Toxic Substances and Inducers

indings฀indicate฀that฀carcinogen฀clearance฀is฀decreased฀in฀slow฀acetylators,฀with฀the฀result฀ that฀these฀individuals฀are฀at฀greater฀risk฀for฀tumour฀development฀ [375] .฀Also,฀as฀a฀result฀of฀ genetic฀polymorphism,฀aromatic฀amine฀acetyltransferase฀NAT-1฀activity฀in฀the฀urinary฀ bladder฀ mucosa฀ causes฀ increased฀ bioactivation฀ of฀ N-hydroxy฀ arylamines฀ into฀ reactive฀ N-acetoxy฀esters฀that฀form฀DNA฀adducts฀ [376] .฀Tobacco฀smoke฀is฀reported฀to฀induce฀the฀ CYP2E1฀enzyme฀in฀renal฀tissue,฀leading฀to฀DNA฀strand฀breaks฀ [377] . Infections฀with฀the฀human฀papilloma฀virus฀HPV฀are฀reported฀to฀encourage฀the฀devel- opment฀of฀cancer฀of฀the฀cervix฀in฀female฀smokers฀because฀HPV฀promotes฀the฀breakdown฀ of฀tobacco฀constituents฀such฀as฀benzo[a]pyrene,฀giving฀rise฀to฀highly฀reactive฀products฀ e.g.฀[3H]B[a]P-9,10-diol฀or฀[3H]trans-anti-B[a]P-tetraol฀which฀form฀increased฀levels฀of฀ DNA฀adducts,฀a฀prerequisite฀for฀malignant฀cell฀growth฀ [378] . In฀ addition,฀ smoking฀ causes฀ a฀ fourfold฀ increase฀ in฀ micronucleated฀ cells฀ in฀ urothelial฀ ฀tissue;฀no฀difference฀was฀observed฀between฀micronucleated฀cell฀rates฀of฀smokers฀and฀ex-฀ smokers,฀suggesting฀that฀smoking฀may฀generate฀clones฀of฀these฀cells฀ [379] .฀Little฀is฀known฀ concerning฀the฀causation฀of฀urothelial฀cancer.฀In฀one฀study฀conducted฀in฀West฀Berlin฀between฀ 1990฀and฀1995,฀it฀was฀shown฀that฀the฀risk฀for฀such฀cancer฀is฀increased฀more฀by฀current฀smok- ing฀OR฀=฀3.46;฀CI:฀2.50–4.78฀than฀by฀previous฀but฀now฀abandoned฀smoking฀OR฀=฀1.51;฀ CI:฀1.09–2.81฀ [380] . Tissue฀factor฀TF฀encrypted฀in฀the฀plasma฀membrane฀of฀renal฀cells฀is฀a฀physiological฀ initiator฀of฀blood฀coagulation฀and฀is฀thought฀to฀be฀important฀in฀a฀variety฀of฀solid฀malignan- cies,฀particularly฀where฀angiogenesis฀is฀a฀critical฀factor.฀TF฀is฀also฀excreted฀in฀the฀urine,฀but฀ excreted฀levels฀are฀not฀affected฀either฀by฀age฀or฀by฀smoking฀ [381] . Smokers฀who฀consume฀more฀than฀10฀g฀tobacco฀daily฀excrete฀more฀b-hexosaminidase฀ a฀marker฀of฀renal฀injury฀than฀non-smokers฀ [382] .

7.6.2 Kidney Cancer

According฀to฀an฀analysis฀of฀the฀incidence฀of฀kidney฀cancer฀in฀Central฀Europe,฀the฀highest฀ observed฀rate฀was฀recorded฀in฀the฀former฀Czechoslovakia฀with฀8.37฀cases100,000฀popula- tion฀1990–1994:฀this฀igure฀is฀expected฀to฀rise฀to฀10.38฀cases100,000฀for฀the฀period฀2000– 2004.฀Alcohol฀and฀cigarette฀consumption฀are฀cited฀as฀the฀most฀important฀determining฀factors฀ [383] .฀In฀a฀study฀of฀133฀histologically฀conirmed฀cases฀of฀kidney฀cancer,฀multivariate฀analy- sis฀revealed฀that฀smoking฀habits฀accounted฀for฀26฀of฀cases,฀while฀genetic฀factors฀accounted฀ for฀only฀3฀ [384] . Concurrent฀ presence฀ of฀ b-carotene฀ deiciency฀ was฀ associated฀ with฀ an฀ additional฀ increase฀in฀the฀risk฀of฀kidney฀cancer.฀Adolescents฀who฀start฀to฀smoke฀before฀the฀age฀of฀18฀ double฀their฀risk฀of฀developing฀cancer฀of฀the฀renal฀pelvis,฀whereas฀renal฀cell฀cancer฀was฀ observed฀only฀after฀25฀years฀of฀smoking฀ [385] .฀According฀to฀one฀recent฀study,฀cigarette฀ smoking฀was฀found฀to฀increase฀the฀risk฀of฀kidney฀cancer฀among฀males฀OR฀=฀1.8;฀CI:฀ 1.3–2.7฀more฀than฀among฀females฀OR฀=฀1.2;฀CI:฀0.8–1.8฀ [386] .฀A฀case฀of฀papillary฀ kidney฀cancer฀has฀been฀reported฀in฀a฀young฀man฀who฀had฀smoked฀marijuana฀heavily฀for฀ years฀ [387] .

7.6.3 Bladder Cancer

The฀causes฀of฀bladder฀cancer฀are฀to฀be฀sought฀in฀genetic฀changes฀in฀various฀key฀enzymes฀see฀ Sects.฀7.6.1฀and฀7.6.4฀and฀in฀the฀renal฀excretion฀of฀the฀combustion฀products฀of฀smoking. Chromosome฀9฀alterations฀have฀been฀described฀in฀smoking-related฀bladder฀cancer฀ [388] .฀ Half฀of฀all฀kidney฀and฀bladder฀cancers฀in฀men฀are฀related฀to฀smoking.฀According฀to฀an฀Italian฀ study,฀46฀of฀bladder฀cancers฀are฀attributable฀to฀smoking฀ [389] .฀In฀male฀smokers,฀the฀risk฀of฀ bladder฀cancer฀is฀3–7฀times฀higher฀than฀in฀non-smokers฀ [390–392] .฀Among฀women฀37฀of฀ bladder฀cancers฀and฀12฀of฀kidney฀cancers฀are฀smoking-related฀ [393,฀394] ,฀and฀odds฀ratios฀ of฀2.4฀CI:฀1.5–4.0฀and฀2.8฀CI:฀1.2–6.3฀have฀been฀reported฀ [391] .฀Frequent฀coffee฀consump- tion฀has฀been฀cited฀as฀an฀additional฀risk฀factor฀for฀bladder฀cancer.฀Twenty฀years฀ago,฀a฀case– control฀study฀detected฀an฀increased฀smoking-related฀risk฀for฀bladder฀cancer฀in฀men฀RR฀=฀4.8;฀ CI:฀2.4–9.3฀and฀women฀1.7;฀CI:฀1.0–2.7,฀with฀the฀extent฀of฀smoking฀inluencing฀the฀risk฀of฀ cancer฀ [395,฀396] .฀In฀particular,฀heavy฀cigarette฀smokers฀³2฀pack-years฀who฀inhaled฀deeply฀ increased฀their฀risk฀sevenfold฀whereas฀cigar฀smoking฀had฀no฀effect฀on฀the฀development฀of฀ bladder฀cancer฀ [397] .฀Transitional฀cell฀carcinomas฀also฀occurred฀primarily฀in฀smokers,฀with฀ military฀personnel฀being฀at฀greater฀risk฀than฀other฀population฀groups฀ [398] .฀The฀results฀of฀ treatment฀for฀bladder฀cancer฀also฀depend฀on฀smoking฀cessation฀ [399] .฀Differences฀in฀terms฀of฀ increased฀risk฀have฀been฀shown฀between฀smokers฀of฀cigarettes฀OR฀=฀3.5;฀CI:฀2.9–4.2,฀pipes฀ OR฀=฀1.9;฀CI:฀1.2–3.1฀and฀cigars฀OR฀=฀2.3;฀CI:฀1.6–3.5,฀but฀the฀duration฀of฀cigar฀or฀ciga- rette฀ smoking฀ had฀ no฀ effect฀ on฀ the฀ incidence฀ of฀ carcinoma฀ [400] .฀ Non-transitional-cell฀ carcinomas฀are฀reported฀principally฀in฀smokers฀OR฀=฀3.61;฀CI:฀2.08–6.28,฀with฀extremely฀ heavy฀smokers฀being฀at฀even฀greater฀risk฀OR฀=฀7.01;฀CI:฀3.60–13.66฀ [401] .

7.6.4 Cancer of the Cervix

A฀ high฀ proportion฀ of฀ cervical฀ cancers฀ and฀ of฀ cases฀ of฀ cervical฀ intraepithelial฀ neoplasia฀ stage฀III฀may฀be฀regarded฀as฀smoking-related฀ [402–408] ,฀as฀shown฀by฀the฀studies฀from฀ countries฀all฀over฀the฀world.฀Genetic฀polymorphism฀at฀detoxifying฀enzyme฀loci฀such฀as฀ CYP2D6฀ and฀ glutathione฀ S-transferase฀ GSTM1฀ may฀ determine฀ susceptibility฀ to฀ these฀ cancers฀ [408,฀409] .฀Smoking฀is฀an฀independent฀risk฀factor฀ [410] ฀which฀also฀correlates฀with฀ pack-years฀of฀smoking,฀causing฀the฀risk฀to฀increase฀by฀as฀much฀as฀12-fold฀ [411] .฀In฀one฀ case–control฀study฀conducted฀in฀a฀relatively฀large฀population฀in฀UtahUSA,฀the฀risk฀of฀cer- vical฀cancer฀was฀increased฀depending฀on฀pack-years฀of฀smoking฀ever-smokers฀vs.฀smok- ers฀5฀pack-years:฀OR฀=฀2.21;฀CI:฀1.44–3.39฀vs.฀3.42;฀CI:฀2.10–5.57฀ [412] .฀One-third฀of฀all฀ 1,993฀newly฀diagnosed฀cases฀of฀cervical฀cancer฀were฀attributable฀to฀smoking฀ [412,฀413] ,฀ and฀in฀these฀tumours฀too฀the฀breakdown฀products฀of฀smoke฀excreted฀via฀the฀cervical฀epithe- lium฀act฀as฀inducers฀of฀carcinogenesis฀ [413,฀414] .฀Nicotine฀and฀cotinine฀have฀been฀detected฀ in฀the฀cervical฀mucus฀their฀levels฀correlate฀with฀the฀number฀of฀cigarettes฀smoked฀ [415] ,฀ and฀passive฀smokers฀are฀also฀affected.฀In฀particular,฀one฀carcinogenic฀tobacco-speciic฀nit- rosamine,฀NNK฀see฀Sect.฀7.6.1,฀has฀been฀detected฀in฀the฀cervical฀mucus฀of฀current฀smok- ers฀in฀concentrations฀that฀were฀three฀times฀higher฀than฀those฀in฀non-smokers฀ [416] .฀NNK฀