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• Response to Bashash et al.
  William E Stephens
  Published on: 20 March 2018
• Vapourised nicotine products: Lower concentration does not mean safe
  Morteza Bashash, Michael Chaiton and Robert Schwartz
  Published on: 22 January 2018

• Published on: 20 March 2018

  Response to Bashash et al.

  • William E Stephens, Senior Research Fellow University of St Andrews

  I am grateful to Bashash et al. for raising some important methodological and policy-related issues. Responding to their specific points:

  (1) Very high formaldehyde concentrations may arise in aerosols when atomisers generate excessive heat[1]. Under these circumstances recommended safety limits for formaldehyde may indeed be exceeded and this compound contributes most to the cancer potency summation.

  (2) Goodson et al. [2] provide a framework for assessing whether low dose compounds that are not necessarily individual carcinogens may become involved in carcinogenesis when acting in concert. Although discussed under "Strengths and limitations" synergystic phenomena were not accommodated in the cancer potency model as it is not yet possible to predict the mechanism and magnitude of such interactions in tobacco or e-cigarette aerosols. Under the Goodson et al. model adverse effects reflect adventitious synergystic combinations. These may be statistically more likely in tobacco smoke where the number of different compounds greatly exceeds those of simpler aerosols, however this effect is expected to be minor compared with the exceptionally high carcinogenic potencies of some well-established carcinogens in tobacco smoke.

  (3) Lifetime cancer risk is linearly dependent on the daily volume of vapour inhaled (equation 7) and the effect on risk of increased consumption after switching to heat not burn (HnB) products is directly related to the chang...

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  I am grateful to Bashash et al. for raising some important methodological and policy-related issues. Responding to their specific points:

  (1) Very high formaldehyde concentrations may arise in aerosols when atomisers generate excessive heat[1]. Under these circumstances recommended safety limits for formaldehyde may indeed be exceeded and this compound contributes most to the cancer potency summation.

  (2) Goodson et al. [2] provide a framework for assessing whether low dose compounds that are not necessarily individual carcinogens may become involved in carcinogenesis when acting in concert. Although discussed under "Strengths and limitations" synergystic phenomena were not accommodated in the cancer potency model as it is not yet possible to predict the mechanism and magnitude of such interactions in tobacco or e-cigarette aerosols. Under the Goodson et al. model adverse effects reflect adventitious synergystic combinations. These may be statistically more likely in tobacco smoke where the number of different compounds greatly exceeds those of simpler aerosols, however this effect is expected to be minor compared with the exceptionally high carcinogenic potencies of some well-established carcinogens in tobacco smoke.

  (3) Lifetime cancer risk is linearly dependent on the daily volume of vapour inhaled (equation 7) and the effect on risk of increased consumption after switching to heat not burn (HnB) products is directly related to the change in number of sticks. Any implication that HnB products pose acceptable risks was certainly not intended: the adjective 'safe' should never be used to encourage the use of HnB products, nor indeed any VNP with the possible exception of medicinal devices.

  (4) Neither emissions nor biomarkers are suitable for accurate determination of absolute risks; long-term clinical evidence is needed for reliable estimates. In the meantime the emissions data used in the paper suggest that the relative lifetime cancer risk from HnB devices may be up to 50 times less than that of combustible cigarettes. The risk is still large - about 10,000 times greater than inhaling an equivalent volume of ambient air. In contrast the modelling suggests that many e-cigarettes pose cancer risks within a factor of 10 of a nicotine inhaler that has been approved for use by the public. E-cigarettes, if used as the manufacturer intended, appear to offer significantly lower risk alternatives to HnB for the smoker intent on using these novel products as aids to quitting to avoid cancer. The relative risks of other diseases are yet to be quantified.

  References
  [1] Farsalinos KE, Voudris V, Spyrou A, Poulas K. E-cigarettes emit very high formaldehyde levels only in conditions that are aversive to users: A replication study under verified realistic use conditions. Food and Chemical Toxicology. 2017;109:90-4.
  [2] Goodson WH, Lowe L, Carpenter DO, Gilbertson M, A. MA, Lopez de Cerain Salsamendi A, et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis. 2015;36 (Suppl 1):S254-S96.

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  Conflict of Interest:
  None declared.

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• Published on: 22 January 2018

  Vapourised nicotine products: Lower concentration does not mean safe

  • Morteza Bashash, Assistant Professor Dalla Lana School of Public Health, University of Toronto
  • Other Contributors:
    • Michael Chaiton, Scientist
    • Robert Schwartz, Executive Director

  NOT PEER REVIEWED The results provided by Stephens [1] may suggest to readers that since the concentrations of carcinogens are lower in vapourised nicotine products (VNPs), the risks of cancer are smaller compared to conventional cigarettes. The article uses the linear non-threshold model for risk assessment (a uniform cancer risk per unit dose from higher to lower doses), which is also used by most regulatory agencies. This model is considered to have a high degree of uncertainty; nevertheless, it implies that any dose of carcinogens increases the risk of cancer. Accordingly, the primary conclusion of Stephens and other’s[2] findings of the presence of carcinogens, particularly in heat-not-burn cigarettes (HNB) is that HNB poses a significant risk of cancer. In addition:
  1) The article highlights a summation approach of overall cancer risk for each product, yet the individual concentrations of human carcinogens (for example, formaldehyde [3]) are still at risk level.
  2) The assessment of carcinogenesis of low-level exposure to a mixture of chemicals is challenging [4]. Stephens’s summation model assumes that the effect of chemicals is independent. Even if we assume that for an individual chemical a lower concentration lowers carcinogenicity, we cannot rule out the potential effects of interactions among chemicals.
  3) The analysis relies on holding consumption constant. However, manufacturer studies have suggested that consumption increases after a swi...

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  NOT PEER REVIEWED The results provided by Stephens [1] may suggest to readers that since the concentrations of carcinogens are lower in vapourised nicotine products (VNPs), the risks of cancer are smaller compared to conventional cigarettes. The article uses the linear non-threshold model for risk assessment (a uniform cancer risk per unit dose from higher to lower doses), which is also used by most regulatory agencies. This model is considered to have a high degree of uncertainty; nevertheless, it implies that any dose of carcinogens increases the risk of cancer. Accordingly, the primary conclusion of Stephens and other’s[2] findings of the presence of carcinogens, particularly in heat-not-burn cigarettes (HNB) is that HNB poses a significant risk of cancer. In addition:
  1) The article highlights a summation approach of overall cancer risk for each product, yet the individual concentrations of human carcinogens (for example, formaldehyde [3]) are still at risk level.
  2) The assessment of carcinogenesis of low-level exposure to a mixture of chemicals is challenging [4]. Stephens’s summation model assumes that the effect of chemicals is independent. Even if we assume that for an individual chemical a lower concentration lowers carcinogenicity, we cannot rule out the potential effects of interactions among chemicals.
  3) The analysis relies on holding consumption constant. However, manufacturer studies have suggested that consumption increases after a switch to HNB devices [5]. For non-smokers or occasional smokers to whom HNBs are introduced as a safe product, any additional burden of toxicants increases the risk of cancer.
  4) The conclusion concentrates on reduced risk of VNPs compared to the most harmful product (i.e tobacco smoke) and should also calculate elevated risk of using VNPs compared to background concentration.

  In summary, smoking imposes exposure to a variety of toxicants with known and/or unknown health effect regardless of name, shape and means of use. These findings suggest that HNB cigarettes should be subject to the same regulations as tobacco cigarettes. The tobacco control community should communicate the absolute risks associated with these products. In particular, there is an urgent need for tobacco control policy actors to understand the potential absolute harms of heat-not-burn (HNB) cigarettes that PMI is pushing as ‘less harmful alternatives to smoking’ in their declared movement toward a smoke-free world (https://www.pmi.com/sustainability).

  References:

  [1] Stephens WE. Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke. Tobacco Control 2017.
  [2] Auer R, Concha-Lozano N, Jacot-Sadowski I, et al. Heat-not-burn tobacco cigarettes: Smoke by any other name. JAMA Internal Medicine 2017.
  [3] Cogliano VJ, Grosse Y, Baan RA, et al. Meeting report: summary of IARC monographs on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol. Environmental health perspectives 2005:1205-1208.
  [4] Goodson III WH, Lowe L, Carpenter DO, et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 2015;36(Suppl_1):S254-S296.
  [5] Lüdicke F, Baker G, Magnette J, et al. Reduced Exposure to Harmful and Potentially Harmful Smoke Constituents With the Tobacco Heating System 2.1. Nicotine & Tobacco Research 2017;19(2):168-175.

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  Conflict of Interest:
  None declared.

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