On 2016 Sep 17, ROBERT COMBES commented:

Professor Michael Balls and Dr Robert Combes respond to Dr Coral Gartner regarding concerns about possible conflicts of interest.

We thank Dr Gartner for her comments, and for the opportunity to clarify potential conflicts of interest relating to our paper [1]. This was written by us as independent individuals, free of any commercial influence or funding, and after both of us had ceased having close ties with FRAME. FRAME is a scientific charity that has openly received financial support from the chemical, cosmetic, household product, pharmaceutical and tobacco industries, to enable it to undertake independent research into the development, validation and acceptance of alternatives to animal experiments.<br> Some of this work included the development, characterisation and preliminary assessment of in vitro models of inhalation toxicology. While we are not in a position to say anything about FRAME’S current policy on industrial funding, we must stress that the tobacco industry funding enabled FRAME to investigate ways to replace highly invasive and complex animal experiments with urgently needed alternatives with the potential for producing more-relevant and more-reliable data for assessing human safety.

As far as personal remuneration is concerned, RDC has acted as an external consultant for the tobacco industry since retiring in 2007 from FRAME. This work was conducted under standard contract research agreements, the last of which terminated over 12 months prior to the writing of our article. The work referred to by Dr Gartner, that was co-authored by RDC with a named individual as lead, relates to research undertaken when this individual and RDC were employed by Inveresk Research International (IRI, now Charles River Laboratories), a contract research establishment. This can be directly verified by opening the authors’ affiliations in PubMed (http://9www.ncbi.nlm.nih.gov/pubmed)for each of the four respective abstracts (PMID: 9491389; PMID: 1600961; PMID: 1396612; and PMID: 7968569). This work was entirely funded by the US Government, as was acknowledged in each of the papers, and also by the inclusion of another co-author, then based at NIEHS (the National Institute of Environmental Health Sciences, Research Triangle Park, USA), who acted as project leader. It should be noted that the lead author of the publications arising from the work conducted at IRI subsequently went to work at BAT, and this might have added to any confusion.

MB has never been a paid consultant for any industrial company. He was honorary Chairman of the FRAME Trustees from 1981 to 2013, and has been honorary Editor of FRAME’s journal, Alternatives to Laboratory Animals, since 1983. He no longer has any influence on FRAME’s policies on the tobacco industry or on any other issue. None of FRAME’s industrial supporters ever attempted to dictate or limit FRAME’s activities, or influence the circulation and/or publication of the results of any FRAME research. While MB was head of the FRAME Alternatives Laboratory at the University of Nottingham Medical School, no tobacco product, or chemical, other material or product of interest to the tobacco industry was involved in FRAME’s research. He left the University of Nottingham in 1993, to become the first head of the European Commission’s European Centre for the Validation of Alternative Methods, a position from which he retired in 2002. We consider that there is a distinction between the above situation, in which, despite previous links of various kinds with the tobacco industry, we wrote our critique [1](ref) without any form of external influence, and that which we referred to, involving alleged conflicts of interest in the MCDA study. However, while we acknowledge that conflicts of interest and their consequences are complex, we hope that we have taken into account as much relevant information as possible to permit a fair and balanced appraisal of the information on which PHE's policy on electronic cigarettes is based. We consider it crucial that scientific opinions, and the policies which result from them, are based on freely-available evidence of high quality, which has been openly conducted and independently assessed. We know of no such evidence to support PHE’s claim that e-cigarettes are 95% safer than tobacco cigarettes.

We welcome Dr Gartner’s comment, we hope that others will address the scientific arguments that we have used to justify our position, since, the validity, or otherwise, of these should be unaffected by any conflicts of interest. There is a great deal at stake, including the future well-being of those who have opted for vaping as an alternative to tobacco smoking. We stand by our belief, expressed in a letter published in The Times on 18 February 2016, that “The human respiratory system is a delicate vehicle, on the which the length and quality of our lives depend. For governments and companies to condone, or even suggest, the regular and repeated inhaling of a complex mixture of chemicals with addictive and toxic properties, but without comprehensive data, is irresponsible and could have serious consequences.”

1. Combes, R D. & Balls, M. On the safety of e-cigarettes: "I can resist anything except temptation". ATLA. (2015) 43, 417-425.

On 2016 Sep 15, Coral Gartner commented:

Combes and Balls raise the issue of potential conflicts of interest in their critique of the PHE-commissioned report on e-cigarettes.

Indeed, links between scientists and industry are regularly raised in the debate concerning tobacco harm reduction, and Tobacco Industry funding is of particular concern generally. For example, Simon Chapman writes, "Tobacco-funded research and the conduct of the industry which oversees it has arguably the worst of all reputations. This explains why that industry is unique among all others in being barred from funding research and scholarships at many universities."

Given this context and the general sensitivity around tobacco-industry funded researchers, I was somewhat surprised that Robert Combes didn't address his own history of being a paid consultant for British American Tobacco over at least two decades (Combes R, 2013 ; Combes R, 2012 ; Dillon D, 1994; Dillon D, 1998 ; Dillon D, 1992 ; Dillon D, 1992) when raising the issue of conflicts of interest in this article.

It would be very helpful if both authors could clarify the nature of their past and present relationships with BAT, and any other tobacco companies they have performed consultancy work for, and confirm when they last performed consultancy work for a tobacco company. Also could they advise what their current position is on undertaking further consultancy work for the tobacco industry in the future?

Similarly, it would be helpful to know if FRAME currently or previously has received funds from a tobacco company and what the organisation's current official policy on receipt of tobacco industry funds is.

On 2016 Sep 15, Coral Gartner commented:

Combes and Balls raise the issue of potential conflicts of interest in their critique of the PHE-commissioned report on e-cigarettes.

Indeed, links between scientists and industry are regularly raised in the debate concerning tobacco harm reduction, and Tobacco Industry funding is of particular concern generally. For example, Simon Chapman writes, "Tobacco-funded research and the conduct of the industry which oversees it has arguably the worst of all reputations. This explains why that industry is unique among all others in being barred from funding research and scholarships at many universities."

Given this context and the general sensitivity around tobacco-industry funded researchers, I was somewhat surprised that Robert Combes didn't address his own history of being a paid consultant for British American Tobacco over at least two decades (Combes R, 2013 ; Combes R, 2012 ; Dillon D, 1994; Dillon D, 1998 ; Dillon D, 1992 ; Dillon D, 1992) when raising the issue of conflicts of interest in this article.

It would be very helpful if both authors could clarify the nature of their past and present relationships with BAT, and any other tobacco companies they have performed consultancy work for, and confirm when they last performed consultancy work for a tobacco company. Also could they advise what their current position is on undertaking further consultancy work for the tobacco industry in the future?

Similarly, it would be helpful to know if FRAME currently or previously has received funds from a tobacco company and what the organisation's current official policy on receipt of tobacco industry funds is.

On 2016 Sep 17, ROBERT COMBES commented:

Professor Michael Balls and Dr Robert Combes respond to Dr Coral Gartner regarding concerns about possible conflicts of interest.

We thank Dr Gartner for her comments, and for the opportunity to clarify potential conflicts of interest relating to our paper [1]. This was written by us as independent individuals, free of any commercial influence or funding, and after both of us had ceased having close ties with FRAME. FRAME is a scientific charity that has openly received financial support from the chemical, cosmetic, household product, pharmaceutical and tobacco industries, to enable it to undertake independent research into the development, validation and acceptance of alternatives to animal experiments.<br> Some of this work included the development, characterisation and preliminary assessment of in vitro models of inhalation toxicology. While we are not in a position to say anything about FRAME’S current policy on industrial funding, we must stress that the tobacco industry funding enabled FRAME to investigate ways to replace highly invasive and complex animal experiments with urgently needed alternatives with the potential for producing more-relevant and more-reliable data for assessing human safety.

As far as personal remuneration is concerned, RDC has acted as an external consultant for the tobacco industry since retiring in 2007 from FRAME. This work was conducted under standard contract research agreements, the last of which terminated over 12 months prior to the writing of our article. The work referred to by Dr Gartner, that was co-authored by RDC with a named individual as lead, relates to research undertaken when this individual and RDC were employed by Inveresk Research International (IRI, now Charles River Laboratories), a contract research establishment. This can be directly verified by opening the authors’ affiliations in PubMed (http://9www.ncbi.nlm.nih.gov/pubmed)for each of the four respective abstracts (PMID: 9491389; PMID: 1600961; PMID: 1396612; and PMID: 7968569). This work was entirely funded by the US Government, as was acknowledged in each of the papers, and also by the inclusion of another co-author, then based at NIEHS (the National Institute of Environmental Health Sciences, Research Triangle Park, USA), who acted as project leader. It should be noted that the lead author of the publications arising from the work conducted at IRI subsequently went to work at BAT, and this might have added to any confusion.

MB has never been a paid consultant for any industrial company. He was honorary Chairman of the FRAME Trustees from 1981 to 2013, and has been honorary Editor of FRAME’s journal, Alternatives to Laboratory Animals, since 1983. He no longer has any influence on FRAME’s policies on the tobacco industry or on any other issue. None of FRAME’s industrial supporters ever attempted to dictate or limit FRAME’s activities, or influence the circulation and/or publication of the results of any FRAME research. While MB was head of the FRAME Alternatives Laboratory at the University of Nottingham Medical School, no tobacco product, or chemical, other material or product of interest to the tobacco industry was involved in FRAME’s research. He left the University of Nottingham in 1993, to become the first head of the European Commission’s European Centre for the Validation of Alternative Methods, a position from which he retired in 2002. We consider that there is a distinction between the above situation, in which, despite previous links of various kinds with the tobacco industry, we wrote our critique [1](ref) without any form of external influence, and that which we referred to, involving alleged conflicts of interest in the MCDA study. However, while we acknowledge that conflicts of interest and their consequences are complex, we hope that we have taken into account as much relevant information as possible to permit a fair and balanced appraisal of the information on which PHE's policy on electronic cigarettes is based. We consider it crucial that scientific opinions, and the policies which result from them, are based on freely-available evidence of high quality, which has been openly conducted and independently assessed. We know of no such evidence to support PHE’s claim that e-cigarettes are 95% safer than tobacco cigarettes.

We welcome Dr Gartner’s comment, we hope that others will address the scientific arguments that we have used to justify our position, since, the validity, or otherwise, of these should be unaffected by any conflicts of interest. There is a great deal at stake, including the future well-being of those who have opted for vaping as an alternative to tobacco smoking. We stand by our belief, expressed in a letter published in The Times on 18 February 2016, that “The human respiratory system is a delicate vehicle, on the which the length and quality of our lives depend. For governments and companies to condone, or even suggest, the regular and repeated inhaling of a complex mixture of chemicals with addictive and toxic properties, but without comprehensive data, is irresponsible and could have serious consequences.”

1. Combes, R D. & Balls, M. On the safety of e-cigarettes: "I can resist anything except temptation". ATLA. (2015) 43, 417-425.