any changes to the editorial board, responding that “regulatory issues by their very nature affect industry and it is therefore only logical that editorial board members have ties to industry” and that “RTP’s relationship with the ISRTP has been and continues to be a productive one, and we have no intention of encouraging RTP to sever ties with the ISRTP” [6].

As of December, 2016, 8 of the 16 editors listed in the CSPI letter remained on the board [11].

Based on existing literature that had found tobacco [5, 12, 13] and other [14–19] industry-affiliated authors are more likely to find positive outcomes in articles evaluating tobacco, we (1) examined the tobacco affiliations of the RTP editorial board, (2) examined the author affiliation of papers on tobacco or nicotine published in RTP and (3) evaluated the conclusions of these papers as “positive”, “negative” or “neutral” with respect to the tobacco industry.

Methods

RTP editors and editorial board

As of June 2015, the journal’s website listed the editor-in-chief, 7 associate editors and 38 editorial board members [20]. We searched the University of California San Francisco Truth (formerly Legacy) Tobacco Documents Library (TTDL: http://industrydocuments.library.ucsf.edu/tobacco) for these 45 individuals to identify ties to the tobacco companies including full-time employment, contract work and compensation received. (“Ties” do not include indirect affiliation, such as shares in investment companies that have shares in tobacco, information that is not generally available publicly.) We also completed general web searches on these individuals to further identify ties to tobacco. And we identified relationships with industries other than the tobacco industry using general web sources, including SourceWatch.org, the Center for Science in the Public Interest, the individuals’ LinkedIn accounts, online biographies and reported research funding.

Tobacco-related papers published in RTP

We searched the RTP website on June 15, 2015 [20] for “tobacco” in papers published between January 2013 and June 2015. (We used this period of time because we started data collection for this project in June 2015 and wanted to include several years’ data to obtain an adequate sample size.) This search yielded 76 items; we excluded 24 from further analysis because they were not peer-reviewed papers (e.g. letters to the editor or responses) or not related to nicotine-containing products (cigarettes, ‘snus’ [a form of oral tobacco consisting of fine ground tobacco and additives in a teabag-sized pouch], electronic cigarettes, reduced harm products), policy, toxicity and/or their impact on health. We reviewed the remaining 52 papers to determine if the authors disclosed working for a tobacco company or a company consulting for the tobacco company, were funded by a tobacco company, had no obvious affiliations or where the situation was not clear. (Elsevier’s policy change on author disclosure made in response to the CSPI letter allowed us to determine these author affiliations.)

We scored the conclusions of the papers as “positive”, “neutral” or “negative” for the tobacco industry using two independent reviewers, then a third to resolve any differences. We scored conclusions “positive” for industry if they supported claims of lower risk for products, for cessation benefits or challenged conclusions of public health authorities on the dangers of tobacco products; as “negative” if conclusions challenged reduced risk claims or supported conclusions of public health authorities and as “neutral” where we found no clear positive or negative implications for industry positions. Of the 52 papers, the two initial reviewers agreed on scoring for 42 (81%) of the papers. Table 1 lists the 52 papers, links to the tobacco industry and scores.

Table 1.

Papers Related to Tobacco or Nicotine Published in Regulatory Toxicology and Pharmacology. January 2013 through June 2015

Year	Title	PMID	Tobacco industry link	Conclusion for tobacco industry
2013	Changes in levels of biomarkers of exposure and biological effect in a controlled study of smokers switched from conventional cigarettes to reduced toxicant prototype cigarettes	23537587	Yes	Positive
2013	Estimation of mouth level exposure to smoke constituents of cigarettes with different tar levels using filter analysis	24113618	Yes	Positive
2013	The effect of reducing the number of cigarettes smoked on risk of lung cancer, COPD, cardiovascular disease and FEV(1)-a review	24013038	Yes	Positive
2013	Aspects of the design protocol and the statistical methods for analysis of tar, nicotine and carbon monoxide yields in cigarette smoke that can affect the measurement variability within collaborative studies	23959062	Yes	Positive
2013	Good relationship between saliva cotinine kinetics and plasma cotinine kinetics after smoking one cigarette	23933006	Yes	Neutral
2013	A dynamic population model for estimating all-cause mortality due to lifetime exposure history	23933005	Yes	Positive
2013	TSNA exposure from cigarette smoking: 18 years of urinary NNAL excretion data	23920111	Yes	Positive
2013	Pharmacokinetic analysis of nicotine when using non-combustion inhaler type of tobacco product in Japanese adult male smokers	23891672	Yes	Neutral
2013	How rapidly does the excess risk of lung cancer decline following quitting smoking? A quantitative review using the negative exponential model	23764305	Yes	Neutral
2013	TSNA levels in machine-generated mainstream cigarette smoke: 35 years of data	23557986	Yes	Positive
2013	Physical harm due to chronic substance use	23542091	No	Negative
2013	Changes in levels of biomarkers of exposure observed in a controlled study of smokers switched from conventional to reduced toxicant prototype cigarettes	23537587	Yes	Positive
2013	Effect of puffing intensity on cigarette smoke yields	23523712	Yes	Positive
2013	The effect on health of switching from cigarettes to snus—a review	23454227	Yes	Positive
2013	The effect of long-term storage on tobacco smoke particulate matter in in vitro genotoxicity and cytotoxicity assays	23220485	Yes	Neutral
2013	A multi-route model of nicotine–cotinine pharmacokinetics, pharmacodynamics and brain nicotinic acetylcholine receptor binding in humans	23099439	Yes	Neutral
2014	Estimating the decline in excess risk of chronic obstructive pulmonary disease following quitting smoking—a systematic review based on the negative exponential model	24291341	Yes	Neutral
2014	Estimating the decline in excess risk of cerebrovascular disease following quitting smoking–a systematic review based on the negative exponential model	24291341	Yes	Neutral
2014	Health risks related to dual use of cigarettes and snus—a systematic review	24184647	Yes	Positive
2014	Toxicological assessment of kretek cigarettes: Part 1: background, assessment approach and summary of findings	25498000	Yes	Positive
2014	Toxicological assessment of kretek cigarettes: Part 2: kretek and American-blended cigarettes, smoke chemistry and in vitro toxicity	25497993	Yes	Positive
2014	Toxicological assessment of kretek cigarettes Part 4: mechanistic investigations, smoke chemistry and in vitro toxicity	25455230	Yes	Positive
2014	Comparison of select analytes in aerosol from e-cigarettes with smoke from conventional cigarettes and with ambient air	25444997	Yes	Positive
2014	Relationship between cigarette format and mouth level exposure to tar and nicotine in smokers of Russian king-size cigarettes	25146962	Yes	Positive
2014	Evaluating the association between menthol cigarette use and the likelihood of being a former versus current smoker	25017361	Yes	Positive
2014	Patterns of menthol cigarette use among current smokers, overall and within demographic strata, based on data from four U.S. government surveys	24997230	Yes	Positive
2014	Insights from analysis for harmful and potentially harmful constituents (HPHCs) in tobacco products	24973503	Yes	Positive
2014	A review of the evidence on smoking bans and incidence of heart disease	24956588	Yes	Positive
2014	Primary measures of dependence among menthol compared to non-menthol cigarette smokers in the United States	24852490	Yes	Positive
2014	Exposure evaluation of adult male Japanese smokers switched to a heated cigarette in a controlled clinical setting	24819671	Yes	Positive
2014	Investigating predictability of in vitro toxicological assessments of cigarettes: analysis of 7 years of regulatory submissions to Canadian regulatory authorities	24384394	Yes	Positive
2014	Estimating the decline in excess risk of chronic obstructive pulmonary disease following quitting smoking—a systematic review based on the negative exponential model	24361344	Yes	Neutral
2014	Estimating the decline in excess risk of cerebrovascular disease following quitting smoking–a systematic review based on the negative exponential model	24291341	Yes	Neutral
2014	Health risks related to dual use of cigarettes and snus—a systematic review	24184647	Yes	Positive
2014	TSNA exposure from cigarette smoking: 18 years of urinary NNAL excretion data	23920111	Yes	Positive
2014	Measures of initiation and progression to increased smoking among current menthol compared to non-menthol cigarette smokers based on data from four U.S. government surveys	23920111	Yes	Positive
2014	Toxicological assessment of kretek cigarettes part 3: Kretek and American-blended cigarettes, inhalation toxicity	25455226	Yes	Positive
2014	Toxicological assessment of kretek cigarettes Part 6: the impact of ingredients added to kretek cigarettes on smoke chemistry and in vitro toxicity	25496764	Yes	Positive
2014	Toxicological assessment of kretek cigarettes. Part 7: the impact of ingredients added to kretek cigarettes on inhalation toxicity	25455220	Yes	Positive
2015	An approach to ingredient screening and toxicological risk assessment of flavours in e-liquids	26026505	Yes	Positive
2015	Empirical characterisation of ranges of mainstream smoke toxicant yields from contemporary cigarette products using quantile regression methodology	26021184	Yes	Positive
2015	Method for the determination of ammonium in cigarette tobacco using ion chromatography	25934256	No	Negative
2015	An improved method for the isolation of rat alveolar type II lung cells: use in the Comet assay to determine DNA damage induced by cigarette smoke	25846365	Yes	Neutral
2015	A novel approach to assess the population health impact of introducing a Modified Risk Tobacco Product	25819932	Yes	Positive
2015	A longitudinal study of smokers’ exposure to cigarette smoke and the effects of spontaneous product switching	25777840	Yes	Positive
2015	A study to investigate the changes in the levels of biomarkers of exposure to selected cigarette smoke constituents in Japanese adult male smokers who switched to a non-combustion inhaler type of tobacco product	25683775	Yes	Positive
2015	Variation in tobacco and mainstream smoke toxicant yields from selected commercial cigarette products	25620723	Yes	Positive
2015	The combination of two novel tobacco blends and filter technologies to reduce the in vitro genotoxicity and cytotoxicity of prototype cigarettes	25584437	Yes	Positive
2015	Magnitudes of biomarker reductions in response to controlled reductions in cigarettes smoked per day: a one-week clinical confinement study	25572415	Yes	Neutral
2015	Consumption patterns and biomarkers of exposure in cigarette smokers switched to snus, various dissolvable tobacco products, dual use or tobacco abstinence	25549549	Yes	Positive
2015	Effects of using electronic cigarettes on nicotine delivery and cardiovascular function in comparison with regular cigarettes	25460033	Yes	Positive
2015	Is the shape of the decline in risk following quitting smoking similar for squamous cell carcinoma and adenocarcinoma of the lung? A quantitative review using the negative exponential model	25703436	Yes	Neutral

Statistical analysis

We used contingency tables to test the null hypothesis that affiliation with the tobacco industry was not associated with whether the conclusion of the paper was positive, neutral or negative for the tobacco industry. Calculations were done with Stata 14.

Results

Editorial staff and society award recipients

RTP’s Editor-in-Chief, Gio Gori, has been a consultant to the tobacco companies since 1980, when he left the National Cancer Institute (NCI) and became director of the Franklin Institute Center for Policy Studies with support from tobacco companies [21–24]. Federal Judge Gladys Kessler’s 2006 ruling that the major US tobacco companies and their trade organisations had violated the Racketeer Influenced and Corrupt Organizations Act found that “Gori has been a spokesperson and consultant for the industry since leaving the NCI in the 1980s.” and that “In 1999, [Brown and Williamson Tobacco Company] funded a book by [John] Luik and fellow industry consultant Gio Gori through a third party, the Fraser Institute. … The book, titled Passive Smoke: The EPA’s Betrayal of Science and Policy, alleged scientific misconduct on the part of the EPA in conducting its Risk Assessment. … The authors did not acknowledge tobacco industry funding” [25].

Of the 7 associate editors as of June 2015, 4 (57%) had a history of employment or consulting with the tobacco companies and at least 14 of the 38 editorial board members (37%) had either worked for the tobacco companies or consulted with them (Table 2). In addition, at least 11 members of the editorial board, including 3 that also worked for the tobacco industry, had financial ties to other industries (Tables 2, 3).

Table 2.

RTP Editors and Editorial Board Members with Ties to Tobacco Industry (June 2015)

Name	Tobacco Connection
Editor
Gio Gori	Director of the Franklin Institute Center for Policy Studies with support from tobacco companies starting in 1980 [21–24]
Associate Editors
Jay Goodman	RJ Reynolds Scientific Advisory Board in 2004 [26]
A. Wallace Hayes	RJ Reynolds Vice-president of Biochemical/Biobehavioral Research from 1987 until at least 1989 [27]
Friedhelm Korte	Philip Morris Research Prize, 1989 [28, 29]
	Conducted research for Shell (1959–1964) [30]
Michael W. Pariza	Consultant for Philip Morris 1998–2000 [31] and member Philip Morris Scientific Advisory Board [32, 33]
	Advisor to tobacco industry’s The Advancement of Sound Science Coalition [34] send (TASSC)
Editorial Board
Paul Baldrick	Executive Director, Regulatory Strategy within Global Regulatory Affairs at Covance [35] which has done extensive contract work for the tobacco industry, including the March 2011 Industry Menthol Report [36]
George A. Burdock	Billed Philip Morris for monthly consulting services in 1995 [37] and had consulting agreements with Philip Morris in 1997 [38] and 2001 [39]
Michael Dourson	President of consulting company TERA that received funding from tobacco industry Center for Indoor Air Research [40] (CIAR)
W. Gary Flamm	Consultant for the Tobacco Institute and Philip Morris [41, 42]
David Gaylor	Philip Morris advisory board in 2002 [43]
Michael E. Ginevan	Paid by CIAR (as an employee of Environ) to conduct statistical re-analysis of Hirayama data on lung cancer risks of secondhand smoke in 1988 [44]
D. Henschler	Supported by RJ Reynolds [44–47]
Peter Barton Hutt	Lawyer with Covington & Burling for more than 50 years, represented RJ Reynolds; lobbied on behalf of RJR’s “safe” cigarette [48–50]
	Served as director on dozens of boards of pharma and therapeutics companies and as FDA Chief Counsel [10, 51]
L. Daniel Maxim	Contracted with RJ Reynolds to do research in 1999 on “new cigarette product” [52]
Robert Nilsson	Participated in a study sponsored by Swedish Match [53] and coauthored resulting paper [54]
Dennis J. Paustenbach	Consultant to RJ Reynolds [55]
Terry F. Quill	Paid by Philip Morris to attend symposium on secondhand smoke [56] and developed materials for Philip Morris legal [57]
Robert A Squire	RJ Reynolds scientific advisory board (SAB) in 1989 [58] and attended SAB meetings in at least 1990, 1991 [59, 60]
Gary L. Yingling	Lawyer for tobacco, food, drug, medical devices, cosmetics industries [10]

Table 3.

RTP Editorial Board Members with Documented Ties to Other Industries (June 2015)

Name	Industry connection
Richard Adamson	Worked for the American Beverage Association for 10 years [61]
Hugh A. Barton	Research fellow at Pfizer [62]
Michael Bolger	Works for Exponent, a consulting firm that works for industry [63]
John J. Clary	Consulting firm “Bio Risk”; previously managed toxicology groups of DuPont and Hoechst Celanese, and served as Director of Toxicology for Dow Corning and Celanese
Roger Drew	As principal toxicology consultant with Toxicos Pty Ltd, prepared Health Risk & Toxicological Assessment of Emissions from the Upgraded Alcoa Pinjarra Alumina Refinery for Alcoa; Manager of the Toxicology Information Section and Corporate Toxicologist of ICI Australia [64, 65]
Daniel Krewski	Industry Canada hired in 2008 to help develop a “Communication Strategy for Radiofrequency Fields Risk” [66]
Marcello Lotti	Expert witness for defense in Montedison trial in Italy involving workers exposed to polyvinyl chloride, many of whom developed cancer and died; Lotti testified that “despite the numerous studies carried out over the years, still we do not know what causes them, what are the mechanisms that trigger them” [67]
Roger McClellan	Former director of Chemical Industry Institute of Toxicology [10]
Jurgen Pauluhn	Bayer Pharmaceuticals [68]
Otto Wong	Coauthored the Shanghai Health Study of benzene, administered by the American Petroleum Institute with funding by British Petroleum, Chevron, ConocoPhillips, ExxonMobil and Shell Chemical [69]

Peer-reviewed papers

Almost all (96%, 50/52) of the peer-reviewed original research papers on tobacco or nicotine published in RTP were by authors with affiliations with the tobacco industry, and 76% (38/50) of these papers drew conclusions positive for the tobacco industry (Table 4). The other 12 papers were scored neutral; none drew conclusions negative for the tobacco industry. The 2 peer-reviewed papers by authors who were not related to the tobacco industry both reached conclusions that were scored negative for the industry. There was a statistically significant association between the papers’ conclusions and affiliation with the tobacco industry (p <.001 by Chisquare test).

Table 4.

Author relationship with tobacco industry and article conclusions

Author affiliation	Article outcome			Total
	Positive	Neutral	Negative
Affiliated with tobacco industry	38	12	0	50
Unaffiliated/unclear	0	0	2	2
Total	38	12	2	52

Discussion

Consistent with previously expressed concerns [6, 7], the editorial board of the journal Regulatory Toxicology and Pharmacology includes heavy representation by industry, in particular the tobacco industry. This pattern is consistent with earlier research findings that research funded by tobacco [5, 12, 13], chemical [14], pharmaceutical [15–17], mobile phone [18], nutrition [70] and sugar-sweetened beverage [19, 71] industries is more likely to report results consistent with those industries’ interests. In particular, several of the RTP papers we reviewed concluded that traditional cigarettes have become less toxic over time [72, 73] and that new products are less toxic than traditional cigarettes [74–76].

As of 2017, RTP remained an important outlet for the tobacco industry to publish research that supported its positions. For example, 6 of 10 citations on Philip Morris International’s 2017 webpage arguing that its new heat-not-burn product iQOS was safer than conventional cigarettes were published in RTP [9]. Work published in RTP was also being cited in the tobacco product regulatory process in the United States. Philip Morris cites 11 papers published in RTP in the executive summary [77] to its massive applications to the US Food and Drug Administration (FDA) to market iQOS as a modified risk tobacco product (MRTP) [78]. (As of October 2017 the FDA had not released the full MRTP applications, in particular Module 9, the list of scientific references for the full application.) The FDA also cited work in RTP 4 times in its 2017 proposed rule restricting the levels of the carcinogen N-Nitrosonornicotine (NNN) in smokeless tobacco products [79] and once in its 2016 final ‘deeming’ rule, taking jurisdiction over e-cigarettes, cigars and other tobacco products [80].

This paper only discusses one journal, RTP, but, as discussed in the Introduction, RTP is not the only journal with such industry ties. An editor of Mutagenesis (published by Oxford University Press), for example, who received funding from the tobacco industry used the journal to challenge research linking smoking with damage to the p53 tumor suppressor gene [81]. Possible biases in the peer review process associated with journals dominated by editors with ties to industries with a financial interest in the outcome of the research may be a wider problem. It warrants study with a similar approach.

A limitation of this paper is that the available tobacco industry documents may not have reflected all connections between the tobacco industry and RTP editorial board members. Another potential limitation is that we compare 50 articles whose authors are industry affiliated with only 2 articles whose authors are either not affiliated or for which their affiliation is unclear. We do not know whether there were only 2 such articles because RTP is not a preferred journal for independent authors to submit papers to or if many independent submissions that did not serve industry interests were rejected for publication.

Conclusion

The fact that the tobacco industry is heavily represented in the editorial leadership of Regulatory Toxicology and Pharmacology and that almost all the peer-reviewed papers on tobacco topics were written by individuals connected with tobacco companies and found positive results calls into question the confidence that members of the scientific community and tobacco product regulators can have in the conclusions of papers published there. The substantial representation of other industries with a stake in regulatory science (chemical, pharmaceutical, food, as well as lawyers who represent industry) on the editorial board raises similar concerns for research of interest to a wide range of other industries. Regulators, courts and policymakers should not give publications that appear in this journal and other similar industry-dominated journals the same credence as publications in journals that operate independent of industry.

Biographies

Clayton Velicer MPH, was a Research Specialist at the Center for Tobacco Control Research and Education, University of California, San Francisco, USA.

Gideon St. Helen Ph.D., is an Assistant Professor of Medicine and member of the Center for Tobacco Control Research and Education at the University of California, San Francisco, USA.

Stanton A. Glantz Ph.D., is a Professor of Medicine and a Director of the Center for Tobacco Control Research and Education, University of California, San Francisco, USA.