On 2016 Oct 30, Zvi Herzig commented:

The Holm at al. study was cited to show that Scandinavian smokeless tobacco (snus) delivers nicotine at speeds and quantities similar to those of smoking. Meta-analyses indicating that snus is not a significant cause of smoking-related disease are cited further below.

These should indicate that nicotine is not among the top risk compounds in tobacco smoke.

MOE may be a standard approach to minimize potential toxicological risks. But where there is epidemiological evidence from NRT and certain forms of smokeless tobacco showing that nicotine is not one of the major toxicological issues with cigarette smoke, then there is less reason to rely on MOEs.

On 2016 Oct 27, Dirk Lachenmeier commented:

Sorry, but I cannot find any evidence in your cited studies that would refute our conclusions. Especially the Holm et al. (1992) study is absolutely unsuitable to make such a conclusion. This was not even a short term trial, but blood nicotine was studied on a single day. Holm et al. (1992) conclude: "The snuff takers and cigarette smokers reported similar levels of subjective dependence on tobacco. Epidemiological study of Swedish snuff users could clarify whether the cardiovascular risks of tobacco are attributable to nicotine or to other smoke components". The long-term and chronic effects of nicotine were obviously not studied. As toxicologist it is also difficult to accept why a potentially toxic substance with a clear dose-response effect such as nicotine may not be assessed using internationally accepted indicators such as the margin of exposure. Obviously, benchmark dose data from epidemiology would be preferrable over animal data, but as we have detailed in our article, none of the epidemiology studies provided suitable dose-response information.

On 2016 Oct 26, Zvi Herzig commented:

The cited sources refute the report's conclusion that "nicotine is among the top risk compounds in tobacco smoke". They show that nicotine consumption in the context of snus—which delivers equal or more nicotine than smoking, and at similar absorption speeds Holm H, 1992—is not significantly associated with smoking-related disease

The MOE approach shouldn't be used to estimate risk where direct epidemiological evidence for the relevant dose is available. This should be self-evident.

On 2016 Oct 24, Dirk Lachenmeier commented:

Thank you for providing some further references on nicotine. However, none of these provide dose-response information required for quantitative comparative risk assessment. We have carefully screened through the literature to include any usable study, including human data (see table 1). It should also be noted that the European Food Safety Authority (EFSA) also used the Lindgren et al. study (which we have included) as point of departure for their risk assessment of nicotine.

On 2016 Oct 22, Zvi Herzig commented:

It is puzzling that the authors use the indirect margin of exposure (MOE) approach to evaluate harms, when epidemiological evidence is available, showing minimal risk of nicotine (at levels of consumption) in relation to cancer Lee PN, 2009, cardiovascular diseases Hansson J, 2012 Hansson J, 2014, other diseases Lee PN, 2013 or acute poisonings Royal College of Physicians, 2016.

On 2016 Oct 22, Zvi Herzig commented:

It is puzzling that the authors use the indirect margin of exposure (MOE) approach to evaluate harms, when epidemiological evidence is available, showing minimal risk of nicotine (at levels of consumption) in relation to cancer Lee PN, 2009, cardiovascular diseases Hansson J, 2012 Hansson J, 2014, other diseases Lee PN, 2013 or acute poisonings Royal College of Physicians, 2016.

On 2016 Oct 24, Dirk Lachenmeier commented:

Thank you for providing some further references on nicotine. However, none of these provide dose-response information required for quantitative comparative risk assessment. We have carefully screened through the literature to include any usable study, including human data (see table 1). It should also be noted that the European Food Safety Authority (EFSA) also used the Lindgren et al. study (which we have included) as point of departure for their risk assessment of nicotine.

On 2016 Oct 26, Zvi Herzig commented:

The cited sources refute the report's conclusion that "nicotine is among the top risk compounds in tobacco smoke". They show that nicotine consumption in the context of snus—which delivers equal or more nicotine than smoking, and at similar absorption speeds Holm H, 1992—is not significantly associated with smoking-related disease

The MOE approach shouldn't be used to estimate risk where direct epidemiological evidence for the relevant dose is available. This should be self-evident.

On 2016 Oct 27, Dirk Lachenmeier commented:

Sorry, but I cannot find any evidence in your cited studies that would refute our conclusions. Especially the Holm et al. (1992) study is absolutely unsuitable to make such a conclusion. This was not even a short term trial, but blood nicotine was studied on a single day. Holm et al. (1992) conclude: "The snuff takers and cigarette smokers reported similar levels of subjective dependence on tobacco. Epidemiological study of Swedish snuff users could clarify whether the cardiovascular risks of tobacco are attributable to nicotine or to other smoke components". The long-term and chronic effects of nicotine were obviously not studied. As toxicologist it is also difficult to accept why a potentially toxic substance with a clear dose-response effect such as nicotine may not be assessed using internationally accepted indicators such as the margin of exposure. Obviously, benchmark dose data from epidemiology would be preferrable over animal data, but as we have detailed in our article, none of the epidemiology studies provided suitable dose-response information.