Possible Role of Ammonia on the Deposition, Retention, and

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Chem. Res. Toxicol. 2007, 20, 326-343

PerspectiVe Possible Role of Ammonia on the Deposition, Retention, and Absorption of Nicotine in Humans while Smoking† Jeffrey I. Seeman* SaddlePoint Frontiers, 12001 Bollingbrook Place, Richmond, Virginia 23236-3218 ReceiVed October 26, 2006

This perspective presents an overview of the properties of tobacco smoke aerosol and the possible effect of ammonia on the deposition location, retention and the amount and rate of nicotine absorption during cigarette smoking. Three main mechanisms describe the absorption of smoke constituents: (A) gas-phase constituents deposit directly; (B) particles deposit and the constituents then diffuse through the particle into the biological buffer and then into the tissue; and (C) particulate phase constituents evaporate from the particles and then deposit from the gas phase. Nicotine from smoking deposits and is absorbed predominately in the lungs. When particles deposit on the lung-blood interfaces, nicotine is absorbed rapidly, regardless of the acid-base nature of the particles. This is due to the buffering capacity of the lung-blood interfaces and the small mass of nicotine per puff distributed over a large number of particles depositing onto a huge lung surface. The composition of both tobacco smoke aerosol particles and the gas phase are time dependent. Ammonia in mainstream smoke evaporates faster from particles than nicotine. It is, therefore, unlikely that ammonia can significantly affect the volatility of MS smoke nicotine from particles in the smoke aerosol. It is certain that no single measurement of tobacco or of smoke, especially one made under equilibrium conditions, can adequately characterize the time-dependent properties of mainstream smoke aerosol. Thus, the fraction of nonprotonated freebase nicotine in trapped, aged smoke particulate matter has not been shown to be a useful predictor of the amount or total rate of nicotine uptake in human smokers. Similarly, “smoke pH” and “pHeff” are not useful practical parameters for providing understanding or predictability of tobacco smoke chemistry or nicotine bioavailability. 1. Introduction 2. Time-Dependent Nature of Tobacco Smoke Aerosol 2.1. Relative Concentrations of Constituents in MS Smoke Aerosol Particles, including Nicotine and Solanesol, during Human Smoking Studies 2.2. Time-Dependent Concentration of Ammonia, Nicotine, and Solanesol in Fresh Mainstream Tobacco Smoke 2.3. Computational Simulation of the Time-Dependent Volatile Loss of Nicotine, Ammonia, and Acetic Acid from an Aqueous Solution 2.4. On the Time-Dependence of Gas-Phase Constituents of Tobacco Smoke 3. Effect of Ammonia on the Transfer of Nicotine in MS Smoke to and Deposition and Retention in the Buccal Cavity, Trachea, Bronchi, or the Deep Lung-Blood Interfaces 3.1. Ammonia in MS Smoke †

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Dedicated to Dr. A. DelSordo, in honor of his commitment to his patients, colleagues, family, and friends. * To whom correspondence should be addressed. E-mail: jiseeman@ yahoo.com

3.2. Effect of Ammonia on the Deposition, Retention, and Absorption of Nicotine Initially in the Gas Phase (Mechanism A) 3.3. Effect of Ammonia on the Absorption of Nicotine via Particle Deposition (Mechanism B) 3.4. Effect of Ammonia on Enhancing the Evaporation of Nicotine from Particles and the Subsequent Deposition of Nicotine (Mechanism C) 4. Time-Independent Tobacco or Smoke Parameters Are Incapable of Characterizing the Time-Dependent Properties of Mainstream Smoke Aerosol 4.1. Fraction of Nonprotonated Nicotine [Rfb] in Smoke Particles 4.2. “Smoke pH” and pHeff 5. Conclusions

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1. Introduction Cigarette smoking is addictive, and many attribute the tobacco alkaloid nicotine (1) to be the addictive agent in cigarettes (14). Some cigarette manufacturers add ammonia-forming ingredients as flavorants and processing agents (5-11), which can

10.1021/tx600290v CCC: $37.00 © 2007 American Chemical Society Published on Web 02/23/2007

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Chem. Res. Toxicol., Vol. 20, No. 3, 2007 327

Figure 1. Overall schematic for the “global” pathways in the transfer of nicotine from the cigarette to the brains of smokers during smoking. As shown in Figure 2, smoke constituents can evaporate from particles and gas-phase constituents including water vapor can condense onto particles. Details of the partitioning of nicotine, ammonia, and other smoke constituents in smoke aerosol are also shown in Figure 2.

(5, 12), but does not always (11), increase the amount of ammonia in mainstream (MS)1 smoke. Various hypotheses have been proposed that cigarette manufacturers add ammonia to the tobacco to increase ammonia in the smoke, thereby enhancing nicotine’s bioavailability to smokers; the total amount and relative proportions of free base, nonprotonated nicotine (1) relative to its protonated forms 2 and 3 present in MS smoke are widely believed to control the amount and rate of nicotine uptake in smokers and the amount and rate of nicotine delivered to the central nervous system (7, 10, 13-31).

Much of the ammonia added to tobacco blend components, especially reconstituted tobaccos, during manufacture is lost during subsequent heating and drying steps (32). Ammonia also reacts via the Maillard reaction with both endogenous carbohydrates and sugars and those added to the tobacco to form important flavorants (33-36). Ultimately, the ammonia removed or lost from the tobacco or from the smoke is unavailable for any proposed manipulation of nicotine. Each transformation shown in Figure 1 can play a role in affecting the total rate and amount of nicotine uptake by smokers. Cigarette smoking typically consists of two distinct steps: mouth intake, generally followed by inhalation; during 1 Abbreviations: ETS, environmental tobacco smoke; FTC, U.S. Federal Trade Commission; H-C, Health-Canada; ISO, International Organization for Standardization; MDPH, Massachusetts Department of Public Health; MS, mainstream, i.e., the smoke stream issuing from the mouth end of a cigarette; MSS, mainstream smoke; “tar”, the total particulate matter (all of the material trapped on a Cambridge filter pad during a machinesmoking protocol) minus both the mainstream smoke nicotine and water content.

these steps, smoke is mixed with inspired air simultaneously drawn into the mouth (12, 37-41). Some individuals do not inhale cigarette smoke but rather mouth-hold only, as in cigar smoking. Distinctions between mouth intake and alveolar intake have been reported (38, 42). The buccal cavity, the trachea, the bronchi and the deep lung can thus be directly exposed to nicotine in MS smoke. As illustrated in Figure 2, MS smoke is a reactive, dynamic aerosol composed of heterogeneous particles suspended in a gasphase (43-47). Smoke constituents can evaporate from particles; gases can deposit onto particles (48-50). Once MS smoke aerosol enters the body, four discrete mechanisms can describe the deposition of constituents (51) (see Figure 3 and its caption) (13). For the forms of nicotine 1-3, each has its own physical, chemical, and biochemical properties (46, 52-54) and its own deposition sites and retention and absorption characteristics (51, 55-57). The vast array of smoke constituents (58-60) can affect the processes shown in Figures 1-3 (43, 51, 61). No direct experimental study has examined whether ammonia increases the rate or amount of nicotine reaching the brains of smokers. Calls for this types of study have appeared (7, 10, 16, 28). In the absence of such conclusive studies, researchers have relied on indirect experiments to provide insights into the proposed effects of ammonia on nicotine’s transfer to the central nervous system of smokers. These indirect experiments range from the quantification of percent nicotine retention during inhalation by human smokers (12, 51) to studies on aged smoke particulate matter trapped as a thin film on membranes (29). The way a cigarette is smoked, for example, with or without dilution (a stream of air added to the smoke as it passes through the cigarette filter) can in principle affect the nature of the smoke (32, 62-65). Constituent retention by smokers can be dependent on their smoking topographies (51, 66-68), and smoking protocols and methods to quantify both exposure and retention must be considered in human studies (69, 70). Nonetheless, the use of machine-smoking methods to examine the physicochemical properties of smoke aerosol and mechanisms of smoke formation, for example, the relative rates of the evaporation of

328 Chem. Res. Toxicol., Vol. 20, No. 3, 2007

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Figure 2. Illustration of the properties of volatile and semi-volatile neutral, acidic, and basic constituents in tobacco smoke aerosols as well as nonvolatile organics and inorganic constituents in the particles of these aerosols. Only the volatiles and semi-volatiles can evaporate from the particles. In principle, individual molecules (or clusters) of nonvolatile smoke constituents can be in the gas phase, arriving there not by evaporation but by a physical process of “erupting” from the tobacco matrix caused by high flow rates through the cigarette coal during puffing. Air, which is mixed with MS smoke during puffing and inhalation, is not shown.

constituents from smoke particles (50) or tobacco-precursorsmoke product relationships (8, 71-74), provides useful and valid experimental data, even though the smoking protocols do not match any particular smoker or groups of smokers. This perspective reviews the role of ammonia in affecting the deposition and absorption of nicotine by human smokers. Specific attention will be focused on three topics, which have been reported in this journal (13, 27, 29): (1) the fraction of nonprotonated nicotine (1) under various conditions (called Rfb); (2) the role of ammonia in the evaporation of nicotine from tobacco smoke particles; and (3) “smoke pH” and “pHeff”. Emphasis will be placed on experimental data rather than reliance on “basic principles” (6). The major mechanisms of nicotine deposition, retention, and absorption that are illustrated in Figures 1-3 will serve to organize the discussion.

2. Time-Dependent Nature of Tobacco Smoke Aerosol The vast majority of research reported on MS smoke has involved the characterization of MS smoke total particulate matter, the portion of mainstream smoke that is collected on a Cambridge filter pad in a machine-smoking method (66, 7577). In contrast, to understand and evaluate the inhalation properties of MS smoke, one must evaluate the smoke aerosol as a function of time and location within the smoker’s body.

One aspect of MS smoke aerosol that has not been considered in detail previously is its time-dependent nature, a critical factor in the location and percentage of nicotine’s (and other smoke constituents’) deposition and retention by smokers. Sections 2.1-2.3 provide solid data that demonstrates the time-dependent nature of MS smoke aerosol.

2.1. Relative Concentrations of Constituents in MS Smoke Aerosol Particles, including Nicotine and Solanesol, during Human Smoking Studies Over the years, a number of reports have described the retention of MS smoke constituents in human smokers (51). In 1968, Dalhamn et al. (78, 79) reported the retention of acetaldehyde, isoprene, acetone, acetonitrile, toluene, carbon monoxide, and particulate matter in human smokers. Greater than 85% of the smoke constituents were retained except for carbon monoxide (54%) (80). In 1983, Hinds et al. (81) reviewed the literature and found that smoke intake ranges from 22 to 75%, with an average of 47%. In 1989, Ingebrethsen (65) reported on the total retention of eight MS smoke constituents considered to be essentially exclusively in the particles. These smoke constituents were, together with their total percent retention: phenol, 100%; nicotine, 99%; triacetin, 99%; propylene glycol, 99%; 3-hydroxypyridine, 98%; neophytadiene,

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Figure 3. Tobacco smoke aerosol particles, represented by the large open circles and ovals, and tobacco smoke gases, represented by the small circles (open and dark) outside the large open circles and ovals. Tobacco smoke constituents initially in the particles are represented by dark circles. Gas-phase constituents can deposit onto particles (arrows from small open circles into the large open circles). Particulate phase constituents can evaporate from the particles (arrows to the dark small circles). Four mechanisms are shown by which nicotine and other tobacco smoke constituents in tobacco smoke aerosol particles and gases can deposit on a tissue covered by a buffer. Mechanism A: gas-phase constituents deposit directly. Mechanism B: particles deposit. The constituents can then diffuse through the particle, into the buffer, and then into the tissue. Mechanism C: particulate phase constituents evaporate from the particles and then the newly gas-phase constituent deposits. Mechanism D: particles deposit, then constituents evaporate from the particles and deposit by gas-phase diffusion. Evaporation from the particles is the reverse of deposition of gasphase compounds onto the particles, also shown in Figure 3A and C. Geiser et al. pointed out that the surface tension of the epithelial lining fluid is such that particles are wetted and their constituents will not evaporate once the particles have deposited (155). The time freshly deposited smoke particles remain unwetted by the surface fluids of the lung is unknown and may take seconds or longer, especially in a long-term smoker whose lung tissues have been compromised because of smoking. In practice, it may be impossible to experimentally distinguish between Mechanism D and a combination of Mechanism B and Mechanism C. Consequently, Mechanism D is not discussed further in this perspective. Modified from a figure in ref 13. Table 1. Summary of Numerous Human Cigarette Smoke Retention Studies, as Reviewed by Baker and Dixon (51)

a

MS smoke constituent

retention in the human respiratory tract (%)

“particulate matter”a nicotine carbon monoxide nitric oxide “aldehydes”

60-80 90-100 55-65 100 90

See footnote 2.

94%; hydroquinone, 92%; and glycerol, 87%. In fact, Baker and Dixon (51) concluded that Ingebrethsen’s data (65) demonstrated that increased lung retention was in the order of increased constituent volatility. A number of studies have reported that the percent of total mass retention from MS smoke in human smokers was in the range of 20-80+%; the percent nicotine retention was consistently in the 90-100% range (12, 37, 51, 82-86). In their 2006 review, Baker and Dixon (51) concluded that “nicotine and semivolatile smoke constituents are retained to higher levels than particulate matter” (51)2 (see Table 1 for data that includes gases as well). They also pointed out that percent lung retention for smoke particles is dependent on other factors, such as depth of inhalation, hold time in the lungs, and exhalation volume; in contrast, nicotine retention is not significantly influenced by these respiratory parameters. 2 The terms “total particulate matter” and “particulate matter” refer to material captured during a machine-smoking method on, for example, a Cambridge filter pad or in an impaction trap. In contrast, MS smoke aerosol is composed of heterogeneous particles suspended in a gas phase. Trapped particulate matter is thus not the same in terms of physical or chemical properties as the particles in the dynamic aerosol. (For example, see Dube, M. F., and Green, C. R. (1982) Methods of collections of smoke for analytical purposes. Recent AdV. Tob. Sci. 8, 42-102.)

Table 2. Percent Retention of Nicotine and Solanesol during Human Smoking under either Mouth-Hold Only or Inhalation under Varying Conditionsa percent retention (%) nicotine inhalation depth (mL) 0 (mouth-hold only)

46

inhalation with 2-s breath hold 75 90 250 96 500 99 1000 99.5 breath-hold (s) (500 mL inhalation depth) 0 98 2 99 10 99.9

solanesol 34 58 52 68 72 52 68 88

a Data are from Armitage et al. (37). A 10 mg ISO “tar” yield cigarette was used without ammonia or ammonia-forming ingredients added to the blend. For cigarette design characteristics, see Armitage et al. (37).

Recently, Armitage et al. (37) reported the percent nicotine and solanesol (4) retained by human smokers under various mouth-hold and breath-hold conditions (Table 2). Solanesol, a major nonvolatile MS smoke constituent, is a useful marker for MS smoke particles. At five inhalation depths (from zero inhalation and a 2-s mouth-hold up to a 1 L inhalation and a 2-s breath-hold), nicotine retention was ca. 1.5 times greater than that of solanesol with near quantitative nicotine retentions at g250 mL inhalation depth. For three breath-hold durations (0, 2 and 10 s) at 500 mL inhalation depth, nicotine retention was g98%, while solanesol retention ranged from 52 to 88%. As discussed in section 3.2, Armitage et al. (12) examined the


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Table 3. Variation of the Composition of Ammonia and Nicotine in MS Smoke Aerosol Particles from Fresh Cigarette Smoke, as Determined by Denuder Tube Depositiona

run 1

2

3

remaining in the aerosol (% of initial concn)

remaining in the particlesb (mg/cig)

ratio of nicotine/NH3 remaining in particlesb

position (cm)

NH3

nicotine

NH3

nicotine

w/w

mol/mol

15 40 70 100 130 15 40 70 100 130 15 40 70 100 130

56% 49% 44% 42% 39% 57% 51% 46% 43% 40% 57% 51% 46% 43% 41%

99.0% 98.5% 98.2% 97.9% 97.6% 99.0% 98.4% 97.9% 97.2% 96.8% 99.3% 99.0% 98.5% 98.2% 97.9%

0.0167 0.0146 0.0132 0.0124 0.0117 0.0190 0.0169 0.0153 0.0142 0.0134 0.0169 0.0151 0.0137 0.0128 0.0121

0.799 0.795 0.791 0.788 0.785 0.92 0.918 0.926 0.928 0.928 1.04 1.03 1.03 1.03 1.02

47.8 54.6 59.9 63.6 67.0 48.7 54.2 60.6 65.4 69.4 61.5 68.7 75.1 80.4 84.6

5.02 5.73 6.29 6.67 7.03 5.11 5.69 6.36 6.87 7.28 6.45 7.21 7.89 8.43 8.88

a The results are for the industry monitor #16 cigarette. Experimental data are from Seeman et al. (50). b These calculations require knowledge of the initial gas phase-particle phase distribution of each smoke constituent in the aerosol that is being analyzed. The calculations are based on ammonia initially being 85% in the particle phase of fresh MS smoke. Even though ammonia is a gas at room temperature (bp -33 °C at atmospheric pressure), the acidic nature of MS smoke particles (10, 92, 150) assures that the ammonia is present, at least initially, in MS smoke aerosol particles as its ammonium salts (50). Huang et al. (97) recently concluded that >80% of the ammonia in MS smoke is found in the total particulate matter, and their data suggests that as much as 98% of the MS smoke ammonia is trapped in the total particulate matter during the FTC machine-smoking method. It is well established that all of the solanesol and >99% of the nicotine in MS smoke aerosol is in the particles (43, 45, 90). See text for additional information.

possible effect of ammonia-releasing compounds on the percent retention of nicotine and solanesol by human smokers.

In all of the human smoking experiments described above and other human smoking studies reviewed in 2006 by Baker and Dixon (51), nicotine retention was always significantly greater than solanesol retention and greater than the retention for other nonvolatile constituents in MS smoke particles. Because solanesol is nonvolatile, it can reach the lung-blood interfaces only by Mechanism B (Figure 3). That nicotine retention is greater than solanesol retention (and greater than other nonvolatile particle-phase constituents) establishes the importance of Mechanism C during smoking. In conclusion, the fact that different particle phase smoke constituents have different retentions in human smokers demonstrates the time-dependent nature of those particles. That percent particle retention but not percent nicotine retention is highly dependent on smoking behavior (51), combined with the fact that >99% of nicotine is initially in the smoke particles, is further evidence of the time-dependent nature of smoke particle composition. For example, the ratio of nicotine/nonvolatile particle constituent is highest as the smoke aerosol exits the cigarette and decreases from that point.

2.2. Time-Dependent Concentration of Ammonia, Nicotine, and Solanesol in Fresh Mainstream Tobacco Smoke Substances evaporate from aerosol particles at rates dependent on their respective concentrations and vapor pressures (51, 64, 87). Only the nonprotonated forms of organic bases can volatilize from smoke particles. (Similarly, only the protonated forms of organic acids can volatilize from smoke particles.) For all volatile and semi-volatile acids and bases, the extent of ionization, which is controlled by hydrogen ion activity, will

affect the relative concentrations of the neutral and ionic species. Thus, any modification of a cigarette blend that selectively increases the concentration of nonprotonated nicotine (1) in the particles can, in principle, increase the rate of evaporation of nicotine from those particles. Several experimental studies have examined the percent nicotine in the gas phase and relative rates of deposition of nicotine and other MS smoke constituents by passing fresh MS smoke through denuder tubes (48-50, 62, 88-90). Although denuder-tube experiments do not replicate human smoking behavior or the respiratory tract, such studies do provide meaningful information about the physicochemical properties of fresh smoke aerosol. Axial variation of deposited nicotine, ammonia and solanesol is a measure of the time-dependent composition of MS smoke (50). Careful experimental conditions are required to minimize non-laminar flow; turbulence can cause particles to deposit on the denuder tube surface. Sidestream smoke, which contains large amounts of ammonia (43), must be rigorously excluded from entering the denuder tube. Incorporation of the denuder tube into the smoking system must not affect smoke formation. A recent experimental study of fresh MS smoke incorporating the experimental requirements cited immediately above quantified the axial variation of the deposition of nicotine, ammonia, and solanesol (4) along a denuder tube (50). MS smoke was passed directly into the denuder tube without dilution. Table 3 lists the percent of ammonia and nicotine remaining in the smoke aerosol (particle plus the gas phase), the average mass of substance remaining in the aerosol particles, and time-dependent (i.e., agedependent) ratios of these constituents in the particles for the Industry Monitor #16 cigarette smoked according to the FTC machine-smoking protocol (50).3 After the smoke aerosol traveled 130 cm along the denuder tube, ca. 98% of the nicotine originally in the smoke particles remained in the aerosol, 3 The FTC and ISO machine-smoking methods include one 2-s 35 cm3 puff every 60 s. The Massachusetts Department of Public Health protocol is one 2-s 45 cm3 puff every 30 s with 50% of the ventilation holes covered. The Health-Canada protocol is one 2-s 55 cm3 puff every 30 s with 100% of the ventilation holes covered.

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whereas ca. 40% of the ammonia remained. The molar ratio of nicotine/ammonia in Run #1-2 increased from a mean value of 5.5 after 15 cm to 7.7 after 130 cm, on the basis of the partitioning value of 85% of the ammonia being initially in the particles. In Run #3, the molar ratio of nicotine/ammonia increased from a value of 6.5 after 15 cm to 8.9 after 130 cm. Similar results were found for the Marlboro Lights King Size cigarette (data reported in the original publication (50)). After the passage of the MS smoke from the Marlboro Lights King Size 120 cm, ca. 40% of the ammonia and 4% of the nicotine initially present in the aerosol deposited onto the tube. These experiments demonstrate that ammonia, nicotine, and solanesol (and by reasonable extrapolation, other volatile and semi-volatile smoke constituents initially present in the smoke aerosol particles) are depleted from the particles at constituentdependent rates. Thus, their relative concentrations within the smoke particles are time dependent, as illustrated in Table 3. The fact that ammonia evaporates from smoke aerosol particles much faster than nicotine formed the basis of Ingebrethsen’s (64) decision not to include ammonia in his recent numerical simulation of nicotine vapor deposition during smoking.

2.3. Computational Simulation of the Time-Dependent Volatile Loss of Nicotine, Ammonia, and Acetic Acid from an Aqueous Solution A computational simulation of the four component system nicotine, ammonia, acetic acid, and water were recently reported by Seeman et al. (50). The simulation model was limited to consider only the manner in which an aqueous mixture of volatile acids and bases may vary with time as the constituents undergo irreversible volatile loss and is not a model of the complex interior of a tobacco smoke aerosol particle. Similar models were reported by Ingebrethsen and co-workers (49, 64). The fractions of these components are not independent but are linked by hydrogen ion via the self-ionization of water, conservation of charge, and by their relative rates of volatile loss. Although water is a major constituent of both the particles and gas phase of smoke aerosol (43, 91), MS smoke particles are not dilute aqueous solutions. The aqueous assumption does follow numerous literature precedents (13, 14, 48-50, 64, 92, 93). Ideal solution behavior was assumed. Sufficient physical parameters were known to support the computation of the time course of the volatile loss for nicotine, ammonia, and acetic acid (50). Additional calculations were performed using formic and higher acids and also incorporating other initial conditions with similar results (50). The set of simultaneous rate equations that describe the model and full details of the actual simulations are presented in a previous publication (50). Figures 4 and 5 illustrate two model simulations with initial pH values of 6.01 and 8.01, respectively. The pH of aqueous extracts of MS smoke for commercial cigarettes fall within this range of values (10, 13, 94). These two initial conditions were chosen to illustrate the effects of a wide range of initial nicotine-ammonia concentrations in MS smoke (10, 50). In both simulations, after ca. 2 s, >97% of the ammonia had been lost from the model solution, whereas 80% of MS smoke ammonia was found in the total particulate matter, though the limited data presented suggests that >95% of the ammonia was trapped by the Cambridge filter pad. That ammonia, with such a high vapor pressure, is primarily in the total particulate matter is likely due to the acidity of MS smoke (32). It is also possible that some ammonia was in the gas phase of MS smoke but was trapped by the Cambridge filter pad. In principle, MS smoke ammonia could affect the mechanisms of nicotine deposition, absorption, and transfer to the bloodstream (Figures 2, 3, and 7). If the concentration of all of the aerosol particle smoke constituents remained constant except for an increased concentration of ammonia, the equilibrium shown in Figure 2 would result in an increased concentration of nonprotonated nicotine (1). This possibility and its consequences for Mechanisms A, B, and C on human smoking are discussed in the following section.

3.2. Effect of Ammonia on the Deposition, Retention, and Absorption of Nicotine Initially in the Gas Phase (Mechanism A) Nicotine is much less than 1% initially in the gas phase of fresh MS smoke (14, 43, 90). Gas-phase nicotine deposits and absorbes in the buccal cavity (55, 57), in part because of its water solubility. Because of its high vapor pressure and water solubility, ammonia initially in the gas phase of MS smoke (and that which rapidly evaporates from MS smoke particles) will, depending on the amount, primarily deposit in the buccal cavity, trachea, and bronchi before it reaches the deep lung (104-107). Ha¨ger and Niessner (108) reported that nicotine-containing synthetic acidic aerosols did not pick up ammonia when the latter was added to the aerosol as a gas subsequent to aerosol formation. It is thus reasonable to assume that ammonia (and nicotine) in the MS gas phase is more likely to deposit onto the oral cavity and biological tissues of the respiratory tract than redeposit onto MS smoke aerosol particles.

3.3. Effect of Ammonia on the Absorption of Nicotine via Particle Deposition (Mechanism B) 3.3.1. Deposition in the Mouth. For ammonia to increase the concentration of nonprotonated nicotine in an aerosol particle (Figure 2), the ammonia must be present in that particle.

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was studied by Armitage et al. (12) (Table 4). These researchers examined three cigarettes: a control cigarette (C) that contained reconstituted tobacco (6, 32) devoid of ammonia-forming ingredients; a test cigarette (T1) containing various types of reconstituted tobaccos with ammonia-forming compounds used in their preparation (diammonium phosphate, urea and/or ammonium hydroxide); and a second test cigarette (T2) in which urea was added to the tobacco blend. MS smoke ammonia yields from T1 and T2 were both greater than those from C, as expected given the presence of ammonia-forming compounds in the tobacco blend. For a 2 s mouth-hold in the absence of inhalation, nicotine retention was significantly higher for T1 (64 ( 11%) than for T2 (53 ( 11%) or C (46 ( 9%). Although the yield of MS smoke ammonia is T2 > T1, the reverse order was found for nicotine retention in the mouth. That the cigarette with the largest amount of MS smoke ammonia did not have the largest amount of nicotine retention in the mouth indicates that factors other than ammonia are important in controlling retention. Nicotine uptake into venous blood was not statistically different within this series, consistent with an earlier related result (109).

Figure 7. Graphical representation of nicotine equilibration 1 h 2 in a MS smoke particle at the lung-blood interfaces. For simplicity, diprotonated nicotine 3 is not shown because under these conditions, its concentration is likely to be low. The double arrows signify the extremely rapid rate of proton transfer compared to most other chemical reactions, which is certainly much faster than the rate of transfer across the lung-blood interfaces. The solid single arrow across the lungblood interface signifies the transfer of the well-accepted route of transfer of the nonprotonated, non-ionized species 1 into the bloodstream. As nonprotonated nicotine (1) transfers onto the surface of the interface, which is highly buffered, the equilibrium 1 h 2 is rapidly re-established because of the rapidity of proton transfers. Once 1 reaches the bloodstream, the buffering of the bloodstream rapidly re-establishes the equilibrium distribution of 1 h 2. The continuous re-establishment of the 1 h 2 equilibrium, together with the rapid dilution on the blood side by blood flow, permits all of the nicotine to pass through the lungblood interfaces. Of course, other pathways are possible. For example, some of the nicotine can metabolize in the lung. The dashed arrow across the lung-blood interface signifies the transfer of the monoprotonated form of nicotine 2. The results published by Nair et al. (133) and other references cited in the text suggest that this route may be possible.

Ammonia in fresh MS smoke passed through a denuder tube with laminar flow deposits onto the walls of the denuder tube at a much greater rate than nicotine in that MS smoke (50). This is because ammonia has a far greater vapor pressure than nicotine. Another physical phenomena works in the opposite direction though not sufficient to alter the rank order of volatility of ammonia . nicotine. Ammonia is a much stronger base than nicotine. Whatever the effective acidity of tobacco smoke particles, a greater percent of ammonia will be protonated compared with nicotine. Because ammonia evaporates from particles much faster than nicotine from tobacco smoke particles (49, 50), the influence of ammonia is likely to be only during the early lifetime of the particles. Ammonia enhancement of nicotine evaporation from MS smoke particles is most likely to occur in the buccal cavity, if at all. The effect of ammonia-forming ingredients in tobacco on nicotine retention during mouth-hold only by human smokers

For any particular nicotine exposure, to the extent that ammonia increases nicotine deposition and retention in the mouth, the amount of nicotine deposition in the lung must decrease by that amount. The rate and amount of nicotine to the bloodstream and, hence, to the brain of smokers is greater for lung absorption than buccal absorption (55, 110-116). Several studies found no increase in venous nicotine levels in smokers who took smoke into their mouths but did not inhale (109, 117) including two studies that measured significant levels of nicotine retention (12, 37). Arterial levels of nicotine are more indicative of nicotine availability to the central nervous system, but these measurements are far more complex than venous measurements; a recent model has been reported that estimates nicotine concentrations in arterial blood from venous measurements (118, 119). Baker and Dixon (51) reviewed unpublished research results of their British American Tobacco Company colleague Evelyn, who reported in 1968 that the mouth retention of nicotine increased from ca. 13% to 31% during a 5-s mouth hold of smoke because the “smoke pH” of this smoke increased from 5.10 to 7.75. Although these authors acknowledged the deficiencies in the concept of “smoke pH” (see section 4.2), they suggested that the increase in mouth retention of nicotine was due to changes in the “acid-base balance of the smoke particulate phase” (51), though actually it would be the smoke aerosol particles. Unfortunately, the smoke constituents affecting this wide range of “smoke pH” values were not determined. Should ammonia or any variation in the acid-base nature of smoke aerosol increase buccal absorption at the expense of lung absorption of nicotine, the overall amount and rate of nicotine to the bloodstream and to the brain will decrease (10). 3.3.2. Deposition in the Lung. Each puff of MS smoke contains ca. 1010 to 1011 particles and 90% and perhaps nearly 99% of nicotine inhaled by smokers is retained (12, 37, 51, 86). Hence, any role of Rfb(PM) on the magnitude of uptake seems unlikely, given the near quantitative retention of nicotine by smokers. Second, the rate of nicotine uptake is a kinetic (i.e., a time-dependent) phenomenon. As shown in Figure 6, Rfb(PM) is time independent because, as defined, it is determined under equilibrium conditions. In contrast, as shown in section 2, Rfb(t) of MS smoke aerosol is highly time dependent. Pankow et al. (29) reported Rfb(PM) values for 11 U. S. commercial cigarettes and one reference cigarette. Whole smoke (the combined first three puffs and, separately, the remaining puffs) was collected in Teflon bags and allowed to equilibrate. Smoke constituents deposited onto the surface of the Teflon bags. Headspace gases were collected and analyzed for nicotine, and Rfb(PM) values were then calculated. Shortly thereafter, Watson et al. (145) reported Rfb(PM) values for 26 brands of U. S. commercial cigarettes using solid-phase microextraction of the headspace above a Cambridge filter pad onto which had been trapped the total particulate matter from the smoking of each cigarette. These latter authors reported “excellent agreement between the two methods”, that is, their study (145) and that of Pankow et al. (29) published previously. The basis of this comparison is not clear because the pack identities of the cigarettes and their year of manufacture were not given. In addition, the former set of smokings (29) were under nonstandard3 puffing parameters, that is, two cigarettes were jointly smoked for 2-s 90 cm3 puffs (77) without a Cambridge filter pad, whereas the latter (145) was under the Massachusetts Department of Public Health puffing parameters3 (98) with a Cambridge filter pad. These two studies (27, 145) made a number of assumptions worthy of consideration. (a) Neither study performed a single measurement on fresh tobacco smoke aerosol. Rather, both studies examined trapped, aged, and equilibrated particulate matter in which some of the volatile acids and bases may not have been completely trapped, including ammonia and the weak smoke acids, carbonic and acetic acid. In addition, these studies did not follow the exact protocols for the machine-smoking methods that they reference, nor were their methods validated.

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(b) Because nicotine rapidly adsorbs to many surfaces including glass, the measurement of very low concentrations of gasphase nicotine can lead to large experimental errors (146). This may be the source of some of the large standard deviations in the data of Pankow et al. (29), for example, Rfb(PM) ) 0.26 ( 0.26 for Kamel Red and Rfb(PM) ) 0.027 ( 0.030 for Marlboro. (c) These (29, 145) and a related study (27) assumed that a single value of the fraction of nonprotonated nicotine in trapped smoke Rfb(PM) is equal to Rfb(t) of MS smoke aerosol during the lifetime of that aerosol. Even if Rfb(PM) were to equal Rfb(0) (which is not likely to be the case), a single value of Rfb(PM) per cigarette (or per puff) cannot predict the time dependent fraction of nonprotonated nicotine (1) in actual tobacco smoke aerosol particles. (d) In addition, none of these studies (27, 29, 145) related the calculated Rfb(PM) values to either ammonia-forming ingredients in the tobacco or ammonia or nicotine in the smoke. There are additional reasons why Rfb(PM) is unlikely to be a useful predictive of the rate and amount of nicotine uptake by human smokers. For example, smokers modify their own smoking behavior (66-68, 147). Furthermore, variations exist in nicotine metabolism within the smoking population (46). Finally, although nicotine was once thought to cross the deep lung-blood interfaces very rapidly as part of a “bolus” effect (3, 148), nicotine may not enter the systemic circulation as rapidly as previously hypothesized (112, 123, 129). Should there be a delay of nicotine transfer through the lung-blood interfaces (see section 3.3.2) (126, 127), any acid-base phenomena within the particle (and to date, none has been experimentally established) is even less likely to demonstrate an effect on the rate of nicotine transfer from the lung to the bloodstream. Such a delay, essentially a slow step in the overall pathway of nicotine to the bloodstream, will cause a leveling effect and cancel out any minor differences in transfer because of the local variations in the rate of transfer of nicotine through the lung-blood interfaces. For several of the above stated reasons, NMR data of either trapped smoke or solutions of trapped smoke in, for example, DMSO (27, 149) are unlikely to be useful in predicting the timedependent properties of dynamic MS smoke aerosol.

4.2. “Smoke pH” and pHeff Tobacco industry, government, and academic researchers alike have “measured” “smoke pH” during the past few decades (150). The parameter “smoke pH” requires an operation in which a sample of the gas-particle mixture, that is, MS smoke aerosol, is manipulated to yield a sample suitable for pH measurement. Two types of methods have been used. In the more classical approach, MS smoke, or a portion of MS smoke, is trapped, and the pH of an aqueous extract of the trapped material is measured (93). In the second, a special coated electrode that absorbs some of the MS smoke constituents is inserted into the smoke stream, and a pH reading is obtained (92). These “smoke pH” measurements represent the relative molar concentrations of acids and bases extracted under different experimental conditions. There has not been any analysis of the variation, if any, of the chemical constituents in the smoke extract as a function of the resultant measured pH values, nor has there been any evaluation of the non-extractable acids and bases in MS smoke aerosol. “Smoke pH” values have uncertain meaning and lack validated utility. Nonetheless, the procedures are rather simple to perform, and pH values have been widely reported for cigarette and cigar smoke (28, 150) as well as for

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Figure 8. Relationship between “smoke pH” and tar for (A) the ISO-, (B)-MDPH- and (C) Health-Canada machine-smoking paradigms for a series of international commercial Philip Morris brands. Data from Counts et al. (98).

other initially non-tobacco, nonaqueous mixtures, for example, soil samples (151, 152), agar or beads (153), and low-moisture foods (154). “Smoke pH” values for commercial cigarettes fall within a narrow range for any one measurement method. It is well-known that different measurement methods lead to systematic variations in the measured values (5, 10, 13, 150). One variable is whether carbon dioxide in MS smoke is trapped and included in the sample being evaluated; carbonic acid is formed from the reaction of carbon dioxide and water. There are also other systematic variables including laboratory-to-laboratory variation and method-to-method variation, that is, the pH measurement of an aqueous extract of smoke and pH values of an electrode placed into smoke (92). Figure 8 presents the relationships of “smoke pH” versus tar for three machine-smoking methods: the ISO method, the Massachusetts Department of Public Health method, and the Health-Canada3 method. These three protocols have increasing smoking intensity, as shown by their respective increasing tar yields. As can be seen, there is a slight though statistically significant inverse relationship, between “smoke pH” and tar for the ISO and MDPH methods but not for the H-C method. Figures 9 and 10 present the same “smoke pH” data versus MS smoke ammonia and MS smoke nicotine, respectively. Again, there is a slight though statistically significant inverse relationship between “smoke pH” and both MS smoke ammonia and MS smoke nicotine for the ISO and MDPH methods but not

for the H-C method. These latter inverse relationships are worthy of note, given that several authors have considered “smoke pH” to be a surrogate for increased free-base nicotine concentration in MS smoke due to ammonia (7, 13, 15, 16, 28, 31). Several recent publications have properly criticized the continued use of the “smoke pH” (5, 10, 13, 28, 51), primarily because pH refers to a measurement performed on a dilute aqueous solution, and tobacco smoke is certainly not a dilute aqueous solution. For that reason and because of the rather narrow “smoke pH” range observed in commercial cigarettes, the scatter typically observed, and the lack of any relationship reported between “smoke pH” and any relevant pharmacokinetic or pharmacodynamic property, I believe that there is little, if any, use of “smoke pH” for commercial cigarettes. In an attempt to retain some type of “smoke pH” parameter but to overcome the “smoke is not an dilute aqueous solution fatal flaw”, Pankow and co-workers (13, 14, 29) created a parameter, pHeff (eq 1), where “eff” means “effective”. pHeff is calculated for tobacco smoke in the following fashion. First, an experiment is performed in which the fraction of nicotine in its nonprotonated form in a nonaqueous matrix is estimated using some type of experiment, for example, Rfb(PM) (Figure 6). That matrix can be a thin film of smoke particulate matter deposited on the walls of a Teflon balloon (29), particulate matter adsorbed onto a Cambridge filter pad (145), or as an oil in an NMR tube (27, 149). The Henderson-Hasselbalch


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Figure 9. Relationship between “smoke pH” and MS smoke ammonia for (A) the ISO, (B) MDPH, and (C) Health-Canada machine-smoking paradigms for a series of international commercial Philip Morris brands. Data are from Counts et al. (98).

equation relates the pH of an aqueous solution to the percentages of charged and noncharged species in that solution. Generally, the Henderson-Hasselbalch equation is used as follows: the pH of a dilute aqueous solution is measured, and with knowledge of the pK values of the dissolved acids and bases, the percent of each acid and base in its charged and non-charged forms is calculated. Regarding pHeff, the Henderson-Hasselbalch equation was used in a reverse direction (13, 27, 29, 149), from the estimated concentration of noncharged (nicotine) species in a nonaqueous mixture, pHeff is calculated. pHeff is defined as the pH that a hypothetical dilute aqueous solution of nicotine would have to be, such that its fraction of nonprotonated nicotine would equal the value estimated for the nonaqueous matrix under study.

pHeff ) pKa + log

Rfb(PM) 1 - Rfb(PM)

(1)

There are several problems regarding pHeff of smoke particulate matter. (a) Smoke is not a homogeneous, aqueous solution. (b) Nicotine is not at equilibrium in smoke aerosol. (c) A single value of “smoke pH” or pHeff cannot describe the real properties of time-dependent smoke aerosol (section 2). Discussions that have invoked “smoke pH” or pHeff would have been more useful had they evaluated the concentrations of constituents that affect smoke chemistry and bioavailability, not ill-defined surrogates.

5. Conclusions Tobacco smoke is a dynamic aerosol comprising particles suspended in a gas phase. Smoke constituents can both react with each other and can also be lost to the environment, thereby causing significant time-dependent changes in composition. Several independent types of experiments and modeling provide consistent and conclusive evidence that the relative concentration of constituents in tobacco smoke aerosol particles varies with the lifetime of the particle and depends on the vapor pressure of each constituent. Three fundamentally distinct but related mechanisms (AC) of nicotine deposition during smoking have been evaluated in this perspective. Human smoking studies have demonstrated that Mechanism B and Mechanism C are predominant, Mechanism A being minor. Mechanism A: Deposition of nicotine originally in the gas phase of MS smoke is likely to occur in the buccal cavity and upper respiratory tract. Less than 1% of nicotine in MS smoke is initially in the gas phase. Any nicotine depositing in the buccal cavity has a lower efficiency to reach the bloodstream and will do so at a slower rate than the nicotine deposited in the lung. Mechanism B: Deposition of nicotine-containing aerosol particles onto the buccal cavity, trachea, bronchi, or the deep lung-blood interfaces followed by diffusion of the nicotine from the particle to the tissue. For particles that deposit in the buccal cavity, see comments under Mechanism A. When particles deposit on the lung-blood interfaces, nicotine is rapidly

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Figure 10. Relationship between “smoke pH” and MS smoke nicotine for (A) the ISO, (B) MDPH, and (C) Health-Canada machine-smoking paradigms for a series of international commercial Philip Morris brands. Data are from Counts et al. (98).

absorbed, regardless of the acid-base nature of the particles. This is due to the buffering capacity of the lung-blood interfaces and the small mass of nicotine per puff distributed over a large number of particles depositing onto a huge lung surface. Mechanism C: Evaporation of nicotine from an aerosol particle followed by deposition of the resultant gas-phase nicotine onto a biologically relevant surface. Because of its low molecular weight and basicity, ammonia’s influence on the effective acidity of smoke particles is far greater than nicotine’s effect but only when the ammonia remains in the particle. Ammonia evaporates much more quickly than nicotine from smoke particles. If there is any ammonia effect on nicotine’s volatility from tobacco smoke particles, it must be in the early lifetime of MS smoke particles, perhaps only in the buccal cavity. The experimental data do not support any of the ammonia manipulation of nicotine hypotheses as they relate to commercial cigarettes. Attempts to relate the properties of trapped, precipitated, and aged smoke particulate matter to fresh tobacco smoke aerosol must be accompanied with sufficient data to establish the validity of such an extrapolation. No single tobacco or MS smoke

measurement, especially one made under equilibrium conditions (e.g., “smoke pH” or the fraction of nonprotonated nicotine in trapped, aged smoke particulate matter, Rfb(PM)), can adequately characterize the time-dependent properties of smoke aerosol. Thus, “smoke pH”, smoke pHeff, and Rfb(PM) have little value, if any, in understanding, explaining, or predicting tobacco smoke chemistry or nicotine bioavailability from commercial cigarettes. It has not been demonstrated and it is unlikely that values of Rfb(PM) determined for the trapped, aged smoke particulate matter obtained from different cigarettes will translate into ranges in the magnitude and rate of nicotine uptake by smokers. The concentration of constituents of MS smoke can provide more useful leads to explain physicochemical and pharmacological events than “smoke pH,” pHeff, and Rfb(PM). Regarding the ammonia manipulation of nicotine, the definitive human smoking studies have yet to be performed (7, 10, 16, 28): smoke a series of cigarettes having a range of ammoniaforming ingredients in the tobacco and ammonia in the MS smoke and determine nicotine concentrations in the arterial blood and brains of the smokers as a function of time. 6Articles published in the journal Beitr. Tabakfrosch. Int. are available free of charge via the Internet at http://www.beitraege-bti.de/nxt/ gateway.dll?f)templates&fn)default.htm&vid)btfi:btfi.


Acknowledgment. I thank Philip Morris USA and Philip Morris Products S.A. for many years of support during my employment and subsequent consultantship and for commissioning many intellectually challenging and important research topics, some of which have formed the basis of this perspective. This perspective is based, in part, on research now published, which was funded by Philip Morris USA and/or Philip Morris Products S.A. I thank Clarence G. Trowbridge and James P. Snyder (Emory University), Peter N. Lee (P N Lee Statistics and Computing Ltd., a consultant to Philip Morris Products S.A.), and the following current or former employees of Philip Morris USA or Philip Morris Products S.A. for many helpful discussions: Charlene H. Callicutt, Richard H. Cox, Alan I. Goldsmith, Robin D. Kinser, Gerd Kobal, Susan W. Laffoon, Peter J. Lipowicz, Kathleen Mitchell, Michael J. Morton, Kenneth F. Podraza, Edward B. Sanders, and especially Richard A. Carchman. Writing this perspective was entirely funded by SaddlePoint Frontiers. Supporting Information Available: The effect of ammonia on enhancing the evaporation of nicotine from particles and subsequent deposition of nicotine (mechanism C). Supporting Information for section 3.4. This material is available free of charge via the Internet at http://pubs.acs.org.

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