Document zQna70Nx0wD6d3GYaL1wvaDy3

WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 83 Tobacco Smoke and Involuntary Smoking Summary of Data Reported and Evaluation Tobacco smoking and tobacco smoke Involuntary smoking Last updated: 24 July 2002 TOBACCO SMOKING AND TOBACCO SMOKE (Group 1) 5. Summary of Data Reported and Evaluation For definition of groups, see Preamble. VOL.: 83 (2002) 5.1 Exposure data Smoking of tobacco is practised worldwide by over one thousand million people. However, while smoking prevalence has declined in many developed countries, it remains high in others and is increasing among women and in developing countries. Between one-fifth and two-thirds of men in most populations smoke. Women's smoking rates vary more widely but rarely equal male rates. Tobacco is most commonly smoked as cigarettes, both manufactured -- which are a highly sophisticated nicotine delivery system -- and hand-rolled. Pipes, cigars, bidis and other products are used to a lesser extent or predominantly in particular regions. Cigarettes are made from fine-cut tobaccos which are wrapped in paper or a maize leaf. Cigars consist of cut tobacco filler formed in a binder leaf and with a wrapper leaf rolled spirally around the bunch. Bidis contain shredded tobacco wrapped in non-tobacco leaves, usually dried temburni leaves. The chemical composition of tobacco smoke, although influenced by the specific manner in which individuals smoke, is primarily determined by the type of tobacco. It is also influenced by the design of the smoking device or product and, for cigarettes, by the presence or absence of filters, and by other factors including ventilation, paper porosity and types of additives. As a result, concentrations of individual chemicals in smoke vary. Analysis of the ways in which people smoke modern cigarettes shows that actual doses of nicotine, carcinogens and toxins depend on the intensity and method of smoking and have little relation to stated tar yields. The total volume of smoke drawn from cigarettes as a result of specific smoking patterns is the principal determinant of dose to the smoker. All presently available tobacco products that are smoked deliver substantial amounts of established carcinogens to their users. The yields of tar, nicotine and carbon monoxide from cigarettes, as measured by standard machine-smoking tests, have fallen over recent decades in cigarettes sold in most parts of the world, but have remained higher in some countries. The tar and nicotine yields as currently measured are misleading and have only little value in the assessment of human exposure to carcinogens. The regulation of smoking and smoke yields varies widely around the world in scope and degree of enforcement. Certain regulatory actions, such as taxes and workplace smoking bans, are effective in reducing smoking rates and protecting nonsmokers. 5.2 Human carcinogenicity data In the previous 1986 IARC Monograph on tobacco smoking, cancers of the lung, oral cavity, pharynx, larynx, oesophagus (squamous-cell carcinoma), pancreas, urinary bladder and renal pelvis were identified as caused by cigarette smoking. Many more studies published since this earlier Monograph support these causal links. In addition, there is now sufficient evidence for a causal association between cigarette smoking and cancers of the nasal cavities and nasal sinuses, oesophagus (adenocarcinoma), stomach, liver, kidney (renal-cell carcinoma), uterine cervix and myeloid leukaemia. In cancer sites that were causally linked to cigarette smoking in the previous IARC Monograph on tobacco smoking, the observed relative risks ranged generally from approximately 3 for pancreatic cancer to more than 20 for lung cancer. For those cancer sites that were now also linked to cigarette smoking in this Monograph, generally two- to threefold increased risks were observed. Cigarettes Lung Lung cancer is the most common cause of death from cancer in the world. The total number of cases is now estimated to be 1.2 million annually and is still increasing. The major cause of lung cancer is tobacco smoking, primarily of cigarettes. In populations with prolonged cigarette use, the proportion of lung cancer cases attributable to cigarette smoking has reached 90%. The duration of smoking is the strongest determinant of lung cancer in smokers. Hence, the earlier the age of starting and the longer the continuation of smoking in adulthood, the greater the risk. Risk of lung cancer also increases in proportion to the numbers of cigarettes smoked. Tobacco smoking increases the risk of all histological types of lung cancer including squamous-cell carcinoma, small-cell carcinoma, adenocarcinoma (including bronchiolar/alveolar carcinoma) and large-cell carcinoma. The association between adenocarcinoma of the lung and smoking has become stronger over time. The carcinogenic effects of cigarette smoking appear similar in both women and men. Stopping smoking at any age avoids the further increase in risk of lung cancer incurred by continued smoking. The younger the age at cessation, the greater the benefit. Urinary tract Tobacco smoking is a major cause of transitional-cell carcinomas of the bladder, ureter and renal pelvis. Risk increases with the duration of smoking and number of cigarettes smoked. As for lung cancer, stopping smoking at any age avoids the further increase in risk incurred by continued smoking. Evidence from several cohort and case-control studies published since the previous IARC Monograph on tobacco smoking has indicated that renal-cell carcinoma is associated with tobacco smoking in both men and women. The association is not explained by confounding. A dose-response relationship with the number of cigarettes smoked has been noted in most studies, and a few also noted a reduction in risk after cessation. Oral cavity Tobacco smoking, including cigarette smoking, is causally associated with cancer of the oral cavity (including lip and tongue) in both men and women. Since the previous IARC Monograph on tobacco smoking, evidence from many more studies has accumulated that further confirms this association. Use of smokeless tobacco and/or alcohol in combination with tobacco smoking greatly increases the risk of oral cancer. Risk increases substantially with duration of smoking and number of cigarettes smoked. Risk among former smokers is consistently lower than among current smokers and there is a trend of decreasing risk with increasing number of years since quitting. Nasal cavity and paranasal sinuses An increased risk of sinonasal cancer among cigarette smokers has been reported in all nine case-control studies for which results are available. Of seven studies that have analysed dose-response relationships, a positive trend was found in five and was suggested in the other two. In all the five studies that have analysed squamous-cell carcinoma and adenocarcinoma separately, the relative risk was clearly increased for squamous-cell carcinoma. Nasopharynx An increased risk for nasopharyngeal cancer among cigarette smokers was reported in one cohort study and nine case-control studies. Increased relative risks were reported in both high- and low-risk geographical regions for nasopharyngeal cancer. A dose-response relationship was detected with either duration or amount of smoking. A reduction in risk after quitting was also detected. The potential confounding effect of infection with Epstein-Barr virus was not controlled for in these studies; however, such an effect was not considered to be plausible. No important role was shown for other potential confounders. Oropharynx and hypopharynx Oropharyngeal and hypopharyngeal cancer are causally associated with cigarette smoking. The risk increased with increased duration of smoking and daily cigarette consumption and decreased with increasing time since quitting. Oesophagus Tobacco smoking is causally associated with cancer of the oesophagus, particularly squamous-cell carcinoma. Tobacco smoking is also causally associated with adenocarcinoma of the oesophagus. In most of the epidemiological studies, the risk for all types of oesophageal cancer increased with numbers of cigarettes smoked daily and duration of smoking. However, risk for oesophageal cancer remains elevated many years after cessation of smoking. Tobacco and alcohol in combination with tobacco smoking greatly increase the risk for squamous-cell carcinoma of the oesophagus. In India, use of smokeless tobacco in combination with smoking also greatly increases the risk. Larynx Laryngeal cancer is causally associated with cigarette smoking. The risk increases substantially with duration and number of cigarettes smoked. Use of alcohol in combination with tobacco smoking greatly increases the risk for laryngeal cancer. A few studies also reported that relative risks for cancer of the larynx increased with decreasing age at start of smoking. The relative risk decreased with increasing time since quitting smoking. Pancreas Cancer of the pancreas is causally associated with cigarette smoking. The risk increases with duration of smoking and number of cigarettes smoked daily. The risk remains elevated after allowing for potential confounding factors such as alcohol consumption. The relative risk decreased with increasing time since quitting smoking. Stomach The data available in 1986 did not permit the earlier IARC Working Group to conclude that the association between tobacco smoking and stomach cancer was causal. Since that time, further studies have shown a consistent association of cancer of the stomach with cigarette smoking in both men and women in many cohort and case-control studies conducted in various parts of the world. Confounding by other factors (e.g. alcohol consumption, Helicobacter pylori infection and dietary factors) can be reasonably ruled out. Risk increases with duration of smoking and number of cigarettes smoked, and decreases with increasing duration of successful quitting. In studies that had adequate numbers, the relative risks for men and women were similar. Liver In the previous IARC Monograph on tobacco smoking, a causal relationship between liver cancer and smoking could not be established, chiefly due to possible confounding from alcohol intake and hepatitis B and hepatitis C virus infections. Many cohort studies and case-control studies have provided additional information on smoking and liver cancer since then. Most of the cohort studies and the largest case-control studies (most notably those that included community controls) showed a moderate association between tobacco smoking and risk of liver cancer. In many studies, the risk for liver cancer increased with the duration of smoking or the number of cigarettes smoked daily. Former smokers who had stopped smoking for more than 10 years showed a decline in liver cancer risk. Confounding from alcohol can be ruled out, at least in the best case-control studies, by means of careful adjustment for drinking habits. An association with smoking has also been demonstrated among non-drinkers. Many studies, most notably from Asia, have shown no attenuation of the association between smoking and liver cancer after adjustment/stratification for markers of hepatitis B/hepatitis C virus infection. There is now sufficient evidence to judge the association between tobacco smoking and liver cancer as causal. Cervix An association of invasive cervical squamous-cell carcinoma with smoking has been observed in the large number of studies reviewed. The most recent studies have controlled for infection with human papillomavirus, a known cause of cervical cancer. The effect of smoking was not diminished by the adjustment for human papillomavirus infection, or analysis restricted to cases and controls both positive for human papillomavirus (as ascertained by human papillomavirus DNA or human papillomavirus serological methods). There is now sufficient evidence to establish a causal association of squamous-cell cervical carcinoma with smoking. In the small number of studies available for adeno- and adeno-squamous-cell carcinoma, no consistent association was observed. Leukaemia Myeloid leukaemia in adults was observed to be causally related to smoking. Risk increased with amount of tobacco smoked in a substantial number of adequate studies. No clear evidence of any risk was seen for lymphoid leukaemia/lymphoma. Support for a causal relationship of smoking with myeloid leukaemia is provided by the finding of known leukaemogens in tobacco smoke, one of which (benzene) is present in sufficient amounts to account for up to half of the estimated excess of acute myeloid leukaemia. Colorectal cancer There is some evidence from prospective cohort studies and case-control studies that the risk of colorectal cancer is increased among tobacco smokers. However, it is not possible to conclude that the association between tobacco smoking and colorectal cancer is causal. Inadequate adjustment for various potential confounders could account for some of the small increase in risk that appears to be associated with smoking. Female breast Most epidemiological studies have found no association with active smoking, after controlling for established risk factors (e.g. age at time of first birth, parity, family history of breast cancer and alcohol). The large multicentre pooled analysis of the association of smoking with breast cancer in non-drinkers confirms the lack of an increased risk of breast cancer associated with smoking. Endometrium Cigarette smoking is not associated with an increased risk for endometrial cancer. An inverse relationship of cigarette smoking with endometrial cancer is observed consistently in most case-control and cohort studies, after adjustment for major confounders. This pattern is stronger in post menopausal women. Prostate No clear evidence of any risk for prostate cancer is seen in case-control studies or in studies of incident cases in cohort studies. The small excess observed in some analytical mortality studies can reasonably be explained by bias in the attribution of the underlying cause of death. Other There is inconsistent and/or sparse evidence for association between cigarette smoking and other cancer sites that were considered by the Working Group. Cigars and pipes Cigar and/or pipe smoking is strongly related to cancers of the oral cavity, oropharynx, hypopharynx, larynx and oesophagus, the magnitude of risk being similar to that from cigarette smoking. These risks increase with the amount of cigar and/or pipe smoking and with the combination of alcohol and tobacco consumption. Cigar and/or pipe smoking is causally associated with cancer of the lung and there is evidence that cigar and/or pipe smoking are also causally associated with cancers of the pancreas, stomach and urinary bladder. Bidi Bidi smoking is the most common form of tobacco smoking in India and is also prevalent in other south-Asian countries and an emerging problem in the USA. Bidi smoke was considered as carcinogenic in the earlier IARC Monograph on tobacco smoking, and later studies have provided further evidence of causality. Case-control studies demonstrated a strong association at various sites: oral cavity (including subsites), pharynx, larynx, oesophagus, lung and stomach. Almost all studies show significant trends with duration of bidi smoking and number of bidis smoked. Synergy For public health purposes, synergy should be characterized as a positive departure from additivity. The epidemiological literature often inadequately describes combined effects of smoking with co-exposures to other carcinogenic agents and in many studies power is limited for characterizing combined effects. The issue of synergistic effects can be appropriately addressed by epidemiological studies that show stratified analysis and have sufficient power. The studies reviewed found evidence of synergy between smoking and several occupational causes of lung cancer (arsenic, asbestos and radon), and between smoking and alcohol consumption for cancers of the oral cavity, pharynx, larynx and oesophagus and between smoking and human papillomavirus infection for cancer of the cervix. Data were inadequate to evaluate the evidence for synergy between smoking and other known causes of cancer (e.g. hepatitis B and alcohol for liver cancer). 5.3 Animal carcinogenicity data Cigarette smoke has been tested for carcinogenicity by inhalation studies in rodents, rabbits and dogs. The model systems for animal exposure to tobacco smoke do not fully simulate human exposure to tobacco smoke, and the tumours that develop in animals are not completely representative of human cancer. Nevertheless, the animal data provide valuable insights regarding the carcinogenic potential of tobacco smoke. The most compelling evidence for a positive carcinogenic effect of tobacco smoke in animals is the reproducible increase observed in several studies in the occurrence of laryngeal carcinomas in hamsters exposed to whole tobacco smoke or to its particulate phase. In four of five studies in rats, exposure to whole smoke led to modest increases in the occurrence of malignant and/or benign lung tumours. Similarly, in four of eight studies in mice of varying susceptibility to lung tumour development, exposure to whole smoke led to a modest increase in the frequency of lung adenomas. An increased incidence of lung 'tumours' has also been reported in dogs exposed to tobacco smoke, but it is uncertain whether the histopathological features of the lesions are consistent with malignancy. In hamsters exposed to both cigarette smoke and chemical carcinogens (W-nitrosodiethylamine and 7,12-dimethylbenz[a]anthracene), the tumour response in the respiratory tract was higher than in hamsters exposed to either agent alone. The same is true in rats exposed simultaneously to cigarette smoke and radionuclides (radon progeny and plutonium oxide). Cigarette smoke condensate both initiates and promotes tumour development in animals. It reproducibly induces both benign and malignant skin tumours in mice following topical application. Similarly, it produces skin tumours in rabbits following topical application. Topical application to the oral mucosa also produced an increased incidence of lung tumours and lymphomas in mice. In rats, cigarette smoke condensate produced lung tumours after intrapulmonary injection. In initiation/promotion assays in mouse skin, a single topical application of cigarette smoke condensate followed by application of croton oil was sufficient to initiate both benign and malignant skin tumours. Smoke condensates of Indian bidi administered to mice by gavage were found to induce tumours in a number of organs. Collectively, these data provide evidence of the carcinogenic effect of mainstream tobacco smoke in experimental animals. 5.4 Other relevant data Causal associations have been clearly established between active smoking and adverse reproductive outcomes and numerous non-neoplastic diseases, including chronic obstructive pulmonary disease and cardiovascular diseases. Tobacco smoking is addictive, and nicotine has been established as the major addictive constituent of tobacco products. Measurement of the nicotine metabolite, cotinine, in human blood, urine or saliva provides a specific and sensitive test for exposure to tobacco smoke and can be used to distinguish active and passive smokers from nonsmokers. Active smoking raises the concentrations of carbon monoxide, benzene and volatile organic compounds in exhaled air. The concentrations of urinary metabolites of some important tobacco smoke carcinogens and related compounds are consistently higher in smokers than in nonsmokers. These include metabolites of benzene, a known carcinogen in humans, as well as metabolites of several carcinogens that cause lung tumours in rodents. Covalent binding to blood proteins by carcinogens present in tobacco smoke has been demonstrated to occur at significantly higher levels in smokers than in nonsmokers. The adducts are derived from various compounds including aromatic amines (e.g. 4-aminobiphenyl), polycyclic aromatic hydrocarbons (e.g. benzo[a]pyrene), tobacco-specific nitrosamines (e.g. 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone), benzene, acrylamide and acrylonitrile. Smoking-related DNA adducts have been detected by a variety of analytical methods in the respiratory tract, urinary bladder, cervix and other tissues. In many studies the levels of carcinogen-DNA adducts have been shown to be higher in tissues of smokers than in tissues of nonsmokers. Some but not all studies have demonstrated elevated levels of these adducts in the peripheral blood and in full-term placenta. Smokingrelated adducts have also been detected in cardiovascular tissues. Collectively, the available biomarker data provide convincing evidence that carcinogen uptake, activation and binding to cellular macromolecules, including DNA, are higher in smokers than in nonsmokers. The exposure of experimental animals, primarily rodents, to mainstream tobacco smoke results in a number of biological effects that include (i) increases or decreases in the activities of phase I and phase II enzymes involved in carcinogen metabolism, (ii) increases in the activation of antioxidant enzymes, (iii) increased expression of nitric oxide synthase and of various protein kinases and collagenase, (iv) the formation of tobacco smoke-related DNA adducts in several tissues and (v) reduced clearance of particulate material from the lung. Smoking is known to have inhibitory or inducing effects on the activities of many enzymes in human tissues. These include xenobiotic metabolizing enzymes, which affect drug and carcinogen metabolism. Numerous studies have reported effects on enzymes in cells treated in culture with tobacco smoke or tobacco smoke condensates. In humans, smoking produces gene mutations and chromosomal abnormalities. Urine from smokers is mutagenic. Relative to nonsmokers, lung tumours of smokers contain higher frequencies of TP53 and KRAS mutations, and the spectrum of mutations has unique features. Most of the genetic effects seen in smokers are also observed in cultured cells or in experimental animals exposed to tobacco smoke or smoke condensate. Tobacco smoke is genotoxic in humans and in experimental animals. 5.5 Evaluation There is sufficient evidence in humans that tobacco smoking causes cancer of the lung, oral cavity, naso-, oro- and hypopharynx, nasal cavity and paranasal sinuses, larynx, oesophagus, stomach, pancreas, liver, kidney (body and pelvis), ureter, urinary bladder, uterine cervix and bone marrow (myeloid leukaemia). There is evidence suggesting lack of carcinogenicity of tobacco smoking in humans for cancers of the female breast and endometrium. There is sufficient evidence in experimental animals for the carcinogenicity of tobacco smoke and tobacco smoke condensates. Overall evaluation Tobacco smoking and tobacco smoke are carcinogenic to humans (Group 1). For definition of the italicized terms, see Preamble. INVOLUNTARY SMOKING (Group 1) For definition of groups, see Preamble. VOL.: 83 (2002) 5.1 Exposure data 5. Summary of Data Reported and Evaluation Involuntary (or passive) smoking is exposure to secondhand tobacco smoke, which is a mixture of exhaled mainstream smoke and sidestream smoke released from the smouldering cigarette or other smoking device (cigar, pipe, bidi, etc.) and diluted with ambient air. Involuntary smoking involves inhaling carcinogens, as well as other toxic components, that are present in secondhand tobacco smoke. Secondhand tobacco smoke is sometimes referred to as 'environmental' tobacco smoke. Carcinogens that occur in secondhand tobacco smoke include benzene, 1,3-butadiene, benzo[a]pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone and many others. Secondhand tobacco smoke consists of a gas phase and a particulate phase; it changes during its dilution and distribution in the environment and upon ageing. The concentrations of respirable particles may be elevated substantially in enclosed spaces containing secondhand tobacco smoke. The composition of tobacco smoke inhaled involuntarily is variable quantitatively and depends on the smoking patterns of the smokers who are producing the smoke as well as the composition and design of the cigarettes or other smoking devices. The secondhand tobacco smoke produced by smoking cigarettes has been most intensively studied. Secondhand tobacco smoke contains nicotine as well as carcinogens and toxins. Nicotine concentrations in the air in homes of smokers and in workplaces where smoking is permitted typically range on average from 2 to 10 micrograms/m3. 5.2 Human carcinogenicity data Lung cancer Involuntary smoking involves exposure to the same numerous carcinogens and toxic substances that are present in tobacco smoke produced by active smoking, which is the principal cause of lung cancer. As noted in the previous IARC Monograph on tobacco smoking, this implies that there will be some risk of lung cancer from exposure to secondhand tobacco smoke. More than 50 studies of involuntary smoking and lung cancer risk in never-smokers, especially spouses of smokers, have been published during the last 25 years. These studies have been carried out in many countries. Most showed an increased risk, especially for persons with higher exposures. To evaluate the information collectively, in particular from those studies with a limited number of cases, meta-analyses have been conducted in which the relative risk estimates from the individual studies are pooled together. These meta-analyses show that there is a statistically significant and consistent association between lung cancer risk in spouses of smokers and exposure to secondhand tobacco smoke from the spouse who smokes. The excess risk is of the order of 20% for women and 30% for men and remains after controlling for some potential sources of bias and confounding. The excess risk increases with increasing exposure. Furthermore, other published meta-analyses of lung cancer in never-smokers exposed to secondhand tobacco smoke at the workplace have found a statistically significant increase in risk of 12-19%. This evidence is sufficient to conclude that involuntary smoking is a cause of lung cancer in never-smokers. The magnitudes of the observed risks are reasonably consistent with predictions based on studies of active smoking in many populations. Breast cancer The collective evidence on breast cancer risk associated with involuntary exposure of never-smokers to tobacco smoke is inconsistent. Although four of the 10 case-control studies found statistically significant increases in risks, prospective cohort studies as a whole and, particularly, the two large cohort studies in the USA of nurses and of volunteers in the Cancer Prevention Study II provided no support for a causal relation between involuntary exposure to tobacco smoke and breast cancer in never-smokers. The lack of a positive dose-response also argues against a causal interpretation of these findings. Finally, the lack of an association of breast cancer with active smoking weighs heavily against the possibility that involuntary smoking increases the risk for breast cancer, as no data are available to establish that different mechanisms of carcinogenic action operate at the different dose levels of active and of involuntary smoking. Childhood cancer Overall, the findings from studies of childhood cancer and exposure to parental smoking are inconsistent and are likely to be affected by bias. There is a suggestion of a modest association between exposure to maternal tobacco smoke during pregnancy and childhood cancer for all cancer sites combined; however, this is in contrast with the null findings for individual sites. Studies on paternal tobacco smoking suggest a small increased risk for lymphomas, but bias and confounding cannot be ruled out. Other cancer sites Data are conflicting and sparse for associations between involuntary smoking and cancers of the nasopharynx, nasal cavity, paranasal sinuses, cervix, gastrointestinal tract and cancers at all sites combined. It is unlikely that any effects are produced in passive smokers that are not produced to a greater extent in active smokers or that types of effects that are not seen in active smokers will be seen in passive smokers. 5.3 Animal carcinogenicity data Secondhand tobacco smoke for carcinogenicity studies in animals is produced by machines that simulate human active smoking patterns and combine mainstream and sidestream smoke in various proportions. Such mixtures have been tested for carcinogenicity by inhalation studies in rodents. The experimental model systems for exposure to secondhand tobacco smoke do not fully simulate human exposures, and the tumours that develop in animals are not completely representative of human cancer. Nevertheless, the animal data provide valuable insights regarding the carcinogenic potential of secondhand tobacco smoke. A mixture of 89% sidestream smoke and 11% mainstream smoke has been tested for carcinogenic activity in mouse strains that are highly susceptible to lung tumours (strains A/J and Swiss). In strain A/J mice, this mixture consistently produces a significant, modest increase in lung tumour incidence and lung tumour multiplicity when the mice are exposed for 5 months followed by a 4-month recovery period. These lung tumours are predominantly adenomas. Continuous exposure of strain A/J mice to the above mixture of mainstream and sidestream tobacco smoke for 9 months with no recovery period did not increase the incidence of lung tumours. In Swiss strain mice, the same mixture induced lung tumours by both protocols, i.e. when the animals were exposed for 5 months followed by a 4-month recovery period and when they were exposed continuously for 9 months with no recovery period. In addition, exposure of Swiss mice to the tobacco smoke mixture for a shorter period was sufficient to induce lung tumours. Condensates of sidestream and of mainstream cigarette smoke have been tested for carcinogenicity. Both kinds of condensates produced a spectrum of benign and malignant skin tumours in mice following topical application, and the sidestream condensate exhibited higher carcinogenic activity. Sidestream smoke condensate was shown to produce a dose-dependent increase in lung tumours in rats following implantation into the lungs. Increased relative risks for lung and sinonasal cancer have been reported in companion animals (dogs) exposed to secondhand tobacco smoke in homes. 5.4 Other relevant data Involuntary smoking has been associated with a number of non-neoplastic diseases and adverse effects in never-smokers, including both children and adults. Epidemiological studies have demonstrated that exposure to secondhand tobacco smoke is causally associated with coronary heart disease. From the available meta analyses, it has been estimated that involuntary smoking increases the risk of an acute coronary heart disease event by 25-35%. Adverse effects of involuntary smoking on the respiratory system have also been detected. In adults, the strongest evidence for a causal relation exists for chronic respiratory symptoms. Some effects on lung function have been detected, but their medical relevance is uncertain. Data on the hormonal and metabolic effects of involuntary smoking are sparse. However, female involuntary smokers do not appear to weigh less than women who are not exposed to secondhand tobacco smoke, a pattern that contrasts with the findings for active smoking. No consistent association of maternal exposure to secondhand smoke with fertility or fecundity has been identified. There is no clear association of passive smoking with age at menopause. Maternal cigarette smoking has repeatedly been associated with adverse effects on fetal growth; full-term infants born to women who smoke weigh about 200 g less than those born to nonsmokers. A smaller adverse effect has been attributed to maternal passive smoking. Cotinine, and its parent compound nicotine, are highly specific for exposure to secondhand smoke. Because of its favourable biological half-life and the sensitivity of techniques for quantifying it, cotinine is currently the most suitable biomarker for assessing recent exposure to secondhand tobacco smoke uptake and metabolism in adults, children and newborns. Several studies in humans have shown that concentrations of adducts of carcinogens to biological macromolecules, including haemoglobin adducts of aromatic amines and albumin adducts of polycyclic aromatic hydrocarbons, are higher in adult involuntary smokers and in the children of smoking mothers than in individuals not exposed to secondhand tobacco smoke. Protein adduct concentrations in fetal cord blood correlate with those in maternal blood but are lower. Fewer studies have investigated DNA adduct levels in white blood cells of exposed and unexposed nonsmokers, and most studies have not shown clear differences. In studies of urinary biomarkers, metabolites of the tobacco-specific carcinogen, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone, have been found to be consistently elevated in involuntary smokers. Levels of these metabolites are 1-5% as great as those found in smokers. The data demonstrating uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a lung carcinogen in rodents, by nonsmokers are supportive of a causal link between exposure to secondhand tobacco smoke and development of lung cancer. The exposure of experimental animals, primarily rodents, to secondhand tobacco smoke has several biological effects that include (i) increases or decreases in the activity of phase I enzymes involved in carcinogen metabolism; (ii) increased expression of nitric oxide synthase, xanthine oxidase and various protein kinases; (iii) the formation of smoke-related DNA adducts in several tissues; and (iv) the presence of urinary biomarkers of exposure to tobacco smoke. In adult experimental animals, sidestream tobacco smoke has been found to produce changes that are similar to those observed with exposure of humans to secondhand tobacco smoke. These include inflammatory changes in the airways and accelerated formation of arteriosclerotic plaques. Although the changes are often comparatively minor and require exposure to rather elevated concentrations of sidestream smoke, they support the results of human epidemiological studies. During pre- and postnatal exposure, sidestream smoke produces intrauterine growth retardation, changes the pattern of metabolic enzymes in the developing lung, and gives rise to hyperplasia of the pulmonary neuroendocrine cell population. In addition, it adversely affects pulmonary compliance and airway responsiveness to pharmacological challenges. In humans, involuntary smoking is associated with increased concentrations of mutagens in urine. Some studies have shown a correlation of urinary mutagenicity with concentrations of urinary cotinine. Increased levels of sister chromatid exchanges have not been observed in involuntary smokers; however, there is some indication of elevated levels in exposed children. Lung tumours from nonsmokers exposed to tobacco smoke contain TP53 and KRAS mutations that are similar to those found in tumours from smokers. The genotoxicity of sidestream smoke, 'environmental' tobacco smoke, sidestream smoke condensate or a mixture of sidestream and mainstream smoke condensates has been demonstrated in experimental systems in vitro and in vivo. 5.5 Evaluation There is sufficient evidence that involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke) causes lung cancer in humans. There is limited evidence in experimental animals for the carcinogenicity of mixtures of mainstream and sidestream tobacco smoke. There is sufficient evidence in experimental animals for the carcinogenicity of sidestream smoke condensates. In addition, the Working Group noted that there are published reports on possible carcinogenic effects of secondhand tobacco smoke in household pet dogs. Overall evaluation Involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke) is carcinogenic to humans (Group 1). For definition of the italicized terms, see Preamble.