Optimising Nicotine Release Nicotine and Dependence

which฀nicotine฀is฀absorbed฀primarily฀in฀the฀lungs,฀whereas฀the฀nicotine฀from฀alkaline฀cigar฀ smoke฀is฀absorbed฀primarily฀in฀the฀mouth,฀not฀least฀because฀of฀the฀larger฀doses฀of฀nicotine฀ involved฀ [70] .

3.3.7 Importance of Absorption Rate

Since฀physiological฀effects฀are฀to฀be฀anticipated฀very฀much฀more฀rapidly฀from฀non-bound฀ free฀nicotine฀as฀the฀ammonium฀ion฀than฀from฀bound฀nicotine฀as฀ammonium฀chloride,฀ smoke฀with฀a฀high฀pH฀is฀richer฀in฀nicotine.฀Consequently,฀the฀nicotine฀yield฀of฀cigarette฀ smoke฀may฀be฀considered฀as฀a฀measure฀of฀the฀strength฀of฀the฀cigarette฀ [71] ฀because฀more฀ rapid฀absorption฀is฀then฀to฀be฀expected฀ [72] .฀Nevertheless,฀nicotine฀is฀absorbed฀in฀the฀fol- lowing฀three฀forms: • ฀ As฀salt฀from฀the฀particulate฀phase฀1 • ฀ As฀free฀base฀in฀the฀particulate฀phase฀2 • ฀ As฀free฀base฀in฀the฀gas฀phase฀3 The฀ratio฀23฀has฀long฀been฀considered฀to฀be฀important฀for฀the฀nicotine฀effect฀ [73] .฀ Altering฀the฀pH฀of฀cigarette฀tobacco฀was฀intended฀to฀provide฀an฀extra฀“kick”฀ [74,฀75] .฀ Moreover,฀this฀objective฀was฀to฀be฀achieved฀by฀a฀increasing฀the฀Burley฀content฀in฀the฀ tobacco฀blend,฀b฀reducing฀the฀sugar฀casing฀used฀for฀the฀tobacco,฀c฀using฀alkalis฀–฀espe- cially฀ammonium฀compounds฀–฀for฀the฀tobacco฀blend,฀d฀adding฀nicotine฀to฀the฀tobacco฀ blend,฀e฀removing฀acid฀constituents฀from฀the฀tobacco,฀f฀using฀special฀ilter฀systems฀ which฀permit฀removal฀of฀acids฀and฀addition฀of฀alkalis฀to฀mainstream฀smoke฀and฀g฀using฀ ilter฀systems฀that฀dilute฀the฀inhaled฀air฀to฀a฀major฀extent.฀Some฀of฀these฀considerations฀ have฀already฀been฀tested฀at฀Philip฀Morris฀ [76] .

3.3.8 Ammonium and pH Manipulation

During฀cigarette฀smoking,฀the฀free฀nicotine฀base฀is฀absorbed฀in฀the฀pulmonary฀alveoli.฀In฀ many฀cases,฀nicotine฀is฀found฀only฀in฀trace฀amounts฀in฀the฀particles฀of฀exhaled฀mainstream฀ smoke.฀The฀intensity฀of฀nicotine฀delivery฀was฀further฀increased฀by฀the฀addition฀of฀ammo- nium฀salts฀cf.฀the฀practices฀of฀Philip฀Morris฀ [9] .฀At฀the฀same฀time,฀the฀measurements฀of฀ tar฀and฀nicotine฀in฀the฀FTC฀smoking฀machines฀were฀no฀longer฀representative฀Tables฀ 3.5 ฀ and฀ 3.6 ฀because฀the฀ratio฀of฀free฀to฀bound฀nicotine฀could฀not฀be฀determined;฀also฀the฀tar฀ yields฀measured฀were฀lower฀than฀in฀reality฀Tables฀ 3.5 ฀and฀ 3.6 ฀ [77] .฀The฀use฀of฀ammo- nium฀technology฀permitted฀the฀downward฀manipulation฀of฀nicotine฀yields฀measured฀in฀the฀ smoking฀machines,฀but฀the฀smoker฀still฀got฀the฀expected฀“kick”฀ [78] .฀This฀was฀the฀decisive฀ inding:฀the฀greater฀the฀alkalinity฀of฀mainstream฀smoke,฀the฀faster฀the฀build-up฀of฀nicotine฀ in฀the฀blood฀and฀hence฀the฀“kick”.฀The฀tobacco฀industry฀declared฀the฀added฀ammonium฀ salts฀as฀“lavour฀correction฀agents”฀and฀not฀as฀additives฀to฀enhance฀the฀nicotine฀effect.฀ Seen฀in฀these฀terms,฀no฀objection฀to฀these฀pH฀manipulations฀can฀be฀serious฀enough.

3.4 Tobacco Additives

In฀ the฀ EU,฀ more฀ than฀ 600฀ additives฀ are฀ used฀ in฀ the฀ manufacture฀ of฀ tobacco฀ products฀ Table฀ 3.7 .฀Although฀these฀additives฀are฀subjected฀to฀toxicological฀testing,฀it฀is฀unclear฀ what฀effects฀they฀have฀on฀smoking฀behaviour:฀if฀such฀products฀when฀added฀to฀tobacco฀ lead฀to฀accelerated฀dependence,฀hasten฀the฀craving฀to฀smoke฀or฀initiate฀an฀increased฀crav- ing,฀then฀this฀is฀a฀major฀problem฀ [79] .฀With฀more฀than฀1฀million฀people฀dying฀annually฀ from฀smoking-related฀causes,฀a฀mere฀1฀increase฀due฀to฀the฀addition฀of฀a฀chemical฀to฀ tobacco฀may฀result฀in฀the฀premature฀death฀of฀hundreds฀or฀thousands฀of฀smokers.฀For฀this฀ reason,฀additives฀in฀tobacco฀products฀are฀a฀major฀public฀health฀issue฀in฀their฀own฀right. Some฀600฀additives฀have฀been฀approved฀as฀admixtures฀to฀tobacco฀products.฀However,฀ only฀the฀tobacco฀companies฀can฀disclose฀which฀additives฀appear฀in฀which฀cigarette฀brands.฀ Not฀even฀the฀European฀Commission,฀which฀is฀responsible฀for฀the฀regulation฀of฀tobacco฀ products,฀can฀provide฀this฀information฀or฀has฀the฀power฀to฀demand฀it. Additives฀are฀put฀into฀tobacco฀see฀Table฀ 3.7 ;฀ [80] ฀for฀the฀following฀reasons: • ฀ To฀increase฀the฀free฀nicotine฀portion฀because฀this฀boosts฀the฀“kick”.฀Ammonium฀com- pounds฀have฀been฀found฀to฀fulfil฀this฀role฀because฀they฀increase฀the฀alkalinity฀of฀the฀ smoke. • ฀ To฀improve฀the฀lavour฀of฀tobacco฀and฀to฀make฀the฀product฀more฀desirable. • ฀ Sweeteners฀and฀chocolate฀are฀used฀as฀additives฀to฀make฀the฀lavour฀of฀tobacco฀more฀ appealing฀to฀children฀and฀irst-time฀users.฀Eugenol฀and฀menthol฀are฀added฀to฀“mask”฀the฀ harmful฀effects฀on฀the฀respiratory฀tract. • ฀ Cocoa฀is฀added฀as฀a฀bronchodilator฀with฀the฀goal฀of฀achieving฀deeper฀inhalation฀so฀that฀ more฀nicotine฀and฀tar฀reaches฀the฀alveoli฀in฀the฀lower฀pulmonary฀segments. • ฀ Additives฀are฀used฀to฀make฀the฀smell฀and฀visibility฀of฀side-stream฀smoke฀less฀annoying฀ and฀mask฀its฀dangerous฀nature฀and฀thus,฀to฀make฀it฀more฀difficult฀for฀passive฀smokers฀ to฀protect฀themselves฀from฀smoking. Various฀additives฀are฀already฀toxic฀alone฀or฀in฀combination฀with฀other฀additives฀and฀phar- macologically฀active฀or฀toxic฀products฀are฀also฀formed฀during฀the฀combustion฀process. Substances฀intended฀to฀keep฀the฀tobacco฀moist฀see฀above฀may฀account฀for฀up฀to฀5฀ of฀the฀tobacco฀weight฀in฀a฀cigarette:฀one฀such฀example฀is฀glycerol฀which฀undergoes฀trans- formation฀to฀the฀ciliatoxic฀substances฀acrolein฀and฀propylene฀glycol฀ [81] .฀Propylene฀oxide฀ has฀been฀detected฀in฀the฀tobacco฀smoke฀of฀cigarettes฀treated฀with฀propylene฀glycol฀ [82] .฀ Ethylene฀glycol฀has฀also฀been฀used฀to฀moisten฀cigarette฀tobacco;฀however,฀this฀practice฀has฀ been฀banned฀because฀of฀the฀formation฀of฀carcinogenic฀ethylene฀oxide฀following฀combus- tion฀ [83] .฀In฀addition,฀traces฀of฀N-hydroxyethylvaline฀haemoglobin฀217–690฀pmolg฀hae- moglobin฀have฀been฀detected฀in฀the฀blood฀of฀smokers฀ [84] ,฀whereas฀non-smokers฀have฀ only฀about฀15฀of฀such฀levels. Tobacco฀ aroma฀ is฀ intensiied฀ by฀ tobacco-speciic฀ terpenoids,฀ pyrroles฀ and฀ pyrazines฀ [85,฀86] ,฀but฀this฀effect฀is฀attenuated฀in฀turn฀by฀ilter฀tips.฀Tobacco฀aroma฀has฀been฀modiied฀ by฀the฀addition฀of฀mint,฀wood,฀spices,฀fruits฀and฀lower฀essences฀coumarins,฀but฀also฀of฀