A consideration of the role of gas/particle partitioning in the deposition of nicotine and other tobacco smoke compounds in the respiratory tract

Chem Res Toxicol. 2001 Nov;14(11):1465-81. doi: 10.1021/tx0100901.


Tobacco smoke is an aerosol that contains both gaseous and suspended particulate material (PM). The particles are largely liquid droplets containing a wide variety of condensed organic compounds. Each compound in the smoke will partition between the gas and PM phases and will always seek a state of gas/particle equilibrium. When tobacco smoke is inhaled, a compound such as nicotine can deposit in the respiratory tract (RT) by four different mechanisms: (1) direct gas deposition (DGD) of the portion of the compound that is initially in the gas phase of the inhaled smoke; (2) evaporative gas deposition (EGD) of PM-phase compound by evaporation to the gas phase, then deposition; (3) particle deposition, evaporation from the deposited particle, then deposition from the gas phase (PDE); and (4) particle deposition with diffusion (PDD) into RT tissue. Three of the mechanisms (DGD, EGD, and PDE) involve volatilization from the PM phase. The relative importance of all the mechanisms is therefore greatly affected by the volatility of the compound from the PM phase as it is set by the compound's gas/particle partitioning constant K(p) through the compound's vapor pressure. For a largely nonvolatile compound such as benzo[a]pyrene, only PDD will likely be important. For a semivolatile compound such as nicotine, all four mechanisms can be important. Because tobacco smoke alkaloids such as nicotine can exist in protonated as well as free-base form, the fraction alpha(fb) of the compound that is in the neutral free-base form in the PM phase plays a critical, pH-dependent role in determining the relative importance of the four mechanisms. Equations are developed that can be used to ascertain the importance of the DGD and EGD mechanisms. The value of alpha(fb) for nicotine in a tobacco smoke PM is set by pH(eff), the effective pH of the PM phase. Historically, a primary method for measuring "smoke pH" has involved the direct exposure of a pH electrode to tobacco smoke. This method cannot yield direct insight into pH(eff) or alpha(fb) values because (1) problems exist in using such an electrode to measure smoke PM-phase pH, and (2) by itself, a measurement of the pH of tobacco smoke PM says nothing about the effects of PM-phase activity coefficients of protonated and free-base nicotine on the nicotine species distribution. The "acidic" values that have typically been measured for cigarette "smoke pH" by the direct pH electrode method are therefore neither reliable nor useful in determining the relative distribution of PM-phase nicotine among the protonated and free-base forms. The dependence of the volatility of nicotine from tobacco smoke PM on alpha(fb) means that measuring the gas/particle distribution of nicotine under equilibrium conditions in a tobacco smoke by denuder samplers (or by another method) can yield information about the nicotine K(p) for that smoke. Knowledge of K(p,fb), the partitioning constant for nicotine in the free-base form, then allows calculation of alpha(fb) through the relation K(p) = K(p,fb)/alpha(fb). The available data suggest that the smoke PM from some commercial cigarettes can be characterized by alpha(fb) > or = 0.4, i.e., 40% or more of the nicotine in the free-base form. This conclusion is consistent with (1) the gas-sampling denuder results obtained by Philip Morris in which significant tobacco smoke nicotine was observed to deposit in acid-coated denuder tubes, with more depositing when the cigarette tobacco blend was treated with ammonia; (2) the view that the sensory "impact" exhibited by some tobacco smokes is caused by the deposition of gaseous nicotine in the pharynx; (3) the observed throat irritation caused by nicotine inhalers; and (4) the high overall respiratory tract deposition efficiencies for nicotine of 0.9 and greater that have been reported for some cigarette smokes. The available information combines to create a picture of nicotine in cigarette smoke that contradicts the traditional view that cigarette smoke PM is typically acidic, with little free-base nicotine typically present in the smoke PM phase. Government agencies interested in establishing a framework for the testing and monitoring of nicotine delivery may wish to consider requiring the measurement and publication of the PM-phase alpha(fb) values for the cigars and cigarettes marketed in their jurisdictions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Aerosols
  • Chemical Phenomena
  • Chemistry, Physical
  • Ganglionic Stimulants / pharmacokinetics*
  • Gases
  • Humans
  • Inhalation Exposure
  • Models, Theoretical*
  • Nicotine / pharmacokinetics*
  • Reference Values
  • Respiratory System / chemistry*
  • Respiratory System / drug effects
  • Smoke / analysis*
  • Tobacco / chemistry*
  • Tobacco Industry


  • Aerosols
  • Ganglionic Stimulants
  • Gases
  • Smoke
  • Nicotine