# SECOND-HAND TOBACCO SMOKE
    
    
    SECOND-HAND TOBACCO SMOKE
    Second-hand tobacco smoke was considered by a previous IARC Working Group in 2002 as
    “involuntary smoking” (IARC, 2004). Since that time, new data have become available, these
    have been incorporated into the Monograph, and taken into consideration in the present
    evaluation.
    1. Exposure Data
    Second-hand tobacco smoke comprises the
    smoke released from the burning tip of a cigarette (or other burned tobacco product) between
    puffs (called sidestream smoke (SM)) and the
    smoke exhaled by the smoker (exhaled mainstream smoke (MS)). Small additional amounts
    are contributed from the tip of the cigarette and
    through the cigarette paper during a puff, and
    through the paper and from the mouth end of
    the cigarette between puffs (Jenkins et al., 2000).
    Second-hand tobacco smoke is also referred
    as ‘environmental tobacco smoke’, ‘passive
    smoking’ or ‘involuntary smoking’ (IARC,
    2004). The terms ‘passive smoking’ or ‘involuntary smoking’ suggest that while involuntary or
    passive smoking is not acceptable, voluntary or
    active smoking is acceptable. In this document,
    we use the term second-hand tobacco smoke
    (WHO, 2010).
    1.1 Chemical composition
    of mainstream and sidestream smoke is qualitatively similar but quantitatively different. The
    ratios of sidestream to mainstream smoke vary
    greatly depending on the constituent. Some
    representative SS:MS ratios are: nicotine, 7.1;
    carbon monoxide, 4.8; ammonia, 455; formaldehyde, 36.5; acrolein, 18.6; benzo[a]pyrene,
    16.0; N′-nitrosonornicotine (NNN), 0.43;
    (methylnitrosamino)-1-(3-pyridyl)-1-butanone
    (NNK), 0.40 (Jenkins et al., 2000; IARC, 2004).
    The physicochemical properties of secondhand tobacco smoke are different from those
    of mainstream smoke and sidestream smoke
    because of its rapid dilution and dispersion
    into the indoor environment (IARC, 2004).
    Concentrations of individual constituents in
    second-hand tobacco smoke can vary with time
    and environmental conditions. Field studies of
    these constituents and representative data have
    been extensively summarized (Jenkins et al.,
    2000; IARC, 2004). Some representative data are
    presented in Table 1.1 (Jenkins et al., 2000; IARC,
    2004; US Department of Health and Human
    Services, 2006).
    Many studies have examined the concentrations of cigarette smoke constituents in mainstream and sidestream smoke. The composition
    213
    IARC MONOGRAPHS – 100E
    Table 1.1 Concentration of selected constituents in second-hand tobacco smoke
    Constituent
    Concentration
    Nicotine
    Carbon monoxide
    Benzene
    Formaldehyde
    Acetaldehyde
    1,3-Butadiene
    Benzo[a]pyrene
    NNK
    NNN
    10–100 µg/m3
    5–20 ppm
    15–30 µg/m3
    100–140 µg/m3
    200–300 µg/m3
    20–40 µg/m3
    0.37–1.7 ng/m3
    0.2–29.3 ng/m3
    0.7–23 ng/m3
    1.2Sources of exposure
    1.3Measures of exposure
    ￼ Second-hand tobacco smoke is present
    in virtually all places where smoking takes
    place (Navas-Acien et al., 2004): at home, in the
    workplace, in bars, restaurants, public buildings, hospitals, public transport and educational
    institutions. The setting that represents the most
    important source of exposure differs depending
    on the population. For example in children, the
    home environment may constitute a significant
    source of exposure, while other sources that may
    contribute are schools and public transportation. Likewise, for most women, the home environment is the primary source of second-hand
    tobacco smoke, which may be enhanced by exposure at the workplace.
    Biomarker studies have evaluated carcinogen
    uptake in non-smokers to second-hand tobacco
    smoke. The NNK metabolites NNAL and its
    glucuronides (total NNAL) are consistently
    elevated in non-smokers exposed to second-hand
    tobacco smoke, in studies conducted in various
    living and occupational environments, and from
    infancy through adulthood (Hecht et al., 2006;
    Hecht, 2008). Levels of the biomarker of PAHs,
    urinary 1-hydroxypyrene, were significantly
    elevated in a large study of non-smokers exposed
    to second-hand tobacco smoke (Suwan-ampai
    et al., 2009).
    A conceptual framework for considering
    exposure to second-hand tobacco smoke is the
    “microenvironmental model,” which takes the
    weighted sum of the concentrations of secondhand tobacco smoke in the microenvironments where time is spent, with the weights the
    time spent in each, as a measure of personal
    exposure (Jaakkola & Jaakkola, 1997). Direct
    measures of exposure use concentrations of
    second-hand tobacco smoke components in the
    air in the home, workplace, or other environments, combined with information on the time
    spent in the microenvironments where exposure
    took place. Measurements of tobacco smoke
    biomarker(s) in biological specimens also represent a direct measure of exposure to second-hand
    smoke (Samet & Yang, 2001; Table 1.2). Indirect
    measures are generally obtained by survey questionnaires. These include self-reported exposure
    and descriptions of the source of second-hand
    tobacco smoke in relevant microenvironments,
    most often the home and workplace (Samet &
    Yang, 2001).
    ￼ One useful surrogate measure, and the
    only available in many countries, is the prevalence of smoking among men and women. It
    provides a measure of the likelihood of exposure.
    In most countries in Asia and the Middle East,
    214
    Second-hand tobacco smoke
    Table 1.2 Types of indicators measuring exposure to second-hand tobacco smoke
    Measure
    Suggested indicators
    Direct
    Concentration of second-hand tobacco smoke components in the air:
    - Nicotine
    - Respirable particles
    - Other markers
    Biomarker concentrations:
    - Cotinine
    - Carboxyhaemoglobin
    Report of second-hand tobacco smoke exposure at:
    Home
    - Number of smokers
    - Smoking of parents
    - Intensity (number of cigarettes smoked)
    Workplace
    - Presence of second-hand tobacco smoke
    Indirect
    - Number of smokers
    Surrogate
    Pre Prevalence of smoking tobacco in men and in women
    Sel Self reported smoking habits of parents
    Nic Nicotine concentration in house dust
    From Samet & Yang (2001) and Whitehead et al. (2009)
    for example, the very high prevalence of smoking
    among men combined with the low prevalence
    among women would imply that most women
    are exposed to second-hand tobacco smoke at
    home (Samet & Yang, 2001).
    To measure exposure to second-hand tobacco
    smoke in children, self-reported smoking habits
    of their parents are used as a surrogate (US
    Department of Health and Human Services,
    2006). More recently, other surrogate measures
    such as nicotine concentrations in house dust
    have been considered less biased than parental
    smoking as they reflect cumulative smoking
    habits and long-term exposure rather than
    current patterns of smoking (Whitehead et al.,
    2009).
    1.4Prevalence of exposure
    1.4.1 Exposure among children
    (a)Overview
    The most extensive population-based data on
    exposure to second-hand tobacco smoke among
    children are available through the Global Youth
    Tobacco Survey (GYTS) (CDC/WHO, 2009).
    GYTS is part of the Global Tobacco Surveillance
    System (GTSS), developed by the WHO and the
    United States’ Centers for Disease Control and
    Prevention (CDC) in 1998. The GYTS is a schoolbased survey designed to measure tobacco use
    and some key tobacco control measures among
    youth (13–15 years) using a common methodology and core questionnaire. While most GYTS
    are national surveys, in some countries they
    are limited to subnational locations. Further,
    countries conduct the GYTS in different years,
    rendering comparison across countries for the
    same year difficult. The GYTS questionnaire
    215
    IARC MONOGRAPHS – 100E
    Fig. 1.1 Average prevalence (in%) of 13–15 year old children living in a home where others smoke,
    by WHO region, 2007
    ￼
    From CDC (2008)
    asks about children’s exposure to second-hand
    tobacco smoke in their home or in other places
    in the last 7 days preceding the survey. Since its
    inception in 1999, over 2 million students in 160
    countries representing all six WHO regions have
    participated in the GYTS (WHO, 2008, 2009a).
    Country-level estimates on second-hand
    tobacco smoke exposure at home and in public
    places among youth are available in the WHO
    Reports on the global tobacco epidemic (WHO,
    2008, 2009a, 2011).
    (b) Exposure at home
    Nearly half of youth aged 13–15 years are
    exposed to second-hand tobacco smoke in their
    homes (Fig. 1.1; CDC, 2008). Among the six WHO
    regions, exposure to second-hand tobacco smoke
    at home was highest in the European Region
    216
    (77.8%) and lowest in the African region (27.6%).
    In the other four regions, exposure to secondhand tobacco smoke at home ranged from 50.6%
    in the Western Pacific Region to 34.3% in the
    South East Asian Region.
    ￼ Fig. 1.2 shows the range of exposure to
    second-hand tobacco smoke at home by WHO
    region for boys and girls and for both sexes
    combined. The largest variations are observed
    in the Eastern Mediterranean Region and the
    European Region irrespective of sex. These variations are predominantly due to differences in
    parental smoking prevalence between countries,
    as well as the impact of the smoke-free places
    campaigns in place in various countries.
    ￼ Country-level estimates from the Global
    Youth Tobacco Survey (1999–2009) are presented
    in Table 1.3.
    Second-hand tobacco smoke
    Fig. 1.2 Range of prevalence (in%) of exposure of 13–15 year old children to second-hand tobacco
    smoke at home, by WHO region, 2009
    ￼
    From CDC/WHO (2009)
    ￼ Öberg and colleagues have estimated the
    worldwide exposure to second-hand tobacco
    smoke among children by using parent’s current
    smoking status as an indicator of exposure among
    children (WHO, 2010). Four out of ten children
    (approximately 700 million children globally)
    have at least one parent who currently smokes,
    predisposing them to exposure to second-hand
    tobacco smoke at home (Table 1.4). Children in
    the Western Pacific Region had the highest level
    of potential exposure (68%) while Africa had
    the lowest, with about 13% of children having
    at least one parent who smoked. In the 2010
    WHO Report on global estimate of the burden
    of disease from second-hand smoke (WHO,
    2010), country-level estimates were collected or
    modelled from various sources. [Data partially
    overlap with those of the Global Youth Tobacco
    Survey].
    (c) Exposure outside home
    Similar to second-hand tobacco smoke exposure at home, almost half of the youth are exposed
    to second-hand tobacco smoke in public places,
    according to estimates from the Global Youth
    Tobacco Survey (Fig. 1.3; CDC, 2008). Exposure
    was highest in Europe (86.1%); for the other
    five regions, exposure to second-hand tobacco
    smoke in public places ranged from 64.1% in the
    Western Pacific to 43.7% in Africa.
    217
    218
    WHO region
    EMRO
    EURO
    AFRO
    AMRO
    AMRO
    EURO
    AMRO
    EMRO
    SEARO
    AMRO
    AMRO
    AFRO
    SEARO
    AMRO
    EURO
    AFRO
    AMRO
    EURO
    AFRO
    AFRO
    WPRO
    AFRO
    AFRO
    AFRO
    AFRO
    AMRO
    WPRO
    AMRO
    AFRO
    AFRO
    WPRO
    Country
    Afghanistan
    Albania
    Algeria
    Antigua and Barbuda
    Argentina
    Armenia
    Bahamas
    Bahrain
    Bangladesh
    Barbados
    Belize
    Benin
    Bhutan
    The Plurinational State of Bolivia
    Bosnia and Herzegovina
    Botswana
    Brazil
    Bulgaria
    Burkina Faso
    Burundi
    Cambodia
    Cameroon
    Cape Verde
    Central African Republic
    Chad
    Chile
    China
    Colombia
    Comoros
    Congo
    Cook Islands
    Kabul
    National
    Constantine
    National
    National
    National
    National
    National
    National
    National
    National
    Atlantique Littoral
    National
    La Paz
    National
    National
    São Paulo
    National
    Ouagadougou
    National
    National
    Yaounde
    National
    Bangui
    National
    Santiago
    Shanghai
    Bogota
    National
    National
    National
    National survey, or
    jurisdiction where
    survey conducted
    2004
    2009
    2007
    2009
    2007
    2009
    2009
    2002
    2007
    2007
    2008
    2003
    2009
    2003
    2008
    2008
    2009
    2008
    2009
    2008
    2003
    2008
    2007
    2008
    2008
    2008
    2005
    2007
    2007
    2009
    2008
    Year
    38.8
    49.7
    38.7
    26.7
    54.7
    70.6
    25.1
    38.7
    34.7
    25.9
    25.7
    21.5
    29.5
    34.3
    77.3
    38.5
    35.5
    63.9
    29.2
    33.9
    47.0
    21.7
    13.9
    35.2
    33.9
    51.7
    47.0
    26.2
    35.2
    22.3
    61.9
    43.4
    48.6
    39.8
    22.5
    51.7
    69.2
    23.4
    37.2
    37.8
    25.9
    26.2
    23.7
    29.2
    34.3
    74.0
    38.2
    31.9
    61.5
    28.9
    35.2
    48.9
    25.0
    13.9
    29.9
    34.1
    48.9
    46.6
    25.3
    35.7
    24.7
    58.8
    33.3
    50.9
    37.9
    29.7
    57.7
    71.6
    27.0
    39.5
    32.4
    26.0
    25.1
    18.3
    29.5
    34.4
    80.3
    38.6
    38.7
    66.3
    29.2
    31.7
    44.5
    19.1
    13.7
    40.7
    31.2
    54.4
    47.4
    27.0
    34.9
    19.6
    64.5
    45.0
    64.5
    60.2
    47.5
    68.6
    78.3
    51.0
    45.3
    42.2
    59.6
    50.4
    38.0
    59.4
    52.9
    84.0
    62.1
    51.3
    70.1
    47.5
    49.3
    58.5
    45.8
    25.4
    52.4
    55.1
    68.3
    35.2
    56.1
    58.3
    44.4
    73.8
    60.2
    65.3
    66.0
    45.0
    66.4
    80.7
    50.8
    49.7
    47.1
    59.7
    52.1
    41.3
    58.6
    54.4
    82.3
    60.0
    48.2
    66.7
    53.5
    54.0
    60.6
    49.3
    27.0
    49.9
    54.0
    63.4
    34.2
    55.1
    66.7
    46.8
    70.3
    Boys
    23.6
    63.9
    56.2
    49.6
    70.7
    76.4
    52.7
    40.9
    38.7
    59.6
    48.6
    33.5
    59.7
    51.4
    85.6
    63.7
    54.1
    73.7
    42.2
    45.3
    56.5
    42.4
    24.2
    53.8
    56.2
    73.0
    36.2
    56.9
    52.9
    41.5
    76.8
    Girls
    Total
    Girls
    Total
    Boys
    Exposed to second-hand
    tobacco smoke outside
    their homes
    Exposed to second-hand
    tobacco smoke at home
    Table 1.3 Prevalence of exposure to second-hand tobacco smoke at home and outside home among 13–15 year olds, by
    country and sex, from the Global Youth Tobacco Survey (participating countries only) — 1999–2009
    IARC MONOGRAPHS – 100E
    WHO region
    AMRO
    AFRO
    EURO
    AMRO
    EURO
    EURO
    AFRO
    EMRO
    AMRO
    AMRO
    AMRO
    EMRO
    AMRO
    AFRO
    AFRO
    EURO
    AFRO
    WPRO
    AFRO
    EURO
    AFRO
    EURO
    AMRO
    AMRO
    AFRO
    AFRO
    AMRO
    AMRO
    AMRO
    EURO
    SEARO
    SEARO
    Country
    Costa Rica
    Côte d’Ivoire
    Croatia
    Cuba
    Cyprus
    Czech Republic
    Democratic Republic of the Congo
    Djibouti
    Dominica
    Dominican Republic
    Ecuador
    Egypt
    El Salvador
    Equatorial Guinea
    Eritrea
    Estonia
    Ethiopia
    Fiji
    Gambia
    Georgia
    Ghana
    Greece
    Grenada
    Guatemala
    Guinea
    Guinea-Bissau
    Guyana
    Haiti
    Honduras
    Hungary
    India
    Indonesia
    Table 1.3 (continued)
    National
    National
    National
    Havana
    National
    National
    Kinshasa
    National
    National
    National
    Quito
    National
    National
    National
    National
    National
    Addis Ababa
    National
    Banjul
    National
    National
    National
    National
    National
    National
    Bissau
    National
    Port-au-Prince
    Tegucigalpa
    National
    National
    National
    National survey, or
    jurisdiction where
    survey conducted
    2008
    2009
    2007
    2004
    2005
    2007
    2008
    2009
    2009
    2004
    2007
    2009
    2009
    2008
    2006
    2007
    2003
    2009
    2008
    2008
    2009
    2005
    2009
    2008
    2008
    2008
    2004
    2005
    2003
    2008
    2009
    2009
    Year
    22.1
    33.0
    75.7
    65.7
    89.1
    38.9
    27.0
    35.3
    27.4
    34.5
    30.2
    45.9
    16.5
    45.8
    14.8
    42.8
    12.8
    39.6
    44.4
    62.8
    17.9
    …
    29.7
    22.1
    28.1
    29.7
    30.6
    29.6
    31.6
    45.3
    18.8
    65.3
    Girls
    41.5
    74.4
    82.5
    65.0
    87.8
    75.2
    36.8
    44.7
    62.3
    41.9
    52.5
    52.2
    33.7
    61.7
    37.3
    68.5
    41.2
    55.1
    59.2
    74.4
    32.3
    …
    53.1
    40.8
    52.3
    35.3
    61.1
    43.2
    42.2
    72.6
    36.6
    78.1
    40.0
    75.9
    81.2
    64.6
    85.4
    71.6
    37.4
    44.8
    61.4
    38.5
    49.5
    57.7
    36.7
    64.0
    40.4
    68.2
    45.1
    55.2
    61.6
    75.5
    33.9
    …
    50.5
    43.8
    57.0
    36.6
    62.9
    46.2
    46.9
    70.0
    39.0
    83.7
    Boys
    42.8
    72.3
    84.2
    65.8
    90.4
    79.5
    34.7
    44.8
    62.5
    44.9
    54.6
    47.5
    30.7
    59.8
    32.3
    68.7
    37.4
    54.9
    57.2
    73.4
    30.4
    …
    55.7
    37.9
    48.1
    34.1
    59.1
    40.4
    38.4
    74.7
    33.1
    73.1
    Girls
    Total
    20.8
    33.1
    71.4
    59.1
    86.8
    37.3
    32.5
    36.2
    25.2
    31.1
    27.5
    50.1
    19.3
    47.8
    20.4
    39.3
    15.5
    45.4
    45.8
    62.4
    19.6
    …
    24.9
    23.9
    27.6
    32.1
    36.6
    34.7
    26.2
    39.9
    24.1
    72.6
    Boys
    Total
    21.6
    33.1
    73.4
    62.4
    87.9
    38.0
    30.2
    36.0
    26.9
    33.1
    28.9
    47.6
    17.9
    47.5
    18.4
    41.1
    14.9
    42.1
    45.8
    62.7
    19.1
    …
    27.3
    23.1
    27.7
    31.0
    33.4
    32.3
    29.6
    43.0
    21.9
    68.8
    Exposed to second-hand
    tobacco smoke outside
    their homes
    Exposed to second-hand
    tobacco smoke at home
    Second-hand tobacco smoke
    219
    220
    WHO region
    EMRO
    EMRO
    AMRO
    EMRO
    AFRO
    WPRO
    EMRO
    EURO
    WPRO
    EURO
    EMRO
    AFRO
    AFRO
    EURO
    AFRO
    AFRO
    WPRO
    SEARO
    AFRO
    WPRO
    AFRO
    AFRO
    AMRO
    WPRO
    WPRO
    EURO
    EMRO
    AFRO
    SEARO
    AFRO
    SEARO
    WPRO
    Country
    Islamic Republic of Iran
    Iraq
    Jamaica
    Jordan
    Kenya
    Kiribati
    Kuwait
    Kyrgyzstan
    Lao People’s Democratic Republic
    Latvia
    Lebanon
    Lesotho
    Liberia
    Lithuania
    Madagascar
    Malawi
    Malaysia
    Maldives
    Mali
    Marshall Islands
    Mauritania
    Mauritius
    Mexico
    Federated States of Micronesia
    Mongolia
    Montenegro
    Morocco
    Mozambique
    Myanmar
    Namibia
    Nepal
    New Zealand
    Table 1.3 (continued)
    National
    Baghdad
    National
    National
    National
    National
    National
    National
    Vientiane Capital
    National
    National
    National
    Monrovia
    National
    National
    National
    National
    National
    National
    National
    National
    National
    Mexico City
    National
    National
    National
    National
    Maputo
    National
    National
    National
    National
    National survey, or
    jurisdiction where
    survey conducted
    2007
    2008
    2006
    2009
    2007
    2009
    2009
    2008
    2007
    2007
    2005
    2008
    2008
    2009
    2008
    2009
    2009
    2007
    2008
    2009
    2009
    2008
    2006
    2007
    2007
    2008
    2006
    2007
    2007
    2008
    2007
    2008
    Year
    35.4
    32.3
    32.5
    53.6
    24.7
    68.3
    49.8
    33.4
    40.3
    55.2
    78.4
    36.9
    23.6
    38.3
    49.5
    19.7
    48.7
    48.3
    48.5
    52.1
    37.5
    36.1
    46.2
    60.7
    54.4
    76.8
    27.1
    22.5
    34.1
    38.1
    35.3
    36.0
    38.1
    30.3
    32.2
    50.6
    25.4
    68.7
    46.9
    35.1
    41.2
    55.1
    76.0
    34.2
    22.2
    34.1
    55.0
    25.0
    49.6
    49.4
    50.1
    54.7
    39.8
    38.5
    46.3
    60.4
    53.7
    73.5
    24.7
    25.2
    38.8
    38.0
    38.5
    38.5
    32.7
    34.4
    32.5
    55.5
    23.6
    68.3
    52.0
    31.9
    39.5
    55.1
    80.4
    37.3
    24.5
    42.6
    44.9
    14.0
    47.6
    47.1
    46.9
    50.5
    35.0
    34.1
    45.5
    59.6
    54.3
    79.9
    29.2
    19.6
    29.4
    37.9
    31.7
    33.1
    44.8
    29.2
    60.5
    50.5
    48.2
    65.8
    53.3
    57.7
    55.4
    72.7
    74.4
    52.6
    45.5
    64.9
    62.9
    29.5
    64.1
    68.0
    81.4
    59.7
    50.9
    73.6
    60.2
    71.3
    55.5
    69.9
    41.1
    26.2
    46.4
    49.9
    47.3
    67.2
    49.8
    27.8
    59.9
    50.6
    48.6
    67.9
    54.3
    58.7
    57.7
    73.2
    73.9
    50.2
    45.1
    66.5
    69.5
    32.9
    67.7
    70.6
    83.1
    60.5
    55.4
    77.2
    61.6
    73.3
    60.7
    68.8
    41.1
    28.6
    51.2
    47.7
    49.5
    63.3
    Boys
    39.6
    30.7
    61.6
    49.7
    47.6
    64.0
    52.4
    56.8
    53.2
    72.3
    74.7
    53.2
    45.4
    63.3
    57.5
    26.1
    60.2
    65.4
    79.2
    60.6
    47.1
    70.7
    59.0
    68.7
    50.7
    70.8
    40.9
    23.0
    42.1
    51.5
    44.7
    71.3
    Girls
    Total
    Girls
    Total
    Boys
    Exposed to second-hand
    tobacco smoke outside
    their homes
    Exposed to second-hand
    tobacco smoke at home
    IARC MONOGRAPHS – 100E
    WHO region
    AMRO
    AFRO
    AFRO
    EMRO
    EMRO
    WPRO
    AMRO
    WPRO
    AMRO
    AMRO
    WPRO
    EURO
    EMRO
    WPRO
    EURO
    EURO
    EURO
    AFRO
    AMRO
    AMRO
    AMRO
    WPRO
    EURO
    EMRO
    AFRO
    EURO
    AFRO
    AFRO
    WPRO
    EURO
    EMRO
    AFRO
    Country
    Nicaragua
    Niger
    Nigeria
    Oman
    Pakistan
    Palau
    Panama
    Papua New Guinea
    Paraguay
    Peru
    Philippines
    Poland
    Qatar
    Republic of Korea
    Republic of Moldova
    Romania
    Russian Federation
    Rwanda
    Saint Kitts and Nevis
    Saint Lucia
    Saint Vincent and the Grenadines
    Samoa
    San Marino
    Saudi Arabia
    Senegal
    Serbia
    Seychelles
    Sierra Leone
    Singapore
    Slovakia
    Somalia
    South Africa
    Table 1.3 (continued)
    Centro Managua
    National
    Abuja
    National
    Islamabad
    National
    National
    National
    National
    National
    National
    Warsaw
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    Somaliland
    National
    National survey, or
    jurisdiction where
    survey conducted
    2003
    2009
    2008
    2007
    2003
    2009
    2008
    2007
    2008
    2007
    2007
    2009
    2007
    2008
    2008
    2009
    2004
    2008
    2002
    2007
    2007
    2007
    2009
    2007
    2007
    2008
    2007
    2008
    2000
    2007
    2007
    2008
    Year
    43.2
    20.4
    12.8
    11.2
    21.7
    …
    21.5
    72.2
    30.1
    24.2
    53.1
    54.6
    35.2
    41.6
    20.1
    55.4
    78.5
    18.0
    15.3
    22.6
    30.9
    56.4
    34.0
    26.4
    42.5
    80.0
    46.1
    42.9
    35.2
    46.9
    21.9
    31.5
    Girls
    54.1
    54.3
    39.7
    27.4
    33.9
    79.2
    40.3
    86.4
    55.3
    46.8
    64.8
    76.8
    45.9
    70.8
    57.0
    59.1
    89.4
    …
    48.8
    64.0
    59.7
    62.8
    65.8
    38.2
    48.3
    71.9
    57.1
    56.5
    65.1
    69.3
    48.7
    41.1
    56.4
    58.8
    43.6
    29.8
    42.5
    70.4
    38.9
    87.0
    57.3
    46.9
    67.2
    75.5
    52.1
    67.3
    59.4
    57.1
    89.0
    …
    48.0
    61.1
    56.5
    64.8
    62.8
    45.1
    48.3
    68.1
    54.3
    59.9
    64.0
    68.0
    50.2
    43.5
    Boys
    51.9
    50.2
    36.0
    25.2
    26.4
    85.3
    41.4
    85.6
    53.4
    46.4
    62.8
    77.8
    42.8
    74.8
    54.8
    61.3
    89.9
    …
    49.0
    65.7
    61.8
    60.5
    69.3
    31.6
    45.0
    74.8
    60.6
    53.4
    66.0
    70.5
    41.8
    39.4
    Girls
    Total
    43.9
    28.1
    29.2
    16.7
    32.1
    …
    22.2
    75.4
    35.1
    26.2
    55.7
    42.8
    36.3
    33.8
    20.6
    50.0
    74.3
    19.9
    16.2
    28.4
    31.7
    60.8
    31.8
    28.9
    49.9
    73.4
    38.2
    46.3
    34.8
    42.4
    30.8
    32.7
    Boys
    Total
    43.7
    24.1
    21.7
    13.9
    26.6
    …
    21.9
    73.9
    32.5
    25.5
    54.5
    49.1
    35.7
    37.6
    20.3
    52.8
    76.4
    19.2
    16.5
    25.2
    31.5
    59.1
    32.9
    27.9
    47.6
    76.9
    42.3
    44.2
    35.1
    44.9
    29.1
    32.1
    Exposed to second-hand
    tobacco smoke outside
    their homes
    Exposed to second-hand
    tobacco smoke at home
    Second-hand tobacco smoke
    221
    222
    SEARO
    EMRO
    AMRO
    AFRO
    EMRO
    SEARO
    EURO
    SEARO
    AFRO
    AMRO
    EMRO
    EURO
    WPRO
    AFRO
    EMRO
    AFRO
    AMRO
    AMRO
    EURO
    WPRO
    AMRO
    WPRO
    EMRO
    EMRO
    EMRO
    AFRO
    AFRO
    Sri Lanka
    Sudan
    Suriname
    Swaziland
    Syrian Arab Republic
    Thailand
    The former Yugoslav Republic of Macedonia
    Timor-Leste
    Togo
    Trinidad and Tobago
    Tunisia
    Turkey
    Tuvalu
    Uganda
    United Arab Emirates
    United Republic of Tanzania
    United States of America
    Uruguay
    Uzbekistan
    Vanuatu
    Venezuela (Bolivarian Republic of)
    Viet Nam
    West Bank*
    Gaza Strip*
    Yemen
    Zambia
    Zimbabwe
    * Refers to a territory
    From WHO (2008, 2009a)
    WHO region
    Country
    Table 1.3 (continued)
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    National
    Arusha
    National
    National
    Tashkent
    National
    National
    National
    West Bank
    Gaza Strip
    National
    Lusaka
    Harare
    National survey, or
    jurisdiction where
    survey conducted
    2007
    2009
    2009
    2009
    2010
    2009
    2008
    2009
    2007
    2007
    2007
    2009
    2006
    2007
    2005
    2008
    2009
    2007
    2008
    2007
    1999
    2007
    2009
    2005
    2008
    2007
    2008
    Year
    35.4
    27.6
    46.6
    23.3
    60.1
    45.7
    67.5
    59.4
    20.2
    40.1
    51.9
    48.6
    76.6
    20.0
    25.3
    15.7
    35.7
    50.5
    17.3
    59.3
    43.5
    58.5
    63.0
    47.4
    44.9
    23.1
    20.9
    37.6
    26.0
    44.2
    21.8
    58.7
    46.6
    64.7
    66.7
    23.5
    36.3
    53.1
    43.8
    77.8
    20.7
    24.3
    16.4
    35.3
    47.6
    17.6
    62.8
    40.7
    59.0
    61.6
    48.0
    48.2
    21.2
    22.0
    33.4
    28.7
    47.7
    24.3
    61.7
    44.7
    70.5
    52.1
    15.7
    43.6
    50.6
    53.0
    75.8
    18.8
    25.4
    14.9
    36.1
    52.5
    15.8
    56.7
    45.3
    58.0
    64.4
    46.5
    37.8
    24.3
    19.4
    65.9
    33.1
    53.3
    55.6
    58.4
    67.6
    66.0
    61.3
    41.6
    64.2
    65.2
    79.9
    76.7
    45.6
    31.6
    34.7
    42.8
    68.6
    46.7
    75.9
    47.8
    71.2
    61.6
    46.1
    42.7
    45.5
    40.1
    66.5
    33.8
    51.4
    52.1
    61.1
    68.0
    63.7
    66.7
    45.1
    62.8
    69.7
    80.1
    72.0
    46.1
    34.3
    35.2
    38.2
    64.0
    47.5
    78.7
    47.0
    71.4
    67.6
    51.9
    49.8
    43.2
    40.5
    Boys
    65.1
    32.0
    53.8
    58.0
    55.7
    67.1
    68.3
    56.0
    36.7
    65.9
    61.0
    79.6
    79.3
    45.2
    28.4
    33.9
    47.6
    72.1
    42.4
    73.9
    48.4
    71.0
    55.8
    40.6
    30.7
    47.1
    39.5
    Girls
    Total
    Girls
    Total
    Boys
    Exposed to second-hand
    tobacco smoke outside
    their homes
    Exposed to second-hand
    tobacco smoke at home
    IARC MONOGRAPHS – 100E
    Second-hand tobacco smoke
    Table 1.4 Proportion of children under 15 years with one or more parent who smokes, by WHO
    subregion (based on survey data and modeling)
    Subregion
    Africa (D)
    Africa (E)
    The Americas (A)
    The Americas (B)
    The Americas (D)
    Eastern Mediterranean (B)
    Eastern Mediterranean (D)
    Europe (A)
    Europe (B)
    Europe (C)
    South-eastern Asia (B)
    South-eastern Asia (D)
    Western Pacific (A)
    Western Pacific (B)
    GLOBAL
    Parental smoking (%)
    13
    13
    25
    29
    22
    37
    34
    51
    61
    61
    53
    36
    51
    68
    41
    WHO subregional country grouping (adapted from WHO, 2002):
    Africa. Region D: Algeria, Angola, Benin, Burkina Faso, Cameroon, Cape Verde, Chad, Comoros, Equatorial Guinea, Gabon, The Gambia, Ghana,
    Guinea, Guinea-Bissau, Liberia, Madagascar, Mali, Mauritania, Mauritius, Niger, Nigeria, Sao Tome and Principe, Senegal, Seychelles, Sierra
    Leone, Togo; Region E: Botswana, Burundi, Central African Republic, Congo, Côte d’Ivoire, Democratic Republic of the Congo, Eritrea, Ethiopia,
    Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, South Africa, Swaziland, Uganda, United Republic of Tanzania, Zambia, Zimbabwe
    The Americas. Region A: Canada, Cuba, USA; Region B: Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Brazil, Chile, Colombia,
    Costa Rica, Dominica, Dominican Republic, El Salvador, Grenada, Guyana, Honduras, Jamaica, Mexico, Panama, Paraguay, Saint Kitts and Nevis,
    Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago, Uruguay, Venezuela; Region D: Bolivia, Ecuador, Guatemala,
    Haiti, Nicaragua, Peru
    Eastern Mediterranea. Region B: Bahrain, Islamic Republic of Iran, Jordan, Kuwait, Lebanon, Libyan Arab Jamahirya, Oman, Qatar, Saudi
    Arabia, Syrian Arab Republic, Tunisia, United Arab Emirates; Region D: Afghanistan, Djibouti, Egypt, Iraq, Morocco, Pakistan, Somalia, Sudan,
    Yemen
    Europe. Region A: Andorra, Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland,
    Israel, Italy, Luxembourg, Malta, Monaco, Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland, United Kingdom;
    Region B: Albania, Armenia, Azerbaijan, Bosnia and Herzegovina, Bulgaria, Georgia, Kyrgyzstan, Poland, Romania, Serbia and Montenegro,
    Slovakia, Tajikistan, Former Yugoslav Republic of The former Yugoslav Republic of Macedonia, Turkey, Turkmenistan, Uzbekistan; Region C:
    Belarus, Estonia, Hungary, Kazakhstan, Latvia, Lithuania, Republic of the Republic of Moldova, Russian Federation, Ukraine
    South-eastern Asia. Region B: Indonesia, Sri Lanka, Thailand; Region D: Bangladesh, Bhutan, Democratic People’s Republic of Korea, India,
    Maldives, Myanmar (Burma), Nepal, Timor-Leste
    Western Pacific. Region A: Australia, Brunei Darussalam, Japan, New Zealand, Singapore; Region B: Cambodia, China, Cook Islands, Fiji,
    Kiribati, Lao People’s Democratic Republic, Malaysia, Marshall Islands, Federated States of Micronesia, Mongolia, Nauru, Niue, Palau, Papua
    New Guinea, Philippines, Republic of Korea, Samoa, Solomon Islands, Tonga, Tuvalu, Vanuatu, Viet Nam
    Regions are categorized as follows (WHO-approved classifications): A = very low child mortality and very low adult mortality; B = low child
    mortality and low adult mortality; C = low child mortality and high adult mortality; D = high child mortality and high adult mortality; E = high
    child mortality and very high adult mortality.
    223
    IARC MONOGRAPHS – 100E
    Fig. 1.3 Average prevalence (in%) of exposure of 13–15 year old children to second-hand tobacco
    smoke in public places, by WHO region, 2007
    ￼
    From CDC (2008)
    ￼ Fig. 1.4 presents the range of exposure to
    second-hand tobacco smoke outside home by
    WHO region for boys and girls and for both sexes
    combined. There are wide variations in secondhand tobacco smoke exposure outside home
    within each region. The largest variations are
    observed in the African region and the Western
    Pacific region irrespective of sex. This is largely
    influenced by the presence of smoke-free legislation for public paces in the countries, as well
    as levels of enforcement and public’s compliance
    with these laws.
    224
    1.4.2.Exposure among adults
    (a)Overview
    While the GYTS offers a valuable global
    source for estimating exposure to second-hand
    tobacco smoke among children, there is no such
    extensive source of data for adults. Estimates of
    second-hand tobacco smoke exposure among
    adults have used the definitions of exposure
    based on having a spouse who smokes or exposure to tobacco smoke at work. For the countries
    lacking such data, exposure was estimated using
    a model based on smoking prevalence among
    men from the WHO Global InfoBase.
    About one third of adults worldwide are
    regularly exposed to second-hand tobacco smoke
    (Table 1.5). The highest exposure was estimated
    in European Region C with 66% of the population
    Second-hand tobacco smoke
    Fig. 1.4 Range of prevalence (in%) of exposure of 13–15 year old children to second-hand tobacco
    smoke outside their home, by WHO region, 2009
    ￼
    From CDC/WHO (2009)
    being regularly exposed to second-hand tobacco
    smoke. The lowest regional exposure was estimated in the African region (4%). Differences
    between men and women were generally small,
    except in Eastern Mediterranean Region D and
    South East Asia Region B.
    (b) Exposure at home
    The Global Tobacco Surveillance System,
    through its adult household survey “Global Adult
    Tobacco Survey” (GATS), collects information on
    key tobacco control indicators including information on second-hand tobacco smoke exposure
    at home, at work and several public places (WHO,
    2009b). GATS is a nationally representative survey
    conducted among persons aged ≥ 15 years using a
    standardized questionnaire, sample design, data
    collection method, and analysis protocol. GATS
    results are available from 14 countries with a
    high tobacco burden. Additionally since 2008,
    The WHO STEPwise approach to surveillance
    (STEPS) surveys have started to collect information on exposure to second-hand tobacco smoke
    at home and at work, now available for 7 countries (WHO, 2009c).
    In the 21 countries that have reported data on
    exposure to second-hand tobacco smoke, large
    numbers of people are exposed at home (Fig. 1.5).
    Exposure was highest in Sierra Leone (74%)
    and lowest in the British Virgin Islands (3%).
    Overall, differences between men and women
    were relatively small in most countries; in China,
    Cambodia and Mongolia, more women reported
    being exposed to second-hand tobacco smoke
    225
    IARC MONOGRAPHS – 100E
    Table 1.5 Proportion of non-smoking adults exposed regularly to second-hand tobacco smoke,
    by WHO region (based on survey data and modeling)
    Exposure in men
    Exposure in women
    WHO Subregion
    (%)
    (%)
    Africa (D)
    Africa (E)
    The Americas (A)
    The Americas (B)
    The Americas (D)
    Eastern Mediterranean (B)
    Eastern Mediterranean (D)
    Europe (A)
    Europe (B)
    Europe (C)
    South-eastern Asia (B)
    South-eastern Asia (D)
    Western Pacific (A)
    Western Pacific (B)
    GLOBAL
    7
    4
    16
    13
    15
    24
    21
    34
    52
    66
    58
    23
    50
    53
    33
    11
    9
    16
    21
    18
    22
    34
    32
    53
    66
    41
    18
    54
    51
    31
    From WHO (2010)
    For the WHO subregional country grouping, see footnote of Table 1.4.
    in their homes then men. This lack of difference
    implies that even when prevalence of smoking
    among women is low, they are exposed to secondhand tobacco smoke at home as much as men.
    (c) Exposure at the workplace
    The same magnitude of second-hand tobacco
    smoke exposure at the workplace was reported
    as at home (Fig. 1.6). Exposure to second-hand
    tobacco smoke at the workplace was highest
    in Sierra Leone (74%) and lowest in the British
    Virgin Islands (3%). However, more men reported
    being exposed to others’ smoke at their workplace as compared to women in all countries.
    This difference was most significant in Libyan
    Arab Jamahirya and Bangladesh. These differences could be explained by the fact that women
    either tend to work in places where smoking is
    banned, such as education or health facilities, or
    work predominantly with other women.
    226
    1.5Regulations
    The World Health Organization’s Framework
    Convention on Tobacco Control (WHO FCTC)
    is a multilateral treaty with legally binding
    obligations for its 174 Parties (as of November
    2011) (WHO, 2003). This comprehensive treaty
    contains supply and demand reduction measures available to countries to counter the tobacco
    epidemic. Article 8 of the Treaty specifically
    addresses the need for protection from secondhand tobacco smoke, and articulates the “adoption and implementation of effective legislative,
    executive, administrative and /or other measures” by Parties to the Convention to this effect.
    Guidelines to Article 8 specify key elements
    needed in legislation to help countries meet the
    highest standards of protection from secondhand tobacco smoke and provide a clear timeline for Parties to adopt appropriate measures
    (within five years after entry into Force of the
    WHO FCTC) (WHO, 2007).
    Second-hand tobacco smoke
    Fig. 1.5 Prevalence of adults exposed to second-hand tobacco smoke in their homes, in the
    countries that completed the Global Adult Tobacco Survey (GATS) and WHO STEPwise approach
    to surveillance (STEPS) surveys, 2008–2009
    ￼
    From WHO (2009b, c)
    GATS defines second-hand tobacco smoke exposure at home as reporting that smoking inside their home occurs daily, weekly, or monthly.
    STEPS defines second-hand tobacco smoke exposure at home as reporting exposure in the home on one or more days in the past 7 days.
    All countries, regardless of their FCTC ratification status, are taking steps to reduce secondhand tobacco smoke in public places, through
    either planning the steps to or implementing
    national smoke-free laws for public places or
    workplaces. In 2008, approximately 5% of the
    world’s population (354 million) had national
    smoke-free laws. Fig. 1.7 provides details on the
    number of public places with national smokefree legislation for all WHO Member States.
    ￼ As of December 2008, fifteen countries
    across the globe have legislation that provide
    the highest level of protection against secondhand tobacco smoke exposure. These include:
    Albania, Australia, Bhutan, Canada, Colombia,
    Guatemala, Islamic Republic of Iran, Ireland,
    Marshall Islands, New Zealand, Panama, Turkey,
    Turkmenistan, United Kingdom of Great Britain
    and Northern Ireland and Uruguay.
    2 Cancer in Humans
    2.1Cancer of the lung
    More than 50 epidemiological studies
    since 1981 have examined the association
    between second-hand tobacco smoke and lung
    cancer resulting in the conclusion that exposure of non-smokers to second-hand tobacco
    smoke is causally associated with lung cancer
    risk (IARC, 2004). Many studies previously
    227
    IARC MONOGRAPHS – 100E
    Fig. 1.6 Prevalence of adults exposed to second-hand tobacco smoke in their workplaces, in
    the countries that completed the Global Adult Tobacco Survey and WHO STEPwise approach to
    surveillance (STEPS) surveys, 2008–2009
    ￼
    GATS defines second-hand tobacco smoke exposure at work as indoor workers who were exposed at work in the past 30 days.
    STEPS defines second-hand tobacco smoke exposure at work as reporting exposure in the workplace on one or more days in the past 7 days
    From WHO (2009b, c)
    available assessed the lung cancer risk among the
    nonsmoking spouses of smokers since it is one
    of the sources of adult exposure to second-hand
    tobacco smoke that is less likely to be subject to
    exposure misclassification or other bias. Several
    important new, cohort, case–control studies and
    meta-analyses have been published since 2004
    that provide additional evidence confirming
    the causal association (Table 2.1 available at
    http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.1.pdf, Table 2.2 available
    at http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.2.pdf, and Table 2.3
    available at http://monographs.iarc.fr/ENG/
    Monographs/vol100E/100E-02-Table2.3.pdf ).
    These new studies also expand our assessment of
    228
    the effect of second-hand tobacco smoke in the
    workplace allowing for more refined estimates of
    lung cancer risk. Preliminary data also suggest
    significant interactions between several genetic
    polymorphisms, second-hand tobacco smoke
    and lung cancer risk.
    In a meta-analysis of 55 studies, including 7
    cohort, 25 population based case–control studies
    and 23 hospital based case–control studies the
    pooled relative risk (RR) for lung cancer for
    never smoking women exposed to second-hand
    tobacco smoke from spouses was 1.27 (95%CI:
    1.17–1.37). The relative risk for studies in North
    America was 1.15 (95%CI: 1.03–1.28), in Asia 1.31
    (95%CI: 1.16–1.48) and Europe 1.31 (1.24–1.52)
    (Taylor et al., 2007).
    Second-hand tobacco smoke
    Fig. 1.7 Number and percentage of countries with number of public places covered by smoke free
    legislations, by income status (as of 31 December 2008)
    ￼
    From WHO (2009a)
    In a meta-analysis of 22 studies that assessed
    the effect of second-hand tobacco smoke exposures at work, the relative risk for lung cancer
    among exposed non-smokers was 1.24 (95%CI:
    1.18–1.29) and among those workers classified as
    highly exposed to second-hand tobacco smoke at
    work 2.01 (95%CI: 1.33–2.60) compared to those
    with no exposure at work (Stayner et al., 2007).
    In a large cohort study conducted in 10
    European countries (European Prospective
    Investigation into Cancer and Nutrition, EPIC),
    it was estimated that the hazard ratio (HR) for
    lung cancer risk from second-hand tobacco
    smoke exposure at home and/or at work for
    never smokers and ex-smokers (at least 10 years)
    was 1.34 (0.85−2.13) (Vineis et al., 2007a). The
    main component of this risk was attributable to
    exposure at the workplace, resulting in a hazard
    ratio of 1.65 (1.04–2.63). The overall hazard ratio
    between childhood exposure and the risk of lung
    cancer in adulthood was 2.00 (0.94–4.28); among
    children with daily exposure for many hours
    each day the hazard ratio was 3.63 (1.19–11.12).
    In a separate analysis of workplace exposure
    to second-hand tobacco smoke in this cohort
    women were observed to have a lung cancer
    hazard ratio of 2.13 (1.6–3.4) (Veglia et al., 2007).
    In a large population-based cohort study
    conducted in Japan, findings confirmed that
    exposure to second-hand tobacco smoke is
    229
    IARC MONOGRAPHS – 100E
    a risk factor for lung cancer among Japanese
    women (Kurahashi et al., 2008). Compared with
    women married to never smokers, the hazard
    ratio for all lung cancer incidence was 1.34
    (95%CI:0.81–2.21) and for adenocarcinoma
    2.03 (95%CI:1.07–3.86). For adenocarcinoma
    dose–response relationships were seen for both
    intensity (P for trend = 0.02) and total amount
    (P for trend = 0.03) of the husband’s smoking.
    Exposure to second-hand tobacco smoke at the
    workplace also increased the risk of lung cancer
    (HR, 1.32; 95%CI: 0.85–2.04).
    Data from a cohort study of women from
    Shanghai, China also found that exposure to
    second-hand tobacco smoke is associated with
    lung cancer mortality. Exposure to second-hand
    tobacco smoke at work was associated with a
    significantly increased mortality to lung cancer
    (HR 1.79, 95%CI: 1.09–2.93) but the risk was not
    significant for exposure to husband’s secondhand tobacco smoke (HR 1.09, 95%CI: 0.74–1.61)
    (Wen et al., 2006). In a case–control study of lung
    cancer among lifetime non-smoking Chinese
    men living in Hong Kong Special Administrative
    Region a non-significant association between all
    lung cancer and ever being exposed to household
    and/or workplace second-hand tobacco smoke
    was observed (OR, 1.11, 95%CI: 0.74–1.67) but a
    significant increase was observed for adenocarcinoma (OR, 1.68, 95%CI: 1.00–2.38) (Tse et al.,
    2009).
    In a long-term case–control study of lung
    cancer cases at the Massachusetts General
    Hospital, study participants exposed to secondhand tobacco smoke at work and at leisure were
    at a significantly greater risk (OR, 1.30, 95%CI:
    1.08–1.57) if the exposure occurred between
    birth and 25 years of age. If the exposures
    occurred after the age of 25 years the risk was
    not elevated (OR, 0.66, 95%CI: 0.21–1.57) but
    the confidence limits are wide for this subgroup
    analysis (Asomaning et al., 2008).
    In two other cohort studies, one conducted
    in California (Enstrom & Kabat, 2003) and
    230
    another in New Zealand (Hill et al., 2007) no
    excess risk was observed among lifelong nonsmokers exposed to second-hand tobacco smoke.
    In the California study the relative risk was 0.99
    (95%CI: 0.72–1.37) based on 126 lung cancer
    cases. [The confidence intervals in this study
    are relatively wide and they include the current
    IARC estimate of lung cancer risk from secondhand tobacco smoke exposure. In addition the
    opportunity for substantial misclassification of
    second-hand tobacco smoke exposure is great
    because exposures outside the home were not
    assessed and the second-hand tobacco smoke
    exposures were not re-evaluated after enrollment
    into the study.] Hill et al. (2007) observed no
    association between second-hand tobacco smoke
    exposure in a census enumeration of current
    second-hand tobacco smoke exposure at home
    and linkage to cancer registries three years later.
    The authors suggest that this may be a result of
    either the misclassification of total second-hand
    tobacco smoke exposure since exposures outside
    the home were not assessed and/or the fact that
    a 3-year follow-up after exposure ascertainment
    may have been too short to capture important
    exposures before the diagnosis of lung cancer.
    One case–control study (Wenzlaff et al.,
    2005) and one case-only study (Bonner et al.,
    2006) assessed lung cancer risk associated with
    second-hand tobacco smoke exposure and
    several polymorphisms. In the case–control
    study, individuals were stratified by household
    second-hand tobacco smoke exposure (yes/no),
    those with CYP1B1 Leu432Val genotype alone or
    in combination with Phase II enzyme polymorphisms were more strongly associated with lung
    cancer risk if they also were exposed to at least
    some household second-hand tobacco smoke
    exposure compared to those that had no exposure. In the case-only study a significant interaction was observed between lung cancer risk,
    second-hand tobacco smoke and a GSTM1 (null)
    genotype (OR, 2.28, 95%CI:1.15–4.51).
    Second-hand tobacco smoke
    2.2Cancer of the breast
    2.2.1 Overview of studies
    The relationship between exposure to
    second-hand tobacco smoke and breast cancer
    has been comprehensively reviewed in the peer
    reviewed literature (Johnson, 2005; Miller et al.,
    2007) and in reports from national and international committees (IARC, 2004, 2009; California
    Environmental Protection Agency, 2005; US.
    Department of Health and Human Services,
    2006; Collishaw et al., 2009). These reviews have
    drawn different conclusions. IARC (2004) characterized the evidence as “inconsistent,” based
    on studies published or in press by June, 2002.
    A US Surgeon General Report (2006) concluded
    that the evidence was “suggestive but not sufficient” to infer a causal relationship between
    second-hand tobacco smoke and breast cancer,
    whereas reviews by the California Environmental
    Protection Agency (CalEPA) in 2005 and by
    a panel of researchers in this area convened in
    Canada (Collishaw et al., 2009) designated the
    evidence for second-hand tobacco smoke as
    “consistent with a causal association in younger
    primarily premenopausal women.”
    A total of 16 new studies have been published
    since the previous IARC Monograph (IARC,
    2004). These include three cohort studies
    (Reynolds et al., 2004; Hanaoka et al., 2005; Pirie
    et al., 2008) (Table 2.4 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E02-Table2.4.pdf), and 13 new case–control
    studies (Lash & Aschengrau, 2002; Alberg
    et al., 2004; Gammon et al., 2004; Shrubsole
    et al., 2004; Bonner et al., 2005; Sillanpää et al.,
    2005; Lissowska et al., 2006; Mechanic et al.,
    2006; Roddam et al., 2007; Rollison et al., 2008;
    Slattery et al., 2008; Ahern et al., 2009; Young
    et al., 2009) (Table 2.5 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E02-Table2.5.pdf). Table 2.5 also presents two
    case–control studies not discussed previously
    (Zhao et al., 1999; Liu et al., 2000). Several metaanalyses have also been published as new data
    became available (California Environmental
    Protection Agency, 2005; Johnson, 2005; US.
    Department of Health and Human Services,
    2006; Pirie et al., 2008; IARC, 2009).
    The largest of the cohort studies, identified
    2518 incident breast cancers among 224917 never
    smokers followed for an average of 3.5 years in
    the British Million Women Study (Pirie et al.,
    2008). The cohort was drawn from women, age
    50–64 years, participating in mammography
    screening programmes. Nearly all cases were
    post-menopausal and the overall analyses
    pertain to postmenopausal breast cancer. No
    relationship was observed between breast cancer
    risk and smoking by a parent at the time of birth
    and/or age 10 years (HR, 0.98; 95%CI: 0.88–
    1.08); the results were also null for smoking by
    a current partner (HR, 1.02; 95%CI: 0.89–1.16)
    or exposure to the combination of parental and
    spousal smoking (HR, 1.03; 95%CI: 0.90–1.19).
    Pirie et al. (2008) also present a meta-analysis of
    studies of second-hand smoke and breast cancer
    risk, separating studies by cohort or case–control
    design. No overall association was observed in
    the cohort studies. These largely represent postmenopausal breast cancer, so the analysis was
    not stratified by menopausal status. An overall
    association was seen in the case–control studies,
    similar to the findings of other meta-analyses
    (California Environmental Protection Agency,
    2005; US. Department of Health and Human
    Services, 2006; IARC, 2009). [Pirie et al. (2008)
    focus on the discrepancy between the cohort and
    case–control results and propose that the associations observed in early case–control studies
    can likely be explained by recall bias. The study
    has been criticized for the lack of information on
    occupational exposures to second-hand smoke
    (Collishaw et al., 2009).]
    A second large cohort study (Reynolds et al.,
    2004) identified 1998 women diagnosed with
    breast cancer during five years of follow-up of the
    231
    IARC MONOGRAPHS – 100E
    California Teachers Study. Analyses were based
    on 433 women with pre/peri-menopausal breast
    cancer and 1361 women with postmenopausal
    cancer. No association was observed between
    post-menopausal breast cancer and residential exposure to second-hand tobacco smoke
    in childhood or adulthood. No association was
    initially reported with pre/peri-menopausal
    breast cancer in analyses based on menopausal
    status at enrollment (RR 0.93, 95%CI: 0.71–1.22).
    When menopausal status was defined by age at
    diagnosis rather than by age at enrollment, the
    hazard ratio for premenopausal breast cancer
    among women exposed in both childhood and
    adulthood increased to 1.27 (95%CI: 0.84–1.92)
    (Reynolds et al., 2006).
    Hanaoka et al. (2005) identified 162 incident
    breast cancer cases during a nine-year followup of 20169 Japanese women, age 40–59 years,
    who reported no history of active smoking when
    enrolled in the Japan Public Health Center
    (JPHC) study in 1990. Nearly three quarters
    (72%) of the women reported exposure to secondhand tobacco smoke. About half of the women
    were premenopausal when enrolled in the study,
    although there were only nine unexposed cases
    among the pre-menopausal women. The multivariate-adjusted relative risk for breast cancer
    among all exposed women irrespective of menopausal status was 1.1 (95%CI: 0.8–1.6) compared
    to those classified as unexposed. The corresponding relative risks for women who were preor postmenopausal at baseline were 2.6 (95%CI:
    1.3–5.2) and 0.7 (95%CI: 0.4–1.0), respectively.
    Six of the 13 new population-based case–
    control studies included more than 1000 cases
    each (Shrubsole et al., 2004; Bonner et al., 2005;
    Lissowska et al., 2006; Mechanic et al., 2006;
    Slattery et al., 2008; Young et al., 2009; Table 2.5
    on-line). None of these 13 studies showed an
    overall increase in breast cancer risk associated
    with second-hand tobacco smoke exposure in
    Caucasians. The incidence of premenopausal
    breast cancer was associated with one or more
    232
    indices of second-hand tobacco smoke exposure in all four studies that stratified the results
    by menopausal status (Gammon et al., 2004;
    Shrubsole et al., 2004; Bonner et al., 2005; Slattery
    et al., 2008) although the association was not
    always statistically significant (Gammon et al.,
    2004; Bonner et al., 2005; Fig. 2.1). Associations
    were also reported between second-hand tobacco
    smoke exposure and overall breast cancer risk in
    African Americans (Mechanic et al., 2006) and
    with premenopausal breast cancer in Hispanics/
    American Indians (Slattery et al., 2008). The
    associations observed in these case–control
    studies are generally weaker than those reported
    in earlier case–control studies. Whereas the relative risk estimates reported in the earlier studies
    often equalled or exceeded 2.0 (Sandler et al.,
    1985a; Lash & Aschengrau, 1999; Zhao et al.,
    1999; Johnson & Repace, 2000; Liu et al., 2000)
    or 3.0 (Smith et al., 1984; Morabia et al., 1996; Liu
    et al., 2000; Morabia et al., 2000), the estimates in
    the later studies were mostly under 1.5, even in
    studies that reported positive associations.
    2.2.2Issues affecting the interpretation of
    studies
    One important consideration in evaluating these data has been the lack of a strong
    and convincing relationship between active
    smoking and breast cancer. Several theories
    have been advanced to explain why secondhand tobacco smoke might have a stronger
    effect on breast cancer than active smoking
    (California Environmental Protection Agency,
    2005; Johnson, 2005; Collishaw et al., 2009).
    Central to these is the hypothesis that active
    smoking may have counterbalancing protective
    and detrimental effects on breast cancer risk
    that, in combination, produce little or no overall
    association, whereas second-hand tobacco
    smoke may have only an adverse effect on risk.
    The weakness of this theory is that there is little
    direct evidence (see Section 4) identifying the
    Second-hand tobacco smoke
    Fig. 2.1 Relative risk of pre-menopausal breast cancer associated with second-hand tobacco
    smoke. Ever versus never.
    ￼
    Study sorted by calendar year
    mechanism by which active smoking may cause
    the proposed [protective] antiestrogenic effects.
    Without knowing the mechanism, it has been
    impossible to prove that active smoking has
    this effect but exposure to second-hand tobacco
    smoke does not. A second hypothesis that has
    been advanced is that second-hand tobacco
    smoke may have a greater effect on pre- than on
    postmenopausal breast cancer. This theory was
    proposed by CalEPA in 2005 (Johnson & Glantz,
    2008) based on analyses of studies available at
    the time, and was subsequently questioned by
    some (US. Department of Health and Human
    Services, 2006) but not all (Collishaw et al.,
    2009) subsequent reviews. [Because this arose as
    an a posteriori observation rather than as an a
    priori hypothesis, it must be confirmed by independent studies.] The strongest support for the
    hypothesis comes from a cohort study in Japan
    (Hanaoka et al., 2005), which reported significantly increased risk (RR 2.6, 95%CI: 1.3–5.2)
    of premenopausal breast cancer in women who
    previously reported having ever lived with a
    regular smoker or ever being exposed to secondhand tobacco smoke for at least one hour per
    day in settings outside the home. However, the
    233
    IARC MONOGRAPHS – 100E
    referent group in this analysis included only
    nine unexposed cases. No associations were
    observed with post-menopausal breast cancer. A
    weak association between second-hand tobacco
    smoke exposure and premenopausal breast
    cancer was reported in the California Teachers
    cohort, when menopausal status was defined by
    age at diagnosis rather than age at entry into the
    study (Reynolds et al., 2006). In case–control
    studies published since the CalEPA review
    (California Environmental Protection Agency,
    2005) that reported results stratified by menopausal status, Bonner et al. (2005) and Slattery
    et al. (2008) reported stronger associations with
    pre- than with post-menopausal breast cancer,
    although the only statistically significant association with premenopausal breast cancer was in
    Hispanic or American Indian women who had
    second-hand tobacco smoke exposure of more
    than ten hours per week (OR, 2.3, 95%CI:1.2–4.5)
    (Slattery et al., 2008). In a case–control study of
    breast cancer in women age 36–45 years Roddam
    et al. (2007) observed no increased risk in
    premenopausal women who, since age 16, were
    married to or lived with a boyfriend who smoked
    for at least one year.
    Two other explanations for inconsistencies
    in the evidence relate to the fundamental design
    differences between cohort and case–control
    studies. A critical advantage of cohort studies
    is that they collect information on exposures
    before the disease of interest is diagnosed, thus
    preventing knowledge of disease status influencing how participants recall and/or report
    their exposures. Recall bias is especially challenging in case–control studies of exposures that
    are difficult to measure, when recollection of the
    frequency and intensity of exposure is necessarily
    subjective. In counterpart, an important advantage of case–control studies is that they can collect
    more detailed information on the exposure of
    interest than is usually possible in cohort studies.
    Together, these factors create what has been
    described as “a tension” between the potential for
    234
    recall or selection bias in case–control studies,
    and the reduced possibility of collecting full
    “lifetime exposure histories” in cohort studies
    (Collishaw et al., 2009). The discrepancy in the
    results from case–control and cohort studies
    is seen especially in the earlier case–control
    studies, which found much stronger associations
    than those observed in most recent studies. Five
    studies in particular (Smith et al., 1984; Morabia
    et al., 1996; Zhao et al., 1999; Johnson & Repace,
    2000; Kropp & Chang-Claude, 2002) were considered by Collishaw et al. (2009) as having the most
    complete information on lifetime exposure to
    second-hand tobacco smoke from all sources.
    At the same time, these studies are among the
    most susceptible to recall bias for two reasons.
    The first is a general problem of case–control
    studies, in that cases are more likely to remember
    and report potentially hazardous exposures than
    controls. Second, recall bias is potentially more
    problematic when subjective considerations can
    influence reporting. It is easier to report smoking
    by a parent or spouse than it is to remember exposures from other sources that possibly occurred
    many years ago in daily life. Exposure to secondhand tobacco smoke was highly prevalent in
    the decades following World War II in Europe
    and North America. It would be unusual for
    someone not to be exposed. The studies that the
    California Environmental Protection Agency
    (2005) considered to have the best information
    on exposure to second-hand tobacco smoke are
    also those which rely more heavily on recall of
    past exposures outside the home. Moreover,
    inclusion in the referent group in these studies is
    also vulnerable to recall bias. Previous reviews by
    IARC (2004) and the US Surgeon General (US.
    Department of Health and Human Services,
    2006) have expressed concern about potential
    biases that may be introduced by relying on a
    small and unusual subgroup (the unexposed to
    active smoking and second-hand tobacco smoke)
    as the referent category in these studies. Recall
    bias remains a plausible explanation for why the
    Second-hand tobacco smoke
    association with second-hand tobacco smoke is
    stronger in studies that collect “lifetime exposure histories” than in those that rely on parental
    or spousal smoking. In addition, publication
    bias cannot be ruled out because the reporting
    of association limited by subgroup (pre-menopausal) could have been selective.
    [The Working Group noted that adjustment
    for potential confounders using the questionnaire data on other established risk factors for
    breast cancer did not eliminate the association with second-hand tobacco smoke in these
    studies. However, this does not resolve concerns
    about the possibility of recall or publication bias.]
    Several meta-analyses have been published,
    largely showing similar results but leading to
    substantially different interpretations of the
    evidence (California Environmental Protection
    Agency, 2005; US Department of Health and
    Human Services, 2006; Johnson, 2007; IARC,
    2009). The California Environmental Protection
    Agency (2005) calculated a pooled estimate for
    second-hand tobacco smoke and breast cancer
    risk of 1.11 (95%CI: 1.04–1.19) in all women
    and 1.38 (95%CI: 1.21–1.56) in premenopausal
    women, based on 19 studies and a fixed effects
    model. These estimates increased to 1.89 (95%CI:
    1.57–2.27) for all women and 2.18 (95%CI: 1.70–
    2.79) in premenopausal women when the analysis
    was restricted to the subset of studies considered
    to have the best exposure data.
    Based on these analyses, the California
    Environmental Protection Agency (2005) and
    Collishaw et al. (2009) emphasized the positive
    association with premenopausal breast cancer in
    their conclusion that the evidence is “consistent
    with a causal relationship” whereas the US
    Surgeon General (US Department of Health and
    Human Services, 2006) was more cautious in
    characterizing the evidence as “suggestive but
    not sufficient.”
    [The Working Group noted that the criterion used by IARC specifies “sufficient evidence
    of carcinogenicity in which chance, bias and
    confounding could be ruled out with reasonable
    confidence.” This is a more stringent definition
    than “consistent with a causal relationship.”]
    2.3Cancers of the upper
    aerodigestive tract
    2.3.1 Upper areodigestive tract combined
    Cancers of the upper aerodigestive tract
    traditionally comprise cancers of the oral cavity,
    pharynx, larynx and oesophagus. However, some
    epidemiological studies have examined only head
    and neck cancers restricted to tumours of the oral
    cavity, pharynx and larynx. Four case–control
    studies (Tan et al., 1997; Zhang et al., 2000; Lee
    et al., 2008; Ramroth et al., 2008) assessed the
    effects of second-hand tobacco smoke on head and
    neck cancers combined and separately for oral
    cavity, oropharynx or larynx cancers (Table 2.6
    available at http://monographs.iarc.fr/ENG/
    Monographs/vol100E/100E-02-Table2.6.pdf).
    In a hospital-based case–control study in
    the USA, including only non smoking cases and
    controls, Tan et al. (1997) detected high risk of
    head and neck cancer among those ever exposed
    to second-hand tobacco smoke at home or at work.
    Women presented higher risk at home (OR, 7.3;
    P < 0.001) than men (OR, 1.1; P < 0.79). On the
    other hand, men showed higher risk at work (OR,
    11.6; P < 0.001) than women (OR, 8.9; P < 0.002).
    [The authors did not provide the percentages of
    the telephone interviews done with the spouses
    of cases and controls. Probably, this is the main
    weakness of this study and differential misclassification of exposure to second-hand tobacco
    smoke could not be excluded. The analysis
    was performed without adjustment for potential confounding variables.] In a study in the
    USA, Zhang et al. (2000) observed an increased
    risk (OR, 2.4; 95%CI: 0.9–6.8) with lifetime
    second-hand tobacco smoke exposure (ever/
    never) for head and neck cancers, adjusted for
    age, sex, ethnicity, education, alcohol drinking,
    235
    IARC MONOGRAPHS – 100E
    pack-years of cigarette smoking, and marijuana
    consumption.
    Lee et al. (2008) pooled the data from several
    studies including cases of head and neck cancers
    and controls (population and hospital) from
    central Europe, Latin America and United
    States. Two groups were examined separately,
    never tobacco users and never tobacco and
    alcohol users. Among never tobacco users, no
    association was observed between ever exposure to second-hand tobacco smoke at home or
    at work and the risk for head and neck cancers.
    Among never tobacco and alcohol users, a nonstatistically significant risk (or 1.30; 95%ci: 0.94–
    1.81) was observed. When considering specific
    anatomical sites, only laryngeal cancer risk was
    increased when ever exposed to second-hand
    tobacco smoke in a lifetime, detected among
    never tobacco users (OR, 1.71; 95%CI: 0.98–3.00)
    and among never tobacco and alcohol users (OR,
    2.90; 95%CI: 1.09–7.73).
    In Germany, in a population-based case–
    control study on laryngeal cancer, Ramroth et
    al. (2008) observed a non-statistically significant
    risk (OR, 2.0; 95%CI: 0.39–10.7) for exposure to
    second-hand tobacco smoke (ever/never) at home
    and in workplaces among nonsmokers.
    (a) Evidence of a dose–response
    Zhang et al. (2000) observed a dose–response
    relationship with the intensity of exposure to
    second-hand tobacco smoke (never, moderate
    and heavy) on head and neck cancers (P = 0.025);
    those at heavy level of exposure at home or at
    work showed highest risk for head and neck
    cancer (OR, 3.6; 95%CI: 1.1–11.5). However, the
    classification of exposure to second-hand tobacco
    smoke at work as never, occasionally or regularly
    did not show any dose–response effect; and the
    risk for the groups of occasionally or regularly
    exposed at home were similar and non statistically significant.
    Lee et al. (2008) explored the intensity and
    duration of sexposure to second-hand tobacco
    236
    smoke. For intensity the number of hours
    of exposure per day was considered at home
    (0–3 hours, > 3 hours) or at the workplace (never,
    1–3 hours and > 3 hours). Among both groups
    of never tobacco users and never tobacco and
    alcohol users non-statistically significant risks of
    head and neck cancers were observed for those
    exposed for > 3 hours per day at home or at work.
    For duration the number of years of exposure at
    home and at work was considered (never, 1–15
    years, and > 15 years). Among never tobacco
    users, there was a trend of increase in risk for head
    and neck cancers with greater number of years of
    exposure at home, but not at work. Among never
    tobacco and alcohol users, the duration of exposure showed a trend for exposure both at work
    or at home.
    Considering specific anatomical sites, for
    cancer of the oral cavity no dose–response effect
    was observed with increasing number of years of
    exposure to second-hand tobacco smoke at home
    or at work. For cancer of the pharynx, a dose–
    response effect was observed with increasing
    number of years of exposure to second-hand
    tobacco smoke with only at home, in both never
    tobacco users and never tobacco and alcohol
    users. For cancer of the larynx, a dose–response
    effect was noted with increasing number of years
    of exposure to second-hand tobacco smoke at
    home among never tobacco users and at work
    among never tobacco and alcohol users. Among
    never tobacco and alcohol users, all the odd ratios
    (OR) were statistically significantly elevated for
    > 15 years of exposure at home or at work for
    head and neck cancers overall and separately
    for cancer of the pharynx, and only at work for
    cancer of the larynx.
    2.3.2Cancers of the nasopharynx, and nasal
    cavity and sinonasal cavity
    The relationship between exposure to
    second-hand tobacco smoke and risk for these
    rare cancers of the upper respiratory tract has
    Second-hand tobacco smoke
    been examined in one cohort study (Hirayama,
    1984; Table 2.7 available at http://monographs.
    iarc.fr/ENG/Monographs/vol100E/100E-02Table2.7.pdf) and five case–controls studies
    (Fukuda & Shibata, 1990; Yu et al., 1990; Zheng
    et al., 1993; Cheng et al., 1999; Yuan et al., 2000;
    Table 2.6 on-line). A positive association was
    found in most of these studies.
    Hirayama (1984) found an increased risk of
    sinonasal cancer in women (histology not noted)
    associated with increasing numbers of cigarettes
    smoked by husbands of nonsmoking women.
    When compared with nonsmoking women
    married to nonsmokers, wives whose husbands
    smoked had a relative risk of 1.7 (95%CI: 0.7–4.2)
    for 1–14 cigarettes per day, 2.0 (95%CI: 0.6–6.3)
    for 15–19 cigarettes per day and 2.55 (95%CI:
    1.0–6.3) for ≥ 20 cigarettes per day (P for
    trend = 0.03).
    Fukuda & Shibata (1990) reported the results
    of a Japanese case–control study based on 169
    cases of squamous-cell carcinoma of the maxillary sinus and 338 controls matched on sex,
    age and residence in Hokkaido, Japan. Among
    nonsmoking women, a relative risk of 5.4
    (P < 0.05) was associated with exposure in the
    household to second-hand tobacco smoke from
    one or more smokers. Active smoking was associated with an increased risk for squamous-cell
    carcinoma of the maxillary sinus in men in the
    same study.
    Zheng et al. (1993) used data from the 1986
    US National Mortality Followback Survey to
    assess risk for cancer of the nasal cavity and
    sinuses in relation to exposure to second-hand
    tobacco smoke in white men. A total of 147 deaths
    from cancer of the nasal cavity and sinuses was
    compared to 449 controls who had died from
    other causes (excluding any causes strongly
    linked to alcohol and/or tobacco use). Data were
    obtained from postal questionnaires completed
    by next-of-kins. Among nonsmokers, patients
    with nasal cancer were more likely to have a
    spouse who smoked cigarettes (RR, 3.0; 95%CI:
    1.0–8.9) after adjustment for age and alcohol use.
    When the analysis of cases was restricted to those
    with cancer of the maxillary sinus, the risk was
    somewhat higher (RR 4.8; 95%CI: 0.9–24.7). The
    risks reported for active smoking and exposure
    to second-hand tobacco smoke were of similar
    magnitude in this study.
    Neither second-hand tobacco smoke exposure during childhood nor exposure during
    adulthood were positively associated with an
    increased risk for nasopharyngeal cancer in a
    study in Taiwan, China (Cheng et al., 1999).
    Although histological type was not specified,
    all cases were histologically confirmed. Among
    never-smokers, the risk estimates for cumulative
    exposure to second-hand tobacco smoke (packperson-years) in childhood declined as exposure
    increased (P for trend = 0.05); a similar but nonsignificant inverse relationship was found for
    exposure during adulthood. Significant elevations in risk for nasopharyngeal cancer were
    observed for active smokers in this study. [The
    Working Group noted that the exposure assessment was relatively detailed and that the estimates of relative risk were adjusted for age, sex,
    education and family history of nasopharyngeal
    cancer.]
    A large population-based case–control study
    conducted in Shanghai, China, included 935
    cases of nasopharyngeal carcinoma and 1032
    population controls randomly selected from a
    population-registry and frequency-matched by
    sex and 5-year age group (Yuan et al., 2000).
    All cases were histologically confirmed, but the
    cell type was not specified. The study subjects
    were interviewed face to face, and the response
    rates were 84% for cases and 99% for controls.
    In female never-smokers, a consistent increase
    in risk related to exposure to second-hand
    tobacco smoke during childhood was noted.
    The relative risk was 3.4 (95%CI: 1.4–8.1) if the
    mother smoked; 3.0 (95%CI: 1.4–6.2) if the father
    smoked; 2.7 (95%CI: 1.1–6.9) if another household member smoked and 3.0 (95%CI: 1.4–6.2)
    237
    IARC MONOGRAPHS – 100E
    Kasim et al. (2005) analysed the risk of
    leukaemia in adults after exposure to secondhand tobacco smoke (Table 2.8 available at
    http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.8.pdf). This case–
    control study was based on postal questionnaires. There was a slightly increased risk (P
    for trend = 0.001) with increasing duration of
    exposure to second-hand tobacco smoke. The
    association was limited to chronic lymphocytic
    leukaemia and was stronger for occupational
    exposures to second-hand tobacco smoke.
    have been identified: two cohort (Nishino et al.,
    2001; Hooker et al., 2008; Table 2.13 available at
    http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.13.pdf); seven case–
    control (Sandler et al., 1985a, b; Slattery et al.,
    2003; Lilla et al., 2006; Wang et al., 2006; Duan
    et al., 2009; Verla-Tebit et al., 2009; Table 2.14
    available at http://monographs.iarc.fr/ENG/
    Monographs/vol100E/100E-02-Table2.14.pdf)
    and one case-only study (Peppone et al., 2008;
    Table 2.15 available at http://monographs.iarc.fr/
    ENG/Monographs/vol100E/100E-02-Table2.15.
    pdf). Two studies (Sandler et al., 1985a; Wang
    et al., 2006) did not provide risk estimates of
    gastrointestinal cancers for never smokers and
    are not discussed further. [No data for these
    studies are included in the tables.]
    Sandler et al. (1985b) observed a relative risk
    of 0.7 and 1.3 for cancer of the digestive system
    from exposure to maternal and paternal passive
    smoke, respectively. [No CIs were provided and
    the numbers of never smokers exposed were
    small.] Verla-Tebit et al. (2009) found no evidence
    of an increased risk for colorectal cancer associated with exposure to second-hand tobacco
    smoke overall.
    2.5Other cancers in adults
    (a) Cancer of the colorectum
    if any household member smoked. Risks associated with exposure to second-hand tobacco
    smoke during adulthood in women were also
    statistically significantly increased. For male
    never-smokers, the associations were weaker and
    were not statistically significantly elevated for
    exposure during childhood and adulthood. [The
    Working Group noted that this was a large, well
    conducted study that included a detailed exposure assessment and adjustment for numerous
    potential confounders.]
    2.4Leukaemia and lymphomas
    2.5.1 All cancer combined
    Hirayama (1984), Sandler et al. (1985b), and
    Miller (1990) observed a significant association between exposure to second-hand tobacco
    smoke and overall cancer incidence or mortality.
    Nishino et al. (2001) also studied all cancers
    combined and reported a relative risk of 1.1
    (95%CI: 0.92–1.4) associated with husband’s
    smoking.
    2.5.2Cancers of the gastrointestinal tract
    In addition to the studies reviewed previously
    (Sandler et al. 1988; Gerhardsson de Verdier
    et al., 1992; Mao et.al., 2002), ten new studies
    238
    Nishino et al. (2001) observed no association
    with husband’s smoking for cancer of the colon
    (RR 1.3; CI: 0.65–2.4) or of the rectum (RR 1.8;
    0.85–3.9).
    Four studies investigated risk for cancer or the
    colon and/or rectum by sex. Sandler et al. (1988)
    reported an increased risk for colorectal cancer
    in men (RR 3.0; 95%CI: 1.8–5.0) but a protective
    effect in women (RR 0.7; 95%CI: 0.6–1.0). Slattery
    et al. (2003) noted that rectal cancer was significantly associated with exposure to second-hand
    tobacco smoke in men (OR, 1.5; 95%CI: 1.1–2.2 for
    never smokers) but not in women. Hooker et al.
    (2008) reported an effect among men only, with
    a significantly increased risk for rectal cancer in
    the 1963 cohort (RR 5.8, 95%CI: 1.8–18.4) but not
    Second-hand tobacco smoke
    the 1975 cohort. Gerhardsson de Verdier et al.
    (1992) found an increased risk for rectal cancer
    in men (RR 1.9; 95%CI: 1.0–3) and for colon
    cancer in women (RR 1.8; 95%CI: 1.2–2.8). [The
    Working Group noted that it is unclear whether
    the analysis was restricted to never-smokers.]
    When analysing different sources of exposure to second-hand tobacco smoke, Verla-Tebit
    et al. (2009) found no evidence of an increased
    risk for cancer of the colorectum associated with
    exposure to second-hand tobacco smoke specifically during childhood or at work, but observed
    a significant increase in risk associated with
    spousal exposure.
    Peppone et al. (2008) noted that considerable exposure to second-hand tobacco smoke,
    especially during childhood, was more likely to
    lead to an earlier-age diagnosis of cancer of the
    colorectum.
    In exploring the association of cancer of
    the colorectum with exposure to second-hand
    tobacco smoke and NAT1 and NAT2 status, Lilla
    et al. (2006) noted that risk may only be relevant
    among genetically susceptible (NAT1 and NAT2
    status) individuals.
    (b) Cancer of the stomach
    Nishino et al. (2001) observed no association with husband’s smoking for cancer of the
    stomach (RR, 0.95; 95%CI: 0.58–1.6).
    The two studies on the association of exposure to second-hand tobacco smoke with
    stomach cancer by subsite (cardia versus distal)
    gave contradictory results. In one study (Mao
    et al., 2002) a positive trend (P = 0.03) in risk for
    cancer of the gastric cardia was associated with
    lifetime exposure to second-hand tobacco smoke
    (residential plus occupational) in never smoking
    men, with a relative risk of 5.8 (95%CI: 1.2–27.5)
    at the highest level of exposure (≥ 43 years); no
    increased risks or trends were observed for distal
    gastric cancer. In the other study, Duan et al.
    (2009) an increased risk for distal gastric cancer
    was found, but not for gastric cardia [Data were
    not analysed by sex due to small sample size].
    2.5.3Cancer of the pancreas
    Six studies have been identified on the association of exposure to second-hand tobacco
    smoke with cancer of the pancreas: three cohort
    (Nishino et al., 2001; Gallicchio et al., 2006; Bao
    et al., 2009; the latter two are summarized in
    Table 2.17 available at http://monographs.iarc.fr/
    ENG/Monographs/vol100E/100E-02-Table2.17.
    pdf) and three case–control (Villeneuve et al.,
    2004; Hassan et al., 2007; Lo et al., 2007; the
    former two studies are summarized in Table 2.18
    available at http://monographs.iarc.fr/ENG/
    Monographs/vol100E/100E-02-Table2.18.pdf).
    (a) Exposure in adulthood
    Data from the majority of the studies (Nishino
    et al., 2001; Villeneuve et al., 2004; Gallicchio
    et al., 2006; Hassan et al., 2007; Bao et al., 2009)
    suggested lack of an association of cancer of the
    pancreas with never smokers exposed to secondhand tobacco smoke in adulthood at home or at
    work. (RR 1.2 (95%CI: 0.45–3.1) and 1.21 (95%CI:
    0.60–2.44) respectively).
    Lo et al. (2007) reported an odd ratio of 6.0
    (95%CI: 2.4 −14.8) for never smokers (both sexes
    combined) exposed to second-hand tobacco
    smoke in Egypt. [The Working Group noted
    the small numbers of cases, the use of hospital
    controls and the small proportion of the cases
    (35%) with histopathological confirmation. Data
    are not included in Table 2.18 on-line].
    (b) Exposure during childhood
    In the Nurses’ Health Study, Bao et al. (2009)
    noted an increased risk for cancer of the pancreas
    (RR 1.42; 95%CI: 1.07–1.89) for maternal but not
    for paternal smoking (RR 0.97; 95%CI: 0.77–1.21)
    during childhood.
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    IARC MONOGRAPHS – 100E
    2.5.4Cancer of the kidney (renal cell
    carcinoma)
    Two case–control studies have been published
    on the association of exposure to second-hand
    tobacco smoke with cancer of the kidney (specifically renal cell carcinoma) since IARC (2004) (Hu
    et al., 2005; Theis et al., 2008; Table 2.19 available
    at http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.19.pdf). In both studies
    a significantly increased risk associated with
    exposure to second-hand tobacco smoke among
    never smokers was reported.
    2.5.5Cancer of the urinary bladder
    A total of seven studies and one meta-analysis
    have considered the association between exposure
    to second-hand tobacco smoke and cancer of the
    urinary bladder: three cohort studies (Zeegers
    et al., 2002; Bjerregaard et al., 2006; Alberg et al.,
    2007; Table 2.9, available at http://monographs.
    iarc.fr/ENG/Monographs/vol100E/100E-02Table2.9.pdf), four case–control studies (Burch
    et al., 1989; Chen et al., 2005a; Samanic et al.,
    2006; Jiang et al., 2007; Table 2.10 available at
    http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.10.pdf), and one metaanalysis (Van Hemelrijck et al., 2009).
    (a) Population-based exposure-response
    relationship
    Burch et al. (1989) and Zeegers et al. (2002)
    reported no increased risk for cancer of the
    urinary bladder [Data are not included in the
    Tables]. Van Hemelrijck et al. (2009) reported a
    meta-relative risk of 0.99 (95%CI: 0.86–1.14) for
    never smokers exposed to second-hand tobacco
    smoke. [Data not included in Table. The Working
    Group noted the marked variation in risk in the
    analyses by sex and by timing of exposure to
    second-hand tobacco smoke during adulthood
    or childhood].
    In the European Prospective Investigation
    into Cancer and Nutrition (EPIC) study,
    240
    Bjerregaard et al. (2006) compared ever versus
    never exposed to second-hand tobacco smoke
    as an adult or a child: the risk for cancer of the
    urinary bladder increased for exposures during
    childhood (OR, 1.38; 95%CI: 1.00–1.90), and was
    stronger for never-smokers (OR, 2.02; 95%CI:
    0.94–4.35).
    Alberg et al. (2007) analysed data from two
    cohorts of non-smoking women in the USA
    exposed to second-hand smoke at home. An association with exposure to second-hand tobacco
    smoke was found in the 1963 cohort (RR, 2.3;
    95%CI: 1.0–5.4) but not in the 1975 cohort (RR,
    0.9; 95%CI: 0.4–2.3). [The Working Group noted
    the small number of cases available for some of
    the risk estimates.]
    In a study assessing occupational exposure
    to second-hand tobacco smoke (Samanic et al.,
    2006), the risk for cancer of the urinary bladder
    was increased in the highest exposure category
    among women (RR, 3.3; 95%CI: 1.1–9.5) but not
    among men (RR, 0.6; 95%CI: 0.2–1.4).
    (b) Molecular-based exposure-response
    relationship
    4-aminobiphenyl (4-ABP) can form DNA
    adducts and induce mutations, and cigarette smoke is the most prominent source of
    exposure to 4-aminobiphenyl in humans (see
    Section 4). Jiang et al. (2007) used variation in
    4-ABP-haemoglobin adducts levels to assess exposure to second-hand tobacco smoke and reported
    a significantly increased risk with increasing
    lifetime exposure among never-smoking women
    exposed in adulthood or childhood.
    Chen et al. (2005a) hypothesized that the
    ability to detoxify arsenic (a risk factor urinary
    bladder cancer) through methylation may modify
    risk related to second-hand tobacco smoke exposure. Results of the adjusted analyses show that a
    high primary methylation index associates with
    lower risk of cancer of the urinary bladder (OR,
    0.37; 95%CI: 0.14–0.96, p interaction = 0.11) in
    second-hand tobacco smoke exposed subjects
    Second-hand tobacco smoke
    compared to unexposed. In endemic area the
    ability to methylate arsenic may play a role in
    reducing the risk of cancer of the urinary bladder
    associated with second-hand tobacco smoke
    exposure. [The Working Group noted that the
    small number of cases and the use of hospital
    controls limit the validity of inferences from this
    study].
    Using case–control data for never and former
    smokers nested within the EPIC study Vineis
    et al. (2007b) examined susceptibility in genes
    involved in oxidative stress (such as NQO1, MPO,
    COMT, MnSOD), in phase I (such as CYP1A1
    and CYP1B1) and phase II (such as GSTM1, and
    GSTT1) metabolizing genes, and in methylenetetrahydrofolate (MTHFR). GSTM1 deletion was
    strongly associated with risk for urinary bladder
    cancer in never smokers (OR, 1.75; 95%CI: 0.89–
    3.43), and a similar association was noted for
    former smokers and for men.
    2.5.6Cancer of the cervix
    The cohort studies evaluated previously
    (Hirayama, 1984; Jee et al., 1999; Nishino et al.,
    2001) consistently indicated the lack of association between exposure to second-hand tobacco
    smoke and cancer of the uterine cervix, while the
    informative case–control studies (Sandler et al.,
    1985b; Slattery et al., 1989; Scholes et al., 1999)
    suggested a non-statistically significant increase
    in risk.
    A total of 10 new studies have been identified: one cohort study (Table 2.11 available at
    http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.11.pdf) and nine case–
    control studies (Buckley et al., 1981; Brown
    et al., 1982; Hellberg et al., 1986; Hirose et al.,
    1996; Coker et al., 2002; Wu et al., 2003; Tay &
    Tay, 2004; Sobti et al., 2006; Tsai et al., 2007;
    Table 2.12 available at http://monographs.iarc.fr/
    ENG/Monographs/vol100E/100E-02-Table2.12.
    pdf). Three early case–control studies (Buckley
    et al., 1981; Brown et al., 1982; Hellberg et al.,
    1986) did not look at risk of exposure to secondhand tobacco smoke in never smoking women,
    and are not further discussed.
    (a) Squamous cell carcinoma of the cervix
    A significant increase risk for invasive cancer
    of the uterine cervix associated with exposure to
    second-hand tobacco smoke during adulthood
    was found in three case–control studies (Hirose
    et al., 1996; Wu et al., 2003; Tay & Tay, 2004) and
    one cohort study (Trimble et al., 2005).
    (b) Cervical intraepithelial lesions and neoplasia
    An earlier case–control study (Coker et al.,
    1992) found no statistically significant association between exposure to second-hand tobacco
    smoke and CIN II/III in non-smokers, after
    adjustment for age, race, education, number of
    partners, contraceptive use, history of sexually
    transmitted disease and history of Pap smear. A
    later study (Coker et al., 2002) looked at risk of low
    grade and high grade cervical squamous intraepithelial lesions (LSIL and HSIL, respectively) in
    HPV positive never-smokers and reported a
    significant association with exposure to secondhand tobacco smoke. In a community-based
    case–control study, Tsai et al. (2007) observed
    a markedly increased risk for both CIN1 and
    CIN2 in both HPV-positive and HPV-negative
    women exposed to second-hand tobacco smoke.
    Only Coker et al. (2002) and Tsai et al. (2007)
    controlled for HPV status in women.
    Sobti et al. (2006) reported that cervical
    cancer risk is increased in individuals exposed to
    second-hand tobacco smoke with GSTM1 (null),
    GSTT1 (null) and GSTP1 (Ile105Val) genotypes,
    with odd ratios ranging from 6.4 to 10.2.
    2.5.7Cancer of the ovary
    One cohort study (Nishino et al., 2001) and
    two case–control studies (Goodman & Tung,
    2003; Baker et al., 2006; Table 2.16 available at
    http://monographs.iarc.fr/ENG/Monographs/
    241
    IARC MONOGRAPHS – 100E
    vol100E/100E-02-Table2.16.pdf) have been
    published on the association of exposure to
    second-hand tobacco smoke with cancer of the
    ovary. In all three studies a null or inverse association of cancer of the ovary for never smokers
    exposed to second-hand tobacco smoke was
    found. Nishino et al. (2001) observed no association with husband’s smoking (RR 1.7; 95%CI:
    0.6- 5.2). Goodman & Tung (2003) reported no
    association of exposure to second-hand tobacco
    smoke during childhood with risk of cancer
    of the ovary. Baker et al. (2006) reported a
    decreased risk of cancer of the ovary for never
    smokers exposed to second-hand tobacco smoke
    (OR, 0.68; 95%CI: 0.46–0.99), with similar findings for former and current smokers.
    find an association with exposure to secondhand tobacco smoke and hepatocellular cancer,
    while that of McGlynn et al. (2006) did not
    support the hypothesis that maternal smoking
    is related to the development of cancer of the
    testis (Table 2.20 available at http://monographs.
    iarc.fr/ENG/Monographs/vol100E/100E-02Table2.20.pdf). However, these studies provide
    limited information on the association of exposure to second-hand tobacco smoke with the risk
    of these cancers.
    2.5.8Tumours of the brain and CNS
    A large number of studies have evaluated
    the association of cancer risk in childhood with
    exposure to parental smoking. However, childhood cancers are extremely heterogeneous, both
    between major cancer sites and within subtypes.
    In addition, given the rarity of childhood cancers,
    studies of specific cancer sites and subtypes that
    have adequate sample sizes and detailed exposure assessments are difficult to achieve.
    A total of three case–control studies (Ryan
    et al., 1992; Hurley et al., 1996; Phillips et al.,
    2005) have considered the association of secondhand tobacco smoke and cancers of the brain
    and central nervous system. Ryan et al. (1992)
    reported an increased risk of meningioma
    associated with spousal exposure, particularly
    among women (RR 2.7; 95%CI: 1.2–6.1). In a
    case–control study of gliomas in Australia no
    association was found for exposure to secondhand tobacco smoke in never smokers (RR 0.97,
    95%CI: 0.61–1.53) (both sexes combined) (Hurley
    et al., 1996). However Phillips et al. (2005) found
    that spousal smoking was associated with an
    increased risk for intracranial meningioma in
    both sexes combined (OR, 2.0; 95%CI: 1.1–3.5),
    the risk increased with increasing duration of
    exposure (P for trend = 0.02).
    2.5.9Other cancers
    One case–control study on hepatocellular
    cancer (Hassan et al., 2008) and one on cancer of
    the testis (McGlynn et al., 2006) were published
    since IARC (2004). Hassan et al. (2008) did not
    242
    2.6Parental tobacco smoking and
    childhood cancers
    2.6.1.Overview
    (a) Smoking exposure assessment
    Parental smoking before and during pregnancy exposes germ cells (spermatozoa and ova)
    and/or the fetus to the same chemical mixture
    and levels of tobacco smoke as during active
    smoking, while post-natal exposure to parental
    tobacco smoking exposes the offspring to secondhand tobacco smoke. Some studies distinguish
    whether exposure to parental smoking was
    preconceptional, in utero or postnatal. Even
    when a study reports only on one time period,
    exposure may have occurred at all three periods.
    Exposures to tobacco smoking during each of
    these periods tend to correlate, in particular,
    paternal smoking is less likely to change during
    and after pregnancy. In addition, paternal and
    Second-hand tobacco smoke
    maternal smoking habits are highly correlated
    (Boffetta et al., 2000).
    Most studies assessed the number of cigarettes smoked per day (e.g. 0–10, 11–20, 20+) and,
    when data were available, some assessed continuous consumption of cigarettes per day. One
    study reported exposure in pack-years (Lee et al.,
    2009). The SEARC international case–control
    study assessed polycyclic aromatic hydrocarbons (PAHs) as the main exposure of interest and
    obtained information on both tobacco smoke and
    occupational exposures (Cordier et al., 2004).
    Whitehead et al. (2009) evaluated the
    adequacy of self-reported smoking histories on
    469 homes of leukaemia cases and controls and
    found that nicotine concentrations derived from
    interview responses to a structured questionnaire strongly correlated to measured levels in
    dust samples.
    The major confounders for the relationship between parental smoking and childhood
    cancers were markers of socioeconomic status,
    race or ethnicity, birth weight or gestational
    age, parental age, sex and age of the case child.
    In most studies matching or adjusting for these
    confounders was performed as appropriate. In
    some studies matching was performed for birth
    order and centre of diagnosis.
    (a) Intensity and timing of parental smoking
    In a follow-up of the Inter-Regional
    Epidemiological Study of Childhood Cancer
    (IRESCC) by McKinney et al. (1987), a statistically significant positive trend with daily paternal
    smoking before pregnancy was observed when
    cases were compared with controls selected from
    General Practitioners’ (GPs’) lists, but not from
    hospitals; an inverse trend was noted for maternal
    smoking before pregnancy when cases were
    compared with hospital, but not with General
    Practitioners, controls (Sorahan et al., 2001).
    In the United Kingdom Childhood Cancer
    Study (UKCCS), Pang et al. (2003) observed a
    similar pattern of increasing risk with increasing
    intensity of paternal preconception smoking,
    and of decreasing risk for increasing maternal
    smoking before and during pregnancy for all
    diagnoses combined, and for most individual
    diagnostic groups.
    In the most recent report from the Oxford
    Survey of Childhood Cancers (OSCC), the risk
    of death from all childhood cancers combined
    was not associated with maternal smoking,
    but was consistently associated with paternal
    smoking alone or in combination with maternal
    smoking, in both adjusted and unadjusted analyses [Ex-smokers of more than 2 years before
    birth of the survey child were assimilated to nonsmokers] (Sorahan & Lancashire, 2004).
    2.6.2All childhood cancers combined
    (b) Bias and confounding
    (b) Bias and confounding
    In addition to the four cohort and 10 case–
    control studies reviewed by IARC (2004), three
    case–control studies have examined the role of
    second-hand tobacco smoke in relation to risk for
    all childhood cancers combined (Sorahan et al.,
    2001; Pang et al., 2003; Sorahan & Lancashire,
    2004; Table 2.21 available at http://monographs.
    iarc.fr/ENG/Monographs/vol100E/100E-02Table2.21.pdf).
    The significant trends observed by Sorahan
    et al. (2001) and Pang & Birch (2003) did
    not diminish when adjusted for potential
    confounding covariates or with simultaneous
    analysis of parental smoking habits. The relationship between maternal smoking and birth weight
    reported by Sorahan et al. (2001) suggested that
    self-reported maternal smoking was equally
    reliable for cases and for controls. However,
    comparisons of smoking patterns with national
    data suggested that control parents in this study
    were heavier smokers.
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    IARC MONOGRAPHS – 100E
    2.6.3Leukaemias and lymphomas
    Since IARC (2004), one cohort study (Mucci
    et al., 2004) (Table 2.22 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E02-Table2.22.pdf), eleven case–control studies
    (Table 2.23 available at http://monographs.
    iarc.fr/ENG/Monographs/vol100E/100E-02Table2.23.pdf), and one meta-analysis (Lee et al.,
    2009) (Table 2.24 available at http://monographs.
    iarc.fr/ENG/Monographs/vol100E/100E-02Table2.24.pdf) have evaluated the association
    of parental tobacco smoking with the risk for
    lymphatic and haematopoietic cancers.
    (a) Duration and intensity of exposure
    From a meta-analysis of 30 studies published
    before 1999 Boffetta et al. (2000) reported
    no statistically significant association for all
    lymphatic and haematopoietic neoplasms and
    noted evidence of publication bias for the available data.
    Lee et al. (2009) performed a meta-analysis
    of twelve studies on paternal smoking and risk of
    childhood leukaemia. Paternal smoking before
    conception of the index child was significantly
    associated with the risk for acute leukaemia
    (AL) and acute lymphoblastic leukaemia (ALL)
    (Fig. 2.2).
    ￼ In a cohort study, maternal smoking was
    associated with a lower risk of acute lymphoblastic leukaemia, a higher risk of acute myeloid
    leukaemia (AML) particularly among heavy
    smokers, and a slight excess risk for non-Hodgkin
    lymphoma (NHL) (Mucci et al., 2004).
    Because of the diversity of types of exposure (paternal, maternal, parental), of timing of
    exposure (preconception, in utero, post-natally)
    and of the outcome, the case–control studies are
    briefly summarized individually.
    Schüz et al. (1999) showed that the risk
    for acute childhood leukaemias was inversely
    related to maternal smoking during pregnancy.
    Paternal smoking before pregnancy showed no
    244
    association with leukaemia risk for any smoking
    category. Sorahan et al. (2001) reported a nonsignificant positive association between risk for
    acute lymphoblastic leukaemia and daily cigarette smoking by fathers before pregnancy, and
    a non-significant inverse association between
    risk for acute lymphoblastic leukaemia and
    daily smoking by mothers before pregnancy.
    Down Syndrome children are highly susceptible to the development of acute leukaemia. In
    a case–control study of 27 children with acute
    leukaemia and Down Syndrome compared with
    58 Down Syndrome children without acute
    leukaemia Mejía-Aranguré et al. (2003) found
    that paternal smoking of more than 10 cigarettes/
    day, both preconception and after birth of the
    index child was associated with acute leukaemia.
    In the UKCC case–control study (Pang et al.,
    2003), paternal but not maternal preconception
    tobacco smoking of 1–19 cigarettes/day was associated with an increased risk of leukaemia, and
    a similar pattern was reported for lymphoma.
    Menegaux et al. (2005) reported no increased
    risk of acute lymphoblastic leukaemia or acute
    nonlymphocytic leukaemia (ANLL) associated with any category of post-natal exposure
    to tobacco smoking (i.e. maternal smoking
    during breastfeeding or after, paternal smoking
    after birth, other smokers at home), except for
    an increased risk of acute nonlymphocytic
    leukaemia with paternal smoking. In a later study,
    (Menegaux et al., 2007) reported no association
    between acute and parental smoking, by subtype
    (acute myeloid leukaemia or acute lymphoblastic
    leukaemia) or by time of exposure, with the exception of an increased risk of acute lymphoblastic
    leukaemia associated with maternal smoking
    during pregnancy. Chang et al. (2006) reported
    no risk for acute leukaemia, acute lymphoblastic
    leukaemia or acute myeloid leukaemia associated with maternal smoking either by period
    of smoking (preconception, during pregnancy,
    post-natally) or by amount smoked. Paternal
    preconception smoking was strongly associated
    Second-hand tobacco smoke
    Fig. 2.2 Meta-analysis of the association between paternal smoking and childhood leukaemia
    ￼
    with risk for acute myeloid leukaemia both by
    period and intensity of smoking. When both
    paternal preconception smoking and maternal
    postnatal smoking were considered, the risk for
    acute lymphoblastic leukaemia was stronger.
    Rudant et al. (2008) reported a significant positive association between paternal smoking and
    acute lymphoblastic leukaemia, acute myeloid
    leukaemia, Burkitt lymphoma, and anaplastic
    large cell non-Hodgkin lymphoma, with
    increasing relative risks (RR) with increasing
    number of cigarettes smoked. No associations with Hodgkin lymphoma or other types
    of non-Hodgkin lymphoma were observed.
    Non-significantly elevated risks were observed
    for maternal smoking during pregnancy for acute
    lymphoblastic leukaemia and non-Hodgkin
    lymphoma, but not in the highest category of 10
    or more cigarettes/day. MacArthur et al. (2008)
    reported non-significantly elevated risk estimates
    for acute lymphoblastic leukaemia and acute
    myeloid leukaemia with maternal smoking, but
    245
    IARC MONOGRAPHS – 100E
    not with paternal smoking, before and during
    pregnancy. Lee et al. (2009) in Seoul, Republic of
    Korea, reported that paternal smoking was associated with a significantly increased risk of acute
    leukaemia and acute lymphoblastic leukaemia
    in a dose–response manner. The proportion
    of mothers who smoked was too low (6.1% in
    controls) to analyse risk in association with
    maternal smoking.
    (b) Potential confounders
    In the study of Down Syndrome children
    (Mejía-Aranguré et al., 2003), the adjustment
    models did not show any interaction between
    paternal alcoholism and smoking. Menegaux et
    al. (2005) examined the association of parental
    smoking and maternal alcohol and coffee intake
    during pregnancy with the risk for childhood
    leukaemia. They found no association of acute
    lymphoblastic leukaemia or acute nonlymphocytic leukaemia with maternal smoking during
    pregnancy but an association with maternal
    alcohol and coffee consumption.
    (c) Effect modification
    Cigarette smoke is a known germ-cell mutagen
    in mice (Yauk et al., 2007), a likely germ-cell
    mutagen in humans (see Section 4.1.3a) and alters
    gene expression (see Section 4.1.4). Infante-Rivard
    et al. (2000) first assessed the role of parental
    smoking and CYP1A1 genetic polymorphisms
    with leukaemia and reported no statistically
    significant association with leukaemia overall.
    However, a case-only subanalysis suggested that
    the effect of parental smoking may be modified by
    variant alleles in the CYP1A1 gene: CYP1A1*2B
    tended to decrease risks and CYP1A1*2A and
    CYP1A1*4 increased the risks associated with
    smoking in the second and third trimesters of
    pregnancy. Clavel et al. (2005) examined the role
    of metabolic polymorphisms in the CYP1A1,
    GSTM1, GSTP1, GSTT1 and NQO1 genes. The
    slow EPHX1 allele (exon 3 homozygous genotype) was negatively associated with leukaemia,
    246
    in particular acute lymphoblastic leukaemia,
    whereas the fast EPHX1 allele (exon 4 homozygous genotype) was positively associated with
    leukaemia overall. A non-significant association
    with acute lymphoblastic leukaemia was noted
    for the homozygous NQO1*2 genotype. There
    was a significant interaction of the CYP1A1*2A
    allele with smoking in the case-only analysis
    and a not significant interaction, but similar
    in magnitude, in the case–control analysis. A
    significant interaction was also observed with
    the GSTM1 deletion in the case-only analysis, but
    not in the case–control analysis. Lee et al. (2009)
    genotyped five single-nucleotide CYP1A1 polymorphisms: acute lymphoblastic leukaemia risk
    was significantly increased for cases without the
    CGACC haplotype and with paternal smoking or
    the presence of at least one smoker in the home.
    RAS is the second most mutated gene in
    smoking-associated lung tumours (Section
    4.1.3b). RAS mutations have been consistently
    correlated with myeloid leukaemias in adults
    and children, in particular with occupationallyassociated adult myeloid leukemias (Taylor et al.,
    1992; Barletta et al., 2004). Wiemels et al. (2005)
    studied the relationship of RAS mutations,
    hyperdiploidy (> 50 chromosomes) and smoking
    in a case series of 191 acute leukaemia. Smoking
    was negatively associated with hyperdiploidy
    (possibly due to the sensitivity of the hyperdiploid clone and consequent differential survival)
    and hyperdiploid acute leukaemia cases had
    the highest rates of RAS mutations. [Paternal
    smoking in the three months before pregnancy
    was less frequent among hyperdiploids than
    among non-hyperdiploids.]
    2.6.4Cancers of the brain and central
    nervous system
    Since IARC (2004), the association of exposure to parental smoking and risk for childhood
    brain and central nervous system (CNS) tumours
    has been examined in one cohort study (Brooks
    Second-hand tobacco smoke
    et al., 2004; Table 2.25 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E02-Table2.25.pdf), six case–control studies
    (Schüz et al., 1999; Sorahan et al., 2001; Filippini
    et al., 2002; Pang et al., 2003; Cordier et al.,
    2004; Plichart et al., 2008; Table 2.26 available
    at http://monographs.iarc.fr/ENG/Monographs/
    vol100E/100E-02-Table2.26.pdf), and one metaanalysis (Huncharek et al., 2002; Table 2.27
    available at http://monographs.iarc.fr/ENG/
    Monographs/vol100E/100E-02-Table2.27.pdf).
    A meta-analysis of 30 studies published before
    1999 indicated no significant increase in risk for
    CNS tumours associated with maternal smoking
    during pregnancy and an increased risk for brain
    tumours with paternal smoking (Boffetta et al.,
    2000).
    Huncharek et al. (2002) included one cohort
    and eleven case–control studies in a meta-analysis and found no clear association of maternal
    smoking during pregnancy with risk for childhood brain tumours, and a null risk estimate
    for all CNS tumours (even when the analysis
    was restricted to astrocytomas, the main brain
    tumour type). The results were comparable
    and consistently null for all sensitivity analyses
    conducted (Table 2.27 on-line).
    Brooks et al. (2004) analysing the Swedish
    birth cohort study observed that children, in
    particular those aged 2–4 years, whose mother
    smoked during pregnancy, had an increased incidence of childhood brain tumours; the increase
    in risk was similar for benign and malignant
    brain tumours and most apparent for astrocytomas (Table 2.25 on-line).
    Schüz et al. (1999) evaluated parental smoking
    and CNS tumour risk in children < 15 years from
    the German Childhood Cancer Registry (see
    Table 2.26 on-line). No association with risk of
    CNS tumours was observed for either maternal
    smoking during pregnancy or paternal smoking
    before pregnancy. Sorahan et al. (2001) found
    no significant association or trends of risk of
    CNS tumours with either paternal or maternal
    smoking, except for low level of maternal exposure [the latter analysis is based on only eleven
    exposed cases and one control, yielding a very
    wide confidence interval]. Filippini et al. (2002)
    observed no association between risk of childhood brain tumours and parental smoking before
    pregnancy, maternal smoking, regular maternal
    exposure to second-hand tobacco smoke during
    pregnancy, or exposure of the child to secondhand tobacco smoke during its first year of life.
    The results did not vary by child’s age at diagnosis, type of CNS tumour or study centre.
    Plichart et al. (2008) reported no association for
    maternal smoking during pregnancy with CNS
    tumours, while paternal smoking preconception
    showed a significant association, especially for
    astrocytomas. When assessing parental exposure to PAHs, Cordier et al. (2004) observed an
    association of paternal exposure to occupational
    PAHs preconception with all childhood brain
    tumours and with astroglial tumours, but no
    trend of increasing risk with increased exposure.
    Paternal smoking alone was associated with
    a risk for astroglial tumours when compared
    with non-smoking, non-occupationally-exposed
    fathers. Pang et al. (2003) found a decreased
    CNS risk with maternal smoking of more than
    20 cigarettes/day preconception, in both unadjusted and adjusted analyses. In the analyses by
    histological subgroups a statistically significant
    decreased risk was associated with maternal
    smoking during pregnancy for primitive neuroectodermal tumours.
    2.6.5Hepatoblastoma
    Hepatoblastoma is an embryonal tumour
    presumably of fetal origin and prenatal exposures are likely more important than post-natal.
    In some children, a diagnosis of hepatoblastoma
    is evident at birth or shortly thereafter, with a
    median age at diagnosis of 12 months. The ability
    of hepatoblastoma tumour cells to synthesize
    α-fetoprotein (AFP), a major serum protein
    247
    IARC MONOGRAPHS – 100E
    synthesized by fetal liver cells, also suggests a
    fetal origin. Also, hepatoblastomas, like many
    other embryonal tumours, are associated with
    Beckwith-Wiedemann syndrome and hemihypertrophy, further suggesting a gestational
    oncogenic event (DeBaun & Tucker, 1998). Data
    were available for both maternal and paternal
    exposures from two studies (Pang et al., 2003;
    Sorahan & Lancashire, 2004) while two other
    studies (McLaughlin et al., 2006; Pu et al., 2009)
    were limited to data on maternal smoking, available from birth certificates and medical records,
    respectively (Table 2.28). Most of these studies
    had limited sample sizes given the extreme rarity
    of these tumours.
    (a) Parental smoking exposure
    After adjustment for relevant covariates,
    Pang et al. (2003) observed a statistically significant increased risk of hepatoblastoma in association with maternal preconception smoking (OR,
    2.68; 95%CI: 1.16–6.21, P = 0.02) in a somewhat
    dose-dependent manner (P = 0.058). The association with parental smoking was strongest
    (relative to neither parent smoking) when both
    parents smoked (OR, 4.74; 95%CI: 1.68–13.35,
    P = 0.003). Sorahan & Lancashire (2004) found
    no increased risk associated with maternal
    or paternal smoking alone compared to nonsmokers, in both adjusted and unadjusted analyses. In contrast, parental smoking (paternal and
    maternal smoking combined) was strongly and
    consistently associated with an increased risk for
    hepatoblastoma in both adjusted and unadjusted
    analyses.
    In a record-based case–cohort study only
    maternal smoking was examined (McLaughlin
    et al., 2006). Extremely low birth weight (< 1000
    g) was strongly associated with hepatoblastoma.
    After adjustement for birth weight, a statistically
    significant elevated risk for hepatoblastoma was
    found with maternal smoking (RR 2.1; 95%CI:
    1.0–4.2). The increased risk was stronger for
    children diagnosed at the age of two years or
    248
    older (RR 6.0 versus 1.4). Also, the relarive risk
    for maternal smoking and hepatoblastoma was
    stronger for children with normal birth weight
    [> 2500 g] than for low birth weight children.
    For cases of hepatoblastoma diagnosed after the
    age of two years, the relative risk for maternal
    smoking among children with normal birth
    weight was also stronger than that among children with low birth weight.
    Another study on maternal smoking only
    was conducted in Chonquing, China (Pu et al.,
    2009). After adjustment for birth weight, a significantly increased risk for hepatoblastoma was
    found for maternal smoking (RR 2.9; 95%CI:
    1.1–4.2). Adjustments for maternal age, maternal
    body mass index and sex of the baby did not
    change the odd ratios. When analyses were
    stratified by birth weight, the odd ratio associated with maternal smoking for children with a
    birth weight greater than 2500 g was increased
    almost fourfold. Stratification by age at diagnosis
    showed that the risk increased almost fivefold
    with diagnosis at the age of two years or over.
    [The Working Group noted that since information regarding mother’s smoking status for both
    cases and controls was obtained before diagnosis
    the potential for biased recall of maternal exposures during pregnancy is reduced].
    (b) Bias and confounding
    The known risk factors for hepatoblastoma
    include low and very low birth weights (< 2000
    g and < 1000 g, respectively), maternal age and
    use of assisted reproductive technologies. All
    studies adjusted for maternal age, and low birth
    weight was addressed in three of them (Pang &
    Birch, 2003; McLaughlin et al., 2006; Pu et al.,
    2009). Assisted reproductive technologies were
    not considered to be an important potential
    confounder of these studies.
    Spector & Ross (2003) argued that the
    association of hepatoblastoma with parental
    smoking observed by Pang et al. (2003) might be
    confounded by birth weight. In their response,
    Characteristics
    of cases
    3838 childhood
    cancer cases,
    of which 28
    hepatoblastoma;
    Hospital based;
    < 15 yr of age;
    1991–94 in
    Scotland; 1992–
    94 in England
    and Wales
    Birch and
    Kelsey
    diagnostic
    subgroups,
    which group
    biologically
    similar tumours
    together
    (UKCCS
    Investigators,
    2000) excluding
    diagnostic
    subgroups with
    less than 10
    cases
    Reference,
    study
    location and
    period
    Pang et al.
    (2003)
    United
    Kingdom
    Pang & Birch
    (2003)
    United
    Kingdom
    7581 controls;
    matched for
    sex, date of
    birth and
    geographical
    area of
    residence at
    diagnosis;
    randomly
    selected from
    Family Health
    Services
    Authorities in
    England and
    Wales and
    Health boards
    in Scotland
    Face-to-face
    structured
    interviews;
    Computerized
    selfadministered
    questionnaires
    to parents of
    index child
    Characteristics Exposure
    of controls
    assessment
    0
    1–19
    20+
    Trend P
    Maternal
    preconception smoking
    (cigarettes per d)
    0
    1–19
    20+
    P for trend
    Maternal
    preconception smoking
    Both parents
    preconception smoking
    §
    Maternal
    preconception smoking
    §
    Both parents
    preconception smoking
    Parental smoking
    Neither parent
    Mother only
    Father only
    Both parents
    Paternal preconception
    smoking (cigarettes
    per d)
    Exposure categories
    (case/control)
    1 (ref)
    2.99 (1.15–7.76)*
    2.17 (0.65–7.20)
    2.68 (1.16–6.21)*
    4.74**
    (10/3916)
    (9/1490)
    (4/882)
    0.058
    (28/7581)
    (27/6987)
    4.97**
    2.50*
    1 (ref)
    1.88 (0.67–5.26)
    1.65 (0.61–4.45)
    1.00 (ref)
    2.02 (0.40–10.2)
    1.86 (0.46–7.55)
    4.74 (1.68–13.35)
    OR (95% CI)*
    * P < 0.05 **
    P < 0.01
    (11/3082)
    (6/1003)
    (7/1440)
    0.272
    (8/3142)
    (2/574)
    (3/1008)
    (10/1249) **
    (Cases/
    controls)
    Table 2.28 Studies of parental tobacco smoking and childhood hepatoblastoma
    §
    As above,
    additionally
    adjusted for
    birth weight
    Deprivation
    and parental
    age at birth of
    index child
    Adjustment
    for potential
    confounders
    Underreporting
    of smoking by
    case mothers
    Comments
    Second-hand tobacco smoke
    249
    250
    43 deaths from
    hepatoblastoma
    < 16 yr of age
    58 cases of
    hepatoblastoma,
    identified from
    New York State
    Cancer Registry
    58 cases
    Sorahan &
    Lancashire
    (2004)
    United
    Kingdom,
    1953–84
    McLaughlin
    et al. (2006),
    New York,
    USA,
    1985–2001
    Pu et al.
    (2009),
    Chongquing
    China,
    1990–97
    d, day or days; yr, year or years
    Characteristics
    of cases
    Reference,
    study
    location and
    period
    Table 2.28 (continued)
    92 controls,
    appendicitis
    patients,
    matched on
    age, sex, yr
    Matched on
    yr of birth,
    electronic
    birth records
    for 1985–2001
    from New York
    State
    5777 matched
    controls,
    (analysed as
    unmatched
    series)
    Medical
    record of
    mother or
    follow-up
    interviews as
    needed
    Routinely
    recorded
    data on birth
    certificate
    Parental
    smoking
    during yr
    1953–55,
    1971–76,
    1977–81
    Characteristics Exposure
    of controls
    assessment
    Maternal cigarette
    smoking
    Non-smoker
    Smoker
    Paternal cigarette
    smoking
    Non-smoker
    Smoker
    Parental cigarette
    smoking
    Neither parent
    Mother only
    Father only
    Both parents
    Maternal smoking
    Non-smoker
    Smoker
    Birth weight > 2500 g
    Birth weight > 2500 g
    and age > 2 yr
    Maternal smoking
    Non-smoker
    Smoker
    Exposure categories
    (case/control)
    (43/84)
    (15/8)
    (36/3439)
    (12/742)
    (9/1601)
    (3/662)
    (8/1545)
    (20/1800)
    (12/2267)
    (28/3359)
    (19/3191)
    (24/2524)
    (Cases/
    controls)
    Adjustment
    for potential
    confounders
    1 (ref)
    2.9 (1.1–4.2)
    1 (ref)
    2.1 (1.0–4.2)
    2.7 (1.2–5.5)
    5.8 (1.4–25.1)
    1.0 (ref)
    0.85 (0.23–3.19)
    1.23 (0.46–3.28)
    2.69 (1.18–6.13)*
    Birth weight
    Birth yr and
    birth weight
    Sex, age at
    death, yr of
    death, social
    1 (ref)
    1.73 (0.93–3.21) class, sibship
    position, age
    of mother
    and father at
    1 (ref)
    birth of child,
    2.10 (1.03–4.25)* obstetric
    radiography
    OR (95% CI)*
    * P < 0.05 **
    P < 0.01
    Association
    of maternal
    smoking was
    stronger in
    children with
    birth weights
    over 2.5kg.
    Comments
    IARC MONOGRAPHS – 100E
    Second-hand tobacco smoke
    Pang & Birch (2003) showed evidence supporting
    their initial conclusion: the comparable results
    for maternal smoking, smoking by both parents
    and maternal smoking for cases diagnosed at
    an older age, i.e. one year or older, before and
    after adjustment for birth weight, appear to rule
    out low birth weight as an explanation for the
    association.
    Also, both later studies (McLaughlin et al.,
    2006; Pu et al., 2009) reported higher relative risks
    for children with normal birth weight compared
    to those with low birth weight, particularly in
    cases diagnosed after the age of two years.
    2.6.6Other childhood cancers
    Several other childhood cancers have been
    studied in relation to parental tobacco smoke
    exposures, namely neuroblastoma, nephroblastoma, bone tumours, Wilms tumour, soft
    tissue sarcomas, other neoplasms of the reticuloendothelial system, and childhood germ cell
    tumours. The data are few and inconsistent
    (Schüz et al., 1999; Sorahan et al., 2001; Chen
    et al., 2005b; Table 2.28).
    2.7Synthesis
    2.7.1Lung
    The totality of evidence available to date firmly
    establishes that exposure to second-hand tobacco
    smoke at home and at the workplace is causally
    associated with lung cancer risk in both men
    and women. This association has been observed
    in studies from North America, Europe, and
    Asia. Emerging evidence is also suggesting that
    exposure to second-hand tobacco smoke among
    children significantly enhances the risk of lung
    cancer in adulthood.
    2.7.2Breast
    A large number of cohort studies, case–
    control studies and meta-analyses have assessed
    the association between exposure to second-hand
    tobacco smoke and breast cancer. Recent large
    cohort studies in Europe and North America
    showed no association between second-hand
    tobacco smoke and breast cancer. Positive associations in one or more subgroups were reported
    from some case–control studies; however, these
    associations were weaker in more recent studies
    compared with earlier studies.
    Explorative analyses focusing on premenopausal breast cancer have suggested that secondhand tobacco smoke may preferentially cause
    premenopausal breast cancer. Positive associations were largely reported from case–control
    studies, in which both recall and publication bias
    cannot be ruled out. Case–control studies that
    collect a lifetime exposure history are particularly
    vulnerable to subjective and differential reporting
    of exposures that occurred long in the past from
    sources that are difficult to quantify. Overall, the
    results for an association with premenopausal
    breast cancer are also inconsistent.
    2.7.3 Upper aerodigestive tract combined
    Most evidence of the association between
    second-hand tobacco smoke and upper aerodigestive tract cancers, and the subsites of the oral
    cavity, pharynx and larynx, comes from a pooled
    analysis. Overall, the association between secondhand tobacco smoke exposure and cancers of the
    larynx and pharynx is less than causal.
    2.7.4 Nasopharynx, and nasal cavity and
    accesory sinuses
    There is some evidence from a cohort and
    case–control study that exposure to secondhand tobacco smoke increases the risk of sinonasal cancer; for cancer of the nasopharynx, the
    evidence is contradictory.
    251
    IARC MONOGRAPHS – 100E
    2.7.5 Others sites
    Overall, data are conflicting and sparse for the
    association of exposure to second-hand tobacco
    smoke with all cancers combined, cancers of the
    gastrointestinal tract combined, and cancers
    of the stomach, colon, rectum, pancreas, liver
    (hepatocellular carcinoma), kidney (renal cell
    carcinoma), urinary bladder, cervix, ovary, testes,
    and brain and central nervous system.
    2.7.6 Childhood cancers
    (a) All childhood cancers combined
    Four cohort studies, 13 case–control studies
    and one meta-analysis have assessed the association of parental tobacco smoking with childhood
    cancers, all sites combined, in offspring. Most
    of the early studies only assessed the contribution of maternal smoking, whereas recent
    studies generally assessed both paternal and
    maternal smoking, and at various time periods
    (preconception, during pregnancy, post-natally).
    Overall, the evidence for an association between
    parental smoking and childhood cancer (all sites
    combined) remains inconsistent and may be
    subject to bias. Nevertheless, a fairly consistent
    association of paternal tobacco smoking with
    childhood cancers is beginning to emerge, which
    is stronger in studies with more specific exposure
    assessments.
    (b) Leukaemias and lymphomas
    Two cohort studies, 27 case–control studies
    and 2 meta-analyses have examined the association of childhood haematopoietic malignancies (leukaemia and lymphoma) with exposure
    to parental smoking (paternal, maternal or
    both). All studies examined leukaemia, and a
    large number of these addressed non-Hodgkin
    lymphoma.
    The body of evidence suggests a consistent
    association of leukaemia (and lymphoma) with
    paternal smoking preconception and with
    252
    combined parental smoking, with risk ratios
    ranging from 1.5 to 4.0. Maternal tobacco
    smoking during pregnancy generally showed
    modest increases in risk, or null or inverse relationships. The combined effects of preconception
    and post-conception exposures to tobacco smoke
    were highly significant.
    Several studies on lymphoma risk associated with parental smoking showed significantly
    elevated risks associated with paternal tobacco
    smoking preconception. The analyses had small
    samples sizes, and biases due to participation,
    recall and response, especially related to exposure, cannot be ruled out.
    (c) Brain and central nervous system
    The association of childhood tumours of the
    brain and central nervous system with parental
    smoking was assessed in two cohort studies,
    21 case–control studies and 2 meta-analyses.
    Overall these studies do not show an association
    with either paternal smoking, largely preconception, or maternal smoking prior, during or after
    pregnancy, or by CNS types, gliomas and primitive neuroectodermal tumours. The strongly
    positive associations noted in some studies for
    paternal tobacco smoking with astrocytomas
    are offset by the lack of association with childhood brain tumours reported by the large UK
    Childhood Cancer Study.
    (d)Hepatoblastoma
    Four informative case–control studies
    provided data on the association between
    parental smoking and hepatoblastomas. Two
    studies reported on both maternal and paternal
    smoking, while the two others assessed only
    maternal smoking. In one study where a large
    number of categories of childhood cancers
    (n = 25) were assessed, the only childhood cancer
    that showed an association with parental smoking
    was hepatoblastoma. This original observation
    was confirmed in three later studies, with relative
    risks ranging from 2.0 to 5.5. Chance, bias and
    Second-hand tobacco smoke
    confounding were adequately addressed in the
    data from the studies available. The evidence for
    the association of parental smoking with hepatoblastoma is convincing, with an emphasis on
    prenatal exposures.
    (e) Other childhood cancers
    Most of the associations reported for the other
    childhood cancers, notably soft tissue sarcomas,
    rhabdomyosarcomas, Ewing’s sarcoma, neuroblastoma, Wilms tumour, reticuloendothelial
    sarcomas and germ cell tumours were null,
    with a few isolated and inconsistent positive
    observations.
    3. Cancer in Experimental Animals
    3.1 Simulated second-hand tobacco
    smoke
    Simulated second-hand tobacco smoke,
    frequently a mixture of 89% sidestream and 11%
    mainstream smoke, generated from cigarettes by
    smoking machines (Teague et al., 1994) has been
    tested for carcinogenicity in adult mice of strains
    that are genetically susceptible to induction of
    lung tumours (Malkinson, 1992). Mice were
    exposed in inhalation chambers. Several studies
    reported no increase in lung tumour incidence or
    multiplicity in mice exposed to simulated secondhand tobacco smoke for 5–9 months and killed
    immediately thereafter (Witschi et al., 1995,
    1997a; Finch et al., 1996). It was suggested that
    the lack of tumour response in simulated secondhand tobacco smoke-exposed mice might be due
    to treatment-induced stress (as determined by
    the increased plasma corticosterone level) that
    has been shown to attenuate lung tumorigenesis
    (Stinn et al., 2005a).
    In subsequent studies from several laboratories (Table 3.1), an increased multiplicity and
    often increased incidence of lung tumours was
    reported in male and female A/J mice exposed
    for five months and kept in filtered air for another
    four months (Witschi et al., 1997a, b, 1998, 1999;
    D’Agostini et al., 2001) or longer (Witschi et al.,
    2006) before the mice were killed. Similar results
    were obtained with Swiss albino mice (Witschi
    et al., 2002). In these studies, no nasal tumours
    were observed in smoke-exposed mice.
    ￼ In one study, male and female transgenic
    mice with a dominant negative p53 mutation on
    an A/J background were exposed to simulated
    second-hand tobacco smoke for 9.5 continuous
    months or for 5 months followed by recovery in
    air for 4.5 months. Transgenic mice exposed by
    either regimen developed significantly higher
    incidence and multiplicity of lung tumours than
    sham-exposed control transgenic mice (DeFlora
    et al., 2003). Neither lung tumour incidence nor
    multiplicity was increased in smoke-exposed
    wild-type control mice in this study.
    In one study, male and female rats exposed to
    room-aged sidestream cigarette smoke by noseonly inhalation for 24 months and then killed
    had no increased incidence of lung or other
    tumours in comparison with fresh-air controls.
    Lung tumours were not significantly increased
    in rats exposed for 24 months and kept until 30
    months of age (Stinn et al., 2005b).
    3.2Sidestream smoke condensate
    In one study, sidestream cigarette smoke
    condensate applied to the shaved skin of female
    NMRI mice lower back, at total weekly doses of
    5, 10 and 15 mg, for 3 months caused benign and
    malignant skin tumours and mammary carcinomas in mice observed for their lifespan and
    was more potently carcinogenic in this assay than
    mainstream smoke condensate. No cutaneous or
    subcutaneous tumours developed in any of three
    control groups (P < 0.001) (Mohtashamipur et al.,
    1990). In one study, fractionated sidestream cigarette smoke condensates were implanted into the
    lungs of female rats. The fraction containing
    253
    254
    48 animals/group
    Chamber concentration, 0 or 87 mg/m3 total suspended
    particulates; 6 h/d, 5 d/wk for 5 mo followed by 0 or
    4 mo post-exposure recovery
    9 mo
    Animals/group at start
    Dosing regimen
    Duration
    Results
    Target organ
    Incidence and/or
    multiplicity of tumours
    (%)
    NS
    Incidence: P < 0.01
    Multiplicity: P < 0.01
    Incidence: P < 0.01
    Multiplicity: P < 0.01
    Incidence: NS
    Multiplicity: P < 0.05
    Incidence: P < 0.05
    Multiplicity: P < 0.05
    Incidence: P < 0.01
    Multiplicity: P < 0.01
    Incidence: P < 0.05
    Multiplicity: P < 0.05
    NS
    Significance
    a
    Simulated second-hand tobacco smoke: 89% sidestream and 11% mainstream smoke from Kentucky 1R4F or 2R1 reference cigarettes
    d, day or days; F, female; h, hour or hours; M, male; mo, month or months; NR, not reported; NS, not significant; wk, week or weeks
    5 mo: 2/24 (8%, 0.1 ± 0.1);
    6/24 (25%, 0.3 ± 0.1)
    9 mo: 9/24 (38%,
    0.5 ± 0.2); 20/24 (83%,
    1.4 ± 0.2)
    Mice, A/J (F)
    5/20 (25%, 0.25 ± 0.10);
    20 animals/group
    D’Agostini et al.
    Chamber concentration, 0 or 120 mg/m3 total suspended 15/20 (75%, 1.05 ± 0.17)
    particulates; 6 h/d, 5 d/wk, for 5 mo followed by 4 mo
    (2001)
    post-exposure recovery
    9 mo
    A/J mice (sex
    24, 25 controls (12 mo)
    12 mo: 13/24 (54%,
    NR)
    19, 17 controls (24 mo)
    0.9 ± 0.2); 24/25 (96%,
    Witschi et al.
    Chamber concentration, 0 (control) or 158 mg/m3 total
    1.8 ± 0.2)
    suspended particulates; 6 h/d, 5 d/wk, for 6 mo followed 24 mo: 8/9 (89%,
    (2006)
    by 4 or 16 mo post-exposure recovery
    2.1 ± 0.5); 10/10 (100%,
    24 mo
    4.3 ± 0.7)
    (UL53–3xA/J)F1, 222 (108; 114 controls)
    No recovery: NR; 17/30
    Transgenic mice
    (57%, 0.93 ± 0.18)
    Chamber concentration, 0 (control) or 113 mg/m3
    total suspended particulates; 6 h/d for 5 mo or 9.5 mo
    (M, F)
    With recovery: 5/26 (19%,
    followed by 0 or 4.5 mo post-exposure recovery
    De Flora et al.
    0.27 ± 0.10); 15/23 (65%,
    9.5 mo
    (2003)
    0.74 ± 0.11)
    Wistar rats (M, F) 99 rats/group
    24 mo: controls–0/16
    Stinn et al.
    Low dose–0/16
    Nose-only exposure; concentration, 0 (controls) or low
    (2005b)
    High dose–0/16
    dose 3 mg/m3 or high dose 10 mg/m3; 6 h/d, 7 d/wk,
    24 mo followed by 0 or 6 mo post-exposure recovery
    30 mo: controls–2/99 (2%)
    30 mo
    Low dose–4/98 (4%)
    High dose–5/94 (5%)
    Mice, A/J (M)
    Witschi et al.
    (1997a)
    Species, strain
    (sex)
    Reference
    80% of tumours were
    adenomas
    > 80% of tumours were
    adenomas; the rest
    were adenocarcinomas
    Comments
    Table 3.1 Carcinogenicity studies of inhalation exposure to simulated second-hand tobacco smokea in A/J mice, transgenic
    mice with a dominant negative p53 mutation, and Wistar rats as a function of length of the post-exposure recovery period
    IARC MONOGRAPHS – 100E
    Second-hand tobacco smoke
    PAHs with four and more rings (dose, 1.06 mg/rat)
    induced 5 lung carcinomas in 35 treated rats;
    fractions containing no PAHs or PAHs with two
    or three rings (16 mg/rat) had little or no carcinogenic effect (Grimmer et al., 1988).
    3.3Observational studies of
    companion animals
    In one study, sinonasal cancers occurred
    more frequently in pet dogs of long-nosed breeds
    which lived in homes with at least one smoker
    (Reif et al., 1998), but no such excess risk was
    seen in a second study (Bukowski et al., 1998). A
    marginal excess risk of lung cancer was observed
    in dogs aged 10 years or less and exposed to
    household tobacco smoke in one study (Reif
    et al., 1992). Risk of bladder cancer in dogs was
    not related to exposure to household cigarette
    smoke in another study (Glickman et al., 1989).
    Risk of malignant lymphoma was increased
    in pet cats exposed to household tobacco smoke
    in one study (Bertone et al., 2002), but the conclusion that this association was causal has been
    questioned (Denson, 2003). In another study by
    the same group (Bertone et al., 2003), exposure
    of pet cats to household tobacco smoke was also
    associated with a non-significant 2-fold increase
    in risk of oral squamous cell carcinoma.
    3.4Synthesis
    Several studies showed consistent increases
    in lung tumour multiplicity and often lung
    tumour incidence in inbred strain A/J mice and
    in transgenic mice with a dominant negative p53
    tumour suppressor gene exposed by inhalation.
    In addition, in one report, skin and mammary
    tumours were induced in NMRI mice exposed to
    sidestream cigarette smoke condensate applied
    topically to the skin.
    4. Other Relevant Data
    See Section 4 of the Monograph on Tobacco
    Smoking in this volume.
    5.Evaluation
    There is sufficient evidence in humans for the
    carcinogenicity of second-hand tobacco smoke.
    Second-hand tobacco smoke causes cancer of
    the lung. Also, a positive association has been
    observed between exposure to second-hand
    tobacco smoke and cancers of the larynx and the
    pharynx.
    There is sufficient 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
    tobacco smoke condensates.
    Second-hand tobacco smoke is carcinogenic
    to humans (Group 1).
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    * Exceptionally, the most recent updates of well-established ongoing surveys and reports, published after the
    meeting, were included in this Monograph. The methodology and data available at the time of the meeting
    were reviewed by the Working Group; the updates
    reflect the most current estimates of prevalence of
    exposure and therefore have no influence on the final
    evaluation.
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