This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Environmental Health Criteria  211

    First draft prepared by Dr K. Rothwell, Knaresborough, Yorkshire,
    United Kingdom

    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.

    World Health Organization
    Geneva, 1999

    The International Programme on Chemical Safety (IPCS), established in
    1980, is a joint venture of the United Nations Environment Programme
    (UNEP), the International Labour Organisation (ILO), and the World
    Health Organization (WHO).  The overall objectives of the IPCS are to
    establish the scientific basis for assessment of the risk to human
    health and the environment from exposure to chemicals, through
    international peer review processes, as a prerequisite for the
    promotion of chemical safety, and to provide technical assistance in
    strengthening national capacities for the sound management of

    The Inter-Organization Programme for the Sound Management of Chemicals
    (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture
    Organization of the United Nations, WHO, the United Nations Industrial
    Development Organization, the United Nations Institute for Training
    and Research, and the Organisation for Economic Co-operation and
    Development (Participating Organizations), following recommendations
    made by the 1992 UN Conference on Environment and Development to
    strengthen cooperation and increase coordination in the field of
    chemical safety.  The purpose of the IOMC is to promote coordination
    of the policies and activities pursued by the Participating
    Organizations, jointly or separately, to achieve the sound management
    of chemicals in relation to human health and the environment.

    WHO Library Cataloguing-in-Publication Data

    Health effects of interactions between tobacco use and exposure to
    other agents.

         (Environmental health criteria ; 211)

         1.Smoking - adverse effects  2.Tobacco smoke pollution  
         3.Drug interactions 4.Environmental exposure   
         5.Occupational exposure  6.Risk factors
         I.International Programme on Chemical Safety  II.Series

         ISBN 92 4 157211 6      (NLM Classification: QV 137)
         ISSN 0250-863X

    The World Health Organization welcomes requests for permission to
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              (c) World Health Organization 1999

    Publications of the World Health Organization enjoy copyright
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    concerning the legal status of any country, territory, city, or area
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    products does not imply that they are endorsed or recommended by the
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    that are not mentioned. Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.






         1.1. Introduction
         1.2. Examples of combined effects of tobacco smoking and other
         1.3. Composition of tobacco leaf and tobacco smoke
         1.4. Mainstream tobacco smoke
         1.5. Sidestream tobacco smoke
         1.6. Effects of ways of cigarette smoking on smoke
         1.7. Summary of conclusions and recommendations


         2.1. Tobacco and its uses
              2.1.1. Introduction
              2.1.2. Tobacco smoking
              2.1.3.    Tobacco chewing and snuff
         2.2. Responses to mainstream smoke
              2.2.1. Acute responses
                 Acute bronchitis
              2.2.2. Chronic responses
                 Chronic obstructive lung
                                  diseases (COLD)
                 Chronic bronchitis
                 Small airways disease
                 Pulmonary fibrosis
                 Effects on the immune system
              2.2.3. Cancer
              2.2.4. Cardiovascular effects
              2.2.5. Smoking and occupational accidents, injuries and
         2.3. Health risks from smokeless tobacco use
              2.3.1. Introduction
              2.3.2. Cancer
              2.3.3. Cardiovascular disease


         3.1. Introduction
              3.1.1. Interaction
              3.1.2. Measuring interaction
              3.1.3. Effects of tobacco smoking on lung deposition 
                        and clearance of particles
         3.2. Interactions between tobacco smoke and other agents
              3.2.1. Asbestos
                 Asbestos and lung cancer
                 Asbestos and pleural
                 Asbestos and other forms of cancer
         3.3. Non-asbestos fibres
              3.3.1. Glass fibre
              3.3.2. Rockwool, slagwool and ceramic fibres
         3.4. Inorganic chemicals
              3.4.1. Arsenic
              3.4.2. Beryllium
              3.4.3. Chromium
              3.4.4. Nickel
              3.4.5. Manganese
              3.4.6. Platinum
              3.4.7. Silica
         3.5. Organic chemical agents
              3.5.1. Chloromethyl ethers
              3.5.2. Tetrachlorophthalic anhydride
              3.5.3. Dyestuffs
              3.5.4. Polycyclic aromatic hydrocarbons
              3.5.5. Ethanol
              3.5.6. Other organic compounds
         3.6. Physical agents
              3.6.1. Radiation
                 Radon in mines (high linear energy
                                  transfer (LET) alpha-radiation)
                 Environmental radon (high linear
                                  energy transfer (LET) alpha-radiation)
                 Atomic bomb site radiation
                                  (low linear energy transfer (LET)
                 Therapeutic X-rays (low linear
                                  energy transfer (LET) radiation)
                 Nuclear plant
              3.6.2. Vibration
              3.6.3. Noise
              3.6.4. Dupuytren's contracture
         3.7. Biological agents
              3.7.1. Biological (vegetable) dusts
                 Cotton dust
                 Wood dust
                 Allergic responses

              3.7.2. Other biological agents
              3.7.3. Agents found in factory farming
                        (animal confinement effects)
              3.7.4. Laboratory animals
              3.7.5. Schistosomiasis
              3.7.6. Other urinary tract infections
              3.7.7. Sarcoidosis
         3.8. Vector effects
              3.8.1. Polytetrafluoroethylene
              3.8.2. Mercury
         3.9. Effects of tobacco smoking and metabolism
              of drugs and other chemicals
              3.9.1. Oral contraceptive use
              3.9.2. Drug and chemical metabolism
         3.10. Animal studies of the interactions between
              cigarette smoke exposure and other agents
              3.10.1. Non-cancer end-points
              3.10.2. Cancer studies: tobacco (cigarette)
                        smoke plus other chemicals
              3.10.3. Cancer studies: cigarette smoke plus


         4.1. Coal mining
              4.1.1. Coal dust
              4.1.2. Bronchitis in coal miners
              4.1.3. Emphysema and pneumoconiosis in coal miners
              4.1.4. Lung cancer in coal miners
         4.2. Other mineral dusts
              4.2.1. Talc
              4.2.2. Kaolin
              4.2.3. Alumina
         4.3. Fibrous minerals
         4.4. Metals
              4.4.1. Antimony
              4.4.2. Cadmium
              4.4.3. Cobalt
              4.4.4. Lead
         4.5. Rubber industry
         4.6. Petroleum industry
         4.7. Pesticides


         5.1. Conclusions
         5.2. Recommendations for protection of human health






    Every effort has been made to present information in the criteria
    monographs as accurately as possible without unduly delaying their
    publication.  In the interest of all users of the Environmental Health
    Criteria monographs, readers are requested to communicate any errors
    that may have occurred to the Director of the International Programme
    on Chemical Safety, World Health Organization, Geneva, Switzerland, in
    order that they may be included in corrigenda.

                               *     *     *

    A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
    356, 1219 Châtelaine, Geneva, Switzerland (telephone no. + 41 22 
    - 9799111, fax no. + 41 22 - 7973460, E-mail irptc@unep.ch).

                               *     *     *

    This publication was made possible by grant number 5 U01 ES02617-15
    from the National Institute of Environmental Health Sciences, National
    Institutes of Health, USA, and by financial support from the European

    Environmental Health Criteria



    In 1973 the WHO Environmental Health Criteria Programme was initiated
    with the following objectives:

    (i)       to assess information on the relationship between exposure
              to environmental pollutants and human health, and to provide
              guidelines for setting exposure limits;

    (ii)      to identify new or potential pollutants;

    (iii)     to identify gaps in knowledge concerning the health effects
              of pollutants;

    (iv)      to promote the harmonization of toxicological and 
              epidemiological methods in order to have internationally 
              comparable results.

    The first Environmental Health Criteria (EHC) monograph, on mercury,
    was published in 1976 and since that time an ever-increasing number of
    assessments of chemicals and of physical effects have been produced. 
    In addition, many EHC monographs have been devoted to evaluating
    toxicological methodology, e.g., for genetic, neurotoxic, teratogenic
    and nephrotoxic effects.  Other publications have been concerned with
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    Since its inauguration the EHC Programme has widened its scope, and
    the importance of environmental effects, in addition to health
    effects, has been increasingly emphasized in the total evaluation of

    The original impetus for the Programme came from World Health Assembly
    resolutions and the recommendations of the 1972 UN Conference on the
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    The recommendations of the 1992 UN Conference on Environment and
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    The criteria monographs are intended to provide critical reviews on
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    The layout of EHC monographs for chemicals is outlined below.

    *    Summary -- a review of the salient facts and the risk evaluation
         of the chemical
    *    Identity -- physical and chemical properties, analytical methods
    *    Sources of exposure
    *    Environmental transport, distribution and transformation
    *    Environmental levels and human exposure
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    *    Conclusions and recommendations for protection of human health
         and the environment

    *    Further research
    *    Previous evaluations by international bodies, e.g., IARC, JECFA,

    Selection of chemicals

    Since the inception of the EHC Programme, the IPCS has organized
    meetings of scientists to establish lists of priority chemicals for
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    Carolina, USA, 1995. The selection of chemicals has been based on the
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    on the hazards are available.

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    All Participating Institutions are informed, through the EHC progress
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    request.  The Chairpersons of Task Groups are briefed before each
    meeting on their role and responsibility in ensuring that these rules
    are followed.



    (Geneva, 25-26 April 1966)


    Dr G. Finch, Inhalation Toxicology Research Institute, Lovelace
         Biomedical and Environmental Research Institute, Albuquerque, New
         Mexico, USA

    Professor G. Pershagen, Division of Epidemiology, Institute of
         Environmental Medicine, Karolinska Institute, Stockholm, Sweden

    Dr K. Rothwell, Knaresborough, Yorkshire, United Kingdom

    Professor H.-P. Witschi, Institute of Toxicology and Environmental
         Health, University of California, Davis, California, USA


    Dr E. Smith, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland

    Mr N.F. Collishaw, Tobacco or Health, Programme on Substance
         Abuse, World Health Organization, Geneva, Switzerland


    (Geneva, 18-21 February 1997)


    Dr G. Finch, Lovelace Respiratory Research Institute, Inhalation
         Toxicology Research Institute, Albuquerque, New Mexico, USA 
         ( Chairman)

    Dr L. Fishbein, Fairfax, VA, USA ( Joint Rapporteur)

    Dr Dorota Jarosinska, Institute of Occupational Medicine and
         Environmental Health, Sosnowiec, Poland

    Professor G. Kazantzis, Royal School of Mines, London, United
         Kingdom ( Joint Rapporteur)

    Professor U. Keil, Institute for Epidemiology and Social Medicine,
         Münster, Germany

    Dr D. Krewski, Environmental Health Directorate, Health Canada,
         Ottawa, Ontario, Canada

    Dr K. Rothwell, Knaresborough, Yorkshire, United Kingdom
         ( Vice-Chairman)

    Dr L. van Bree, Laboratory of Health Effects Research, National
         Institute of Public Health and the Environment, Bilthoven, The


    Dr G. Minotti, Catholic University of the Sacred Heart, Rome, Italy
         ( representing the International Union of Pharmaceutical


    Dr E. Smith, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland ( Secretary)

    Mrs B.F. Goelzer, Occupational Health, World Health Organization,
         Geneva, Switzerland

    Mr N.E. Collishaw, Programme on Substance Abuse, World Health
         Organization, Geneva, Switzerland


    A WHO Task Group on Health Effects of Interactions Between Tobacco Use
    and Exposure to Other Agents met at the World Health Organization,
    Geneva, from 18 to 21 February 1997. Dr E. Smith, IPCS, welcomed the
    participants on behalf of Dr M. Mercier, Director IPCS, and the
    cooperating organizations. The Task Group reviewed and revised the
    draft monograph and developed a new text.

    The first draft of the monograph was prepared by Dr K. Rothwell,
    Knaresborough, Yorkshire, United Kingdom. This draft was further
    developed by a Working Group held in WHO, Geneva, 25-26 April 1996,
    and then circulated for international comment to IPCS contact points
    for  Environmental Health Criteria monographs. Comments were
    incorporated in a second draft prepared by Dr K. Rothwell. This draft
    was reviewed at the Task Group meeting and a text given further
    limited circulation to Task Group members and a number of other
    experts, including the US EPA National Center for Environmental
    Assessment under the coordination of Dr D. Mukerjee, for final
    comment. In the development of the monograph, contributions were made
    by a number of authors listed below.

    Dr E. Smith (IPCS Unit for the Assessment of Risk and Methods) was
    responsible for the scientific content of the monograph and Dr P.G.
    Jenkins (IPCS Central Unit) for the technical editing.

    The efforts of all who helped in the preparation and finalization of
    the monograph are gratefully acknowledged.

         The authors were:

    Main authors

    Dr K. Rothwell, Knaresborough, Yorkshire, United Kingdom
         ( Coordinating author)

    Dr G. Finch, Lovelace Respiratory Research Institute, Albuquerque,
         New Mexico, USA

    Dr L. Fishbein, Fairfax, Virginia, USA

    Dr D. Krewski, Environmental Health Directorate, Health Canada,
         Ottawa, Ontario, Canada

    Professor G. Pershagen, Institute of Environmental Medicine,
         Karolinska Institute, Stockholm, Sweden

    Professor H-P. Witschi, Institute of Toxicology and Environmental
         Health, University of California, Davis, California, USA

    Contributing authors

    Dr D. Jarosinska, Institute of Occupational Medicine and
         Environmental Health, Sosnowiec, Poland

    Professor G. Kazantzis, Royal School of Mines, London, United

    Professor U. Keil, Institute for Epidemiology and Social Medicine,
         Munster, Germany

    Dr E. Smith, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland

    Dr L. van Bree, National Institute of Public Health and the
         Environment, Bilthoven, the Netherlands

                                       * * *

    The IPCS expresses its gratitude to the external reviewers who
    provided comments and other relevant material, in particular the
    United Kingdom Department of Health, London, and the US Environmental
    Protection Agency's Office of Research and Development, National
    Center for Environmental Assessment, Cincinnati, Ohio, USA.

    The funds for the preparation, review and publication of this
    monograph were generously provided by Health Canada.


    BCME    bis(chloromethyl) ether
    CMME    chloromethyl methyl ether
    COLD    chronic obstructive lung disease
    CHD     coronary heart disease
    CVD     cardiovascular disease
    ERR     excess relative risk
    FIV1    forced expiratory volume (1 second)
    IARC    International Agency for Research on Cancer
    LET     linear energy transfer
    MMAD    mass median aerodynamic diameter
    NOx     nitrogen oxides
    SAD     small airways disease
    TSNA    tobacco-specific nitroasamines
    URT     upper respiratory tract

    1.  OVERVIEW

    1.1  Introduction

    Tobacco use, particularly smoking, causes a range of adverse health
    effects, is directly implicated in a number of serious diseases, and
    can increase adverse effects of other chemical, physical and
    biological agents. Chemicals and other agents in workplaces can cause,
    if not controlled, disease, incapacity and early death. In the
    workplace it is clear that adverse effects can be produced by the
    synergistic interaction of tobacco smoking and other hazards. The
    majority of interactions of harmful tobacco smoke constituents with
    toxic chemicals occur when the latter are airborne, although
    interactions of smoking with ingested and/or absorbed harmful agents
    have also been reported.

    Tobacco use is widespread throughout the world, from countries with
    low income economies to the most affluent industrialized nations.
    Tobacco is used by men and women, by children and adults, and millions
    of people are involuntarily subjected to environmental tobacco smoke.
    There are numerous explanations for the tobacco habit but the main
    reason for its ubiquity is the addictive drug nicotine present in all
    forms of tobacco leaf and delivered in varying amounts to the user by
    the various methods of tobacco use (chapter 2). The advent of the
    cigarette, mass produced, easily obtainable, relatively cheap and
    light in weight, so it can be held in the mouth leaving the hands
    free, has had a major impact on smoking habits, in general and in

    In many countries tobacco smoking is recognized as a serious health
    hazard and a major contributing factor to deaths from a number of
    common diseases. In these countries health warning legislation and
    measures to control consumption by taxation have been implemented, as
    well as public education programmes on the dangers of smoking and the
    benefits to be gained from not starting or from stopping. However,
    there are still countries where decisive action has yet to be taken to
    deal with the problem of tobacco use.

    Many work situations involve an element of risk. The nature of the
    work may generate harmful effects on health, and working activities
    may cause environmental contamination. Tobacco growing itself involves
    the use of pesticides, harvesting of tobacco leaf can cause sickness
    due to skin absorption of nicotine, and processing exposes workers to
    health hazards from airborne dust and fungal spores. A high male
    cancer incidence has been reported in areas with tobacco industries.
    In mining there are airborne mineral dusts and, in farming and
    industries using biologically produced raw materials, biological dusts
    are found. Fumes are produced during welding, and gases, smokes, mists
    and vapours containing inorganic and/or organic toxic substances
    present hazards in many industries. Excessive heat or exposure to
    ultraviolet light can be detrimental to the well-being of workers.
    Ionizing radiation in mining and modern technology is recognized as a
    workplace hazard. In many occupations workers are subjected to

    excessive noise or harmful mechanical vibration. Working conditions
    can impact adversely on health to a greater extent in smokers than
    non-smokers. In many countries, smoking at the workplace is 
    prohibited, primarily for reasons of fire/explosion safety. However, 
    in some countries, regulations are not always enforced. In some newly 
    industrializing countries health problems associated with work have 
    not yet been fully addressed and many employers and workers are 
    ignorant of the dangers to health of their occupations. In addition, 
    there is the large "informal sector" of industry, particularly in 
    developing countries, where the home is the workplace, chemicals are 
    used (including solvents, resins, and synthetic dyestuffs), the whole 
    family is exposed, and there are no restrictions on exposure to work
    hazards or smoking.

    The situation for adverse health effects resulting from combined
    exposure to tobacco smoke, mainstream or environmental, and agents in
    the domestic environment is much less defined. However, the incidence
    of lung cancer and the concentration of radon in homes has a similar
    dose-response to lung cancer and radon in mines, and the risk is
    higher in smokers.

    1.2  Examples of combined effects of tobacco smoking and other

    There is evidence for synergism in the production of adverse effects
    (cancer) between tobacco smoking and exposure to arsenic, asbestos,
    ethanol, silica and radiation (radon, atomic bomb, X-ray). On the
    other hand there is evidence for antagonism in the case of tobacco
    smoking and the carcinogenic chloromethyl ethers, i.e. chloromethyl
    methyl ether (CMME) and bis(chloromethyl) ether (BCME) (Hoffmann &
    Wynder, 1976; IARC, 1986), tobacco smoking and allergic alveolitis,
    and tobacco smoking and chronic beryllium disease. Tobacco smoking
    affects the health risks of exposures in coal mining, pesticide
    handling, and in the rubber and petroleum industries. Coal miners who
    smoke are at greater risk of developing chronic bronchitis and
    obstructive airway disease but not emphysema. Lung cancer in coal
    miners has been attributed entirely to tobacco smoking. Tobacco
    smoking can increase the health risks of exposure to vegetable dusts
    that produce chronic respiratory conditions, such as byssinosis
    produced by cotton dust, and nasal cancer caused by wood dusts.

    1.3  Composition of tobacco leaf and tobacco smoke

    More than 3040 chemical compounds have been isolated from processed
    tobacco leaf (Roberts, 1988). Most are leaf constituents, but some
    arise from growing conditions such as the soil and atmosphere in an
    area, while others originate from the use of agricultural chemicals,
    from casings, humectants and flavourings added to the leaves, and from
    curing methods. Different tobacco varieties grown in different
    countries, and cured and processed in various ways show differences.
    The proportions of individual constituents may differ but not the
    overall composition. Among important toxic compounds identified, other
    than nicotine, are carcinogenic nitrosamines, derived from nitrites,

    amines, proteins and alkaloids present in the leaf, polycyclic
    aromatic hydrocarbons resulting from the curing process, radioactive
    elements absorbed from the soil and the air, and cadmium in tobacco
    grown on cadmium-rich soils. When tobacco is burned in the course of
    smoking, many pyrolysis and other reaction products are formed.

    1.4  Mainstream tobacco smoke

    Tobacco smoke is an aerosol consisting of a particulate phase of
    liquid droplets dispersed in a gas/vapour phase. When a cigarette is
    smoked, many compounds are formed by pyrolysis of the tobacco. These
    either pass through the cigarette as mainstream smoke, some being
    condensed a short distance behind the burning cone, or they are
    emitted into the air from the burning end as sidestream smoke. With
    each puff the smoke becomes progressively stronger because previously
    condensed material is added to the smoke and the length of cigarette
    available for further condensation is decreasing. The physicochemical
    nature of the smoke depends on the processing and burning of the
    tobacco, the porosity and treatment of the paper wrapper, and on the
    type of filter tip (Hoffmann & Hoffmann, 1997). In the case of a
    cigarette or Asian "bidi" (tobacco wrapped in vegetable leaf), the
    smoke chemistry is affected by such factors as dimensions, wrapper
    porosity and the smoking parameters of puff volume, frequency and
    duration (NIH, 1998). Variations in smoke chemistry are mainly in the
    balance of smoke constituents rather than the presence or absence of
    particular compounds.

    Mainstream smoke is generated in a comparatively low-oxygen atmosphere
    at a burning temperature of 850-950°C in the fire cone. Initially,
    mainstream smoke particles have a mass median aerodynamic diameter
    (MMAD) of 0.2 to 0.3 µm; however, as soon as they encounter the 100%
    humidity of the respiratory tract, they coalesce into larger particles
    and behave as if their MMAD was in the micrometre range. Between 50
    and 90% of all inhaled particulate matter may be retained in the
    respiratory tract (Wynder & Hoffmann, 1967; Hinds et al., 1983). From
    size considerations, the aerosol particulate matter, the vapour phase
    constituents and the permanent gases are capable of reaching the
    alveoli when smoke is inhaled. Deposition in the tracheobronchial tree
    is complicated by the behaviour of hydrophilic constituents in the
    high humidity conditions, but smoke reaches every part of the airways.

    Mainstream smoke contains nearly 4000 identified chemicals and an
    unknown number of unidentified chemicals (Roberts, 1988). Mainstream
    smoke can be divided into particulate and gas phases. Mainstream smoke
    particulate phase contains nicotine, nitrosamines such as
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and
     N-nitrosonornicotine (NNN), metals such as cadmium, nickel, zinc and
    polonium-210, polycyclic hydrocarbons, and carcinogenic amines, such
    as 4-aminobiphenyl. The vapour phase contains carbon monoxide, carbon
    dioxide, benzene, ammonia, formaldehyde, hydrogen cyanide,
     N-nitrosodimethylamine,  N-nitrosodiethylamine and other compounds.
    Compounds in tobacco smoke can be classified by their biological
    activity as asphyxiants, irritants, ciliatoxins, mutagens,

    carcinogens, enzyme inhibitors, neurotoxins or pharmacologically
    active compounds. The main point of entry of cigarette smoke into the
    body is via the airways, but many constituents, particularly from pipe
    and cigar smoke, dissolve in saliva and are absorbed in the buccal
    cavity or are swallowed. Cigar and pipe smokers generally do not
    inhale the smoke and it remains in the oral cavity, is dissolved in
    the saliva and absorbed through the mucous membranes or swallowed
    (NIH, 1998). Alcoholic drinks have a solvent effect for the smoke
    constituents facilitating their absorption.

    1.5  Sidestream tobacco smoke

    Sidestream smoke is generated at lower burning temperature (500-600°C)
    in a reducing atmosphere. Fresh sidestream smoke particles are about
    the same size as mainstream smoke particles with a mass median
    aerodynamic diameter (MMAD) of approximately 0.2 µm. Qualitatively,
    sidestream smoke composition is similar to the composition of
    mainstream smoke. Some chemicals in sidestream smoke are emitted at
    higher concentrations per gram of tobacco burned than in mainstream
    smoke. This is particularly so for carcinogens such as
     N-nitrosodimethylamine and  N-nitrosodiethyl-amine, and for metals
    such as nickel or cadmium. Many carcinogenic compounds are more
    concentrated in sidestream than in mainstream smoke. Mouse
    skin-painting bioassays have shown that condensate of sidestream smoke
    is more carcinogenic than that of mainstream smoke (Wynder & Hoffmann,
    1967; US Surgeon General, 1986; NIH, 1998).

    1.6  Effects of ways of cigarette smoking on smoke toxicity

    The nicotine content of different cigarettes varies, and the smoker
    adjusts the smoking intensity and depth of inhalation to satisfy the
    acquired nicotine need. Consequently, the smoker of a filter cigarette
    with a low nicotine yield (<1.2 mg) smokes more intensively and this
    influences toxicity (NIH, 1998).

    1.7  Summary of conclusions and recommendations

    Tobacco use, particularly smoking, is a most important public health
    hazard and a major preventable cause of morbidity and mortality. In
    addition to the adverse health effects of active tobacco use, adverse
    health effects have been demonstrated to result from exposure to
    environmental tobacco smoke. The risks from tobacco smoking are also
    increased through interactions with certain chemical, physical and
    biological hazards found in the workplace and general environment.
    There are a few instances of antagonistic interactions, but the health
    risks of tobacco smoke far outweigh any apparent protective effects.

    All possible measures should be taken to eliminate tobacco use,
    particularly smoking, and smoking in public places should be strongly
    discouraged. To avoid interaction with occupational exposures and to
    eliminate the risk of exposure to environmental tobacco smoke, smoking
    in the workplace should be prohibited.

    To protect health, in particular that of children, smoking in domestic
    environments should be strongly discouraged. This will prevent
    possible harmful interactions between tobacco smoke and residential
    exposures to other hazards. There is a pressing need for educational
    programmes on the health hazards of smoking. Health professionals
    should provide assistance to help smokers quit. Since smoking may
    result in altered response or adverse reactions to drugs and other
    treatments, appropriate dose adjustments and patient surveillance
    should be taken into consideration by clinicians.


    2.1  Tobacco and its uses

    2.1.1  Introduction

    The genus  Nicotiana, a member of the plant family  Solanaceae, is
    represented by about 100 species and sub-species (Cromwell, 1955; Tso,
    1990) widely distributed throughout the world. The species  N.
     tabacum and  N. rustica are the principal sources of tobacco. The
    primary intention in using tobacco is to obtain the alkaloid nicotine
    and, once the habit has been established, nicotine appears to fulfil
    both a pharmacological and psychological need (US Surgeon General,
    1988; NIH, 1998).

    Tobacco and its uses were unknown outside America before its discovery
    by Columbus. In a description of tobacco use in South America at that
    period, Wilbert (1987) used information from European explorers.

    There were six types of tobacco use: chewing, drinking, licking,
    rectal insertion, nasal and oral snuffing, and smoking. Smoking was by
    far the most common, while rectal application was only used
    occasionally. Tobacco smoke was inhaled via the mouth through tubes or
    rolls of tobacco leaf, or through the nostrils using a Y-shaped tube.
    Alternatively, it was swallowed and belched back, blown from one
    person to another, or blown into the eyes. Leaves were chewed, alone
    or mixed with ash, powdered shells or honey, or they were held in the
    mouth and sucked. Infusions were drunk or a concentrated infusion was
    licked or even used as an enema. Many ways of preparing and taking
    snuff among different tribes were reported. Tobacco use was linked to
    religious rituals.

    The rest of the world adopted tobacco use in the forms of smoking,
    chewing and snuffing. Smoking has remained the most popular. Tobacco
    smoking consists of burning the cured leaf, perhaps mixed with
    fragrant additives, in a pipe or tube. Cigarette smoking has largely
    replaced other methods in many countries. Reasons for the popularity
    of cigarettes include their ready availability resulting from
    large-scale manufacture and their greater convenience over other forms
    of tobacco use (IARC, 1986). In developed countries, cigarettes
    account for at least 80% of overall tobacco consumption, but in most
    developing countries other ways of using tobacco predominate, although
    cigarette smoking is increasing. Fig. 1 shows estimated daily
    cigarette consumption on a regional basis, Tables 1 and 2 show daily
    smoking prevalences on a regional and national basis and Table 3 shows
    trends in cigarette consumption.

    FIGURE 1

    2.1.2  Tobacco smoking

    Smoking prevalence data and most studies into the effects of smoking
    have concentrated on cigarette smoking, yet worldwide only about 55%
    of tobacco is used for cigarettes. The rest, along with significant
    amounts traded in "farm gate" and "local market" sales or "home
    grown", is smoked in "bidis" or other hand-rolled devices, or in some
    form of pipe (IARC, 1986). Tobacco consumption data give an insight
    into tobacco-related disease distribution, as can information on ways
    of smoking.

    Table 1.  Estimated smoking prevalence by WHO Region, early 1990s
    (from WHO, 1997)

                                              Men              Women
                                              (%)              (%)

    WHO Regions:
      African Regiona                         29               4
      Region of the Americas                  35               22
      Eastern Mediterranean Region            35               4
      European Region                         46               26
      South-East Asia Region                  44               4
      Western Pacific Region                  60               8
    More developed countries                  42               24
    Less developed countries                  48               7
    World                                     47               12

    a  Smoking prevalence estimates for African Region are based on
       very limited information

    Differences in smoke chemistry occur with different tobacco cultivars
    and curing methods. Curing removes moisture so that the leaf can be
    stored without fermenting or rotting, and the time and temperature of
    curing influences enzyme reactions such as deamination and oxidation,
    and the content of oils and resins. Air-, flue-, sun-, and fire-curing
    methods are employed and each produces distinctive tobaccos which are
    intended for smoking in a specific way or to suit a particular

    Between 1933 and the late 1940s, the yields from an average cigarette
    varied from 33 to 49 mg tar and from < 1 to 3 mg nicotine (Creek et
    al., 1994). However, in the 1960s and 1970s, the average yield from
    cigarettes in Western Europe and the USA was around 16 mg tar and 1.5

    mg nicotine per cigarette. Current average levels are lower. Changes
    in the levels of tar and nicotine have resulted in the characteristic
    more intense puffing and smoke inhalation pattern of smokers of
    low-yield cigarettes (Djordjevic et al., 1995; NIH, 1996). The 
    high tar yields measured in the smoke of cigarettes in developed
    countries before 1950 are comparable with current tar yields of
    "bidis", which range from 23 to 48 mg per cigarette (Hoffmann et al.,
    1974; Jayant & Pakhale, 1985; Ball & Simpson, 1987.) The "kretek" (a
    cigarette of strong tobacco and cloves) of Indonesia yields up to
    71 mg tar (WHO, 1985). Smoking materials in northern Thailand
    (cigarette or cigar of strong tobacco plus various vegetable
    materials) produce high levels of tar and nicotine (Simarak et al.,

    For smoking, tobacco leaf can be flue-cured, light air-cured,
    fire-cured or sun-cured, and can be of dark, oriental or  N. rustica
    type. Flue-cured tobacco is used for cigarettes and pipe tobacco.
    Air-cured tobacco is used in blended cigarettes. Dark tobaccos are
    widely grown, usually air-cured, and mostly used in their countries of
    origin for dark cigarettes, "bidis", cigars, in pipes and "sheeshas",
    and for chewing tobaccos and snuff (Voges, 1984). Some tobaccos have
    low nitrate levels ranging up to 0.9% (Neurath & Ehmke, 1964; Wynder &
    Hoffmann, 1967) and their smoke contains low nitrogen oxide levels in
    the range of 50-200 mg NOx/cigarette (Norman et al., 1983). In the
    reducing atmosphere of the burning cone, NOx gives rise to amino
    radicals, which react with benzene, biphenyl, naphthalene and other
    ring hydrocarbons to form aromatic amines. Aniline, alkylated
    anilines, aminobiphenyls, and naphthylamines are therefore found in
    higher quantities in the smoke of tobaccos with a high nitrate content
    (Patrianakos & Hoffmann, 1979; Pieraccini et al., 1992; Grimmer et
    al., 1995). Smokers of these tobaccos can inhale greater quantities of
    aromatic amines, such as the human bladder carcinogens
    2-naphthyl-amine and 4-aminobiphenyl, and have higher concentrations
    of haemoglobin adducts in their blood (Bartsch et al., 1993). This is
    the basis for the higher risk of bladder cancer among the smokers of
    cigarettes made from dark tobaccos (Vineis et al., 1984; D'Avanzo et
    al., 1990; Vineis, 1992).

    In the Indian subcontinent, the "bidi" is the common smoking device.
    It consists of tobacco flakes, loosely packed and hand-rolled in a
    tendu or temburni leaf ( Diospyros melanoxylon). It contains less
    tobacco (0.223 g) than a cigarette (0.782 g) (Ramakrishnan et al.,
    1995) but up to 8.2% nicotine compared with up to 3.7% in cigarette
    tobacco. "Bidi" smoke contains 23 to 48 mg tar and 1.7 to 2.9 mg
    nicotine per cigarette (Hoffmann et al., 1974; Jayant & Pakhale,
    1985). In India, where around 7% of world tobacco is consumed (US DA,
    1990), around 30% of tobacco is smoked as cigarettes, 50% as "bidis",
    10% in other ways, and 10% is used for chewing. "Bidis" need to be
    puffed frequently to ensure even burning and can generate up to 70 mg
    of carbon monoxide, while a US non-filter cigarette smoked under
    identical conditions generated 25 mg carbon monoxide (Hoffmann et al.,
    1974; Jayant & Pakhale, 1985).

        Table 2. Estimated smoking prevalence, ranked in order of male smoking prevalencea


    Rank Countryb                      Men            Women             Rank   Country                     Men            Women
                                       (%)            (%)                                                  (%)            (%)

    1    Republic of Korea (1989)      68.2           6.7               21     Seychelles (1989)           50.9           10.3
    2    Latvia (1993)                 67             12                22     Bolivia (1992)              50             21.4
    2    Russian Federation (1993)     67             30                23     Albania (1990)              49.8           7.9
    4    Dominican Republic (1990)     66.3           13.6              24     Cuba (1990)                 49.3           24.5
    5    Tonga (1991)                  65             14                25     Bulgaria (1989)             49             17
    6    Turkey (1988)                 63             24                25     Thailand (1995)             49             4
    7    China (1984)c                 61             7                 27     Spain (1993)                48             25
    8    Bangladesh (1990)             60             15                28     Mauritius (1992)            47.2           3.7
    9    Fiji (1988)                   59.3           30.6              29     Greece (1994)               46             28
    10   Japan (1994)                  59             14.8              29     Papua New Guinea (1990)     46             28
    11   Sri Lanka (1988)              54.8           0.8               31     Israel (1989)               45             30
    12   Algeria (1980)                53             10                32     Cook Islands (1988)         44             26
    12   Indonesia (1986)              53             4                 33     Czech Republic (1994)       43             31
    12   Samoa (1994)                  53             18.6              33     Jamaica (1990)              43             13
    15   Saudi Arabia (1990)           52.7           N/Ad              33     Philippines (1987)          43             8
    16   Estonia (1994)                52             24                33     Slovakia (1992)             43             26
    16   Kuwait (1991)                 52             12                37     Cyprus (1990)               42.5           7.2
    16   Lithuania (1992)              52             10                38     Austria (1992)              42             27
    16   South Africa (1995)           52             17                39     Malaysia (1986)             41             4
    20   Poland (1993)                 51             29                39     Peru (1989)                 41             13
    41   Uruguay (1990)                40.9           26.6              66     Colombia (1992)             35.1           19.1
    42   Argentina (1992)              40             23                67     Costa Rica (1988)           35             20
    42   France (1993)                 40             27                67     Slovenia (1994)             35             23
    42   Hungary                       40             27                69     Swaziland (1989)            33             8
    42   India (1980s)                 40             3                 70     Luxembourg (1993)           32             26
    42   Iraq (1990)                   40             5                 71     Singapore (1995)            31.9           2.7
    42   Malta (1992)                  40             18                72     Belgium (1993)              31             19
    50   Brazil (1989)                 39.9           25.4              72     Canada (1991)               31             29
    51   Egypt (1986)                  39.8           1                 72     Iceland (1994)              31             28
    52   Morocco (1990)                39.6           9.1               75     Australia (1993)            29             21
    53   Lesotho (1989)                38.3           1                 75     Ireland (1993)              29             28
    53   Mexico (1990)                 38.3           14.4              77     UK (1994)                   28             26
    55   El Salvador (1988)            38             12                78     USA (1993)                  27.7           22.5

    Table 2. (cont'd)


    Rank Countryb                      Men            Women             Rank   Country                     Men            Women
                                       (%)            (%)                                                  (%)            (%)

    55   Italy (1994)                  38             26                79     Pakistan (1980)             27.4           4.4
    55   Portugal (1994)               38             15                80     Finland (1994)              27             19
    58   Chile (1990)                  37.9           25.1              81     Turkmenistan (1992)         26.6           0.5
    59   Guatemala (1989)              37.8           17.7              82     Nigeria (1990)              24.4           6.7
    60   Denmark (1993)                37             37                83     Paraguay (1990)             24.1           5.5
    61   Germany (1992)                36.8           21.5              84     Bahrain (1991)              24             6
    62   Norway (1994)                 36.4           35.5              84     New Zealand (1992)          24             22
    63   Honduras (1988)               36             11                86     Sweden (1994)               22             24
    63   Netherlands (1994)            36             29                87     Bahamas (1989)              19.3           3.8
    63   Switzerland (1992)            36             26

    a  Adapted from: WHO (1997).
    b  The year given in parentheses is the latest available year for data.
    c  Some 1991 data suggest that there has been little change in smoking prevalence since 1984.
    d  Data not available.

    Table 3.  Trends in adult consumption of cigarettes from 1970-1972 to 1990-1992 (Adapted from WHO, 1997)


                                                      Annual % change
                                                      1970-1972 to 1990-1992
    WHO Regions:
         African Region                               +1.2
         Region of the Americas                       -1.5
         Eastern Mediterranean Region                 +1.4
         European Region                              0
         South-East Asia Region                       +1.8
         Western Pacific Region                       +3
    More developed countries                          -0.5
    Less developed countries                          +2.5
    World                                             -0.8

    Tar yields for Russian cigarettes were found to be high (21.6-29.2
    mg) and cigarettes containing  N. rustica produced high smoke
    concentrations of tobacco-specific nitrosamines (TSNA) (up to 620 ng
    total TSNA/cigarette) (Djordjevic et al., 1991). Indigenous cigarettes
    and cigars in Thailand, containing tobacco and other vegetable
    materials, have up to 41 mg and 200 mg tar, up to 5.5 mg and 11.4 mg
    nicotine, and 41 mg and 820 mg carbon monoxide in cigarette and cigar
    smoke, respectively. Indonesian cigarette smoke contains up to 100 ng
    of carcinogenic volatile  N-nitrosamines and up to 1580 ng of
    carcinogenic tobacco-specific  N-nitrosamines (Mitacek et al., 1990,
    1991), and high tar cigarettes contain up to 28.1 mg tobacco-specific
     N-nitrosamines per cigarette (Brunnemann et al., 1996).

    Many cigar-like devices are smoked throughout Asia. The tobacco can be
    rolled in a tobacco leaf or in the leaves of the jackfruit tree
    ( Artocarpus integrifolia), banana ( Musa paradisiaca) or hansali
    ( Grewia microcos) (Bhonsle et al., 1976). They may be smoked
    conventionally or in the reverse manner with the burning end inside
    the mouth (Reddy, 1974). In Thailand they can contain strong tobacco
    and a mixture of koi bark ( Streblus asper), dry tamarind pod
    ( Tamarindus indica), khai bark ( Homonoia riparia, Euphorbiaceae),
    Areca palm bark ( Areca catechu) or other tree bark; they can be
    rolled in a banana leaf or have fragrant additives such as sandalwood
    Mougne et al. (1982). They contain high levels of tar and nicotine
    (Simarak et al., 1977; Mitacek et al., 1999).

    Additives are used to enhance the fragrance or taste of smoke
    (Hoffmann & Hoffmann, 1997). "Casing sauces", consisting of sugars,
    aromatic substances and compounds such as glycerol, propylene glycol,
    ethylene glycol and diethylene glycol, which resist changes in
    moisture content, are sprayed on the leaf before it is cut to
    condition it for processing. Flavouring and dressing compounds are
    added to cut tobacco after drying and include licorice, menthol,
    cocoa, chocolate, ginger, cinnamon, vanilla, molasses, angelica,
    honey, essential oils from anise, clove and juniper, resins and plant
    extracts and organic compounds such as coumarins. Additives have been
    widely used in pipe and chewing tobaccos. They have also become
    important in cigarette tobacco with the development of low-tar and
    low-nicotine tobaccos and the use of stem, midrib or reconstituted
    leaf (which lacks the aromas and flavours of natural tobacco leaf
    lamina) and of tobacco dust requiring additives to ensure its
    adherence to cut tobacco.

    Added glycerol is transferred to mainstream smoke: 3-6% in cigarette
    smoke and 35-43% in pipe smoke (IARC, 1986) and one of its pyrolysis
    products is acrolein. Levels of acrolein ranging from 69 mg to 230 mg
    per cigarette have been reported and air concentrations as high as
    0.46 mg/m3 have been found in smoke-filled rooms (Izard & Liberman,
    1978). Acrolein is extremely irritating to the eyes and nasal mucosa,
    it affects mitotic and ciliary activity, at the cellular level it has
    cytotoxic and cilia-depressant effects, and it can act as a mutagen
    (Izard & Liberman, 1978).

    In the USA, additives used in cigarette manufacture are food additive
    compounds that are "generally recognized as safe (GRAS)" and,
    therefore, also considered "safe" as additives to tobacco. However,
    the non-volatile additives are to some extent pyrolized during smoking
    and can give rise to toxic and/or carcinogenic agents in the smoke. A
    major group of compounds formed during pyrolysis is that of the
    polynuclear aromatic hydrocarbons. Ethylene glycol is pyrolytically
    converted to the human carcinogen ethylene oxide (IARC, 1994a).

    Another example of carcinogen formation during tobacco curing and
    smoking is the case of MH-30, a sucker growth control agent formulated
    from maleic hydrazide in diethanolamine. Residual MH-30 on tobacco
    leads to the formation of  N-nitrosodiethanolamine (NDELA) in the
    smoke (Brunnemann & Hoffmann, 1981). The use of MH-30 on tobacco has
    been forbidden in the USA since 1981, and NDELA levels in tobacco and
    its smoke have declined (Brunnemann & Hoffmann, 1991).

    The use of cloves as a tobacco additive can have health effects. In
    Indonesia, the smoke of "kreteks", a blend of ground cloves with 
    60-65% of tobacco, contains between 41 and 113 mg of tar, and between 
    1.2 and 4.5 mg nicotine (WHO, 1985; Wise & Guerin, 1986). Mainstream 
    smoke of kreteks without filter tips contains 19-23 mg of eugenol 
    released from the cloves, while filter-tipped kretek smoke contains up
    to 15 mg (LGC, 1982; Wise & Guerin, 1986). Inhalation of eugenol in 
    the smoke of kreteks can lead to interstitial haemorrhaging and 
    congestion of the lung, acute emphysema and acute pulmonary oedema. 
    These effects were also seen in Syrian golden hamsters exposed to the
    smoke of kreteks (LaVoie et al., 1986).

    Menthol and other additives that produce a sensation of coolness but
    without a mint flavour have also been used in cigarettes. There is no
    evidence that these additives result in a higher risk (Cummings et
    al., 1987; Sidney et al., 1989).

    Many shapes and sizes of smoking pipes are found worldwide (Voges,
    1984). Various types of tobacco are used and the smoke can range from
    mild to very strong. In the sheesha water pipe the tobacco is kept
    alight by pieces of glowing charcoal and the smoke is drawn through
    water before being inhaled. Sheesha smoke is mild and low in
    particulate matter, benzo( a) pyrene and volatile phenols (Hoffmann
    et al., 1961), but it has a high level of carbon monoxide, in part
    from the charcoal that keeps the tobacco burning, and smokers have
    high carboxyhaemoglobin levels and a reduced FEV1 (8.5% in women, 45%
    in men) (Zahran et al., 1985; Al-Fayez et al., 1988).

    2.1.3  Tobacco chewing and snuff

    The popularity of tobacco chewing and snuff (finely powdered tobacco
    leaf) has varied. Nasal inhalation of snuff has given way to the oral
    application of snuff and other tobacco-containing mixtures between the
    gum and lip, or gum and cheeks, or under the tongue. Chewing tobacco
    comes in several forms and may have flavour added from syrups,
    liquorice and brandy. Tobacco chewing has retained its popularity in

    heavy industries, such as steel and coal mining, woodworking and the
    petroleum industry, where the flammability hazard precludes smoking.
    In Sweden, 17% of the population uses oral snuff. In the USA, sales of
    chewing tobacco have declined but sales of oral snuff have increased
    by 61% (US DA, 1997) owing to the popularity of the latter with
    teenagers and young adult men. Oral tobacco use in India is very
    common but, generally, in developing countries it is declining because
    urban populations and younger age groups are smoking cigarettes.

    "Betel-quid" chewing is common in Asia and Africa. The basic contents
    of a betel-quid are slices of areca nut ( Areca catechu), lime and
    tobacco, wrapped in a betel pepper leaf ( Piper betle), but it may
    also contain dried dates, menthol and spices such as cardamom, cloves,
    coriander, mace and cinnamon.

    Other tobacco preparations for oral use often contain lime, calcium
    carbonate, sodium carbonate, some form of ash or flavouring materials.
    The lime and other agents assist the release of nicotine (Voges, 1984;
    Idris et al., 1991).

    2.2  Responses to mainstream smoke

    Tobacco use has direct effects on health and is responsible for a
    variety of diseases. These form a basis for studying interactions
    between tobacco use and chemical, physical and biological agents, and
    associated effects on health.

    2.2.1  Acute responses

    Inhaled irritant chemicals cause inflammation of the upper respiratory
    tract (URT) and paranasal sinuses, sore throat and bronchial oedema.
    Pulmonary oedema may follow if irritants penetrate the lower
    respiratory tract. Acute irritation of the URT usually follows
    inhalation of highly soluble gases. Slightly less soluble gases cause
    URT and bronchial irritation, while relatively insoluble gases
    penetrate deeply into the lung and can have delayed effects including
    pulmonary oedema (Miller & Kimbell, 1995). Cigarette smoke is a
    complex mixture of organic and inorganic constituents with particulate
    and vapour phases and highly reactive free radicals (Hocking & Golde,
    1979). It contains many compounds with irritant properties, which can
    affect all parts of the lung. Kremer et al. (1994) examined the
    association between occupational exposures to a variety of airway
    irritants and respiratory system effects, and whether the association
    was modified by smoking, airway hyperresponsiveness and allergy. The
    irritants were SO2, HCl, SO42-, polyester vapour, polyamide vapour,
    and oil mist and vapour. Current smoking, airway hyperresponsiveness
    and allergy were significantly associated with a higher prevalence of
    chronic respiratory symptoms, independent of each other and of
    irritant exposure. The association between exposure and the prevalence
    of chronic respiratory symptoms was greater in smokers than in non- or
    ex-smokers.  Acute bronchitis

    Acute bronchitis is an inflammation of the bronchial mucous membrane,
    initially accompanied by a dry painful cough and followed by
    mucopurulent sputum. The cause may be infectious agents or chemical
    agents such as tobacco smoke, dusts, fumes, vapours or gases.  Asthma

    Asthma is a chronic pulmonary inflammatory disease associated with
    bronchial hyperreactivity causing paroxysmal dyspnoea due to spasm of
    the bronchial musculature, swelling of the mucous membranes and the
    production of viscid mucus. In the majority of asthma cases a clear
    association exists with atopic IgE-mediated hypersensitivity. Allergic
    asthma is a response to a specific agent. Many chemical agents,
    including mixtures such as tobacco smoke, can induce asthma. Smoking
    enhances the effect of other agents and can reduce the latent period
    from first exposure to onset of sensitization.

    There has been an increase in the prevalence of asthma in many
    countries, and roles for environmental factors, increased
    susceptibility and tobacco smoking have been suggested (ISAAC, 1998).
    Cigarette smoking together, with atopic status, age, URT infection and
    genetic factors, has been considered to increase susceptibility
    (Venables et al., 1985; Seaton et al., 1993). Studies have shown a
    relationship between cigarette smoking and serum IgE levels. Smokers
    have higher levels of IgE with increasing age, compared to non-smoking
    controls. A relationship has also been observed between IgE level and
    the number of cigarettes smoked (Sherrill et al., 1994).

    2.2.2  Chronic responses  Chronic obstructive lung diseases

    The chronic obstructive lung diseases (COLD) are chronic bronchitis,
    small airways disease, toxic bronchiolitis obliterans, emphysema and
    fibrosis (Niewoehner et al., 1974; Niewoehner, 1991).

    These diseases form an important group of pulmonary diseases caused by
    smoking (and by chemical atmospheric pollution) (US Surgeon General,
    1984). In a study by Simecek et al. (1986) of 215 229 adults in a
    region of former-Czechoslovakia, smoking was the most important risk
    factor in COLD. Risks for male non-smokers and light smokers under 30
    years of age were 1.18% and 2.28%, respectively; for men aged 50
    years, smoking more than 20 cigarettes a day, the risk was 20.36%
    compared with 3.31% for non-smokers of the same age. In the USA, 
    80-90% of the mortality from COLD has been attributed to cigarette
    smoking. Cigar and pipe smokers who inhale the smoke also have an
    increased death rate from COLD (US Surgeon General, 1984, 1989; NIH,
    1998). Between 1979 and 1993, the age-adjusted annual death rate from

    COLD in women increased by 122% to 17.1 per 100 000, while in men it
    increased by 14% to 27.8 per 100 000. The greater increase of COLD
    among women during this period reflected the increase in smoking by
    women.  Chronic bronchitis

    Chronic bronchitis has been variously defined. The United Kingdom
    Medical Research Council (MRC, 1965) considered it to be a condition
    with persistent production of sputum, which might be associated with
    cough, occurring on most days for at least three months in the year
    for at least two successive years. The Council recommended a
    classification of simple chronic bronchitis, chronic or recurrent
    mucopurulent bronchitis or chronic obstructive bronchitis. In a
    workplace context, Morgan (1982) defined it as "a condition
    characterized by cough and sputum for at least three months of the
    year, which may or may not be accompanied by airways obstruction, and
    which is a consequence of prolonged inhalation of dust or irritant
    gases at the workplace". Fletcher & Pride (1984) suggested an improved
    terminology with the term chronic bronchitis meaning chronic or
    recurrent bronchial hypersecretion only, abandoning the term chronic
    obstructive bronchitis because this implies a causal connection
    between mucus hypersecretion and airflow obstruction. In smokers'
    lungs the irritant constituents of tobacco smoke cause hypersecretion
    of mucus, alter its physical properties and chemical structure, and
    impair the mucociliary clearance mechanism. Removal of major
    ciliatoxins (hydrogen cyanide and volatile aldehydes) from the smoke
    stream by charcoal filter tips reduces the effects on the lung
    epithelium (Friedman et al., 1972). Mineral dusts, particularly those
    encountered in mining, many biological dusts, irritant vapours and
    gases, inorganic and organic chemical dusts and sprays can all cause
    chronic bronchitis.  Small airways disease

    Small airways disease (SAD) is a widespread narrowing of membranous
    bronchioli. It is inflammatory in origin and is often associated with
    excess mucus and an accumulation of macrophages in the respiratory
    bronchioli. SAD is mainly caused by smoking, but can be associated
    with environmental and industrial pollutants (Cosio et al., 1980).  Emphysema

    Emphysema has been defined as a condition of the lung characterized by
    an abnormal enlargement of the airspaces distal to the terminal
    non-respiratory bronchioli, accompanied by destructive changes in the
    alveolar walls, and without obvious fibrosis. It tends to be prevalent
    in older age groups and follows SAD. For purposes of postmortem
    examination of lung slices of miners, Ruckley et al. (1984) defined
    emphysema as the presence of air spaces of 1 mm or more in size.
    Macrophages that have engulfed foreign particles, including smoke
    particulate matter in the lungs of smokers, and which have been found
    accumulated in the bronchioli (Niewoehner et al., 1974) and in the

    lung parenchyma (McLaughlin & Tueller, 1971) have been implicated in
    the pathogenesis of emphysema. There are different forms of emphysema,
    which vary with the nature of the insult to the tissues. One
    hypothesis is that tobacco smoke causes increased production and
    release of proteolytic enzymes, such as elastase, and interferes with
    normal antiproteolytic mechanisms. Emphysema has been induced
    experimentally in animals by endotracheal installation of elastase or
    homogenates of alveolar macrophages or polymorphonuclear leukocytes.
    Chronic exposure to tobacco smoke has a number of effects on alveolar
    macrophages, including changes in metabolism, alteration of the enzyme
    content and impairment of RNA and protein synthesis (Hocking & Golde,
    1979). The function of alveolar macrophages is to remove inhaled
    foreign material from the alveoli and respiratory bronchioles, and
    their numbers increase when the lungs are exposed to particles and
    gases. It has been demonstrated that the macrophage count is higher in
    people exposed to cigarette smoke than in non-exposed people (Harris
    et al., 1974; Rylander et al., 1979). Alveolar macrophages from
    smokers are more active than those from non-smokers, numbers are
    increased, there are morphological changes with an increased cell
    diameter, crystalline inclusions and surface membrane alteration
    (Sopori et al., 1994).  Pulmonary fibrosis

    Pulmonary fibrosis is the abnormal formation of fibrous or scar tissue
    and is the response of bronchiolar tissue to the deposition of an
    inhaled inciting agent. Mineral and other dusts are causes of
    pulmonary fibrosis. The radiological changes seen in early stages of
    dust fibroses are associated with relatively minor lung function
    impairment, but continuous exposure leads to a greater degree of
    fibrosis and to progressive massive fibrosis in some subjects. On
    histological, animal experimental and radiographic evidence, Weiss
    (1984) concluded that cigarette smoking could cause diffuse fibrosis.  Effects on the immune system

    Tobacco smoking and exposure to environmental tobacco smoke increase
    susceptibility to pulmonary infections, and changes in immune
    processes may be involved. Tobacco smoking affects humoral and
    cellular immunity in humans and experimental animals, but the
    magnitude of the changes vary widely among studies. In humans,
    cigarette smoke has marked effects on alveolar macrophage morphology
    and physiology, it decreases serum immunoglobulin (IgA, IgG, IgM) but
    increases IgE, and has a range of effects on B- and T-lymphocytes.
    Similar effects are found in experimental animals (Sopori et al.,
    1994). Studies in rats and mice show that cigarette smoke or nicotine
    induces impaired responses of systemically distributed B- and
    T-lymphocytes to antigen-induced signalling (Geng et al., 1995, 1996).
    T-lymphocyte unresponsiveness, with decreased antibody response to
    T-dependent antigens, is important in response to infection (Sopori et
    al., 1998).

    2.2.3  Cancer

    Many forms of cancer have been associated with inhaled particulate
    matter, vapours, fumes and gases. Examples are lung cancer associated
    with tobacco smoking and inhalation of asbestos, fumes from metal
    moulding and coking plants, particles and gases inhaled by motor
    vehicle drivers, dusts in several types of mines where there is an
    accumulation of alpha-emitting radioisotopes, and contact with
    materials such as arsenic, chromates, nickel, chloromethyl ethers,
    mustard gas and polycyclic aromatic hydrocarbons. Pleural mesothelioma
    has been associated with asbestos, nasal and sinus cancer with nickel
    refining and wood dust exposure, leukaemia with ionizing radiations
    and benzene, bladder cancer with the manufacture and use of dyes and
    in the rubber industry, and liver cancer with the use of vinyl
    chloride (IARC, 1987).

    Cigarette smoke contains many toxic chemicals, including chemicals
    that are DNA reactive and cytotoxic or become DNA reactive upon
    metabolic activation. Consequently, cigarette smoke has the potential
    to initiate genetic lesions. Moolgavkar et al. (1989) postulated
    mechanisms by which cigarette smoke induces lung cancer by fitting the
    two-stage clonal expansion model of carcinogenesis to lung cancer
    mortality data derived from a large cohort of British doctors who
    smoked. This analysis suggested that tobacco smoke affected both the
    rates of mutation and cell proliferation involved in the model,
    supporting the hypothesis that tobacco smoke acts as a complete

    Cigarette smoking is causally associated with cancer of the lung,
    larynx, pharynx, oesophagus, pancreas, kidney and urinary bladder. It
    is also associated with cancer of the nasal cavity, liver, uterine
    cervix and myeloid leukaemia (RCP, 1962; US Surgeon General, 1982,
    1989; IARC, 1986; Winkelstein, 1990; Brownson et al., 1993; Roush,

    In 1991, in the USA, it was estimated that 90.3% of the lung cancer
    deaths in men and 78.5% of lung cancer deaths in women were
    attributable to cigarette smoking. Deaths from oesophageal cancer were
    linked to smoking in 78.2% of the cases in men and 74.3% of the cases
    in women. Smoking was held responsible for 81.2% of deaths from
    laryngeal cancer in men and 86.7% in women, for 91.5% and 61.2%,
    respectively, of deaths from oral cancer, and 46.5% and 36.7%,
    respectively, of deaths from bladder cancer. Smoking-attributable
    deaths from cancer of the kidney in men and women were 47.6 and 12.3%,
    respectively, and for pancreatic cancer the figures were 28.6% and
    33.3% respectively. In women, 32.4% of uterine cervical cancer deaths
    were attributed to cigarette smoking (Shopland et al., 1991).

    There has been a change in the rates of different types of lung cancer
    among smokers. In 1950, squamous cell carcinoma (SCC) occurred 17
    times more often than adenocarcinoma (AC) (Wynder & Graham, 1950) in
    cigarette smokers. In 1991, Devesa et al. (1991) reported that in male
    cigarette smokers the ratio of SCC to AC was 2.4:1 between 1969 and

    1971, and changed to 1.4:1 between 1984 and 1986; in cigarette-smoking
    women, the SCC to AC ratio changed from 3.6:1 in 1950 to 0.57:1 in
    1984-1986. Between 1970 and 1980 some studies showed a 20-50%
    reduction in risk of lung cancer for long-term smokers of filter
    cigarettes as compared to smokers of non-filter cigarettes (IARC,
    1986) but later studies indicated a similar risk for lung cancer in
    smokers of filter and non-filter cigarettes (Stellman et al., 1997;
    Thun et al., 1997). The changes in the ratio of SCC to AC, and the
    disappearance of an advantage of filter cigarette smoking in terms of
    lung cancer risk, have been related to changes in smoke yields, which
    have caused smokers to modify patterns of puff drawing and smoke
    inhalation. Smokers regulate the speed and the quantity of their
    nicotine uptake to achieve the desired pharmacological effects
    (Benowitz et al., 1988; Djordjevic et al., 1995). Smokers of lower
    nicotine cigarettes draw puffs of greater volume, at a higher
    frequency, and inhale more deeply; this is governed by the amount of
    nicotine in the smoke (Wynder & Hoffmann, 1994).

    Smoking is a major risk factor for the early stage development of
    oesophageal and gastric adenocarcinomas, accounting for 40% of cases,
    and may have contributed to the increase in the incidence of these
    cancers, especially in older people (Gammon et al., 1997).

    Cigar smoking is causally associated with cancer of the oral cavity,
    the pharynx and the lung, even though for cigar smokers, who do not or
    only minimally inhale the smoke, the lung cancer risk is considerably
    lower than that for cigarette smokers. Cigar smoking is also
    associated with cancer of the pancreas and of the urinary bladder
    (NIH, 1998). Oral snuff users have an increased risk of cancer of the
    oral cavity and, possibly, cancer of the oesophagus, pancreas and
    urinary bladder (US Surgeon General, 1986).

    It has been suggested that around 4-5% of all lung cancer is related
    to occupational exposure (Wynder & Gori, 1977; Doll & Peto, 1981;
    Morgan, 1982 ). Occupational and any other forms of exposure to
    chemical compounds are of limited importance in the etiology of lung
    cancer whereas tobacco smoking is the cause of approximately 85-90% of
    cases (Shopland et al., 1991).

    "Reverse smoking", in which rolled tobacco leaves are smoked with the
    burning end inside the mouth, has been linked to carcinoma of the hard
    palate (Reddy & Rao, 1957; Mehta et al., 1971; Pindborg et al., 1971;
    Reddy, 1974; Bhonsle et al., 1976). Reddy et al. (1960) simulated the
    effect of reverse smoking experimentally by painting the skin of male
    and female mice on alternate days with the tar from Indian cigars and
    exposing the painted skin to a temperature of 58°C for 3 min; the heat
    treatment enhanced the dermal tumour response.

    2.2.4  Cardiovascular effects

    Cigarette smoking is a major independent risk factor for
    cardiovascular disease (CVD). Cigarette smoking acts synergistically
    with other risk factors, such as elevated cholesterol levels and

    hypertension (Wilhelmsen, 1977; Gibinski, 1977; US Surgeon General,
    1983). Prospective studies indicated that elevated cholesterol and
    hypertension appear to be prerequisites for CVD in cigarette smokers
    (Kimura, 1977). It has been estimated that in countries with a long
    history of cigarette smoking the tobacco habit is responsible for 
    26-30% of early deaths from CVD (US Surgeon General, 1983; Wald et 
    al., 1985). Those who smoke several cigars a day and inhale the smoke 
    also face an increased risk of CVD (NIH, 1998).

    The major contributors to the cardiovascular effects of tobacco smoke
    are carbon monoxide and nicotine (Lakier, 1992), as well as nitrogen
    oxides (NOx), hydrogen cyanide and tar; minor contributors are
    cadmium, zinc and carbon disulfide (US Surgeon General, 1983). The
    smoke of cigarettes can be slightly acidic (pH 5.6-5.9) or weakly
    alkaline (pH 6.7-7.9) depending on the type of tobacco and the blend
    (Brunnemann & Hoffmann, 1974). In the slightly acidic smoke, nicotine
    is protonated, i.e., bound to a salt or acid moiety and is part of the
    particulate phase. Weakly alkaline smoke contains a small percentage
    of protonated nicotine (often up to 50% of the nicotine is
    unprotonated) in the vapour phase. In contrast to the protonated
    variety, unprotonated nicotine is rapidly absorbed through the oral
    mucosa and this is why smokers of cigarettes with weakly acidic smoke
    and smokers of cigars do not need to inhale into the lung to
    experience the pharmacological effects of nicotine. Protonated
    nicotine in the particulate matter of slightly acidic cigarette smoke
    is not or is only minimally absorbed through the oral mucosa, so that
    smokers inhale the smoke and absorption into the bloodstream takes
    place in the lung (Armitage & Turner, 1970; Russell, 1976; Benowitz et
    al., 1988).

    Smoking has been associated with a two-to-fourfold increased risk of
    coronary heart disease (CHD), a greater than 70% excess rate of death
    from CHD, and an elevated risk of sudden death (Lakier, 1992).
    Nicotine causes increases in heart rate and blood pressure, stimulates
    nerve endings that are activated by acetylcholine, causes increased
    mobilization of free fatty acids in the serum and enhances platelet
    adhesiveness. These effects increase cardiac load (which for
    individuals with some forms of heart disease will not be met by
    increased coronary blood flow) and interfere with metabolic exchange
    across capillary walls, leading to ischaemic episodes and thrombosis.
    Carbon monoxide increases carboxyhaemoglobin concentrations in the
    blood and lowers its oxygen-carrying capacity: increased oxygen debt
    after exercise and impairment of endurance performance are evident in
    smokers, compared to non-smokers. Carbon monoxide also has an affinity
    for myoglobin and interferes with oxygen uptake by the myocardium.

    "Bidi" smoke contains a higher concentration of carbon monoxide than
    cigarette smoke (Hoffmann et al., 1974; Jayant & Pakhale, 1985; Ball &
    Simpson, 1987). Most of the Asian smoking devices with their
    non-porous wrappers and dark tobacco contain higher levels of nicotine
    (Simarak et al., 1977; WHO, 1985). High nicotine and carbon monoxide
    are also obtained from many dark tobacco cigarettes and from cigars.
    "Sheesha" water pipe smoke contains small amounts of nicotine but is

    rich in carbon monoxide; the blood carboxyhaemoglobin concentration in
    sheesha smokers is higher than in cigarette smokers (Zahran et al.,

    Cigarette smoking has been considered to be the primary cause of
    Buerger's disease (thromboangiitis obliterans), an inflammatory
    obliterative, non-atherosclerotic, vascular disease. The disease
    usually becomes quiescent if the patient stops smoking cigarettes
    (Olin, 1994). It was rare in women but an increasing number of cases
    has been observed and ascribed to the increased use of tobacco by
    young women (Yorukoglu et al., 1993).

    Cardiovascular disease has been associated with exposure to other
    factors, which can be classified as physical, chemical and biological,
    and with occupation or life-style. The combination of smoking with any
    of these factors will predispose to an increased detrimental
    cardiovascular effect.

    In women who smoke, peripheral vasoconstriction (PV) leading to acute
    intervillous placental blood flow was measured during smoking and
    attributed to nicotine, which simultaneously caused increases in heart
    rate and blood pressure. It was suggested that PV explained fetal
    growth retardation and other complications of pregnancy (Lehtovirta &
    Forss, 1978).

    2.2.5  Smoking and occupational accidents, injuries and

    A survey of public employees found that cigarette smokers took 23%
    more sick leave than non-smokers (Van Tuinen & Land, 1986). In another
    study among 2537 postal workers in the USA, cigarette smokers had a
    1.29 times higher accident rate (CI 1.07-1.55), and a 1.55 times
    higher injury rate (CI 1.11-1.77) than non-smokers (Ryan et al.,
    1992). Other studies confirm the higher rates of injury, occupational
    accidents and absenteeism in smokers (Naus et al., 1966; Parka, 1983;
    US Surgeon General, 1985; Hawker & Holtby, 1988). There are higher
    costs of illness for cigarette smoking employees compared to
    non-smokers (Van Peenen et al., 1986; Penner & Penner, 1990.

    2.3  Health risks from smokeless tobacco use

    2.3.1  Introduction

    Oral cancers have been linked with oral tobacco use. The consequences
    of chewing tobacco can be reactional keratosis, irreversible gingival
    recession, periodontitis, oral dysplasia and leukoplakia, cancer and
    cardiovascular effects (Chakrabarti et al., 1991; Guggenheimer, 1991).
    In India, chewing material containing tobacco has been shown to be a
    primary cause of oral cancer (Jussawalla & Deshpande, 1971).

    2.3.2  Cancer

    Leukoplakia and oral cancer are common results of oral tobacco use,
    particularly in the countries of Asia (IARC, 1985a). Simarak et al.
    (1977) reported a strong association between betel chewing and oral
    cancer in northern Thailand. Sankaranarayanan et al. (1989a,b, 1990)
    associated oral cancers in southern India with tobacco chewing.
    Chakrabarti et al. (1991) reported much higher levels of pre-malignant
    and malignant lesions of the oral cavity in tobacco chewers;
    Nandakumar et al. (1990) found the relative risk to be elevated in
    both sexes, but appreciably higher in females. From chemical analysis
    of Indian tobacco products, it was concluded that their use may lead
    to high exposures to carcinogenic tobacco nitrosamines (Nair et al.,

    Case-control studies reported a higher incidence of oral cancer in
    oral snuff users than in those not using any form of tobacco. There
    was up to a 50-fold excess risk of cancer of the cheek and gum in
    long-term oral snuff users (Axéll et al., 1978; US Surgeon General,
    1986a; Winn, 1997). Idris et al. (1991, 1994), reported a high
    incidence rate of oral cancer in men in northern Sudan who used an
    oral snuff with relatively high concentrations of nicotine (0.8-3.2%)
    and nornicotine. In a study of baseball players who chewed or (the
    majority) used snuff orally, there was higher prevalence of
    leukoplakia, plaque formation, gingivitis and dental disorders
    compared to non-users (Robertson et al., 1997).

    A case-control study on nasal cavity and paranasal sinus cancer and
    snuff use showed that snuff users have a significantly increased risk
    for adenocarcinoma and squamous cell carcinoma in the nasal cavity
    (Brinton et al., 1984).  N'-nitrosonornicotine is present and is an
    organ-specific carcinogen that induces benign and malignant tumours of
    the nasal cavity in rats, hamsters and mink (Rivenson et al., 1991;
    Koppang et al., 1992, 1997; Hoffmann et al., 1994). Studies conducted
    in South Africa showed that people using local snuff made from tobacco
    and aloe plant ash as nasal applications have an increased risk for
    tumours of the maxillary antrum (Keen et al., 1955). It was thought
    that this snuff mixture contained high levels of nickel and chromium,
    which may be associated with the induction of these tumours (Baumslag
    et al., 1971).

    Instillation of snuff into the lips of rats induced benign and
    malignant tumours in the oral cavity (Hirsch & Thilander, 1981; Hecht
    et al., 1986; Johansson et al., 1989; Larsson et al., 1989).
    Instillation of snuff into the buccal pouch of hamsters, which were
    repeatedly infected with  Herpes simplex virus type I or II, led to
    oral tumours, although no tumours occurred when either the virus or
    tobacco was applied alone (Park et al., 1991b).

    More than 3050 chemical compounds have been identified as tobacco
    constituents (Roberts, 1988) and 50 are known carcinogens (Brunnemann
    & Hoffmann, 1992). Nitrosamines, especially the tobacco-specific
    nitrosamines (TSNA), must be regarded as major oral carcinogens. Oral

    tumours were elicited when an aqueous solution of N-nitrosonornicotine
    (NNN) and 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was
    applied to the oral surfaces of rats (Hecht et al., 1993).

    2.3.3  Cardiovascular disease

    The effect of tobacco chewing on cardiovascular disease has received
    less attention than the effect of cancer. Benowitz et al. (1988)
    compared the cardiovascular effects of smokeless tobacco, cigarettes
    and nicotine gum and reported that all tobacco use increased heart
    rate and blood pressure. Nanda & Sharma (1988) recorded incremental
    increases in heart rate and blood pressure following tobacco chewing.
    However, Eliasson et al. (1991) found no significant elevation of
    diastolic blood pressure in young snuff users. Bolinder et al. (1994)
    found an excess risk of death from cardiovascular and cerebrovascular
    disease among smokeless tobacco users. Tobacco chewing has detrimental
    effects on pregnancy (Krishna, 1978) which, in the absence of any
    anoxia due to carbon monoxide found in smokers, could result from
    nicotine-induced vasoconstriction.

    O'Dell et al. (1987) reported a case of Buerger's disease in a
    38-year-old man that was associated with the use of smokeless tobacco.
    A regimen which included complete abstinence from tobacco resulted in
    a resolution of the symptoms. Buerger's disease is the commonest
    vascular disease in the Indian subcontinent where tobacco consumption
    is high (Jindal & Patel, 1992). In a study of the disease in
    Bangladesh, 39 patients (38 males, 1 female) were investigated. All
    but two were current long-term smokers, one male had given up smoking
    6 months previously and the one woman with the disease (it is uncommon
    in women) was a tobacco chewer (Grove & Stansby, 1992).


    3.1  Introduction

    3.1.1  Interaction

    To discuss the interaction between tobacco and other agents as risk
    factors for cancer and other adverse health effects, it is necessary
    to define what is meant by the term "interaction". In general terms,
    interaction represents a departure from additivity, in which the
    combined effect of exposure to two agents is in some sense the sum of
    the effects of the individual agents (US EPA, 1988). Synergism occurs
    when the combined effect is greater than the sum of the component
    effects; antagonism occurs when the effect of the combination is less
    than would be suggested by summing the effects of the components.

    3.1.2  Measuring interaction

    To make these concepts precise, the scale in which risk is measured
    and the manner in which risks are summed must be specified (Kaldor &
    L'Abbe, 1990). In epidemiological investigations, the age-adjusted
    relative risk is often used to characterize risk. In risk assessment
    applications involving chronic health effects such as cancer, the
    cumulative risk over a period of time may be of more direct interest.
    In laboratory studies of carcinogenicity, for example, the lifetime
    probability of tumour induction is often used to describe risk. In
    order to take into account the age at which an adverse effect is
    induced, the expected loss in life expectancy has also been used to
    evaluate risk (UNSCEAR, 1988).

    Kodell & Pounds (1991) discuss interaction in terms of departures from
     response additivity and  dose additivity. Dose additivity occurs
    when the combined effect of two agents can be expressed in terms of a
    total dose of the two agents, taking into account their relative
    potencies. Dose additivity presumes that the two agents act by the
    same biological mechanism, and that the effective dose of one agent is
    simply a dilution of the dose of the other agent. Response additivity
    occurs when the two agents act independently of each other. In this
    case, the probabilities of an adverse effect due to each of the agents
    can be treated as statistically independent and can be combined

    The quantification of interaction may be illustrated using the
    age-specific relative risk (A,B) associated with exposure to two
    agents A and B. The relative risk is formally defined as:

              relative risk (A,B) = I(A,B)/I(0,0)

         where I(A,B) denotes the incidence rate of the disease of
         interest at a specified age in the presence of exposure and
         I(0,0) is the incidence rate in the absence of exposure. Lack of
         interaction then corresponds to additivity of the excess relative
         risk (ERR = relative risk - 1).


              ERR(A,B) = ERR(A,0) + ERR(0,B)

         where ERR(A,0) and ERR(0,B) denote the excess relative risks for
         A and B alone, respectively. In terms of relative risk,
         additivity is equivalent to:

         relative risk (A,B) = relative risk (A,0) + relative risk 
         (0,B) - 1

    For a supra-additive relative risk relationship, such as the
    multiplicative relative risk model:

         relative risk (A,B) = relative risk (A,0)RR(0,B)

    and reflects a synergistic effect.

    It is of interest to note that as the relative risk (A,0) and relative
    risk (0,B) become small, the multiplicative relative risk model
    approximates the additive relative risk model. Under this 
    multiplicative model, a strong synergistic relationship may be 
    apparent at high exposures, yet become negligible at low exposures. 
    This, along with the realization that relative risks of less than 
    about two are difficult to detect epidemiologically, suggests that 
    relatively high exposures are likely to be required to evaluate 
    interactive effects reliably.

    Brown & Chu (1989) and Kodell et al. (1991) investigated the type of
    interactions that might be expected under both the Armitage-Doll
    multi-stage model and the Moolgavkar-Venzon-Knudson two-stage model of
    carcinogenesis following exposure to two carcinogens that may affect
    different stages in the model. These theoretical results indicate that
    a variety of synergistic interactions are possible, including
    supra-additive, multiplicative, and supra-multiplicative.

    Although the additive excess relative risk model described above
    provides a useful baseline for evaluating interaction, it is not the
    only model that has been proposed for this purpose. Kaldor & L'Abbe
    (1990) pointed out that the multiplicative relative risk model will
    become the baseline model for evaluating interactions following a
    logarithmic transformation of the relative risk. Thomas & Whittemore
    (1988) review arguments in favour of the additive and multiplicative
    models as the basis for evaluating interaction. Steenland & Thun
    (1986) illustrate how these two models can be applied in evaluating
    tobacco/occupation interactions in the causation of lung cancer.

    This brief overview illustrates that interaction can be measured in
    different ways, with the most appropriate depending on the nature of
    the problem at hand. In general, however, all of the commonly
    encountered measures of synergism indicate that the risk associated
    with combined exposure to two agents is in some sense greater than
    would be expected based on the risks of individual exposures. Although

    no attempt is made throughout this monograph to systematically specify
    the precise nature of the interactive effects reported in the
    literature, most interactive effects documented in this monograph have
    been identified through epidemiological investigations, in which the
    additive age-specific relative risk model is the predominant approach
    to describing interaction (Saracci, 1987; Greenland, 1993).

    There are four principal ways in which tobacco smoke can interact with
    other chemicals to impair the health of the smoker. They are not
    mutually exclusive and in fact there are many situations in which they
    may occur together, particularly in the workplace or the environs of

    a)  Modification of effects

    Cigarette smoke can modify the harmful effects associated with other
    toxic agents, in some cases causing a highly elevated risk, e.g., the
    effects of smoking on diseases related to asbestos, alpha-radiation,
    arsenic and some organic compounds.

    b)  Increased concentration effects

    Chemical compounds hazardous to health are often found in both tobacco
    smoke and the working environment and each source can augment the dose
    obtained from the other, e.g., carbon monoxide, acrolein, benzene and
    heavy metal elements.

    c)  Vector effects

    Materials used in the workplace that produce harmful chemical agents
    when they are burnt or vaporized can contaminate smoking materials and
    cause the smoke to be far more injurious when the tobacco is smoked,
    e.g., polytetrafluoroethylene and methylparathion.

    d)  Other interactions

    Tobacco smoke can affect a physiological process and increase the
    impairment of physical or physiological functions caused by another
    activity. For instance, impaired lung clearance will affect the
    residence time of inhaled toxic materials, the effect of smoking on
    the peripheral vascular system can enhance the detrimental effects of
    vibration and noise, and smoking may alter the effect of drugs taken
    for other purposes.

    3.1.3  Effects of tobacco smoking on lung deposition and clearance of

    Pulmonary deposition of inspired particles depends on their
    physicochemical properties and on airway structure and geometry.
    Mathematical models describing the deposition of particles in the
    various airway sections show that in compromised airways, as is the
    case in patients suffering from asthma and chronic obstructive lung
    diseases, particle deposition is enhanced several-fold (ICRP, 1994).

    Tobacco smoking can be an indirect cause of enhanced deposition of
    inspirable particles. In addition, during tobacco smoking the
    breathing pattern is changed to more frequent and deeper inhalation,
    especially in the case of low-nicotine cigarettes, which can result in
    an increased inhaled dose and dose rate of inspirable compounds (IARC,

    Clearance of particles deposited in the lung is a complex
    physiological process involving relatively rapid tracheobronchial
    clearance, in which mucus is moved upward by ciliary action to the
    pharynx and swallowed, and slower deep-lung clearance, in which
    phagocytic cells remove inhaled particles. These processes are
    balanced by the solubility of the inhaled particles, with relatively
    insoluble particles having a longer residence time in the alveolar
    portions of the lungs. A longer residence time in the lung would be
    accompanied by a greater possibility that harmful effects could occur.
    Both rapid and slow clearance phases are reduced by smoking, although
    probably by different mechanisms. Cigarette smoke contains significant
    concentrations of ciliatoxic agents, such as hydrogen cyanide,
    formaldehyde, acetaldehyde, acrolein and nitrogen oxides, which
    greatly contribute to retarded clearance of inhaled particles by
    inhibiting lung clearance mechanisms (Battista, 1976). Retardation of
    clearance has been seen for airway-deposited particles, in which
    decreased mucus transport velocities slow this normally relatively
    rapid phase of clearance (Lourenco et al., 1971; Chopra et al., 1979).

    The deep-lung clearance of relatively insoluble particles is retarded
    in smokers. Cohen et al. (1979) found that 1 year after a tracer
    particle exposure, some 50% and 10% of the original lung burden
    remained in the lungs of smokers and non-smokers, respectively.
    Bohning et al. (1982) and Philipson et al. (1996) found that smoking
    retarded long-term particle clearance from the lungs. The mechanism(s)
    for interference with this longer-term phase of clearance has not been
    shown definitively, but may be related to impairment of phagocyte
    function and/or smoke-induced lung damage.

    3.2  Interactions between tobacco smoke and other agents

    3.2.1  Asbestos

    Asbestos is a generic name for a group of fibrous silicates, differing
    in colour, fibre arrangement and length. Recognition of the health
    risks of asbestos has led to major reductions in production and uses.
    Asbestos types are classified according to their physical
    characteristics as serpentine or amphibole and differ in their
    relative carcinogenic potential. Amosite and crocidolite are
    amphiboles and have short and straight needle-like fibres. Chrysotile
    is a serpentine and consists of long, pliable white fibres. The longer
    fibre varieties of asbestos can be spun into yarn which can be woven
    into fabric; short fibre varieties can be incorporated into cement,
    asbestos board and tiles. Asbestos products have been used in a
    variety of applications including electrical and thermal insulation in
    buildings, fire and safety equipment, brake linings of motor vehicles,

    and shipbuilding. Workers in asbestos mining and processing and a wide
    range of manufacturing industries are exposed to various forms of
    asbestos, while others are exposed in maintenance work, demolition and
    recycling operations.

    Occupational exposure to asbestos is associated with asbestosis and
    cancers at various sites, notably pleural mesothelioma and lung
    cancer. Differences between the effect of asbestos on the health of
    smokers and non-smokers have been reported, and studies have been
    conducted aimed specifically at elucidating the combined effects of
    smoking and asbestos exposure. Perioccupational exposure to asbestos
    is a hazard to household contacts of asbestos workers, who bring home
    dust on their clothes, and to people living in areas where there is
    environmental contamination by asbestos dust from industry (Anderson
    et al., 1979).

    The amphibole varieties of asbestos (crocidolite and amosite) have the
    highest carcinogenic risk. Crocidolite presents a greater risk than
    amosite, which in turn is more dangerous than chrysotile, a serpentine
    variety. Erionite and tremolite are non-asbestos fibrous minerals used
    in building in some parts of the world and there is a high prevalence
    of mesothelioma in these regions (Baris et al., 1979; Yazicioglu et
    al., 1980).

    Because there are many different occupations and environmental
    situations in which asbestos exposure might occur, along with a wide
    range of possible levels of exposure and variety of types of asbestos
    in use, it is difficult to define clearly asbestos exposure or the
    smoking habits of those exposed. The smoking history of the population
    sampled is important, because there have been changes in smoking
    materials and prevalences of smoking in many countries (Cheng & Kong,
    1992). In many studies, only the number of smokers within sub-groups
    of workers with asbestos-related disease have been reported, rather
    than the detailed smoking habits of the exposed population. A widely
    used assumption is that the smoking habits of asbestos-exposed workers
    reflect those of blue collar workers and are thus higher than national
    average figures. Table 5 gives examples of smoking prevalence in
    different groups of asbestos-exposed workers.  Asbestos and lung cancer

    Exposure to asbestos dust carries a risk of parenchymal and pleural
    fibrosis, mesothelioma and lung cancer. Selikoff et al. (1968) and
    Berry et al. (1972) showed that cigarette smoking was an added hazard
    among asbestos workers. In combination, the two hazards are associated
    with very high lung cancer rates. Studies were carried out (e.g.,
    Hammond & Selikoff, 1973; Martischnig et al., 1977; Hammond et al.,
    1979; Selikoff et al., 1980; Acheson et al., 1984; Berry et al., 1985)
    to determine whether cigarette smoke and asbestos act independently, 

        Table 5.  Smoking prevalence in asbestos-exposed workers

    Exposure                                Smoking habits                     References


    Asbestos textile workers                75% smokers                        Weiss (1971)
                                            46% cigarette smokers
                                            36% ex-cigarette smokers
                                            5.5% pipe/cigar smokers

    Electrochemical plant                   84% to 87% were smokers
    (two areas)                             or ex-smokers                      Kobusch et al. (1984)

    Population in Telemark,                 Asbestos exposed:                  Hilt (1986)
    Norway                                  44.6% smokers
                                            36.0% ex-smokers
                                            Not exposed:
                                            40.95% smokers
                                            28.6% ex-smokers

    Survey of 800 000 American              Asbestos exposed:                  Stellman et al.  (1988)
    men and women in 1982                   33.6% smokers
                                            47.3% ex-smokers

    Lung cancer case-referent               Men: 95% smokers                   Järvholm (1993)
    study; Swedish industrial city          Women: 78% smokers

    Shipyard workers in                     46% smokers                        Sanden et al. (1992)
    Gothenburg, Sweden                      31% ex-smokers
    December 1987                           21% non-smokers
                                            2% not known

    Asbestos factory workers                Men: 74% smokers                   Newhouse & Berry (1979)
                                            (male population average 66%)
                                            Women: 49% smokers
                                            (female population average 40%)

    their combined effect being the sum of the individual effects, or
    there is an interaction with the ultimate effect being a product of
    the two risk factors. In some studies, the effects of smoke and
    asbestos appeared to be additive, in others multiplicative and in
    others somewhere between the two. Reasons for the lack of consistency
    among the studies may relate to the size of the population sampled,
    its average age, social class and residential area, the type of
    asbestos involved, the time scale covered and the intensity of
    exposure to asbestos. The weight of evidence favours a synergistic or
    multiplicative model for the interaction of asbestos and smoking.
    While the differences may be partly linked to the carcinogenic
    potential of different types of asbestos and to different smoking
    materials and ways of smoking, including passive smoking (Cheng &
    Kong, 1992), they also reflect the complex nature of tobacco smoke,
    which contains complete carcinogens, tumour promoters and
    co-carcinogens and other compounds that can influence the multistage
    carcinogenic process. However, whatever the type of smoking/asbestos
    interaction influencing the incidence of lung cancer, there is a
    greatly increased risk for the asbestos-exposed worker who smokes
    (Table 6).

    Hammond et al. (1979) found a very strong synergistic effect and this
    was supported by studies of shipyard workers in Italy (Bovenzi et al.,
    1993), asbestos factory workers in London (Newhouse & Berry, 1979),
    Finnish anthophyllite miners and millers (Meurman et al., 1979),
    chrysotile workers in China (Cheng & Kong, 1992; Zhu & Wang, 1993) and
    workers exposed to crocidolite in Western Australia (de Klerk et al.,
    1991). Cheng & Kong (1992) reported a lower ratio of non-smoking to
    smoking lung cancer death rates and suggested that this reflected
    passive smoking among non-smokers and the use by most smokers of
    hand-rolled cigarettes. Liddell et al. (1984) found that their data
    fitted both an additive model and a multiplicative model and concluded
    that the combined relative risk lay somewhere between the two.
    Selikoff et al. (1980), from a study of amosite factory workers, and
    Berry et al. (1985), from a study of asbestos factory workers,
    favoured an additive model. However, caution is required because of
    the definitions of additive and multiplicative used by different
    authors and the overlap between these terms and such words as
    synergism and promoter.

    Molecular biology studies of autopsy specimens of lung tumour tissue
    from of cigarette smokers have revealed that cigarette smoking induces
    K-ras mutation (Rodenhuis & Slebos, 1992). It has been suggested that
    such cigarette-smoke-induced K-ras oncogene mutations are promoted by
    the presence of asbestos, which creates selective growth conditions
    for the mutated cells (Vainio et al., 1993). Vainio & Boffetta (1994)
    concluded that both tobacco smoke and asbestos fibres can be genotoxic
    and cytotoxic, and cause proliferative lesions in the lungs. Tobacco
    smoke contains carcinogens that bind to critical genes and cause
    mutations. Asbestos fibres cause chronic inflammation of the lungs,
    which releases various cytokines and growth factors, and may provide a
    selective growth advantage for mutated cells.

        Table 6.  Age-standardized lung cancer death ratesa for cigarette smoking and/or 
    occupational exposure to asbestos dust compared with no smoking and no occupational
    exposure to asbestos dust (from: Hammond et al., 1979)

    Group                Exposure to   History cigarette  Death   Mortality   Mortality
                         asbestos?     smoking?           rate    difference  ratio


    Control              No            No                 1.3     0.0         1.00

    Asbestos workers     Yes           No                 58.4    +47.1       5.17

    Control              No            Yes                122.6   +111.3      10.85

    Asbestos workers     Yes           Yes                601.6   +590.3      53.24

    a  Rate per 100 000 man-years standardized for age on the distribution of the
       man-years of all the asbestos workers; number of lung cancer deaths based on
       death certificate information
  Asbestos and pleural mesothelioma

    There is an established relationship between exposure to asbestos 
    - crocidolite, amosite, chrysotile - and pleural mesothelioma
    (Stellman, 1988). In shipyard workers mainly exposed to chrysotile,
    Sanden et al. (1992) found an increase in pleural mesotheliomas up to
    15 years after cessation of exposure. Asbestos is also linked with
    peritoneal mesothelioma (Newhouse & Berry, 1976). The risk of lung
    cancer was found to fall after exposure ceased, suggesting that
    asbestos acted as a lung cancer promoter, but the risk of mesothelioma
    long after cessation of exposure indicated that asbestos acted as a
    complete carcinogen. Mesothelioma can have an extremely long latent
    period, with cases presenting even 30 years or more after first
    exposure (Newhouse & Berry, 1976). Up to 90% of cases of pleural
    mesothelioma have been attributed to asbestos but there is no evidence
    directly associating smoking with the disease, or showing that smoking
    has any influence on the incidence of asbestos-related pleural
    mesothelioma (Berry et al., 1985; Hughes & Weill, 1991; Sanden &
    Jarvholm, 1991; Muscat & Wynder, 1991).  Asbestos and other forms of cancer

    Asbestos fibres have been found in many tissues, other than the lungs,
    of asbestos workers. There is evidence that an asbestos/smoking
    interaction increases the incidence of cancer of the oesophagus,
    pharynx, buccal cavity and larynx but not of pleural or peritoneal
    mesothelioma, or of cancer of the stomach, colon-rectum or kidney, for
    which smoking and non-smoking asbestos workers are at equal risk
    (Hammond et al., 1979; Selikoff & Frank, 1983; US ATSDR, 1995).  Asbestosis

    Asbestosis is a fibrotic reaction to asbestos in the lungs. In a
    review of histological, animal experimental and radiological evidence,
    Weiss (1984) concluded that cigarette smoking could result in diffuse
    fibrosis similar to that caused by asbestos, and the fibrosis showed a
    dose-response to the duration and degree of smoking. Prevalence
    studies are consistent in showing a higher frequency of diffuse small
    irregular opacities in asbestos workers who are smokers than in those
    who are non-smokers. It has been suggested that the effects may be
    additive. Tobacco smoke affects lung clearance and hence the retention
    of asbestos fibres in the lungs. In asbestosis the intensity of
    fibrosis correlates with the number of asbestos bodies in the lungs,
    and Murai et al. (1994) concluded that reduction of lung clearance by
    tobacco smoke could increase the intensity of fibrosis. Crocidolite
    fibres are the most fibrogenic of the various types of asbestos but
    De Klerk et al. (1991) concluded that smoking had no measurable effect
    on crocidolite asbestosis.

    An interaction between asbestos and smoking causing a greater
    frequency of obstructive airways disease in asbestos workers who smoke
    was found in a study of pulmonary function changes caused by
    asbestosis (Selikoff & Frank, 1983). Miller (1993) presented similar

    results suggesting an interaction between asbestos and smoking. In a
    prospective mortality study, Hughes & Weill (1991) concluded that
    asbestosis is a precursor of asbestos-related lung cancer, but they
    were unable to assess an interaction between tobacco smoking and
    asbestosis because all the cases were in smokers and there were no

    In rats, asbestos fibres stimulate alveolar macrophages to generate
    the inflammatory and fibrogenic mediators, tumour necrosis
    factor-alpha (TNF-alpha), and this may be the cause of inflammation 
    and lung fibrosis due to asbestos (Ljungman et al., 1994). In  in vitro
    studies Morimoto et al. (1993) found synergism between chrysotile
    fibres and cigarette smoke in the stimulation of the formation of
    TNF-alpha by rat alveolar macrophages.

    3.3  Non-asbestos fibres

    3.3.1  Glass fibre

    IARC (1988) classified glasswool as possibly carcinogenic to humans
    (Group 2B) and glass filaments as not classifiable as to their
    carcinogenicity to humans (Group 3), based on sufficient evidence for
    the carcinogenicity of glasswool and inadequate evidence for the
    carcinogenicity of glass filaments in experimental animals and
    inadequate evidence for the carcinogenicity of glasswool and glass
    filaments in humans. There are data on exposure to glass fibre and
    tobacco smoke. Enterline et al. (1987a) carried out a case control
    study of 7586 glasswool workers in four plants producing small
    diameter fibres, less than 3 µm in diameter. Smoking histories were
    obtained for 75% of the workers. Analysis of data by logistic
    regression showed that smoking was a powerful variable and multiplied
    the effect of fibre exposure. In a case-control study of the influence
    of non-workplace factors on respiratory disease in employees of a
    glass fibre manufacturing facility, Chiazze et al. (1992, 1995)
    concluded that smoking, and not exposure to glass fibre, was the most
    important risk factor for the increased lung cancer risk but was not
    as important for non-malignant respiratory disease. In a further
    analysis, using data not previously available, Chiazze et al. (1995)
    estimated the extent of confounding by cigarette smoking, and
    suggested that adjusting for the confounding effect could reduce the
    lung cancer standardized mortality ratio to a non-statistically
    significant level.

    3.3.2  Rockwool, slagwool and ceramic fibres

    IARC (1988) concluded that there was limited evidence for the
    carcinogenicity of rockwool and inadequate evidence for the
    carcinogenicity of slagwool in experimental animals, with limited
    evidence for the carcinogenicity of rock-/slagwool in humans: the
    overall evaluation for both was Group 2B, possibly carcinogenic to
    humans. For ceramic fibres there was sufficient evidence for their

    carcinogenicity in experimental animals, with no data on their
    carcinogenicity in humans: the overall evaluation for ceramic fibres
    was also Group 2B, possibly carcinogenic to humans.

    In a study of insulation workers using rock and glass wool, (Clausen
    et al., 1993) concluded that exposure was associated with an increased
    risk of developing obstructive lung disease. In a study of respiratory
    health in 628 workers in seven European plants manufacturing ceramic
    fibres, skin, eye and nasal irritation, breathlessness and wheezing
    were common findings (Trethowan et al., 1995). Respiratory symptoms
    were more frequent in smokers and increased with the amount smoked.
    The authors concluded that exposure caused irritation, similar to that
    caused by other man-made fibres, and that cumulative exposure could
    cause airways obstruction by promoting the effects of cigarette smoke.

    Ljungman et al. (1994) demonstrated in rats that rock wool, slag wool,
    kaolin ceramic fibre and silicon carbide fibre stimulated alveolar
    macrophages to generate tumour necrosis factor-alpha (TNF-alpha), a
    potent inflammatory and fibrogenic mediator. In  in vitro studies
    Morimoto et al. (1993) found synergism between mineral fibres
    (chrysotile and alumina silicate ceramic fibres) and cigarette smoke
    in the stimulation of the formation of TNF-alpha by rat alveolar
    macrophages. Leanderson & Tagesson (1989) found that cigarette smoke
    potentiated the DNA-damaging effect of man-made mineral fibres
    (rockwool, glasswool and ceramic fibres).

    3.4  Inorganic chemicals

    3.4.1  Arsenic

    Compounds of arsenic have been used as pesticides and as preservatives
    of wood and leather. Arsenic is present in many metal ores and is
    released during smelting Radon progeny are frequently encountered as a
    contaminant of arsenic. In some parts of the world arsenic is found in
    drinking-water in relatively high concentrations.

    Arsenic and its compounds are carcinogenic (WHO, 1980; IARC, 1987;
    Tsuda et al., 1990, 1995). Skin cancer can occur after ingestion of
    arsenic (Tseng et al., 1968; Smith et al., 1992), and lung cancer
    after inhalation of arsenic by smelter workers or by people living
    nearby (Welch et al., 1982; Pershagen, 1985; Pershagen et al., 1987)
    or by agricultural workers exposed to the pesticide lead arsenate
    (Wicklund et al., 1988). IARC (1987) classed arsenic and arsenic
    compounds as Group 1, carcinogenic to humans. It has been suggested
    that arsenic in drinking-water may also cause liver, lung, kidney and
    bladder cancer (Smith et al., 1992).

    A study of the lung cancer risk among cadmium-exposed workers
    suggested that exposure to arsenic and tobacco smoke may have been the
    cause of an increased rate of lung cancer, rather than exposure to
    cadmium particulates (Lamm et al., 1992). Tsuda et al. (1990)
    suggested an interaction between arsenic and smoking in exposed
    workers in a small Japanese village where arsenic was mined and

    refined. However, the village water and air were highly polluted by
    emissions from the smelter and from slag disposal, making interaction
    between arsenic and smoking difficult to assess. A study of copper
    smelter workers in the USA indicated that the effect of arsenic was
    probably more important in lung cancer than that of tobacco smoke
    (Welch et al., 1982). Studies in Sweden showed increased lung cancer
    risks from arsenic exposure at a copper smelter; a multiplicative
    effect for smoking and arsenic was found and age-standardized rate
    ratios for lung cancer mortality were 3.0 for arsenic-exposed workers,
    4.9 for smokers with no arsenic exposure and 14.6 for arsenic-exposed
    smokers (Pershagen et al., 1981). In a later study, Pershagen (1985)
    reported an additive effect for smoking and arsenic exposure on lung
    cancer incidence in situations where the arsenic exposure was lower.
    In a cohort of 3916 Swedish copper smelter workers, the risk of
    developing lung cancer from the interaction between arsenic and
    smoking was intermediate between additive and multiplicative and
    appeared to be less pronounced among heavy smokers (Jarup & Pershagen,

    There was no evidence of synergism between arsenic and tobacco smoke
    in tin miners in Yunan Province, China. The lung cancer risk was
    greater for arsenic than for smoking, and simultaneous assessment of
    arsenic and radon exposure revealed radon to be the greater risk
    (Taylor et al., 1989). In Ontario it was concluded that the excess
    lung cancer mortality of gold miners and uranium miners was probably
    due to exposure to arsenic and short-lived radon decay products
    (Kusiak et al., 1991). This was consistent with the hypothesis that
    the risk of lung cancer from exposure to arsenic is enhanced by
    exposure to other carcinogens (Kusiak et al., 1993).

    Hertz-Picciotto et al. (1992) assembled data from several studies to
    examine possible synergism between smoking and exposure to arsenic and
    an increased risk of lung cancer. The joint effect from both exposures
    consistently exceeded the sum of the separate effects: a minimum of
    30% to 54% of lung cancer cases among those with both exposures could
    not be attributed to either one or the other exposure alone. The
    conclusion was that arsenic and smoking acted synergistically to cause
    lung cancer. Arsenic-induced lung cancer was not limited to exposure
    to inhaled arsenic because there was evidence of synergism between
    ingested arsenic and smoking (Tsuda et al., 1995). An association of
    arsenic exposures with bladder cancer was confined to subjects who had
    been smokers Bates et al. (1995).

    In a Swedish study of lung cancer in arsenic workers, it was found
    that cases among smelter workers who had never smoked showed a
    histological distribution resembling that of smokers, probably
    reflecting an exposure to carcinogenic agents at the smelter which
    influence the risk of different histological types in the same way as
    smoking (Pershagen et al., 1987). Tobacco smoking primarily induces
    epidermoid and small cell carcinomas but there are also increased
    risks for other cell types. The proportion of small cell carcinomas
    was greater in uranium miners than in the general population (Kusiak

    et al., 1993). In smokers, there were no pronounced differences in the
    histological type of lung carcinomas between arsenic exposed smelter
    workers and controls (Pershagen et al., 1987).

    It has been suggested that the potentiation of the carcinogenic
    properties of arsenic by smoking could be due to inorganic arsenic
    requiring a strong co-carcinogen to manifest a carcinogenic effect, or
    that arsenic itself might be acting as co-carcinogen rather than as a
    direct carcinogen (Stohrer, 1991; Tsuda et al., 1995).

    3.4.2  Beryllium

    Beryllium is a metal with a number of uses including alloys, nuclear
    energy applications, and in the rocket and aerospace industry (IPCS,
    1990; IARC, 1993). Fine dusts and fumes of the metal and some of its
    salts are hazardous and when inhaled are deposited in the lungs from
    where beryllium may be widely distributed throughout the body.

    Beryllium metal, oxide and some salts give rise to acute inflammation
    on skin contact, particularly when accompanied by friction or
    perspiration. Short exposure to dusts and fumes can cause acute
    inflammation of mucous membranes: conjunctivitis, bronchitis,
    pneumonitis. Granulomatous reaction can follow chronic inflammation of
    the skin, and lesions may appear in the liver and elsewhere after long
    periods of absorption from the lungs. Beryllium and its compounds are
    a cause of delayed pneumonitis and pulmonary granulomas. IARC (1993)
    classified beryllium and beryllium compounds as Group 1, carcinogenic
    to humans, on the basis of sufficient evidence in humans and in
    experimental animals. However, in epidemiological studies the
    information on smoking was incomplete and the data did not rule out
    the possibility that the few excess deaths observed could have been
    due to smoking rather than to any other cause (Steenland & Ward, 1991,
    1993; Eisenbud, 1993; MacMahon, 1994; Kotin, 1994).

    The prevalence of chronic beryllium disease (CBD) is reduced in
    smokers compared with non-smokers. The disease is preceded by the
    development of beryllium-specific sensitization. In two studies
    examining different worker populations, the prevalence of smoking in
    those with clinically diagnosed CBD was lower than in those that were
    sensitized but did not have the disease (Kreiss et al., 1993; Kreiss
    et al., 1996).

    3.4.3  Chromium

    Chromium and its compounds are used in metallurgical, chemical,
    electroplating and leather tanning industries (IARC, 1990). The
    principal route of entry to the body is through the lungs. Chromium
    ulcers of the skin and dermatitis can result from handling chromium
    products and deposition of chromates on mucous membranes can also
    cause ulceration which, in the nasal septum, can lead to perforation
    (Lindberg & Hedenstierna, 1983; IARC, 1990). Chromium and some
    chromium compounds are respiratory tract sensitizers and a cause
    asthma. Hexavalent chromium salts have been associated with lung

    cancer both in experimental animals and in epidemiological studies.
    IARC (1990) concluded that there is sufficient evidence in humans for
    the carcinogenicity of hexavalent chromium compounds as encountered in
    chromate production, chromate pigment production and chromium plating

    Langård & Norseth (1975) suggested that cigarette smoking increases
    the risk for lung cancer in workers exposed to chromate dust. Other
    studies (Abe et al., 1982; Langård & Vigander, 1983; Yoshizawa, 1984;
    Nishiyama et al., 1985) have suggested that workers with exposure to
    chromium compounds who are also smokers may be at greater risk than
    non-smokers. However, the numbers were too small for conclusions on
    interactions to be drawn.

    3.4.4  Nickel

    Exposure to nickel or its compounds occurs in mining, refining,
    smelting and alloying the metal, in nickel plating and in welding. It
    is used in battery manufacture, electroplating, enamelling, ceramics,
    the chemical and petroleum industries and in dyestuffs and ink making.
    Exposure may be by skin contact or inhalation of dusts, fumes, mists
    or gaseous nickel carbonyl (IPCS, 1991a). In occupational exposure the
    daily intake and absorption/retention vary widely between industries
    (IARC, 1990).

    Nickel is absorbed from the soil by the tobacco plant. During smoking,
    up to 20% of the nickel in the tobacco is transferred to mainstream
    smoke. This high transfer rate, compared to the much lower transfer
    rates of other metals, has been explained by the formation of the
    volatile nickel carbonyl (Sunderman & Sunderman, 1961). Nickel
    carbonyl is a strong lung carcinogen in rats (IARC, 1990).

    IARC (1990) evaluated the carcinogenicity of nickel and nickel
    compounds and classified nickel compounds as carcinogenic to humans
    (Group 1) and nickel as possibly carcinogenic to humans (Group 2B). In
    an epidemiological study on a cohort of 916 workers in a Norwegian
    nickel refinery, four work categories were defined: i) roasting and
    smelting; ii) electrolysis; iii) other processes; and iv) other work
    groups. All groups showed an excess risk of respiratory cancer. In the
    roasting and smelting department there were excess risks for lung
    cancer (O/E = 12/2.5) and nasal cavity cancer (O/E = 5/0.1). In the
    electrolysis department there were also excess risks of lung cancer
    (O/E = 26/3.6) and nasal cavity cancer (0/E = 6/0.2) (Pedersen et al.,
    1973). Magnus et al. (1982) updated this study and found evidence of
    an additive effect of smoking and nickel exposure in the induction of
    respiratory cancer. Histological examination of nasal biopsy specimens
    from 59 retired nickel workers, 21 of whom were smokers and snuff
    users, showed a higher score of nasal epithelial dysplasia in smokers
    than in non-smokers, and 4 workers with nasal carcinoma were smokers
    (Boysen et al., 1984). In monitoring nickel exposure by imaging

    cytometry of nasal smears (Reith et al., 1994), it was possible to
    distinguish between workers who were exposed to different nickel
    compounds and to distinguish between smoking and non-smoking nickel

    3.4.5  Manganese

    There is occupational exposure to manganese in its mining, the
    ferromanganese and iron and steel industries, the production of dry
    cell batteries, and the manufacture and use of welding rods. Manganese
    is released by the combustion of the gasoline additive,
    methylcyclopentadienyl manganese tricarbonyl (MMT), used in some
    countries. However, the amount in gasoline (approximately 10 mg/litre)
    and emitted in vehicle exhausts is small and does not to lead to human
    exposure (Health Canada, 1994). The principal route of entry of
    manganese is through the lungs but, because most of the compounds are
    insoluble, only the smallest particles, as contained in furnace and
    welding fume, are capable of reaching the alveoli and being
    phagocytosed and absorbed (IARC, 1986).

    Manganese is present in tobacco leaves and it has been reported (IARC,
    1986) that 0.003 µg of manganese appears in the mainstream smoke from
    one cigarette and thus contributes to a smoker's manganese intake in
    the form of small and dangerous particles.

    Manganese is neurotoxic and long-term occupational exposure can cause
    a condition resembling Parkinson's disease. It causes lung damage
    leading to an increased incidence of pneumonia and a higher rate of
    acute and chronic bronchitis. In studies of manganese alloy production
    workers and chronic lung disease, smokers were more affected than
    non-smokers and the relationship between the number of cigarettes
    smoked and the prevalence of respiratory tract symptoms suggested that
    smoking acted synergistically with manganese (Saris & Lucic-Palaic,
    1977). In a study of workers producing manganese salts and oxide
    (Roels et al., 1985) smoking and manganese exposure were additive in
    producing preclinical toxic effects. In studies on workers producing
    iron-manganese alloys, one concerned with chronic bronchitis
    (Misiewicz et al., 1994) and the other with pulmonary ventilatory
    disturbance (Misiewicz et al., 1992), there was no relationship
    between the occupational exposure or its duration and health effects.
    The chronic bronchitis and ventilatory disturbance were attributed to
    cigarette smoking.

    3.4.6  Platinum

    Platinum is used as a catalyst in many chemical processes and in motor
    vehicle exhausts. Chloroplatinic acid is an intermediate in the
    preparation of a large number of complex salts, which are used in
    platinum refining, the chemical industry and, therapeutically, in
    cancer chemotherapy.

    Platinum salt sensitivity is an IgE-mediated immune response (IPCS,
    1991b). Ammonium hexachloroplatinate is used as an intermediate in
    platinum refining, and its inhalation provokes asthmatic responses and
    elicits immediate skin test responses in sensitized individuals (Pepys
    et al., 1972). In a cohort study of 91 workers in a platinum refinery
    (Venables et al., 1989), 22 developed respiratory symptoms and an
    immediate skin test response to ammonium hexachloroplatinate. The risk
    was greatest in the first year of employment and smokers had an
    increased risk of becoming sensitized. In another study, out of 78
    workers at a platinum refinery, 32 (41%) had developed platinum salts
    sensitivity after 24 months of exposure and the risk of sensitization
    was about 8 times greater for smokers (Calverley et al., 1995).

    Baker et al. (1990) conducted a cross-sectional study of respiratory
    and dermatological effects of platinum salt sensitization in 136
    workers (107 current employees and 29 former employees) at a precious
    metal refinery. Twenty three workers (22%) had become sensitized.
    Platinum salts sensitivity was not associated with atopicity but was
    strongly associated with cigarette smoking status.

    3.4.7  Silica

    Silicosis (lung fibrosis caused by silica) is not only a hazard of
    mining. It is also found in bricklayers, cement makers, workers in
    pottery, porcelain and ceramics, rock drillers, workers chipping,
    grinding or polishing stone, in sandblasting, using grinding stones to
    smooth or polish precious stones, metals or optical glass, and in the
    manufacture of polishing materials such as metal polishes and
    toothpaste. The number of industries generating silica dust is large.
    The amount of respirable dust varies from one to another and, because
    silica is an active adsorbent, it can become contaminated and have its
    toxic potential changed. Furthermore, freshly fractured silica dust
    may exhibit a different surface reactivity and cytotoxicity from that
    of aged silica (Vallyathan et al., 1988).

    Hnizdo & Sluis-Cremer (1991), in a study of gold miners, linked high
    exposure to silica dust with lung cancer and found a combined effect
    of dust and smoking that fitted a multiplicative model for lung
    cancer. Amandus et al. (1992) studied lung cancer in men with
    diagnosed silicosis and suggested that there was an association
    between the two diseases. In a study of iron foundry workers
    (Andjelkovich et al., 1994), cigarette smoking was a strong predictor
    of lung cancer whereas silica exposure showed no association with the

    Chronic silicosis develops after 20 to 40 years of exposure to silica
    dust. There are also other types of pneumoconiosis related to the
    nature of the dust, and chronic bronchitis and airways obstruction
    have been associated with silica dust exposure. A hypothesis for the
    pathogenesis of chronic silicosis is that silica particles are
    phagocytosed by the alveolar macrophages for which they have a marked
    selective toxicity. Permanent macrophage activation initiates
    inflammatory reactions leading to the formation of collagenous fibres.

    Acute silicosis arises from the inhalation of more highly reactive
    silica (Vallyathan et al., 1988). The link between silicosis and
    smoking was examined in a study of smoking and silica exposure on
    pulmonary epithelial permeability. Faster clearance of a radioaerosol
    from the upper lung regions was found for smokers (Nery et al., 1988,
    1993). The question of silica clearance was considered in an analysis
    of an association between silicosis and smoking: differences in
    collagenization for smokers and non-smokers were attributed to
    differences in the interception of silica particulate matter by mucus
    (Hessel et al., 1991). In studies by Ng et al. (1987, 1992), smoking
    was not considered to affect the progression of silicosis in granite
    quarry workers. However, examining the association of silicosis with
    lung cancer, Ng et al. (1990) concluded that the excess lung cancer
    risk in silicosis is attributable to smoking, and there appeared to be
    a synergistic effect between smoking and silica/silicosis regarding
    the risk of developing lung cancer.

    In a study of 562 South African gold miners exposed to low levels of
    dust with a high (50-70%) silica content, the incidence of chronic
    bronchitis was higher than in non-dust-exposed controls. Although the
    percentage of smokers was higher in those with chronic bronchitis in
    both groups, there was a significant excess in the dust-exposed
    smokers (Sluis-Cremer et al., 1967). The authors concluded that there
    was a factor in dust-exposed smokers that increased the incidence of
    chronic bronchitis above that expected from smoking alone. In a study
    of 2209 South African gold miners and 483 non-miners on the effect of
    silica dust and tobacco smoking on mortality from chronic obstructive
    lung disease, it was found that miners who smoked and were exposed to
    silica dust were at higher risk of dying from chronic obstructive lung
    disease than smokers not exposed to silica dust. In South African gold
    mines about 30% of the respirable dust is free silica. It was
    concluded that tobacco smoking and silica dust acted synergistically
    in causing chronic obstructive lung disease (Hnizdo, 1990). Hnizdo et
    al. (1990) applied additive and multiplicative relative risk models to
    the same sample and found that departure from additivity increased
    progressively with the severity of obstructive impairment. They
    concluded that tobacco smoking potentiated the effect of dust in
    causing respiratory impairment and that severe respiratory impairment
    could have been prevented through elimination of tobacco smoking
    (Hnizdo et al., 1990). Oxman et al., (1993) analysed the relationship
    between occupational dust exposure and chronic obstructive lung
    disease in both gold and coal miners and found a significant
    association between loss of lung function and cumulative respirable
    dust exposure, which was greater in gold miners. In this study there
    was no evidence of interaction with tobacco smoking for gold miners,
    and the authors suggested that the increased risk of lung function
    loss was due to exposure to dust having a higher silica content than
    coal dust. Among iron ore miners in Sweden, Jörgensen et al. (1988)
    found a strong relationship between chronic bronchitis and smoking,
    but not with working underground. The two risk factors, silica dust
    and smoking, appeared to be additive but the smoking effect was far
    greater than that of silica dust. In a study of small airway disease
    in patients with silica dust exposure, with and without radiographic

    evidence of silicosis, and smoking, Avolio et al. (1986) found no
    differences in lung function and prevalence of small airways disease
    with silicosis. However, in both groups small airway disease was
    significantly related to tobacco smoking, indicating that this had a
    more powerful effect than silicosis.

    3.5  Organic chemical agents

    Many organic compounds with properties covering a wide spectrum of
    molecular structure and biological activity are encountered in a
    variety of industries. The effects of a few compounds, some of which
    are encountered in specific industries, and smoking have been studied.
    Where organic compounds occur in both tobacco smoke and the workplace,
    the effect of smoking becomes one of dose augmentation, although
    modification of effect can also occur. Some organic compounds would
    normally not be found in tobacco smoke but are present because
    workplace materials have contaminated smoking materials and they are
    then pyrolysed or volatilized during smoking.

    3.5.1  Chloromethyl ethers

    Chloromethyl methyl ether (CMME) and its contaminant bis(chloromethyl)
    ether (BCME) are used in the synthetic chemical industry, in the
    manufacture of ion exchange resins and in polymer production. They are
    carcinogenic when inhaled, BCME more so than CMME. In a long-term
    study of chemical workers, 93 had exposure to chloromethyl ethers and
    22 died from lung cancer. Of 32 workers who had no exposure, 3 died
    from lung cancer (Weiss & Boucot, 1975; Weiss, 1976, 1980, 1982). For
    the 22 cases in of lung cancer in the exposed workers, a dose-response
    relationship was established. In the groups with heavy occupational
    exposure, there were fewer heavy smokers (>20 cigarettes per day)
    than in the groups with lower occupational exposure. This
    statistically significant shift might be explained by self-selection
    of heavy smokers out of the high occupational exposure groups because
    of the bronchial irritation that is caused by the exposure to
    chloromethyl ethers, or cigarette smoking might have an antagonistic
    activity (Steenland & Thun, 1986; Thomas & Whittemore, 1988; Weiss &
    Nash, 1997).

    3.5.2  Tetrachlorophthalic anhydride

    Tetrachlorophthalic anhydride (TCPA) is used as an epoxy resin curing
    agent. It is respiratory tract sensitizer and causes asthma (Schlueter
    et al., 1978). In a study using a radio allergosorbent test with a
    TCPA human serum albumin conjugate, specific IgE antibody was detected
    in serum from 24 out of 300 factory floor workers exposed to TCPA. Of
    these 24, 20 (83%) were current smokers, compared with 133 (48%) of
    276 without antibody (p<0.01), and there was a weaker association
    with atopy, defined by skin tests with common allergens. Smoking and
    atopy interacted, the prevalence of antibody being 16% in atopic
    smokers, 12% in non-atopic smokers, 8% in atopic non-smokers and none

    in the non-atopic non-smokers. It was concluded that smoking may
    predispose to, and interact with atopy in the production of specific
    IgE antibody to this hapten protein conjugate.

    3.5.3  Dyestuffs

    There is an established relationship between bladder cancer and
    exposure to certain aromatic amines encountered in the dyestuffs
    industry, e.g., benzidine, 4-aminobiphenyl and 2-naphthylamine (IARC,
    1987), and smoking is causally associated with bladder cancer (IARC,
    1986; US Surgeon General, 1989). From an analysis of 991 cases by
    Cartwright (1982), a significant risk of bladder cancer was associated
    with cigarette smoking, and a dose-response relationship, based on
    years of employment, was found in workers in dyestuffs manufacturing.
    The risks were considered to be additive. Overall, there was a
    significant risk of bladder cancer associated with cigarette smoking,
    a risk ratio of 1.8 for males, and there were significant overall
    risks associated with occupations such as those of process workers in
    the dye manufacturing industry who had a risk of 2.9 for males. When
    dye manufacturing process workers who were smokers were compared with
    non-smoking workers, the risk for smokers was 4.6, while for
    non-smokers the risk was 1.9.

    Boyko et al. (1985) concluded that arylamines in the dyestuffs
    industry posed a major threat of bladder cancer. However, there was
    little evidence to support an effect due to smoking or an interaction
    between smoking and occupational exposure.

    In an area of Spain where 44% of the adult population worked in dyeing
    and printing textile fabrics, there was an increased risk of bladder
    cancer for smokers (OR 2.3) (Gonzalez et al., 1985). The estimated
    risks for occupation and for smoking and occupational exposure were OR
    5.5 and 11.7, respectively. The observed effect was multiplicative.
    Tobacco smoke contains many amines, including the bladder carcinogens
    4-aminobiphenyl (>9 ng/cigarette) and 2-naphthylamine (54
    ng/cigarette) (Patrianakos & Hoffmann, 1979; Pieraccini et al., 1992;
    Grimmer et al., 1995).

    In a study of risk factors for bladder cancer in Spain (Bravo et al.,
    1987), the results were considered to corroborate previous data that
    bladder cancer does not have a single cause. Cigarette smoking was
    considered an important cause but one which was additional to
    urological disease or occupational exposure, among other factors. In a
    study of men in Spain (Gonzalez et al., 1989), increased risks of
    bladder cancer were found for textile workers (OR 1.97), mechanics and
    maintenance workers (OR 1.86), and workers in the printing industry
    (OR 2.06). The highest risk was in those who were employed in the
    textile industry before the age of 25 and prior to 1960. Among
    mechanics the highest risk was for those who started after the age of
    25 and after 1960. The OR for smokers who had also been employed in
    one of the high-risk occupations was 7.82, which is compatible with a
    multiplicative effect of joint exposure to tobacco smoke and
    occupational hazards. In an Italian study (D'Avanzo et al., 1990),

    risk additivity was found for the interaction between tobacco smoke
    and several occupations associated with bladder cancer but the
    occupations were not specified. The bladder cancer risk for smokers of
    black tobacco was higher (OR = 3.7) compared with smokers of blond
    tobacco cigarettes (OR = 2.6). A higher risk for black tobacco than
    for blond varieties and a protective effect for smokers of tipped
    cigarettes was also reported in a study in Northern Italy where a
    multiplicative effect for smoking and high risk occupations was also
    found (Vineis et al., 1984).

    Bartsch et al. (1993) correlated the higher incidence of bladder
    cancer among smokers of black tobacco with high yield aromatic amines,
    particularly 4-aminobiphenyl from black tobacco (5 times greater than
    from blond tobacco). The concentrations of urinary mutagens and of
    4-aminobiphenyl adducts in the blood were also higher in smokers of
    black tobacco.

    A Chinese study of bladder cancer incidence and mortality in workers
    with benzidine exposure found a marked dose response and an elevated
    risk for both producers and users of benzidine. Workers exposed to
    benzidine who were smokers had a 31-fold risk, while the risk for
    exposed workers who were non-smokers was 11-fold, and a multiplicative
    interaction was suggested (Bi et al., 1992).

    3.5.4  Polycyclic aromatic hydrocarbons

    Tobacco smoke contains many polycyclic aromatic hydrocarbons (PAHs)
    (IARC, 1986), a number of which, such as benz( a)pyrene and
    dibenz( a,h)anthracene, are known to be carcinogenic (IARC, 1987;
    Hoffmann & Hoffmann, 1997). PAHs are generated by incomplete
    combustion of organic matter in many industrial processes and
    constitute a hazard not only in occupations but also as environmental
    pollutants, representing primary risk factors as lung and bladder
    carcinogens. A tobacco smoker can obtain one dose of PAHs from tobacco
    smoke and another from the industrial or environmental source.
    Furthermore, an interaction of tobacco smoke and an occupational
    hazard is a possibility. PAHs in the workplace are often accompanied
    by many other toxic compounds, particularly irritants, and, in
    addition to carcinogenic PAHs, tobacco smoke contains co-carcinogens
    and tumour promoters as well as ciliatoxic agents, irritants and other
    biologically active species.

    PAHs occur in coal gas manufacture, coking oven fumes, aluminium
    smelting, in the use of tar and asphalt, in oil refining and the
    exhaust from internal combustion engines. They are frequently
    accompanied by irritant fumes or aerosols and potentially harmful
    particulate matter. There is a lack of smoking data for workers in
    many of these industries, but it has been assumed that the smoking
    prevalence is at least as high as the average for blue collar workers.
    At a Norwegian smelter 69% of workers were smokers when the expected
    prevalence of smoking was 52% (Abramson et al., 1989). The percentage

    of smokers and ex-smokers among workers exposed to chemicals and coal
    tar pitch in a 1982 survey of 800 000 men and women in the USA was
    49.9% against 46.1% for the average worker (Stellman et al., 1988).

    A Canadian study found a high prevalence of bladder cancer in
    aluminium smelter workers, particularly among those employed in
    Söderberg potrooms where carbon electrodes made from a mixture of
    petroleum pitch and coal pitch are used and PAH levels are high
    (Thériault et al., 1984). Changing electrodes, breaking the crust that
    forms on top of the molten metal and cleaning out the "pots" are
    activities that create air pollution by tar volatiles including
    carcinogenic PAHs which, measured as benzo( a)pyrene, could reach a
    concentration of 800 µg/m3/8 h (Bjorseth et al., 1978). High levels
    of PAHs were found in urine samples from aluminium plant workers
    (Haugen et al., 1986). Lung cancer rates among aluminium reduction
    plant workers are also high (Gibbs & Horowitz, 1979). Tobacco smoke
    appears to increase the risk. In a study by Thériault et al. (1984),
    the numbers were too small to determine whether the interaction was
    additive or multiplicative, but in another study (Bjorseth et al.,
    1978) there was suggestive, but not conclusive, evidence that the
    relative risks from combined exposure to tar volatiles and cigarette
    smoke were multiplicative. In a study in which the preceding data were
    augmented (Armstrong et al., 1986), the tar volatiles were confirmed
    as the cause of bladder cancer and the results suggested that a
    multiplicative risk arose from a combined exposure to tar volatiles
    and cigarette smoke.

    Gullvåg et al. (1985) found that the alveolar macrophage count for
    workers in the potrooms of an aluminium reduction plant was elevated
    and for workers who were also smokers the count was further elevated.
    The conclusion was that smoking and workplace pollution act
    synergistically in increasing the number of alveolar macrophages.

    Workers in coke oven plants have a higher incidence of lung cancer
    than the general population and a measurable concentration of PAHs in
    urine, which is higher in smokers than non-smokers (Haugen et al.,
    1986). Van Schooten et al. (1990) analysed blood samples from coke
    oven workers for PAH-DNA adducts and urine for 1-hydroxypyrene and
    compared the results with those of non-exposed workers. Levels were
    elevated in coke oven workers and in both exposed and control groups
    the PAH-DNA adduct levels were higher among smokers than among

    Professional drivers are exposed to benzene and carcinogenic PAHs and
    nitroarenes through the exhaust of petrol (gasoline) and,
    particularly, diesel engines. An excess of lung cancer has been found
    in this occupational group, with a suggestion of a synergistic
    interaction between smoking and occupational exposure (Damber &
    Larsson, 1985a).

    Diesel exhaust contains large quantities of carbonaceous particulates
    with adsorbed PAHs. The association between lung cancer and diesel
    exhaust and the contributing role of cigarette smoking has been

    considered to be problematic (Garshick et al., 1987, 1988; Boffetta et
    al., 1988; Stöber & Abel, 1996; IPCS, 1996). In its evaluation, IARC
    (IARC, 1989c) considered diesel engine exhaust to be probably
    carcinogenic to humans (group 2A) and gasoline engine exhaust as being
    possibly carcinogenic to humans (group 2B).

    In most of the workplaces where PAHs contaminate the atmosphere, there
    are also gases, fumes and aerosols that contain other hazardous
    materials that act as irritants; they may play a role in the etiology
    of chronic obstructive lung disease. It is important to include
    smoking in epidemiological studies. In a study of lung cancer
    mortality rates and smoking patterns in workers in the motor vehicle
    industry, proportionate mortality rates were considerably reduced when
    smoking rates were taken into account. An increased lung cancer risk
    has been described among foundry workers; PAHs and silica were
    considered to be possible etiological factors (Sherson et al., 1992).
    IARC (IARC, 1984, 1985b) considers the following technical products as
    carcinogenic to humans: coal tar and coal tar pitches, shale oils,
    soots, effluent aerosols from coal gasification, and emissions from
    coke ovens. Exposure occurring in the production of aluminium is
    classified as probably carcinogenic to humans, whereas the exposures
    to aerosol emissions from iron and steel foundries are classified as
    possibly carcinogenic to humans.

    3.5.5  Ethanol

    Clinical and epidemiological studies have established a strong
    relationship between smoking and drinking (Istvan & Matarazzo, 1984;
    Bien & Burge, 1990; Zacny, 1990).

    Elevated tobacco and alcohol consumption are regarded as the major
    risk factors for oropharyngeal and oesophageal cancer in many
    developed countries (Herity et al., 1982; Tuyns, 1983, 1991; Boyle et
    al., 1990; Muir & McKinney, 1992; Negri et al., 1992).

    It has been difficult to distinguish the separate effects of these
    agents since many smokers tend to consume alcoholic beverages and
     vice versa. In addition, the consumption of one substance may have
    an effect on the use of the other substance. The possible interactions
    (e.g., multiplicative effect) of tobacco smoking and alcohol
    consumption for cancers of the oral cavity, pharynx and larynx have
    been evaluated by IARC (1986). IARC (1986) concluded that tobacco
    smoking was an important cause of oral, oropharyngeal, hypopharyngeal,
    laryngeal and oesophageal cancers and combined ethanol consumption
    increased the risk substantially. In a case control study of 1114
    patients with oropharyngeal cancer, Blot et al. (1988) showed that the
    risk to consumers of tobacco and alcohol was multiplicative rather
    than additive and increased 35-fold in those who consumed two or more
    packs of cigarettes and more than four alcoholic drinks per day. The
    risk was higher in those consuming spirits or beer than in those
    consuming wine and was lower in lifetime smokers of filter cigarettes.

    Alcohol consumption and smoking affect fetal outcome, leading to
    infants with low birth weight (Wright et al., 1983, 1984; Smith et
    al., 1986).

    In contrast to the many studies in laboratory animals of the
    interactions of ethanol with tobacco-smoke condensate (TSC) and
    specific tobacco constituents, e.g., nicotine (receptor studies)
    (Collins, 1990), (gastric-mucosal damage) (Wong et al., 1986; Cho et
    al., 1990), tobacco-smoke-specific nitrosamines, e.g.,
     N-nitrosonornicotine (metabolism and carcinogenicity) (McCoy et al.,
    1981; Castonguay et al., 1983, 1984) and
    4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) (Jorquera et al.,
    1992; Schüller et al., 1993), there has been a relative paucity of
    studies involving ethanol and tobacco smoke  per se. These latter
    studies have included fetotoxicity in mice (Peterson et al., 1981),
    gastric mucosal damage (Iwata et al., 1995; Chow et al., 1996), and
    mechanisms underlying behavioural association between alcohol and
    tobacco consumption (Zacny, 1990).

    In  in vitro studies on the effect of tobacco smoke condensate on rat
    buccal mucosa cells following exposure to ethanol, the level of
    adducts was higher than in controls, suggesting an increased uptake of
    carcinogens in the condensate (Autrup et al., 1992). Hsu et al. (1991)
    studied  in vitro genotoxicity of tobacco smoke condensate in
    conjunction with 2% and 4% ethanol in human lymphoid cell lines.
    Ethanol potentiated clastogenicity, measured by frequency of
    chromosome breaks per cell, in a dose-dependent manner, and the
    results indicated that ethanol at relatively high doses inhibited DNA
    and chromosome repair systems.

    Swiss Albino mice fetuses prenatally exposed to both tobacco smoke and
    ethanol had a high resorption frequency, a significant reduction in
    fetal weight and length, and neonatal growth retardation, indicating
    that ethanol and tobacco smoke may interact to produce fetotoxicity
    (Peterson et al., 1981).

    Both cigarette smoking and ethanol consumption individually have been
    associated with gastric and duodenal ulcers in humans and animals.
    Exposure to cigarette smoke significantly potentiated ethanol-induced
    gastric mucosal damage in Sprague-Dawley rats (Iwata et al., 1995;
    Chow et al., 1996).

    The effect of smoking on the incidence of cancers of the oral cavity,
    oropharynx, hypopharynx and larynx is often combined with other
    factors, principally alcohol, in the Western world. The possibility of
    interaction between cigarette smoking and alcohol consumption is
    complex (Burch et al., 1981).

    Rothman & Keller (1972) reviewed the effect of joint exposure to
    tobacco and alcohol with regard to oral cancers alone (based on data
    published earlier by Keller & Terris, 1965) and concluded that a

    single multiplicative function of the relative risks associated with
    alcohol and tobacco separately provided an adequate summary of their
    joint effect.

    Wynder & Bross (1961) studied etiological factors in cancer of the
    oesophagus, considered the consumption and effects of tobacco and
    alcohol separately and together, and considered that the combined
    effect was multiplicative. Tuyns et al. (1977) reported a similar
    pattern of joint effect of tobacco and alcohol in a retrospective
    study of oesophageal cancer in Brittany, France. The relative risk of
    developing oesophageal cancer increased linearly with daily
    consumption of alcohol and tobacco independently. The combined effect
    fitted a multiplicative model.

    Wynder et al. (1976) analysed environmental factors in cancer of the
    larynx and showed a combined effect of tobacco and alcohol. In the
    presence of smoking, heavy drinking increased the risk of cancer of
    the larynx, especially for cancer of the supraglottic portion of the
    larynx. Similar findings were reported by Burch et al. (1981).

    In a prospective epidemiological study, the relative risk of incurring
    a single primary carcinoma of the oral cavity, pharynx, larynx and
    oesophagus in any one of these sites was increased independently by
    the duration and intensity of exposure to tobacco or alcohol and
    sustained exposure enhanced the risk in a multiplicative or
    synergistic fashion (Schottenfeld et al., 1974) The relative risk of
    multiple primary cancers in the sub-group with combined exposures to
    high levels of tobacco and alcohol was 3.9 times that of patients
    exposed previously to low levels of alcohol and tobacco.

    3.5.6  Other organic compounds

    Exposure situations involving compounds and mixtures of organic
    compounds for which no definite smoking interactions have been
    established but which are known to present serious health hazards are
    summarized in chapter 4.

    3.6  Physical agents

    3.6.1  Radiation

    The harmful forms of ionizing radiation that are of concern are
    alpha- and beta-particles and gamma- and X-rays. All cause cellular
    damage and have been implicated in carcinogenesis. IARC (1988)
    classified radon and its decay products as Group 1 (carcinogenic to
    humans) on the basis of sufficient evidence in humans and in
    laboratory animals. The interaction of the effects of these radiations
    with the effects of tobacco smoke has been studied. Radium is present
    in uranium and other minerals and in all rocks and soils. It emits
    alpha- and beta-particles and gamma-rays and decays to form the
    chemically inert radioactive gas radon, which is released in tiny
    amounts into the atmosphere where its concentration is extremely small
    because of dilution. It can, however, become more concentrated in some

    locations, particularly in uranium and other mines and in residential
    buildings. Radon is an inspirable gas and its radioactive decay
    products are ionized metal atoms, which adhere to inspirable dust
    particles. These atoms are themselves undergoing radioactive decay and
    emitting damaging alpha- and beta-particles and gamma-rays. In
    addition to interactions of tobacco smoke with radon in mines and
    residential situations, other effects of tobacco smoke and radiation
    interactions have been studied in atom-bomb survivors and in the low
    energy transfer radiation involved in the use of therapeutic radiation
    (X-rays).  Radon in mines (high linear energy transfer (LET)

    Unless mines are well ventilated, the atmospheric concentration of
    radon becomes significant. The gas and its radioactive decay products,
    the radon daughters, can be inhaled. The daughters have short
    half-lives and their decay is proceeding while the particles to which
    they adhere are resident in the lungs and before they can be removed
    by normal lung clearance. Thus radiation is delivered directly to the
    delicate lung tissues where it causes an excess of lung cancer among
    some miners.

    Observations in several mining communities, e.g., among uranium miners
    in the USA, Czechoslovakia, Canada and France, workers in a niobium
    mine in Norway, iron ore miners in Sweden, tin miners in China and the
    United Kingdom, and fluorspar miners in Newfoundland, showed a
    significant dose-related increase in lung cancer risk with exposure to
    radon and radon daughter elements (Archer, 1988). In miners who were
    cigarette smokers, there was an interaction between the radiation
    exposure and the smoke exposure leading to more than the expected
    number of cases of cancer. The latent period for induction of lung
    cancer was longer when the exposure to radioactivity started at a
    younger age, it was shortened by high exposure rates and by cigarette
    smoking, and lung cancers developed at lower levels of exposure to
    radioactivity in miners who smoked than in those who were non-smokers.
    In Bulgaria, Michaylov et al. (1995) used sputum cytology to study
    bronchial cell dysplasia in 334 miners (uranium and metal mines)
    exposed to 222Rn progeny, and 100 control miners from a metal mine
    where radon was virtually absent. The dust and silica concentrations
    and exposure to diesel exhaust and explosion gases were similar. The
    frequency of bronchial cell dysplasia was significantly higher in
    radon-exposed miners than in controls and the frequency of dysplasia
    in smokers was significantly greater than in non-smokers.

    The lower prevalence of lung cancer among coal miners than among other
    underground workers is probably because coal mines are well ventilated
    to reduce fire and explosion risk, and no build up of radioactivity
    occurs. Attempts to reduce silicosis by ventilation have achieved a
    similar effect. In some Swedish mines, because freezing occurred when
    outside air was used for ventilation, filtration was achieved in the
    1920s by circulating the air through old underground mine workings,
    with the result that the potential for silicosis was reduced. However,

    an increase in lung cancer was found because radioactive materials
    built up, a fact that only became evident many years later (Archer,

    The nature of the interaction between radon and cigarette smoke is not
    clear. In a study by Edling (1982), the effects of smoking and radon
    were considered to be additive, whereas in another by Damber & Larsson
    (1985b) the effect was multiplicative. From a long-term study on
    Swedish iron ore miners (Jörgensen, 1984), it was concluded that
    tobacco smoke acts as a tumour promoter, an effect that has been
    demonstrated in almost all animal studies. The concept that radon
    serves as a tumour initiator and tobacco smoke as the tumour promoter
    for the induction and development of lung cancer is supported by a
    sequence of studies. Tobacco contains small amounts of polonium-210
    (210Po), which primarily originates from phosphate fertilizers (Tso et
    al., 1966) and, to a minor extent, from airborne 210Po trapped by the
    glandular hairs (trichomes) found on the soil-facing surfaces of
    tobacco leaves (Martell, 1974). 210Po is a decay product of radon -222
    and an emitter of alpha-particles. It is present in cigarette smoke,
    and the bronchial epithelium of smokers contains 2-10 times more 210Po
    than is found in these tissues in non-smokers (Harley et al., 1980).
    The alpha-radiation of 210Po damages DNA in the bronchial airways and
    serves as a tumour inhibitor, and the tar in the tobacco smoke acts as
    a tumour promoter.

    The frequencies of different histological types of lung cancer among
    miners have varied with working conditions and follow-up time. It has
    also been shown (Archer, 1988) that the age range of the population
    under observation can influence the conclusion. Thus, the 
    smoking-radon relationship appears to be multiplicative only for the 
    group aged 35-65 years. Steenland (1994) found the death rates from 
    lung cancer in smoking uranium miners to be intermediate between 
    additive and multiplicative for the two exposures, but, when 
    stratified for age, the multiplicative model fitted well for the 
    youngest and oldest categories but poorly for the middle range. In a 
    comprehensive analysis of data from 11 studies of radon-induced health
    risks (Lubin et al., 1995), it was concluded that the joint effect of 
    radon progeny exposure and smoking is greater than the sum of the 
    individual effects and for smokers is higher by a factor of at least 
    three. The tobacco of cigarettes contains 0.1-1.0 pCi of 210Po 
    (Cohen et al., 1985; Hoffmann et al., 1986).

    The conclusion reached by the US Surgeon General (1985) was that the
    smoking-radon interaction consists of two parts: an additive effect of
    the contribution of the two agents on the number of tumours produced
    and an accelerating effect due to tumour promoters in cigarette smoke.
    Thus for a miner who smokes, not only is the chance of lung cancer
    greater but the latent period is shorter and therefore the cancer
    appears sooner in smokers.  Environmental radon (high linear energy transfer (LET)

    Alpha-radiation from radon daughters in the home or in other
    situations where there are enclosed spaces with poor ventilation,
    e.g., where strict energy conservation measures have been adopted,
    presents an elevated health hazard to occupants, particularly smokers,
    and is a matter of public health concern. The ease with which ionized
    radon daughters could be attracted to environmental tobacco smoke
    particles and the possibility of a higher than additive combined
    effect of radon progeny and smoke clearly indicate the importance of
    residential contamination by radon.

    The relative risk in the range of exposure experienced by miners has
    been found to be linear, and it has been suggested from extrapolation
    that exposures at the lower levels found in homes would carry some
    risk (Lubin et al., 1995). Steindorf et al. (1995) calculated that 7%
    of all lung cancer deaths in the western part of Germany may be due to
    residential radon.

    Axelson (1995) reviewed cancer risks from exposure to radon in the
    home and suggested that cancers other than lung cancer may also be
    related to indoor radon, especially leukaemia, kidney cancer and
    malignant melanoma. However, it was acknowledged that studies of radon
    and miners gave no clear support for this. Alavanja et al. (1995)
    listed other risk factors as being responsible for lung cancer in
    lifetime non-smokers and found a small non-significant risk for
    subjects exposed to domestic radon at median concentrations. In a
    case-control study of lung cancer in relation to exposure to radon in
    homes (Letourneau et al., 1994), no increase in the relative risk for
    any of the histological types of lung cancer was detected in relation
    to cumulative exposure to radon. On the other hand, Biberman et al.
    (1993) found an increased risk for small cell lung cancer following
    residential long-term exposure to radon at a low-dose level. In a
    large case-control study in Sweden, Pershagen et al. (1994) reported
    an increased relative risk of lung cancer within the highest exposure
    group. In an attempt to resolve the conflicting epidemiological data,
    Lubin & Boice (1997) conducted a meta-analysis of eight large-scale
    case-control studies of residential radon and lung cancer. This
    analysis was consistent with an excess lung cancer risk. Furthermore,
    the slope of the exposure- response curve derived from this
    meta-analysis was comparable with that obtained from a combined
    analysis of eleven miner cohorts exposed to radon (Lubin et al.,

    The combined analysis of the miner data also confirmed the strong
    synergistic relationship between radon and tobacco at high levels of
    exposure to these two agents (Lubin et al., 1997), although it is
    difficult to determine whether the interaction is closer to additive
    or multiplicative (Chaffey & Bowie, 1994). When extrapolated to lower
    levels of exposure, however, the magnitude of this interaction is
    substantially diminished (Moolgavkar et al., 1993). However, Pershagen
    et al. (1994) reported some evidence of a synergistic effect between

    tobacco and residential radon exposure, with the relative risk of
    radon-induced lung cancer being highest among heavy smokers. In a
    case-control study of 982 subjects with lung cancer and 3185 hospital
    or population control subjects, lung cancer risk was examined in
    relation to residential radon concentration and length of time that
    subjects were resident, and adjusted for age, sex and smoking (Darby
    et al., 1998). The relative risk increased in an exposure-related
    manner with time-weighted residential radon concentration and fitted
    the data from studies in miners and the effect of smoking. Regardless
    of the magnitude of any interaction between tobacco smoking and
    residential radon, the lung cancer risks due to smoking exceed the
    risk associated with radon in homes.  Atomic bomb site radiation (low linear energy transfer (LET)

    In tobacco-smoking survivors of atomic bombing in Hiroshima and
    Nagasaki, Japan, elevated levels of cancer of several sites have been
    reported. In the case of lung cancer both additive and multiplicative
    models fit the data (Prentice et al., 1983; US NRC, 1988).  Therapeutic X-rays (low linear energy transfer (LET)

    Lung cancer as a possible side effect of the radiation therapy used to
    treat breast cancer has been studied by Neugut et al. (1993, 1994) and
    discussed by Inskip & Boice (1994). Neugut et al. (1993) reported that
    the risk was greater in the ipsilateral than in the contralateral
    lung. In a second study (Neugut et al., 1994), a three-fold relative
    risk was found for the effect of radiation therapy among 10-year
    survivors, a 14-fold risk was associated with smoking alone, and a
    33-fold risk was found among irradiated smokers; in each case the
    effect was most pronounced for ipsilateral lung cancer. A
    multiplicative interaction was proposed and the implications of the
    results for the design of treatment of breast cancer in smokers was
    considered. The increased risk of lung cancer among survivors of
    Hodgkin's disease(HD) was studied by van Leeuwen et al. (1995). Their
    overall conclusions were that the risk of lung cancer increased more
    with increasing radiation dose in HD patients who smoked than among
    those who did not smoke. Thus, smokers were at greater risk from the
    radiotherapy than non-smokers. The interaction between the
    carcinogenic effects of smoking and radiation was significantly
    stronger than multiplicative, and the low lung cancer rate found among
    women with HD was attributable to the delayed popularity of smoking
    among Dutch women, a fact shown by the male/female lung cancer ratio
    (13:5) in the Netherlands in 1980.  Nuclear plant

    Ongoing epidemiological studies are being conducted on the workforce
    exposed to radiation at the Mayak plant in Russia. Of 500 workers
    examined in a case-control study (Tokarskaya et al., 1995), 162

    workers had contracted lung cancer, and the remaining 338 served as
    radiation-exposed, non-tumour-bearing controls. Both the incidence and
    duration of smoking was significantly higher in workers contracting
    tumours compared to combined male and female controls. The strongest
    smoking-related effect was for squamous cell carcinomas, followed by
    adenocarcinomas, then small cell carcinomas. However, the findings are
    complicated by the fact that the great majority of the workforce was
    male, and there was only one of the 148 "never smokers" among the male
    lung cancer cases.  Summary

    In summary, miners subjected to chronic exposure throughout a working
    lifetime to high-LET radiation show a radiation/tobacco smoke
    interaction greater than additive and sometimes multiplicative. Atomic
    bomb survivors exposed instantaneously to low-LET radiation show in
    some cases an additive and in others a multiplicative interaction. The
    results for residentially exposed smokers, subjected to a lifetime of
    very low dose exposure, tend to show similar interactions to those for
    miners. Tobacco-smoking patients subjected to therapeutic radiation
    (low-LET) show a multiplicative interaction.

    3.6.2  Vibration

    Raynaud's phenomenon is an episodic disorder that produces
    intermittent attacks of blanching in the extremities and there may be
    numbness or tingling in the hands and fingers. There are several
    causes (the term "Raynaud's disease" is applied when the cause is not
    known). It was first associated with the use of vibrating tools among
    Italian miners in 1911, and the association has since been reported
    for a wide range of hand-held vibrating tools such as impact hammers,
    chipping hammers, grinders, riveters and the motor-driven chain-saws
    used in forestry. The terms vibration white finger (VWF), vibration
    syndrome, traumatic vasospastic disease and dead finger have been used
    for this condition that begins with numbness and tingling, followed by
    blanching and can include intermittent episodes of hand and finger
    pain and flushing. With continuing exposure to vibration the symptoms
    may become more severe and continue after the cessation of exposure.
    Damage to digital arteries and narrowing of the lumen has been
    associated with vibration syndrome (JOM, 1984) and, because nicotine
    acts as a vasoconstrictor, it has been suggested (JOM, 1984) that
    limiting smoking could aid blood flow to the extremities and thus
    reduce the condition. In a survey of forestry workers in Quebec in
    1977-1978 (Thériault et al., 1982), a prevalence of Raynaud's
    phenomenon among 1540 woodcutters was found in 30.5% of chain-saw
    users and there was a strong association between this and cigarette
    smoking; the relative risks were 3.60 for non-smokers, 6.55 for
    smokers and 1.72 for smokers who had not used a chain-saw:
    corresponding to an additive effect for the two risk factors. From
    another study of the effect of tobacco use on a cohort of men with
    VWF, in which the extent of tobacco use was confirmed by blood
    nicotine and cotinine measurements (Ekenvall & Lindblad, 1989), it was

    shown that tobacco aggravates the symptoms of VWF. Patients with
    advanced symptoms were found to use tobacco more frequently and to
    have higher blood cotinine levels than patients with less advanced
    disease. In a study of the prognosis of VWF (Petersen et al., 1995),
    an improvement in the condition occurred when there was no exposure to
    either vibration or smoking, whereas an aggravation of the condition
    was most notable in smokers. Whole-body vibration has been associated
    with persistent severe neck trouble, and smoking was an added
    predictor for this condition (Viikari-Juntura et al., 1994). Finger
    temperature changes have been measured after smoking a cigarette; in
    all cases a reduction in temperature was recorded (Saumet et al.,1986;
    Bornmyr & Svensson, 1991).

    3.6.3  Noise

    In a study of aviators in 1963 at the US Naval Aerospace Medical
    Research Laboratory (Thomas et al., 1981), two hearing level groups
    were identified, one with normal and the other with impaired hearing.
    The impaired hearing group had smoked more cigarettes for a longer
    period of time than had those in the normal hearing group. In another
    study the relationship between cigarette smoking and hearing loss was
    studied in 2348 noise-exposed workers at an aerospace company and it
    was found that smoking was a clear risk factor in noise-induced
    hearing loss: the OR was 1.27 for "ever smokers" and 1.39 for present
    smokers, compared with non-smokers (Barone et al., 1987). Vascular
    insufficiency of the cochlear organ has been cited as the predominant
    cause of progressive hearing loss that occurs with age. It was
    suggested that smoking reduces the cochlear blood supply by:
    a) vasospasm induced by nicotine; b) atherosclerotic narrowing of
    vessels; and c) thrombotic occlusions (Zelman, 1973). In a study of
    1000 subjects at a Veterans Hospital, Zelman (1973) found that whilst
    age and sex were the most important variables, at all measured
    frequencies the percentage of loss was greater for smokers, the
    differences being greater at higher frequencies. From a retrospective
    analysis of audiograms taken between 1984 and 1990 of a cohort of 119
    workers, 78.8% of smokers compared with 25.7% of non-smokers had
    noise-induced hearing loss (ILO, 1991). Although these studies
    demonstrated a positive correlation between smoking and hearing loss,
    Friedman et al. (1969) and Pyykko et al. (1987) were not able to show
    that smoking was a significant risk factor to hearing loss.

    3.6.4  Dupuytren's contracture

    Dupuytren's contracture is a contracture of some muscle membranes of
    the palm of the hand that causes the little finger and ring finger to
    be drawn into the palm from where they cannot be extended. It is
    characterized by a retractile sclerosis of the palmar aponeurosis,
    which may progress to an irreducible flexion of the fingers. Opinions
    differ on the influence of occupation, handedness and hand injury on
    Dupuytrens contracture which Dupuytren himself attributed to chronic
    occupational injury. Some people assert that heavy work always causes
    the disease, while others claim that it is not responsible. Mikkelsen

    (1978) studied 901 cases in an epidemiological study of 15 950 and
    concluded, after isolating hand trauma, that Dupuytren's contracture
    is caused by heavy work. The contribution made by tobacco has been as
    contentious as has the cause of Dupuytren's contracture. Hand
    thermography of affected fingers in Dupuytren's contracture shows a
    drop in temperature of up to 3 degrees; and hand temperature falls by
    a similar amount during smoking. In a study of 84 men and 16 women
    with Dupuytren's contracture, Fraser-Moodie (1976) found no evidence
    that smoking was connected with the condition, a conclusion also
    reached by Mackenney (1983). However, cigarette smoking was listed
    among the responsible factors for Dupuytren's contracture by Attali et
    al. (1987), as well as by An et al. (1988), who found that cigarette
    smoking was linked statistically to Dupuytren's contracture and
    suggested that it may be involved in its pathogenesis by producing
    microvascular occlusion and subsequent fibrosis and contracture. An et
    al. (1988) concluded that cigarette smoking was one of the most
    significant factors in the development of peripheral vasculopathy
    Abelin et al. (1990) showed a significant association between
    Dupuytren's contracture and smoking habits.

    3.7  Biological agents

    3.7.1  Biological (vegetable) dusts

    Uncontrolled exposure to airborne vegetable dusts can affect health
    and occurs worldwide in many workplaces, e.g., in agricultural
    operations, textile industries, construction, carpentry and the
    furniture industry. The population exposed is large, particularly in
    developing countries where whole families, from young children to the
    elderly, may engage in agricultural activities and small scale
    manufacturing operations using vegetable products. These agents can
    take the form of vegetable dusts, airborne fungal spores and
    microorganisms, animal danders and feathers, herbicides and pesticides
    and their residues. Processing of agricultural products, such as
    cotton, flax, hemp, grain, tobacco, paprika and tea, and the milling
    of certain varieties of wood are occupations where vegetable dust
    exposures have been associated with detrimental health effects.

    In addition to the irritation and bronchitis that is associated with
    exposure to almost any dust, biological dusts can cause byssinosis,
    allergic and immunological responses and, in some cases, nasal and
    paranasal cancer. All these conditions can be affected in different
    measure by tobacco smoking.  Cotton dust

    Byssinosis is a respiratory disease of textile workers. The disease is
    found in many cotton processing countries. It is more prevalent in the
    dusty stages of cotton processing, such as carding, than in weaving.
    Byssinosis, or similar symptoms, and bronchitis have also been found
    in flax, hemp, jute and sisal workers. The characteristic symptoms are

    tightness of the chest and shortness of breath on returning to work
    after a period of absence. There is the possibility of progression to
    permanent respiratory disability.

    In a study of textile workers in South Carolina, USA, in 1973, the
    smoking prevalence was almost the same for workers as for controls
    (Beck et al., 1984). In another study of cotton workers in 1963-1966
    (Molyneux & Tombleson, 1970), the percentage of male current smokers
    was 62.5% and of ex-smokers 16.4%; among females the figures were
    33.9% and 6.1%, respectively. Among flax scutchers in Normandy in
    1986-1987, 56% were smokers and 18% were ex-smokers; compared with 45%
    and 15%, respectively, for the controls (Cinkotai et al., 1988a). In
    31 Lancashire textile factories (1988) 47.5% of the 4656 workers
    interviewed were smokers (Cinkotai et al., 1988b). Of 800 000 American
    workers surveyed (Stellman et al., 1988) for smoking habits in 1982,
    5.9% were exposed to textile fibres or dust: 28.5% of these were
    regular cigarette smokers and 44.9% were former cigarette smokers;
    compared with 23.5% and 43.5%, respectively, in other occupations not
    exposed to textiles.

    Increases in both byssinosis and bronchitis were attributed to cotton
    dust exposure and smoking in the cotton industry (Molyneux &
    Tombleson, 1970; Merchant et al., 1973). From an industrial study of
    the effects of cotton dust and cigarette smoke, Merchant et al. (1972)
    concluded that smokers showed an increase in both the prevalence and
    severity of cotton dust-induced byssinosis and that cigarette smoke
    also increased the detrimental effect of cotton dust on ventilatory
    capacity. It was suggested that the impairment of lung clearance
    mechanisms by cigarette smoke could be responsible for the deleterious
    effect of cotton dust and that smoking might lower the threshold of
    susceptibility to the effects of inhaled cotton dust. Additivity and
    the equal importance of the effects of smoke and cotton dust have been
    suggested (Beck et al., 1984) but since different lung function
    parameters are affected it would seem that the two factors affect
    different sites. The fact that workers who stopped smoking, whilst
    remaining in the same job, lost their byssinotic symptoms was
    significant. A survey by Cinkotai et al. (1988a) of workers in 31
    textile factories in Lancashire, United Kingdom, showed that
    byssinotic symptoms (in decreasing order) were related to years in the
    industry, degree of dust exposure, quality of cotton in use, ethnic
    origin of workers and smoking habits. Symptoms of chronic bronchitis
    were related primarily to smoking habits and then to factors connected
    with the occupation. In a study of hemp workers (Bouhuys & Zuskin,
    1976), decline in ventilatory function was more pronounced in smokers.
    It was suggested (Cinkotai et al., 1988b) that a surprisingly low
    prevalence of byssinotic symptoms in 12 flax scutching mills in
    Normandy may have been due to either self selection of the workforce
    or to an absence of the causative agent in the dust. Persistent cough
    and phlegm production were associated with tobacco use.

    In textile-related pulmonary disease, smoking as a primary causative
    factor was reported by Pratt et al. (1980), and a similar conclusion
    was arrived at from lung function tests carried out over a 3-year

    period on 153 women (103 smokers, 50 non-smokers) with grades 2 and 3
    byssinosis by Honeybourne & Pickering (1986). Cancer deaths in general
    and lung cancer in particular were lower in workers exposed to cotton
    dust than in others (Enterline et al., 1985). Kilburn (1989) suggested
    that the effect of byssinosis on mortality of textile workers from
    pulmonary disease needed more comprehensive study.  Wood dust

    IARC (1995) evaluated the carcinogenic risk of wood dust and
    classified it as carcinogenic to humans (Group 1), based on sufficient
    evidence in humans and inadequate evidence in animals. The risk of
    developing cancer of the nasal cavity among workers manufacturing
    wooden furniture has been shown to be up to 100 times greater than for
    the general population (Rang & Acheson, 1981). The effect is worst in
    the most dusty areas (Rang & Acheson, 1981; Hayes et al., 1986). The
    association of risk with certain hardwoods and the finishing of fine
    furniture, rather than with woodworking in general, suggests that it
    may be allied to both the chemical and physical nature of the dust. In
    the study where the nasal cancer incidence was 100 times greater than
    for the general population, it did not appear to be affected by
    smoking habits. A similar conclusion was reached in a study in an area
    of Italy with a large number of cases of nasal cancer among wood and
    leather workers (Cecchi et al., 1980). An association with smoking was
    established in other studies, and current and past smoking habits were
    shown to be a risk factor for developing squamous cell cancer of the
    sinus in men (Fukuda et al., 1987). A case-control study of 121 male
    woodworkers who were examined for cancer of the nasal cavity or
    paranasal sinus, in British Columbia in Canada between 1939 and 1977
    (Elwood, 1981), showed increased relative risks associated with
    occupations involving exposure to wood (relative risk 2.5) and with
    smoking (relative risk 4.9). In a study in North Carolina and Virginia
    in the USA between 1970 and 1980 (Brinton et al., 1984), a major
    finding was the elevated risk of nasal cavity and sinus cancer among
    cigarette smokers. However, the nature of any interaction of wood dust
    and tobacco smoking needs further study because adenocarcinomata
    appear to be the tumour type associated with wood dust, whereas the
    relative risks for squamous-cell and small-cell cancers tend to be
    higher for smokers. The available data do not permit an assessment of
    the degree of interaction between smoking and wood dust exposure.  Allergic responses

    This type of response can occur in the upper airways, where it is
    manifest as hay fever, in response to certain types of pollen, or in
    the bronchi as asthma, or it may appear in both. Some of the dusts
    that cause allergic airways responses (occupational asthma) are grain
    dusts from various cereals and their products, wood dusts particularly
    from red cedar and iroko, and dusts from teas and tobacco. Among
    asthmatics, environmental cigarette smoke makes the effect of the
    asthma worse (Shim & Williams, 1986), and smoking effects appear to be
    additive to that of asthma from other causes (Conolly et al., 1988).

    Grain dust exposure and smoking have been found to cause increases in
    the prevalence of respiratory symptoms and reductions in pulmonary
    function of grain elevator workers. The effect of smoking was slightly
    more pronounced; the combined effect of grain dust and smoking
    appeared to be additive, except in the least exposed workers (5 years
    or less) where a synergistic effect was observed in tests for
    peripheral airways dysfunction (Cotton et al., 1983). Chan-Yeung et
    al. (1985) stated that the effect of grain dust and smoking was
    additive and not synergistic in causing a decrease in lung function.
    In 303 workers in the animal feed industry exposed to dusts of grains
    and cassava, 61 (20%) showed respiratory symptoms; in office staff in
    the same plant the prevalence was similar. The plant workers had a
    higher prevalence of smoking than office staff. Current smoking was
    strongly associated with respiratory complaints in both groups (Post
    et al., 1994).

    Occupational asthma also occurs in flour, tea, coffee and rice
    handlers. In Italian bakers and pastry makers De Zotti et al. (1994)
    found that 54 (23%) of the 226 subjects were atopic. Forty (18%) were
    skin-test-positive to storage mites, 27 (12%) to wheat flour and 17
    (8%) to alpha-amylase. Skin sensitization to these occupational
    allergens was significantly associated with atopy, smoking and
    duration of exposure. In a study of 401 workers in bakeries or flour
    mills, Cullinan et al. (1994a) found that work-related symptoms of
    allergy were more common in smokers, with little difference between
    atopic and non-atopic workers. However, smoking was not independently
    related to either symptoms or positive skin test.

    Zetterstrom et al. (1981) skin-prick-tested 129 workers in a coffee
    roastery with green coffee bean and castor bean extracts. There was a
    significantly increased prevalence of positive skin prick tests in
    smokers. In enzyme detergent workers with occupational asthma, it was
    found that twice as many smokers as non-smokers exhibited asthmatic
    symptoms (Greenberg et al., 1970; Mitchell & Gandevia, 1971).

    Smokers are more likely to show higher specific antibody production
    and correspondingly be more susceptible to asthma.

    3.7.2  Other biological agents

    Although many biological dusts are known to have detrimental health
    effects, there have been few studies of any interaction of smoking
    with these agents. Extrinsic allergic alveolitis may be caused by
    spores from a number of fungi which are small enough to reach the
    pulmonary compartment. There are several forms of allergic alveolitis,
    of which farmer's lung, bagasse pneumonitis, and bird fancier's lung
    are examples. These are caused by fungal spores in mouldy hay or
    mouldy sugar cane or an agent in bird feathers, respectively, and are
    immunologically mediated (Lancet, 1985). Extrinsic allergic alveolitis
    is a rare example of a respiratory disease which is more prevalent in
    non-smokers than in smokers. In one study, 14 of 18 patients (11 with

    farmer's lung and 7 with bird fancier's lung) were non-smokers, twice
    the proportion of non-smokers in patients with cryptogenic fibrosing
    alveolitis or in the local population (Warren, 1977). Carrillo et al.
    (1991) investigated IgG response to pigeon serum and its relation to
    tobacco smoking in 160 pigeon fanciers. The sensitization rate was
    31.9%. Pigeon fanciers who were current smokers had significantly
    lower levels of IgG antibodies to pigeon serum (P<0.001).
    Precipitating antibodies to  Micropolyspora faeni, a common cause of
    farmer's lung, were found to be twice as common in the area of
    non-smokers in farming communities compared with smokers (Morgan et
    al., 1975). Alveolar macrophage phagocytosis has been shown to be
    depressed by cigarette smoke and it has been suggested this may
    explain its apparent protective effect (Hocking & Golde, 1979).

    3.7.3  Agents found in factory farming (animal
           confinement effects)

    Factory farming of pigs, where the animals are kept in confined
    conditions, is common practice in livestock production in many
    developed countries and it has been found to be accompanied by adverse
    respiratory symptoms in workers. Donham et al. (1984) summarized the
    effects as: acute toxicosis and inflammation of the respiratory tract
    from inhaling hydrogen sulfide; acute asthma-like symptoms;
    bronchitis; and delayed or hypersensitivity pneumonitis-like symptoms.
    They found that smoking interacted additively with the bronchitis and
    obstructive symptoms of the condition. In a study of workers in swine
    confinement areas, Zuskin et al. (1992) reported similar effects. They
    also found that smoking aggravated acute and chronic respiratory
    symptoms and impairment of lung function.

    3.7.4  Laboratory animals

    Venables et al. (1988b) examined data from three cross-sectional
    surveys of 296 laboratory workers around 30 years of age exposed to
    small mammals. Two populations were of pharmaceutical research workers
    (N = 133 and 140) and one of research workers in a tobacco company 
    (N = 23). One of the pharmaceutical research worker populations had a
    laboratory animal allergy (LAA) prevalence rate of over 40% (Venables
    et al., 1988a). The tobacco company research workers were exposed only
    to rats while the other two populations were exposed to rats, mice,
    guinea-pigs and rabbits. Atopy was determined by skin prick test to
    non-animal aeroallergens. Sensitization to laboratory animals was
    determined by response to skin prick tests using urinary extracts from
    the species used in each laboratory. Radioallergoabsorbent tests
    (RASTs) were used to measure serum IgE antibody concentration to the
    urinary extracts in two of the populations.

    Atopy in the three populations ranged from 30% to 44%, and positive
    skin response to urinary extract ranged from 13% to 48%. Pooled data
    from the three surveys showed an association between smoking and

    positive skin response to urinary extract. Associations with smoking
    persisted after stratifying by atopic status, suggesting that smoking
    was a risk factor for developing laboratory animal allergy.

    In other studies of 238 laboratory workers without previous
    occupational exposure to rats in three institutions specializing in
    small animal research, atopy was again determined by skin prick test
    response to non-animal aeroallergens and sensitization to laboratory
    rats by response to urinary extract. Exposure to total dust and rat
    urinary aeroallergen was also measured. Allergy to rats was positively
    related to exposure intensity and this was stronger in atopic
    subjects. Positive responses to skin prick testing with rat urinary
    extract were strongly related to atopy and to smoking at all levels of
    exposure (Cullinan et al., 1994b).

    Several studies from Europe have shown an association between
    ownership of pet birds or pigeons and lung cancer (Holst et al., 1988;
    Kohlmeier et al., 1992; Gardiner et al., 1992). The relative risk
    adjusted for smoking was 6.7 (2.2-20.0). However, two community-based
    case-control studies, one from the USA and one from Sweden, could not
    confirm an association between pet birds and lung cancer (Alavanja et
    al., 1996; Modigh et al., 1996). In 1998, a hospital-based
    case-control study conducted in New York City and Washington, DC, with
    887 cases and 1350 controls, did not show an association of keeping
    pet birds with lung cancer in non-smokers. There was a ten-fold
    increase of lung cancer among smokers who were not bird keepers over
    non-smokers, but there was no indication of synergism between smoking
    and keeping a pet bird (Morabia et al., 1998).

    3.7.5  Schistosomiasis

    In a study carried out in Spain, risk factors for urinary bladder
    cancer were identified (Bravo et al., 1987). The factors were listed
    in order of importance and the first three were total number of
    cigarettes smoked, history of urological disease and exposure to an
    occupational risk. Vineis (1992) summarized epidemiological,
    biochemical and molecular evidence that clearly linked smoking with an
    increased risk of bladder cancer. Cohen & Johansson (1992) considered
    smoking to be the most important etiological factor for bladder
    cancer. They also implicated a variety of occupational exposures and,
    in some parts of the world, an association with various endemic
    diseases including schistosomiasis. Schistosomiasis is a waterborne
    parasitic disease found in many developing countries in Africa, Asia
    and South America. It is a widespread occupational disease for
    agricultural workers, and also affects members of the general

    A phase in the life-cycle of the trematodes responsible for the
    disease lives in the blood vessels of visceral organs and their eggs
    are discharged through the bladder or intestine in urine and faeces.
    Some species live in the mesenteric veins and the eggs are discharged
    in the faeces but the eggs of  Schistosoma haematobium mature in the

    veins of the bladder and are discharged in the urine. The eggs mature
    in water and the resultant larvae infect freshwater snails. Within the
    snail the parasites multiply to produce free swimming cercaria larvae
    which can infect humans via skin penetration and repeat the cycle.  S.
    haematobium is found in nearly all countries in the African continent
    and it has been found that the incidence of bladder cancer is higher
    in areas with a high prevalence of infection than in areas with a low
    prevalence. IARC classifies infection with  S. haematobium as
    carcinogenic to humans (Group 1) (IARC, 1994b). In Egypt, the most
    common form of cancer is bladder cancer, accounting for 27.6% of all
    malignancies encountered (38.5% of cancers in males and 11.3% in
    females), and these high levels have been attributed to underlying
    schistosomiasis (Tawfik, 1987). Makhyoun (1974) carried out a
    case-control study of smoking among Egyptian males with and without a
    previous history of  S. haematobium infection. A smoking index was
    calculated (average number of cigarettes per day × duration of smoking
    in years) to categorize subjects. The smoking index (intensity and
    duration of smoking) was higher in all the patients with bladder
    cancer. In the patients with a previous schistosomiasis infection,
    22.7% were moderate or heavy smokers compared with 79.3% of the
    non-schistosomiasis patients. In the latter there was a good
    correlation with the smoking index but in the bladder cancer patients
    with previous schistosomiasis there was no significant difference in
    smoking index between patients and matched controls. It was not
    possible to identify an interaction between smoking and
    schistosomiasis in the production of bladder cancer.

    However, in a review of the role of  S. haematobium in human bladder
    cancer, Badawi et al. (1995) referred to several major studies that
    implicated this infection with the subsequent development of bladder
    cancer. Badawi et al. (1995) listed examples of a co-carcinogenic
    effect of parasitic infection in the presence of chemical carcinogens
    and it has been suggested (Hicks et al., 1980; Hicks, 1982) that
    schistosomiasis could supply the necessary proliferative stimulus to
    accelerate cancer growth from latent tumour foci on exposure to
    carcinogenic nitrosamines. Nitrosamines have been implicated as
    carcinogens among tobacco chewers and oral snuff users (Hecht &
    Hoffmann, 1988, 1991; Hoffmann et al., 1991a), nitrosamines have been
    demonstrated in smoke (Tricker & Preussmann, 1992; Hoffmann et al.,
    1991b) and nicotine-derived  N-nitrosamines cause cancer (Hoffmann &
    Hoffmann, 1991; (IARC, 1991). Some  N-nitrosamines are excreted as
    esters via the urinary tract, e.g.,  N-nitroso-di- n-butanol or NNK
    as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. They may hydrolyse
    in the presence of infectious agents in the bladder, as is the case in
    schistosomiasis, and thus appear in their precarcinogenic form,
    thereby increasing the risk for cancer in the urinary tract.
    Endogenous nitrosation, which is increased by tobacco smoking, chewing
    and oral snuff use has been demonstrated by monitoring urinary
     N-nitrosamino acids (Tsuda & Kurashima, 1991). Badawi & Mostafa
    (1993) and Badawi et al. (1995) suggested that the evidence for an
    association between urinary schistosomiasis and bladder cancer

    development is sufficient to justify the conclusion that  S.
     haematobium infection is a factor in inducing preneoplastic changes
    in the bladder. Infection can reduce detoxification mechanisms (and
    thus prolong retention of carcinogens in the bladder), stimulate
    nitrosamine synthesis, and alter the activity of
    carcinogen-metabolizing enzymes.

    The conclusion is that an interaction is likely between tobacco use
    and schistosomiasis infection.

    3.7.6  Other urinary tract infections

    Kantor et al. (1984) found that the joint effect of urinary tract
    infection and cigarette smoking on bladder cancer was slightly beyond
    that expected under an additive model and suggested that patients with
    cystitis may be especially prone to tobacco-derived carcinogens in the
    urine. La Vecchia et al. (1991) studied cystitis, gonorrhoea and
    condylomata acuminata and found an interaction between urinary tract
    infection and tobacco that appeared to be multiplicative, with
    relative risk 2.4 for "ever smoking", 3.2 for cystitis alone, and 10.3
    for combined exposure. It was concluded that a relationship between
    urinary tract infection (and possibly some genital infections) and
    bladder cancer indicated a cancer promotion role of infection and a
    multiplicative smoking interaction. There have been reports of
    synergism between herpes simplex virus and tobacco-specific
     N-nitrosamines in cell transformation (Park et al., 1991a); an
    additive interaction between smoking and herpes simplex virus type 2
    in the promotion of cervical abnormalities (Mayberry, 1985), and the
    possibility of an interaction between cigarette smoking and herpes
    virus infection leading to cancer of the uterine cervix (Winkelstein
    et al., 1984).

    3.7.7  Sarcoidosis

    Bresnitz & Strom (1983) reviewed sarcoidosis and concluded that
    tobacco smoking might have a protective effect for the pathogenesis of
    sarcoidosis. Sarcoidosis is a generalized granulomatous disease
    involving the reticulo-endothelial system with lesions predominantly
    in the lymphatic system. Harf et al. (1986) investigated the smoking
    habits of 113 cases of histologically confirmed sarcoidosis in a
    case-control study in Lyon, France. Smoking habits were defined in 101
    cases and these were compared with a control group of healthy
    volunteers. There was a highly statistically significant negative
    association between sarcoidosis and smoking (OR = 3.8; 95% confidence
    interval: 2.4, 6.5) in both cases.

    3.8  Vector effects

    Toxic chemicals, as well as harmless materials that produce harmful
    chemical agents when they are burnt or vaporized, can be inadvertently
    transferred to cigarettes or other smoking materials and cause the
    smoke to be more injurious when it is inhaled.

    3.8.1  Polytetrafluoroethylene

    Polytetrafluoroethylene (Teflon(R)) is used in coatings for cooking
    utensils, for making chemical vessels, gaskets and bearings and in
    sprays as a mould release agent. Polytetrafluoroethylene and polyvinyl
    fluoride are inert materials but their thermal decomposition products
    can be very biologically reactive. Cigarettes can be easily
    contaminated in the workplace and, when smoked, the polymer burns to
    form fumes which cause "polymer-fume fever": severe gripping chest
    pain giving rise to difficulty in breathing; trembling and shaking;
    elevated temperature; and severe diaphoresis. The symptoms pass after
    a day or two, but recur on again smoking a contaminated cigarette.
    Before the cause was recognized a case was recorded of a person, who
    used the polymer in a mould release spray, having some 40 attacks
    (Kuntz & McCord, 1974). Another case was a person who referred to the
    disease as "mould machine pneumonia" (Kuntz & McCord, 1974). Other
    cases have been reported (Albrecht & Bryant, 1987) and better
    occupational hygiene and a ban on smoking in the workplace resulted in
    the disappearance of symptoms in those previously affected.

    3.8.2  Mercury

    Inorganic mercury occurs in many industries, as elemental mercury in
    scientific and electrical instruments, as amalgams with many other
    metals, in paints and pigments and in the chemical industry, as well
    as in mining and extraction of the metal. Organic mercury compounds
    are used as antiseptics, disinfectants, fungicides, bactericides and
    herbicides. Contamination of smoking materials can lead to the
    inhalation of mercury vapour. Mercury has been detected by neutron
    activation analysis as a naturally occurring trace element in tobacco
    (<1.0 ng/g) and in the smoke of cigarettes (4 ng/cigarette)
    (Schneider & Krivan, 1993; Krivan et al., 1994).

    3.9  Effects of tobacco smoking and metabolism of drugs and other

    3.9.1  Oral contraceptive use

    In the 1970s it was postulated that an interaction between tobacco use
    and oral contraceptives increased the risk of myocardial infarction in
    women. In a study of women less than 45 years of age, a greater
    proportion of moderate to heavy smokers were found in oral
    contraceptive users experiencing myocardial infarction, compared
    against a control population (Mann et al., 1975, 1976). Sturtevant
    (1982), however, found no "convincing evidence" for an interaction or
    synergism between the factors smoking and oral contraceptive use for
    the major classes of cardiovascular disease. Lidegaard (1993) reported
    no difference in the proportion of smokers between users and non-users
    of oral contraceptives in Danish women experiencing a cerebral
    thromboembolic attack and age-matched controls. Regarding thrombosis,
    the data of Vessey & Doll (1969) suggest an increased thromboembolism

    risk from oral contraceptive use for heavy smokers compared to
    non-smokers. However, other studies reviewed by Sturtevant (1982) and
    Nevius et al. (1982) are said to be ambiguous regarding a possible
    interaction between smoking and oral contraceptive use. On balance,
    there is evidence for certain interactions between smoking and oral
    contraceptive use: the US Surgeon General (1983a), concluded that
    "women who use oral contraceptives and who smoke increase their risk
    of a myocardial infarction by an approximately tenfold factor,
    compared with women who neither use oral contraceptives nor smoke",
    and "the use of both cigarettes and oral contraceptives greatly
    increases the risk for subarachnoid haemorrhage among women."

    3.9.2  Drug and chemical metabolism

    A number of studies have demonstrated that the metabolism of various
    drugs and other chemicals is influenced by the smoking status of the
    individual. This effect is sufficiently noteworthy that the US Surgeon
    General (1979) report concluded that it is "apparent that cigarette
    smoking is one of the primary causes of drug interactions in humans".
    The extensive review of the literature at that time led to the
    conclusions that, with respect to the influence of smoking on the
    disposition/metabolism of other compounds: (a) the dominant effect of
    smoking is enhanced drug disposition caused by the induction of
    hepatic enzymes; (b) tobacco smoke contains many enzyme inducers,
    notably polynuclear aromatic hydrocarbons; and (c) smoking can induce
    the metabolism of various therapeutic agents and their pharmacological
    and/or clinical effects. The metabolism of chemical carcinogens
    involves various isozymes of cytochromes P450 and differences in their
    genotypes or phenotypes may be a main factor responsible for
    differences among individuals in susceptibility to carcinogens.
    Metabolic activation of the procarcinogens such as benzo( a)pyrene to
    the ultimate form is accomplished by cytochrome P450IA1 (Kawajiri et
    al., 1990; Kawajiri & Fujii-Kuriyama, 1991; Nakachi et al., 1991).
    Although the most noteworthy effects of smoking cited were related to
    enzyme induction, it should also be noted that other components of the
    smoke, such as carbon monoxide, nicotine, cadmium, some pesticides,
    cyanide and acrolein, may serve to inhibit the function of some
    enzymes (Jusko, 1978). An example for this phenomenon is the
    inhibition by nicotine of the P450 isozymes that are involved in the
    metabolic activation of NNN and NNK (Murphy & Heiblum, 1990). Nicotine
    levels exceed those of NNN and NNK by more than 500 times. Therefore,
    it was not surprising that even increasing NNN and NNK levels in snuff
    ten-fold by adding the synthetic compounds did not alter the
    carcinogenic potency of snuff in the oral cavity of rats (Hecht et
    al., 1986).

    Miller (1990) reviewed how cigarette smoking affects the
    pharmacokinetic and pharmacodynamic properties of various drugs. The
    drugs pentazocine, phenylbutazone and heparin show increased
    metabolism in smokers. Also in smokers, the metabolism of oestrogen
    and theophylline is increased. In addition, although smoking does not
    pharmacokinetically affect the drugs propranolol and pindolol, the

    nicotine in smoke is associated with elevations in blood pressure, and
    thus smoking might serve to inhibit the antihypertensive effects of
    these beta-adrenergic receptor blockers. On the other hand, smoking
    had no effect on the drug disposition and/or pharmacological effects
    of various other drugs examined (Jusko, 1978; Miller, 1990).

    3.10  Animal studies of the interactions between cigarette smoke
          exposure and other agents

    Fourteen chronic inhalation studies (whole-body or nose-only exposure)
    with mainstream cigarette smoke in rats and mice were reviewed by
    Coggins (1998) and the results and histopathological changes
    contrasted with epidemiological studies in humans. In most of the
    studies there were epithelial changes in conducting airways and
    increased numbers of alveolar macrophages, occasionally associated
    with alveolar metaplasia. Lung adenomas and adenocarcinomas were seen
    in some of the studies but no statistically significant increase in
    the incidence of malignant lung tumours was found in either rats or
    mice. This contrasts with human epidemiology where there is an
    increased lung cancer risk. In an invited commentary, Morgan (1998)
    stated that, based on these differences, rodents may be ineffective
    models for predicting human health risk, at least for certain inhaled
    materials, but stressed the interspecies differences in respiratory
    anatomy and physiology and the need for consideration of the many
    factors that may lead to differences in the effects of tobacco smoke

    The existing animal toxicology studies regarding interactions between
    tobacco smoke and other materials do not form a comprehensive body of
    work on the topic. A number of combinations of exposures between smoke
    and other agents have been studied. Results are at times inconsistent
    or contradictory, and the mechanisms by which interactions occur are
    often not understood. This section provides a brief review of the
    literature. In general, the existing work: (a) was generally performed
    using rodents; (b) usually (but not always) examined the effects of
    cigarette smoking (or components of the smoke) combined with either
    with specific chemical components of the smoke or with radiation; and
    (c) usually examined cancer as the biological response end-point of
    interest. Other studies have focused on the use of cigarette smoke
    components or condensates, and have used models such as  in vitro
    cell systems or mouse skin; a discussion of these studies is beyond
    the scope of this section.

    3.10.1  Non-cancer end-points

    Several studies in experimental animals have examined the effects of
    cigarette smoke administered over short periods of time (from hours to
    daily exposures over several weeks). The cigarette smoke-induced
    increase in the number of pulmonary macrophages and leukocytes noted
    in humans has also been seen in animals such as the guinea-pig, even
    after short exposures (Rylander et al., 1979). In addition, Morimoto
    et al. (1993) observed a synergistic increase between mineral fibres

    and exposure to cigarette smoke in the production of tumour necrosis
    factor by rat alveolar macrophages. On the other hand, a 10-week
    tobacco smoke exposure in rats suppressed radiation- induced pulmonary
    inflammation (Nilsson et al., 1992), and a 12-week exposure of rats to
    smoke did not influence the lung damage caused by an intratracheal
    instillation of cadmium (Lai & Diamond, 1992).

    Nishikawa et al. (1992) studied in guinea-pigs the effects of combined
    exposure and single exposure to ozone and cigarette smoke on airway
    responsiveness and tracheal vascular permeability and found that the
    combined exposure increased airway responsiveness and vascular
    permeability to a greater extent in terms of magnitude, but not in
    duration, than a single exposure. This indicated that combined
    exposure was more harmful than exposure to either agent alone.

    3.10.2  Cancer studies: tobacco (cigarette) smoke plus other chemicals

    Mori (1964) studied rats receiving multiple subcutaneous injections of
    the carcinogen 4-nitroquinoline-1-oxide (NQO) with or without 6-7
    month inhalation of cigarette smoke. Six of eight rats had lung
    carcinomas in the combined exposure group compared to 3 of 9 rats in
    the NQO-only group, and tumours occurred earlier. Davis et al. (1975)
    studied Wistar rats receiving single intratracheal instillations of
    benzo( a)pyrene with or without cigarette smoke inhalation for most
    of the lifespan. Slight elevations of pulmonary squamous neoplasia
    were noted in the combined exposure group compared with the individual
    agents alone. However, the effects were not statistically significant.

    In mice, inhaled cigarette smoke did not influence the occurrence of
    lung tumours in (a) B6C3F1 mice pretreated with 3-methylcholanthrene
    or benzo( a)pyrene (Henry & Kouri, 1984), (b) C57BL mice receiving
    benzo( a)pyrene or influenza virus(Harris & Negroni, 1967), (c) A/J
    mice receiving intraperitoneal injections of the tobacco specific
    nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and a
    6-month inhalation of smoke using a whole-body mode of exposure (Finch
    et al., 1996), or (d) A/J mice exposed to sidestream smoke plus the
    carcinogen 3-methylcholanthrene or urethane (Witschi et al., 1997). On
    the other hand, a carcinogenic synergism in lung adenoma formation was
    reported in Strain A mice some 6 months after initiation of treatment
    with intraperitoneally injected urethane and skin-painted cigarette
    smoke tar (DiPaolo & Sheehe, 1962). However, the non- pulmonary route
    of exposure makes it difficult to interpret the relevance of this

    Several studies in hamsters have combined cigarette smoke exposure
    with other agents. Dontenwill et al. (1973) combined smoke exposure
    with a single intratracheal instillation of asbestos, but found no
    significant differences in laryngeal lesions or tumours in the group
    exposed to both materials, compared with the group receiving smoke
    alone; the asbestos alone was non-tumorigenic. The combination of a
    single intratracheal administration of dimethylbenz( a)anthrene
    (DMBA) and smoke was found to increase the tumour incidence in the

    oral cavity, pharynx, trachea and non-pulmonary tissues, compared to
    the individual agents alone (Dontenwill et al., 1973). A similar
    synergism between DMBA and smoke in producing laryngeal papillomas and
    other oral and laryngeal lesions was reported by Hoffmann et al.
    (1979) and by Kobayashi et al. (1974), and a synergism was also noted
    between the nitrosamine DENA and smoke (Dontenwill et al., 1973).
    Hamsters pretreated with a single dose of either 1.0, 3.3 or 10.0 mg
    of NNK, and subsequently exposed twice daily for up to 72 weeks to
    diluted cigarette smoke developed significantly more tumours in the
    respiratory tract than hamsters receiving the identical dosage of NNK
    and subjected to sham-smoking (Hecht et al., 1983). This supports the
    concept that tobacco smoke has tumour-promoting activity. A
    combination of smoke plus benzo( a)-pyrene adsorbed onto haematite
    produced tracheal and laryngeal hyperplasia, whereas either agent
    alone did not (Hoffmann et al., 1979), but no tumours were produced.

    3.10.3  Cancer studies: cigarette smoke plus radiation

    Dogs were used to study the potential interactions between radon and
    cigarette smoke inhalation in producing lung cancer (Cross et al.,
    1982). The lung tumour incidence in dogs exposed to radon plus
    cigarette smoke for 4-5 years was decreased compared to that of dogs
    receiving a mixture of radon, radon daughters, and uranium ore dust.

    Studies have examined the potential interactions between tobacco smoke
    and the alpha-emitters radon or plutonium-239 in rats or mice. In a
    series of studies, Chameaud et al. (1982) examined the effects of
    combined exposures to radon and cigarette smoke in Sprague-Dawley
    rats, as well as the effects of pre-treatment with either radon or
    smoke exposure. Smoke exposures begun before radon exposure did not
    influence the radon-induced lung tumour incidence, but this increased
    by 2- to 3-fold in the combined exposure group receiving radon before
    cigarette smoke compared to the group receiving radon alone.

    Finch et al. (1995a) examined F-344 rats receiving a single inhalation
    exposure to 239PuO2, combined with chronic (up to 30 months)
    cigarette smoke exposure, and found a synergistic crude tumour
    incidence in rats receiving both agents, compared with animals
    receiving the radiation alone. Most of these effects could be
    explained by a cigarette-smoke-induced retardation of lung clearance
    of the 239PuO2 particles (Finch et al., 1995b). This group is
    continuing to study the potential combined effects of smoke and X-ray
    exposure in rats, and the potential effects of smoke combined with
    either X- or alpha-irradiation in mice (Finch et al., 1995a). Talbot
    et al. (1987) reported results of a study in which mice inhaled
    cigarette smoke, 239PuO2 or both materials. As in the case of rats,
    cigarette smoke exposure caused retarded lung clearance and thus led
    to greater radiation doses in animals receiving both agents.


    4.1  Coal mining

    4.1.1  Coal dust

    Coal miners can suffer from chronic bronchitis, coal workers
    pneumoconiosis, progressive massive fibrosis, and emphysema. The
    respiratory impairment appears as radiologically visible and
    functional changes in the lungs, but although some of these are
    associated solely with coal dust, some are also closely associated
    with smoking. In the past it has been difficult to apportion
    attributable risk to the two causes due to the fact that coalface
    workers, the group subjected to the highest dust exposure, have a
    different smoking pattern and perhaps a different daily consumption of
    smoking materials than non-coalface workers because smoking in the
    mine is forbidden. With the limitation of dust in modern mining, the
    effect of the two factors, dust and smoking, is becoming clearer.
    However, difficulties arise in interpreting data because non-smokers
    may accumulate more dust, as they have less absenteeism, a different
    pattern of lung clearance and a longer life (NIOSH, 1995).

    In most of the countries surveyed, the prevalence of smoking by miners
    tends to have been somewhat higher than in either the male population
    as a whole, or among most other occupational groups, although a
    distinction is seldom drawn between miners and coal miners except in
    studies centred on coal mining populations. Between 1963 and 1975 in
    the United Kingdom, the smoking prevalence fell for the male
    population (and for miners) from 54% (miners 77%) to 47% (miners 49%)
    (Lee, 1976). The figures for 1988 and 1990 were 33% and 31% (Bennett
    et al., 1996) and for face-trained coalminers 35.7% in 1989 (Elliott,
    1995). In a study of 8555 American miners from 29 bituminous coal
    mines (Kibelstis et al., 1973), over 50% were smokers and 25% were
    ex-smokers. In a United Kingdom study (Love & Miller, 1982), only 13%
    of 1677 coal miners from 5 British collieries, who were examined in a
    lung function study, were non-smokers; 66% were regular smokers and
    the remainder were intermittent or ex-smokers. In a 20 year follow-up
    study of a population of coal British miners and others (Cochrane &
    Moore, 1980), 69% of the coal miners were smokers. These examples
    typify the smoking prevalence of coal miners prior to the early
    1980's. A 1982 survey of 800 000 American men and women in relation to
    their occupations (Stellman et al., 1988) found that among miners
    (type unspecified) 29.4% had never smoked regularly, 31.5% were
    current smokers and 39.1% were former cigarette smokers. This may
    reflect a general trend in the countries with higher income economies
    where smoking has been decreasing in many sections of the population.

    4.1.2  Bronchitis in coal miners

    Kibelstis et al. (1973) found that the prevalence of bronchitis in
    coal miners who smoked was higher than in non-smoking coal miners.
    Coalface workers had more bronchitis and more airway obstruction than

    surface workers and the difference between smokers working at the
    coalface and non-smoking surface workers showed that the effect of
    smoking was five times greater than that of coal dust. A German
    epidemiological evaluation of chronic obstructive bronchitis in 5605
    miners, 1276 ex-miners and 3898 individuals who had never worked in a
    mine showed that smoking has a more serious effect on miners than on
    other groups (Roth et al., 1985). It is possible that, within a mining
    community, the other two groups may have a predisposition to the
    disease and have achieved their status by job selection or job escape.
    In a study of new entrants into coal mining McLintock (1971) found
    that those who drop out of mining tend to be less physically fit and
    more prone to chest problems than those who remain.

    Morgan (1982) analysed the effects of cigarette smoking, dust exposure
    and environmental factors on respiratory disease, and concluded that
    bronchitis and airways obstruction were two separate responses to
    cigarette smoking. The airflow obstruction found in smokers is due to
    small airways disease and an involvement of respiratory bronchioles
    leading to the development of emphysema. In coal miners, the
    prevalence of bronchitis among non-smokers is related to the degree of
    dust exposure. Marine et al. (1988) analysed data from studies on 53
    382 coal miners in the United Kingdom and found that smoking miners
    were at greater risk of developing chronic bronchitis. In a study by
    Selig & Nestler (1985) of the relationship between chronic bronchitis,
    smoking and dust (unspecified source), heavy smoking was equated with
    20 years of dust exposure. From postmortem examinations of coal mine
    workers, a correlation was reported between clinical chronic
    bronchitis and smoking (Selig & Nestler, 1985).

    The chronic bronchitis of coal miners is probably a combination of (a)
    mucus hypersecretion caused by dust; (b) mucus hypersecretion, mucus
    modification and clearance impairment caused by tobacco smoke; (c)
    small airways disease caused by tobacco smoke; and (d) the effect of
    dust on small airways tissue already inflamed by smoking. Bronchitis
    due to smoking causes mucus hypersecretion which is much greater than
    that due to coal dust (Morgan, 1982). Cigarette smoke impairs lung
    clearance by changing the physical and chemical properties of mucus
    and causing ciliastasis. Rheological measurement show changes in the
    viscoelastic properties of mucus; chemically the mucus glycoprotein
    structure is changed (King et al., 1989) and the irritant gases in
    smoke cause abnormal mucus secretion and ciliastasis (Holbrook, 1977).
    Small airways disease and bronchiolitis, leading to emphysema, are due
    to smoking rather than to dust (Morgan, 1982).

    4.1.3  Emphysema and pneumoconiosis in coal miners

    Dust in coal mining is considered to be the primary cause of coal
    workers pneumoconiosis. In a study of coalworkers and non-coalworkers,
    Cockroft et al. (1982) concluded, after taking any effect of smoking
    into account, that there was a 7-fold excess of emphysema in
    coalworkers. Results of postmortem examinations of 866 Australian
    miners (Leigh et al., 1983) showed a positive correlation between dust

    exposure and emphysema and pneumoconiosis, with the severity highest
    in non-smokers. However, smoking and non-smoking coalface workers were
    not compared. From a postmortem comparison of lungs from 450 coal
    miners, Rockley et al. (1984) found that emphysema occurred more
    frequently in smokers (72%) than in ex-smokers (65%) or in non-smokers
    (42%) and the relative frequency increased with age at death. The
    study considered the possibility that coal dust might cause emphysema
    which inhibits clearance and, in turn, promotes fibrosis, or
    alternatively that fibrosis caused by dust increases the chance of
    emphysema. However, the findings of a study of South Wales coal miners
    (Fletcher., 1972) militated against dust-induced emphysema. It has
    been suggested that differences in emphysema between coalworkers and
    non-coalworkers can be accounted for by taking into account current
    smokers in the two groups. Morgan (1982) concluded that the evidence
    militates against obstructive emphysema occurring more commonly in
    coal miners than in the general population, or that more dust
    inhalation leads to a greater likelihood of emphysema developing.
    Reviews of small airways disease (SAD) suggested that emphysema
    proceeds from smoking-induced SAD. Cosio et al. (1980) considered that
    their observations supported the hypothesis that SAD is causally
    related to centrilobular emphysema, but not necessarily to panlobular

    4.1.4  Lung cancer in coal miners

    Perhaps as a result of failure to control confounding factors, there
    has been a lack of consistency among reports on the relationship
    between coal mining and lung cancer incidence in miners. In a direct
    evaluation of the relationship between lung cancer mortality and coal
    mine dust exposure, controlling for smoking status, Ames et al. (1983)
    found no evidence of a link between coal mine dust exposure and lung
    cancer risk, nor of an interaction effect, although the expected lung
    cancer risk in cigarette smokers was observed. From a study of dust
    exposure, pneumoconiosis and mortality of coal miners (Miller &
    Jacobsen, 1985) it was found that lung cancer mortality among miners
    who smoked was 5.5 times higher than in "never smokers" but that the
    effect was entirely due to smoking.

    Radon and radon daughter contamination of the dust in coal mines might
    be expected to be as prevalent as in all other mines, and thus the
    apparent very low lung cancer risk in coal mining may seem unexpected.
    However, because of the explosion risk in coal mines, the ventilation
    is usually efficient and a build-up of radioactivity is probably less
    likely than in other types of mine.

    4.2  Other mineral dusts

    4.2.1  Talc

    Talc is a hydrated magnesium silicate, often contaminated with free
    silica or fibrous asbestos-like minerals such as tremolite and
    anthophyllite. The only significant difference in the effects on

    exposed and non-exposed was in the number and severity of cases of
    dyspnoea in the talc workers, and smoking was considered to be an
    aggravating factor (Kleinfeld et al., 1973).

    4.2.2  Kaolin

    Kaolin (pure China clay) is a hydrated aluminium silicate used for
    ceramics and as a filler in the paper, rubber and paint industries.
    The dry powder can give rise to fibrotic nodules in the lungs (Seaton
    et al., 1981; Wagner et al., 1986). Characteristic smoker's inclusions
    have been seen in transmission electron micrographs of pulmonary
    alveolar macrophages obtained from cigarette smokers. The contents of
    these inclusions are heterogeneous and include electron-dense areas,
    lipid material and needle-like structures. These have properties
    consistent with the composition of kaolinite. Kaolinite is present in
    cigarette smoke from different brands, and pulmonary alveolar
    macrophages are able to ingest this material  in vivo (Hocking &
    Golde, 1979).

    4.2.3  Alumina

    Alumina (aluminium oxide) is extremely hard and is used as an abrasive
    (corundum). A cross-sectional study of 788 employees of an aluminium
    production company examined the relationship of radiographic
    abnormalities to smoking and dust exposure during bauxite and alumina
    mining and refining (Townsend et al., 1988). Chest radiographs showed
    a moderate time trend of increasing prevalence of small opacities in
    non-smokers with high cumulative dust exposures. In most exposure
    categories, smokers had a higher prevalence of opacities than
    non-smokers. For cumulative exposures of less than 100 mg/m3-years,
    increasing trends with duration of exposure were accentuated in
    smokers as compared to non-smokers. The stronger effects observed in
    smokers were attributed to the joint effects of duration of smoking
    and duration of occupational exposure (Townsend et al., 1988).

    4.3  Fibrous minerals

    Fibrous minerals have been implicated in pleural thickening, pulmonary
    fibrosis, mesothelioma and lung cancer in some villages in the
    Anatolian region of Turkey (Artvinli & Baris, 1979), where fibrous
    zeolite minerals (chabazite and erionite) are present in volcanic
    deposits and used in buildings. Erionite has been shown to induce
    mesothelioma. The symptoms and pathology of the respiratory disorders
    and malignant disease were similar to those of asbestos. Asbestos-type
    diseases have also been described in communities exposed to zeolite
    minerals and tremolite dust in other similar regions by Baris et al.
    (1979) and Yazicioglu et al. (1980). Non-asbestos fibrous materials
    have been associated with pulmonary fibrosis (Stanton et al., 1977).
    There are no data on any interaction of these minerals with smoking
    but there appears to be a potential for interaction.

    Wollastonite is a fibrous monocalcium silicate, which has been used as
    a substitute for asbestos, as a filler and flux in ceramics, in
    grinding wheels, refractory products, building blocks and acoustic
    tiles. It is weakly fibrogenic. Hanke et al. (1984) studied a small
    population of workers exposed to wollastonite and attributed
    significant levels of chronic cough, phlegm and bronchitis to smoking
    and not to exposure to wollastonite.

    4.4  Metals

    4.4.1  Antimony

    Antimony is chemically similar to arsenic. Arsenic is metalloid,
    antimony is a metal, both have volatile hydrides and form halogen,
    oxygen and sulfur derivatives. Compounds of both frequently occur
    together, particularly in smelter fume. Biological effects are similar
    to those of arsenic (De Wolff & Edelbroek, 1994; De Wolff, 1995).

    The concentrations of antimony, arsenic, cadmium, chromium, cobalt,
    lanthanum, lead, selenium and zinc measured in lung tissues of
    deceased smelter workers suggested that lung cancer risk was
    multifactorial, involving carcinogenic and anti-carcinogenic factors
    (Gerhardsson & Nordberg, 1993). A 30-year study at an antimony smelter
    did not specifically implicate antimony as the cause of excess lung
    cancer because of concurrent exposure to other carcinogens (Jones,
    1994). In another study of smelters, the data suggested an increase in
    lung cancer and non-malignant respiratory and heart disease (Schnorr
    et al., 1995).

    Antimony can have harmful effects on lung tissues, including
    pneumoconiosis. IARC (1989a) evaluated antimony trioxide and antimony
    trisulfide and concluded that the trioxide was possibly carcinogenic
    to humans (Group 2B) and the trisulfide was not classifiable (Group
    3). It is likely that the effects of inhalation of antimony fume/dust
    and tobacco smoke would be worse than inhaling either separately. The
    similarities of antimony to arsenic, both chemically and in some
    biological effects, leads to the conclusion that tobacco smoke and
    antimony could interact like tobacco smoke and arsenic in producing

    4.4.2  Cadmium

    Most zinc and lead-zinc ores contain small amounts of cadmium. It is
    used in electroplating, in metal alloys (with copper for overhead
    wires, and aluminium for casting), in nickel-cadmium dry cells, for
    pigment manufacture and use, added to silver to prevent staining, and
    it is a hazard of welding. The main route of exposure for the
    non-smoking general population is via food, while for exposed workers
    it enters the body mainly by inhalation. Tobacco is an important
    source of cadmium in smokers (IPCS, 1992), and the tobacco source
    affects the level of cadmium exposure (Yue, 1992). Any intake is
    important because cadmium has an extremely long biological half-life.

    It was suggested (Hassler et al., 1983) that higher levels of cadmium
    in the blood and urine of exposed workers could arise both from
    workplace contamination of cigarettes and transfer as fume during

    Cadmium has various toxic effects, the earliest being impairment of
    renal tubular function leading to failure of resorption and excretion
    of low molecular weight protein, glycosuria, aminoaciduria and
    hypercalciuria (IPCS, 1992; IARC, 1993). It has been associated with
    some types of lung disorder (emphysema, obstructive pulmonary disease
    and diffuse fibrosis) (IPCS, 1992) Exposure to cadmium compounds has
    been associated with cancer of the lung. There is some evidence for an
    association with prostatic cancer (IARC, 1993). Other epidemiological
    studies did not confirm an increased risk of prostatic cancer
    (Kazantzis et al., 1992). The evaluation by IARC (1993) concluded that
    cadmium and cadmium compounds are carcinogenic to humans (Group 1).
    The supposition that cadmium in cigarette tobacco or in the workplace
    may cause lung cancer has been questioned (Lamm et al., 1992;
    Hertz-Picciotto & Hu, 1994). In a cohort mortality study of cadmium
    workers in England, an observed increase lung cancer risk could not be
    attributed strictly to cadmium due to the presence of multiple
    confounding factors, particularly arsenic (Kazantzis et al., 1992).
    Lamm et al. (1992) also suggested that arsenic may be responsible for
    the observed lung cancer increased. The many elements in the lung
    tissues of deceased smelter workers (Gerhardsson & Nordberg, 1993)
    illustrates the difficulty in apportioning a role to one material in a
    multifactorial environment.

    Cadmium affects the myocardium and produces hypertension in animal
    studies but the induction of cardiovascular disease and hypertension
    in humans has not been demonstrated in epidemiological studies
    (Kristensen, 1989; IPCS, 1992)). Blood and urine cadmium levels are
    higher in smokers than in non-smokers and were found to be
    considerably elevated in smokers working in an alkaline battery
    factory (Hassler et al., 1983) and in smelter workers who were also
    smokers (Kazantzis & Armstrong, 1984; Lilis et al., 1984a,b).

    Davison et al. (1988) reported a cadmium dose/effect relationship in
    functional and radiological evidence of emphysema in 101 subjects.
    Leduc et al. (1993) described the very rapid development of emphysema
    in a smoker after exposure to very high levels of cadmium. Smoking by
    cumulatively increasing the body burden and hindering the lung
    clearance may have provided an additional cause for the emphysema.
    However, an additive or synergistic mechanism for the cadmium plus
    smoking effect could not be inferred in this case because of the high
    cadmium dose.

    4.4.3  Cobalt

    Cobalt is used in the production of alloys, tungsten carbide tools,
    permanent magnets, and in the electrical industry.

    Cobalt has toxic effects (Beliles, 1994). Cobalt exposure has been
    linked to various allergic reactions (Shirakawa et al., 1992); hard
    metal exposure and smoking together arithmetically increased total IgE
    levels. Interstitial lung disease has been associated with cobalt in
    susceptible individuals (Sprince et al., 1988), although in a study
    involving the manufacture of permanent magnets (Deng et al., 1991)
    abnormalities in pulmonary function and respiratory symptoms were no
    higher than those of a reference population, except for 4 subjects out
    of 362, who showed diffuse patches consistent with pneumoconiosis.

    4.4.4  Lead

    Lead is used in batteries, paint, glass, ceramics, fuel additives and
    other industrial applications. In lead-using industries the main route
    of exposure is by inhalation, mainly as dust and fume. Lead has a
    range of toxic effects on blood, and the renal and nervous systems
    (IPCS, 1995).

    Levels of lead in blood vary from one area to another, between urban,
    rural and occupationally exposed populations, and between men and
    women (IPCS, 1995). The tobacco plant absorbs lead from the soil and
    around 5-6% of that in cigarettes is inhaled in the smoke. Lead
    concentrations in the smoke from one cigarette were found to range
    from 0.017 to 0.98 µg (IARC, 1986). Higher blood lead and erythrocyte
    protoporphyrin levels have been demonstrated in heavy smokers exposed
    to lead (Williams et al., 1983; Landrigan & Straub, 1985); these could
    have been partly due to contaminated cigarettes acting as vectors.
    Other studies on occupationally exposed workers showed a progressive
    increase in blood lead with an increase in the number of cigarettes
    smoked (Maheswaren et al., 1993).

    The association between lead exposure, tobacco smoke exposure and
    blood pressure was examined in a cross-sectional study on 809 men
    occupationally exposed to lead in a battery factory but only a small
    increase in systolic blood pressure was found (Maheswaren et al.,
    1993). There was no evidence of interactive effects between smoking
    and lead exposure, but the absorbed lead from cigarettes added to the
    body burden.

    4.5  Rubber industry

    Some of the principal hazards in the industry are fumes, talc, carbon
    black, chemical additives and organic solvents but the components of
    the hazard mixture differ between different areas of work. A high risk
    of pulmonary disease has been reported in the rubber industry. It was
    elevated for smokers, particularly those employed in areas where there
    were respirable particulates and/or solvents (Lednar et al., 1977).
    The data suggested an interaction between smoking and hazards
    encountered in mixing (particulates), extrusion (solvent sprays and
    mould release agents), and curing (solvents and rubber reaction
    products). A problem in epidemiological studies in the industry arises
    because of movement of workers between jobs. Some high-risk workers

    who were also smokers were involved in finishing and inspection but
    they tended to be older employees who had worked in other areas before
    moving to this particular job. Emphysema was the principal pulmonary
    condition leading to premature termination of employment (Lednar et
    al., 1977).

    IARC (1987) classified the rubber industry as Group 1, based on
    sufficient evidence for carcinogenicity to humans. Excess mortality
    from cancers of various sites, the site usually being associated with
    the nature of the work and types of exposure, has been reported with
    bladder cancer being associated with exposure to aromatic amines (Fox
    et al., 1974; Monson & Nakano, 1976a,b; Monson & Fine, 1978;
    Kilpikari, 1982; IARC, 1987; Zhang et al., 1989; Weiland et al.,
    1996). Lung cancer was associated with curing and inner tube
    manufacture. The use of talc in the rubber industry has been
    associated with pulmonary disease (Kleinfeld et al., 1973). In the
    rubber industry the relative risk of lung cancer for talc-exposed
    workers was 3.2 for men and 4.4 for women (Zhang et al., 1989),
    compared with 2.5 times excess lung cancer risk in talc-using
    industries not associated with rubber manufacture (Thomas & Stewart,
    1986). In jobs where very high lung cancer rates were found, smoking
    levels were also very high, but any possible interaction effect from
    the two exposures could not be assessed.

    Gastrointestinal cancer, bladder cancer and leukaemia were found to be
    associated with jobs in the rubber industry (Monson & Fine, 1978;
    IARC, 1987). Possible causes, such as exposure to carbon black,
    plasticisers, antioxidants, arylamino compounds and benzene have been
    suggested. Urine samples from rubber workers showed a higher mutagenic
    activity in the middle of a working week than at the beginning of a
    week in both smokers and non-smokers, indicating the presence of
    mutagens in the work environment. In a study involving the analysis of
    urine from rubber workers for mutagenic factors, a possible
    synergistic effect of smoking and occupational exposure was found in
    smokers (Wicklund et al., 1988). There was a relationship between skin
    contamination and urinary mutagenicity (Bos et al., 1989). Other
    studies involving the analysis of urine from rubber workers for
    mutagenic factors also suggested a possible synergistic effect of
    smoking and occupational exposure among smokers (Falk et al., 1980;
    Crebelli et al., 1985).

    Andjelkovich et al. (1988) carried out a case-control study of lung
    cancer in workers at a rubber manufacturing plant. There was an
    association between lung cancer mortality risk and work in certain
    areas for smokers and non-smokers, and the risk was greater in
    smokers. Zhang et al. (1989) studied a cohort of 957 men and 667 women
    employed in a rubber factory. The relative risk of lung cancer for
    smokers was 8.5 for men and 11.4 for women, and for those exposed to
    curing agents or talc the relative risk was 3.2 for men and 4.6 for
    women. Additive and multiplicative models were used to evaluate the
    interaction between smoking and occupational exposure on lung cancer.
    The additive interaction term was not statistically significant and

    the multiplicative interaction was negative. Weiland et al. (1996)
    were not able to find interactions between smoking and exposure in the
    rubber industry.

    4.6  Petroleum industry

    Petroleum refining involves exposure of workers to a large number of
    chemical compounds occurring in crude oil or encountered in production
    processes as intermediates, catalysts, additives or in the final
    products. Because of fire risk, there are sections of the industry
    where smoking is not permitted. However, in a study of 10 923 male and
    624 female employees of the Australian petroleum industry between 1981
    and 1984, it was found that the smoking habits did not differ
    substantially from those of the general population (Christie et al.,
    1986), and continued surveillance of these workers showed that
    mortality rates were lower than for the general population (Christie
    et al., 1987).

    IARC (1989b) concluded that there is limited evidence that working in
    petroleum refineries entails a carcinogenic risk. This limited
    evidence applies to skin cancer and leukaemia; for all other cancer
    sites on which information was available, the evidence was inadequate.
    The overall evaluation, taking account of sufficient or limited
    evidence in experimental animals for the carcinogenicity of various
    distillates produced during petroleum refining, was that occupational
    exposures in petroleum refining are probably carcinogenic to humans
    (Group 2A).

    In a study of 92 men with histologically confirmed renal cell
    carcinoma (Domiano et al., 1985), it was concluded that there could be
    an interaction between long-term gasoline exposure and heavy smoking.
    In a case-control study of bladder cancer in New Jersey, USA, Najem et
    al. (1982) found a significantly elevated risk of bladder cancer in
    patients who had worked in the petroleum industry (OR, 2.5, CI, 
    1.2-5.5). While the risk was increased in current smokers (OR, 2.6), 
    it was higher in "never smokers" (OR, 5.6) and only slightly elevated 
    in ex-smokers (OR, 1.4). In another hospital-based study in Argentina 
    an association was found between bladder cancer and oil refinery work,
    along with an elevated risk of lung cancer in smokers, but the numbers
    were too few for any evaluation of the interaction (Iscovich et al.,

    There was no increased mortality from either kidney cancer or
    leukaemia in employees exposed to gasoline (Wong et al., 1993). A low
    frequency of bladder cancer among refinery workers was attributed to
    an assumed lower level of smoking among the group of workers studied
    (Higginson et al., 1984).

    In the study of workers occupationally exposed to gasoline vapour, the
    sister chromatid exchange (SCE) frequency in peripheral blood
    lymphocytes was used as an indicator of genotoxic response. Workers
    employed in gasoline retail outlets were classified according to

    cigarette smoking habits. The SCE frequency in lymphocytes was
    unaffected by cigarette smoke or gasoline exposure alone, but
    increased with combined exposure. The increased SCE frequency observed
    in smokers occupationally exposed to gasoline vapour could be due to
    the activation of hepatic enzymes by cigarette smoke, leading to a
    greater formation of reactive metabolites of gasoline vapour (Edwards
    & Priestly, 1993).

    4.7  Pesticides

    A variety of chemical compounds, natural and synthetic, are used as
    pesticides. The number of individuals exposed during manufacture is
    relatively small, and processes are usually contained, but the
    worldwide population of pesticide users is very large. Most of the
    world's population is exposed to pesticide residues in food and
    drinking-water (Ecobichon, 1995). There is some information concerning
    effects on health from interaction of pesticide exposure and smoking.

    "Vineyard sprayer's lung", is an occupational disease associated with
    the spraying of copper-sulfate-based Bordeaux Mixture. In a study of
    the cytological changes in the respiratory tract of vineyard workers
    spraying Bordeaux Mixture (Plamenac et al., 1985), the macrophages of
    control subjects contained no copper whereas copper was detected in
    64% of the sprayers. Abnormal cytological changes in the sputum were
    found in smokers, in sprayers and controls, and atypical squamous
    metaplasia of the respiratory epithelium was observed in 29% of the
    sprayers who were smokers.

    In a study to evaluate the hypothesis that exposure to lead arsenate
    resulted in an excess mortality from lung cancer, Wicklund et al.
    (1988) compared 155 male orchard workers who had died of respiratory
    cancer with 155 orchard workers who had died of other causes. Two
    groups of non-orchard workers (620) were used as matched controls.
    There was no difference in lead arsenate exposure between the orchard
    worker group. Although cigarette smoking was common among the orchard
    workers, their smoking habits were similar to the non-orchard worker
    control groups. In both groups of orchard workers mortality from
    respiratory cancer was higher in smokers than in non-smokers.

    McDuffie et al. (1990) examined the possibility that pesticide use was
    related to the risk of primary lung cancer. In a case-control study
    using data from a population-based cancer registry, they interviewed
    273 men and 103 women with diagnosed primary lung cancer and compared
    their occupational exposures, medical history and working
    characteristics with 187 male community control subjects. There was no
    correlation of lung cancer risk with exposure to pesticides and
    adjusting for smoking did not alter this.


    5.1  Conclusions

    1.  Tobacco use, particularly smoking, is the single most important
        public health hazard in the world today, and a major preventable
        cause of morbidity and mortality.

    2.  In addition to the adverse health effects of active tobacco use,
        adverse health effects have also been demonstrated as a result of
        exposure to environmental tobacco smoke.

    3.  The risks from tobacco smoke are demonstrably increased through
        interactions with certain chemical, physical and biological
        hazards found in the workplace and general environment.

    4.  Based on this review of the scientific literature, additional
        interactive effects, not yet identified, may exist.

    5.  In addition to synergistic interactions between tobacco smoke and
        other agents, a few instances of antagonistic interactions were
        also noted. However, even in these cases, the health risks of
        tobacco smoke far outweigh any apparent protective effects.

    5.2  Recommendations for protection of human health

    1.  All possible measures should be taken to eliminate tobacco use,
        particularly smoking.

    2.  In order to avoid interaction with occupational exposures, and
        eliminate the risks of exposure to environmental tobacco smoke,
        smoking in the workplace should be prohibited.

    3.  Smoking in public places should be strongly discouraged.

    4.  In order to reduce the risks of exposure to environmental tobacco
        smoke, particularly for children, smoking in domestic 
        environments should be strongly discouraged. Such action will also
        avoid possible deleterious interactions between tobacco smoke and
        residential exposures to other hazards.

    5.  Awareness-building through active educational programmes on the
        health hazards of smoking should be undertaken in both developed
        and developing countries. This should include enhanced
        communication about deleterious interactions between tobacco and
        other agents. Governments, industry, health and educational
        professionals, and the general public should share in this

    6.  Since smoking may result in altered response or adverse reactions
        to drugs and other therapeutic treatments, appropriate dose
        adjustments and patient surveillance should be taken into
        consideration by clinicians.

    7.  Health professionals should provide assistance to smokers to stop
        smoking. This may necessitate the allocation of additional
        resources for this purpose.


    1.  A number of different methodological approaches to investigating
        interactions currently exist. The feasibility of harmonizing
        methodologies for the assessment of potential interactions
        between two or more health hazards should be explored. In the
        interim, investigators should make every effort to state clearly
        which methodologies have been used when reporting their results.

    2.  In many of the observational studies included in this review,
        exposure data were limited. In order to improve future
        investigations of interactions among human health hazards, more
        complete and accurate exposure assessments should be performed.

    3.  Further epidemiological investigations of potential interactions
        between tobacco smoke and other hazards in both the occupational
        and general environments are needed to identify additional
        populations at risk. Such interactive effects can lead to risks
        higher than would be predicted by separate analyses of the risks
        associated with individual hazards.

        Epidemiological investigations in countries where the health
        effects of tobacco have not been extensively studied previously
        are of particular importance. This information would be of value
        in characterizing the morbidity and mortality due to tobacco use
        in those countries.

    4.  Additional research is needed to clarify the toxicological
        mechanisms by which tobacco smoke leads to adverse health
        effects, and by which tobacco smoke and other agents interact.
        This information will be of use in the design and interpretation
        of epidemiological studies on the health effects of tobacco,
        including interactive effects.

    5.  Additional epidemiological research on the health effects of
        passive smoking, particularly carcinogenic, cardiorespiratory and
        allergic effects, would be of value in characterizing the effects
        of low levels of exposure to tobacco smoke. Interactions between
        environmental tobacco smoke and other health hazards also warrant
        further investigation.

    6.  Established biomarker methods should be applied to the monitoring
        of workers for the early detection of harmful exposures to toxic
        or carcinogenic agents, and, in many areas, new biomarker methods
        should be developed to improve hazard identification.
        Consideration should be given to evaluating the ongoing exposure
        of workers to active or passive tobacco smoke by monitoring
        salivary or urinary cotinine, one of the major nicotine

    7.  A comprehensive review of the adverse health effects of
        environmental tobacco smoke should be undertaken. This review
        would provide an authoritative summary of the health impacts of
        environmental tobacco smoke, as well as interactions between
        environmental tobacco smoke and other health hazards.


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    1. Introduction

    Le tabac, notamment lorsqu'il est fumé, exerce divers effets nuisibles
    à la santé; il est directement en cause dans un certain nombre de
    maladies graves et peut accentuer l'action nocive d'autres agents
    chimiques, physiques ou biologiques. Les produits chimiques et autres
    agents présents sur les lieux de travail peuvent, si l'on n'y veille pas
    suffisamment, provoquer diverses pathologies, des invalidités et des
    décès prématurés. Il est clair que sur les lieux de travail, des effets
    indésirables peuvent résulter de la synergie entre le tabagisme et
    d'autres facteurs de risque. La plupart des interactions entre les
    constituants nocifs de la fumée de tabac et certaines substances
    chimiques toxiques se produisent lorsque celles-ci sont présentes dans
    l'atmosphère, mais le tabagisme peut également, comme on l'a observé,
    interagir avec des agents toxiques absorbés par voie buccale ou autre.

    La consommation de tabac est universelle, des pays économiquement
    défavorisés aux nations industrialisées les plus riches. Le tabac est
    consommé par les hommes et les femmes, les enfants et les adultes et des
    millions de gens sont exposés malgré eux à la fumée de tabac présente
    dans l'environnement. Il y a de nombreuses explications au tabagisme,
    mais la raison principale de son universalité tient à la présence, dans
    les feuilles de toutes les variétés de tabac, de nicotine, une substance
    qui engendre la dépendance. Cette dernière pénètre dans l'organisme du
    consommateur en quantité variable, selon le type de tabagisme auquel il
    s'adonne (Chapitre 2). L'apparition de la cigarette, qui peut être
    produite en quantités industrielles, qu'il est facile de se procurer à
    un prix relativement bas et que sa légèreté permet de tenir entre les
    lèvres en gardant les mains libres, a profondément modifié le
    comportement des fumeurs, que ce soit dans la vie en général ou sur les
    lieux de travail.

    Il y a beaucoup de pays où fumer est considéré comme très dangereux pour
    la santé et comme un facteur qui contribue de manière importante à la
    mortalité résultant d'un certain nombre d'affections courantes. Ces pays
    ont adopté une législation qui vise à alerter les consommateurs des
    risques qu'ils courent et ils ont également pris des mesures pour
    freiner la consommation, soit par la taxation, soit par la mise en
    oeuvre de campagnes d'information à destination du grand public qui ont
    pour but d'attirer l'attention sur les dangers du tabagisme et les
    avantages qu'il y a à cesser de fumer ou à ne pas commencer du tout.
    Certains pays n'ont toutefois pas encore pris de mesures décisives pour
    traiter le problème du tabagisme.

    L'activité professionnelle comporte souvent une part de risque. Elle
    peut être de nature à mettre la santé en danger et à contaminer
    l'environnement. La culture du tabac elle-même implique l'utilisation de
    pesticides, la récolte des feuilles peut provoquer des intoxications
    dues à l'absorption percutanée de nicotine et les diverses opérations
    auxquelles elles sont ensuite soumises expose les travailleurs à

    respirer les poussières et les spores de champignons présentes dans
    l'atmosphère. Dans les zones où sont implantées des manufactures de
    tabac, on observe une incidence élevée de cancers chez les sujets de
    sexe masculin. L'air des exploitations minières est chargé de poussières
    minérales et dans l'agriculture ou les industries qui utilisent des
    matières premières d'origine biologique, les travailleurs sont exposés
    à des poussières de même origine. Le soudage donne également lieu à la
    production de vapeurs, et les gaz, fumées, brouillards etc. produits
    dans de nombreuses industries sont aussi source de dangers. Une chaleur
    excessive ou l'exposition aux ultraviolets peuvent nuire au bien-être
    des travailleurs. On admet désormais que les rayonnements ionisants émis
    dans les mines ou par certains appareils modernes constituent un risque
    professionnel. Nombreuses sont les activités professionnelles qui
    entraînent une exposition à des niveaux de bruit excessifs ou à des
    vibrations nocives. Toutes ces conditions de travail ont des effets
    indésirables sur la santé, mais qui peuvent être plus graves pour les
    fumeurs que pour les non fumeurs. Dans un grand nombre de pays, il est
    interdit de fumer sur les lieux de travail, essentiellement d'ailleurs
    en raison des risques d'incendie ou d'explosion. Dans d'autres, cette
    réglementation n'est pas toujours appliquée. Dans certains pays
    nouvellement industrialisés, les problèmes sanitaires liés à l'activité
    professionnelle ne sont pas encore totalement pris en compte et de
    nombreux employés et ouvriers ne sont pas conscients des risques de leur
    métier sur le plan sanitaire. En outre, il existe un vaste secteur
    industriel "non officiel", en particulier dans les pays en
    développement, où le travail, qui se fait à domicile, peut comporter
    l'utilisation de produits chimiques (solvants, résines, colorants de
    synthèse etc.) auxquels toute la famille va donc se trouver exposée. En
    outre, il n'existe pas de réglementation qui restreigne l'exposition ou
    interdise de fumer dans ces circonstances.

    Beaucoup moins bien défini est le cas d'effets nocifs résultant de
    l'action combinée d'une exposition à la fumée de tabac, provenant du
    courant principal ou de l'environnement, et à des agents présents dans
    le milieu domestique. On sait toutefois qu'en ce qui concerne
    l'incidence du cancer du poumon, la courbe dose-réponse obtenue dans le
    cas d'une exposition domestique au radon est analogue à celle qu'on
    obtient chez des mineurs exposés à ce gaz, avec un risque plus important
    chez les fumeurs.

    2.  Exemples d'effets combinés d'une exposition à la fumée de tabac et
        à d'autres agents

    On est fondé à penser que dans le cas de certains effets toxiques (en
    l'occurrence le cancer) il existe une synergie entre le fait de fumer et
    l'exposition à l'arsenic, à l'amiante, à l'éthanol, à la silice et aux
    rayonnements (radon, bombe atomique, rayons X). D'un autre côté, il y a
    également lieu de croire à l'existence d'un antagonisme entre le
    tabagisme et les chlorométhyléthers cancérogènes comme le
    chlorométhyl-méthyléther (CMME) et le bis (chlorométhyléther) (BCME)
    (Hoffmann & Winder, 1976; CIRC, 1986), entre le tabagisme et l'alvéolite
    allergique ou encore entre le tabagisme et la bérylliose chronique.

    Fumer accentue les effets nocifs d'une exposition à la poussière chez
    les mineurs de charbon, ou aux pesticides chez ceux qui en manipulent,
    et cette accentuation du risque s'observe également dans l'industrie du
    caoutchouc et du pétrole. Les mineurs de charbon qui fument risquent
    davantage de contracter une bronchite chronique ou une pneumopathie
    obstructive, mais pas un emphysème. Les cancers du poumon observés chez
    les mineurs de charbon sont attribués en totalité au tabagisme. Fumer
    peut accroître les effets d'une exposition aux poussières végétales qui
    engendrent des affections respiratoires chroniques, comme la byssinose
    produite par la poussière de coton et le cancer des fosses nasales
    provoqué par la poussière de bois.

    3.  Composition des feuilles et de la fumée de tabac

    On a isolé plus de 3040 composés chimiques des feuilles de tabac après
    transformation (Roberts, 1988). La plupart d'entre eux sont des
    constituants de la feuille, mais d'autres résultent des conditions de
    culture (sol et atmosphère de la région) ou encore des produits
    agrochimiques utilisés et des traitements subis (sauçage,
    humidification, aromatisation et séchage). On constate des différences
    selon la région d'origine du tabac, les variétés et les diverses
    méthodes de séchage et de transformation utilisées. Ces différences
    peuvent affecter la proportion des divers constituants mais la
    composition globale ne varie pas. Parmi les importants composés toxiques
    que l'on a mis en évidence, on trouve, à côté de la nicotine, des
    nitrosamines cancérogènes qui proviennent de l'action des nitrites, des
    amines, des protéines et des alcaloïdes d'origine foliaire, des
    hydrocarbures aromatiques polycycliques formés au cours du séchage, des
    éléments radioactifs captés dans le sol et dans l'air ainsi que du
    cadmium dans le cas de tabacs cultivés sur des sols riches en cadmium.
    Lorsque l'on fume, la combustion du tabac conduit à la formation de
    nombreux produits de pyrolyse ou résultant d'autres types de réactions.

    4.  Fumée du courant principal

    La fumée de tabac est un aérosol consistant en une phase particulaire
    constituée de gouttelettes de liquide dispersées dans une phase gazeuse
    ou vapeur. Lorsque l'on fume une cigarette, il se forme de nombreux
    composés qui résultent de la pyrolyse du tabac. Ceux-ci peuvent, soit
    traverser la cigarette dans la fumée constituant le courant
    principal-certains d'entre eux se condensant légèrement en arrière du
    cône incandescent-, soit passé dans l'air à partir de l'extrémité
    incandescente, dans la fumée qui constitue le courant latéral. A chaque
    bouffée, ces composés se concentrent dans la fumée car les produits qui
    s'étaient déjà condensés viennent s'y ajouter -- la zone de condensation
    se réduisant à mesure que la cigarette se raccourcit. La nature
    physicochimique de la fumée dépend du traitement subi par le tabac et de
    sa combustion, de la porosité et du traitement du papier et du type de
    bout-filtre (Hoffmann & Hoffmann, 1997). Dans le cas d'une cigarette ou
    de ce que l'on appelle un "bidi" en Asie (du tabac roulé dans la feuille
    d'une plante), la composition chimique de la fumée dépend de facteurs
    tels que les dimensions et la porosité de l'enveloppe ainsi que des

    paramètres du fumage : volume, fréquence et durée des bouffées (NIH,
    1998). Les variations de composition chimique concernent davantage la
    proportion des différents constituants que la présence ou l'absence de
    tel ou tel composé.

    La fumée du courant principal est produite à l'intérieur du cône
    incandescent dans une atmosphère relativement pauvre en oxygène à une
    température de combustion de 850-950°C. Au départ, les particules de
    cette fumée ont un diamètre aérodynamique massique médian (DAMM) de 0,2
    à 0,3 µm; toutefois, dès qu'elles pénètrent dans les voies
    respiratoires, où le degré d'humidité est de 100%, elles s'agrègent pour
    former des particules de plus grande taille et se comportent alors comme
    si leur DAMM était de l'ordre du micromètre. Environ 50 à 90% des
    particules inhalées peuvent être retenues dans les voies respiratoires
    (Wynder & Hoffmann, 1967; Hinds et al., 1983). Pour des raisons d'ordre
    dimensionnel, les particules présentes dans l'aérosol, les constituants
    de la phase gazeuse et les gaz permanents sont capables d'atteindre les
    alvéoles lors de l'inhalation de la fumée. Le comportement des
    constituants hydrophiles en présence d'une forte humidité fait que le
    dépôt dans l'arbre trachéobronchique revêt un caractère complexe, mais
    de toute manière, la fumée s'insinue dans la totalité des voies

    Près de 4000 constituants ont été répertoriés dans la fumée du courant
    principal à côté d'un nombre indéterminés de substances non identifiées
    (Roberts, 1988). La fumée du courant principal comporte une phase
    particulaire et une phase gazeuse. La phase particulaire contient de la
    nicotine, des nitrosamines telles que la
    4-(méthylnitrosamino)-1-(3-pyridyl)-1-butanone (NKK) et la
     N-nitrosonornicotine (NNN), des métaux comme le cadmium, le nickel, le
    zinc et le polonium-210, des hydrocarbures polycycliques et des amines
    cancérogènes comme le 4-aminobiphényle. La phase gazeuse renferme du
    monoxyde et du dioxyde de carbone, du benzène, de l'ammoniac, du
    formaldéhyde, du cyanure d'hydrogène, de la  N-nitrosodiméthylamine, de
    la  N-nitrosodiéthylamine et un certain nombre d'autres composés. Les
    composés présents dans la fumée de tabac peuvent, selon leurs effets
    biologiques, être classés en asphyxiants, irritants, ciliatoxines,
    mutagènes, cancérogènes, inhibiteurs d'enzymes, neurotoxines ou dérivés
    dotés d'action pharmaceutique. C'est principalement par les voies
    respiratoires que la fumée de tabac pénètre dans l'organisme mais de
    nombreux constituants, présents en particulier dans la fumée de pipe et
    de cigare, se dissolvent dans la salive et sont soit avalés, soit
    absorbés au niveau de la cavité buccale. Les fumeurs de pipe et de
    cigare n'inhalent généralement pas la fumée, qui demeure dans la cavité
    buccale où, on vient de le voir, elle se dissout dans la salive et peut
    être soit absorbée par passage à travers la muqueuse buccale, soit être
    directement avalée (NIH, 1998). Les boissons alcoolisées, par leur effet
    solvant sur les constituants de la fumée, en facilitent la résorption.

    5.  Fumée du courant latéral

    La fumée du courant latéral est généralement produite à une température
    de combustion plus faible (500-600°C) dans une atmosphère réductrice.
    Les particules de cette fumée ont, lorsqu'elles sont fraîchement émises,
    une taille à peu près équivalente à celle des particules du courant
    principal, avec un diamètre aérodynamique massique médian (DAMM)
    d'environ 0,2 µm. Quantitativement, la composition de la fumée du
    courant latéral est analogue à celle de la fumée du courant principal.
    Certaines substances du courant latéral sont émises à une concentration
    (rapportée à 1 g de tabac brûlé) plus élevée que les constituants du
    courant principal. C'est notamment le cas de composés cancérogènes comme
    la  N-nitrosodiméthylamine et la  N-nitrosodiéthylamine ou encore de
    métaux comme le nickel et le cadmium. Beaucoup de dérivés cancérogènes
    sont plus concentrés dans la fumée du courant latéral que dans celle du
    courant principal. Des épreuves biologiques consistant à badigeonner la
    peau de souris avec un condensant de fumée du courant latéral ont montré
    que ce dernier est plus cancérogène que celui de la fumée du courant
    principal (Wynder & Hoffmann, 1967; US Surgeon General, 1986; NIH,

    6.  La manière de fumer la cigarette et ses effets sur la toxicité de la

    Les cigarettes n'ont pas toutes la même teneur en nicotine et le fumeur
    "tire" plus ou moins fort en inhalant plus ou moins profondément pour
    satisfaire son besoin de nicotine. Il s'ensuit qu'en fumant une
    cigarette à bout-filtre pauvre en nicotine (< 1,2 mg) le fumeur va
    tirer plus intensément, ce qui ne sera pas sans effet sur la toxicité
    (NIH, 1998).

    7.  Résumé des conclusions et des recommandations

    La consommation de tabac, notamment en le fumant, constitue un problème
    de santé publique d'une extrême importance en raison de la morbidité et
    de la mortalité qui en résultent. Outre les effets nocifs causés par une
    utilisation active du tabac, on a montré qu'il en existe aussi qui
    résultent de l'exposition passive à la fumée présente dans
    l'environnement. Les dangers du tabagisme sont également accrus par la
    possibilité d'interactions avec certains agents chimiques, physiques ou
    biologiques présents sur les lieux de travail ou dans l'environnement en
    général. On connaît certes quelques cas d'interactions antagonistes,
    mais les risques inhérents au tabagisme l'emportent de très loin sur ses
    effets protecteurs apparents. Tout doit être mis en oeuvre pour faire
    cesser la consommation de tabac et en particulier l'habitude de fumer.
    Il faut s'opposer très vigoureusement au tabagisme sur les lieux
    publics. En outre, pour éviter des interactions avec d'autres types
    d'exposition tout en éliminant le risque d'exposition passive à la fumée
    de tabac, il faut interdire de fumer sur les lieux de travail.

    Il faut aussi vivement inciter les gens à ne pas fumer à la maison afin
    de protéger la santé de la famille et notamment celle des enfants. On
    évitera ainsi également des interactions potentiellement dangereuses
    avec d'autres types d'exposition pouvant survenir dans l'environnement
    domestique. Il est nécessaire d'établir sans attendre des programmes
    éducatifs sur les dangers du tabagisme pour la santé. Les professionnels
    de la santé doivent prêter assistance aux personnes qui désirent cesser
    de fumer. Comme le tabagisme peut entraîner une modification des
    réactions aux médicaments ou autres formes de traitement, voire susciter
    à leur encontre des réactions indésirables, les médecins doivent ajuster
    les doses de leurs patients en conséquence et surveiller leurs


    1. Introducción

    El consumo de tabaco, particularmente el hábito de fumar, provoca una
    serie de efectos nocivos para salud, está directamente relacionado con
    varias enfermedades graves y puede aumentar los efectos adversos de
    otros agentes químicos, físicos y biológicos. Si no se controlan, los
    agentes químicos y de otro tipo pueden producir en el puesto trabajo
    enfermedades, discapacidades y la muerte prematura. Es evidente que en
    el lugar de trabajo los efectos adversos pueden deberse a la interacción
    sinérgica del humo de tabaco con otros peligros. La mayor parte de las
    interacciones de los constituyentes nocivos del humo de tabaco con
    sustancias químicas tóxicas se producen cuando estas últimas están en el
    aire, aunque se han notificado asimismo interacciones del humo con
    agentes perjudiciales ingeridos y/o absorbidos.

    El consumo de tabaco está generalizado en todo el mundo, desde los
    países de bajos ingresos hasta los industrializados más ricos. Lo
    utilizan hombres y mujeres, niños y adultos, y millones de personas
    están involuntariamente expuestas al humo de tabaco en su entorno. Si
    bien hay numerosas explicaciones del hábito de fumar, la razón principal
    de su ubicuidad es el efecto adictivo de la nicotina, droga presente en
    todas las formas de la hoja de tabaco y que llega al consumidor en
    cantidades variables según los distintos tipos de consumo  (capítulo 2).
    La aparición del cigarrillo, de producción masiva, fácil de obtener,
    relativamente económico y ligero de peso, de manera que se puede llevar
    en la boca dejando las manos libres, ha tenido repercusiones importantes
    en el hábito de fumar, tanto en general como en el puesto de trabajo.

    En muchos países se reconoce que el humo de tabaco constituye un peligro
    grave para la salud y es un factor que contribuye de manera importante
    a la muerte causada por diversas enfermedades comunes. En esos países se
    ha aplicado una legislación de alerta sanitaria y medidas impositivas
    para el control de su consumo, así como programas de educación del
    público sobre los peligros del tabaco y las ventajas de no comenzar a
    fumar o de interrumpir el consumo. Sin embargo, todavía hay países donde
    no se han puesto en marcha medidas decisivas para abordar el problema
    del consumo de tabaco.

    Son muchas las situaciones laborales que conllevan un elemento de
    riesgo. El tipo de trabajo puede generar efectos nocivos para salud y
    las actividades laborales pueden provocar la contaminación de medio
    ambiente. El propio cultivo del tabaco requiere el uso de plaguicidas,
    la recolección de la hoja puede ocasionar trastornos debido a la
    absorción de nicotina a través de la piel y su elaboración expone a los
    trabajadores a peligros para la salud provocados por el polvo y las
    esporas de hongos presentes en el aire. Se ha notificado una elevada
    incidencia de cáncer en el sexo masculino en zonas con industrias
    tabaqueras. En la minería existe polvo de minerales en el aire y en la
    agricultura y la industria basadas en materias primas producidas
    biológicamente hay polvo biológico. Durante las actividades de soldadura

    se produce humo y en muchas industrias crean peligro los gases, humos,
    neblinas y vapores cargados de sustancias orgánicas y/o inorgánicas
    tóxicas. Un calor excesivo o la  exposición a luz ultravioleta pueden
    ser perjudiciales para el bienestar de los trabajadores. Está admitido
    que las radiaciones ionizantes en la minería y en la tecnología moderna
    son un peligro en el lugar de trabajo. En numerosas actividades, los
    trabajadores están expuestos a un ruido excesivo o a vibraciones
    mecánicas peligrosas. Estas condiciones laborales pueden afectar más
    negativamente a la salud de las personas fumadoras que a la de las no
    fumadoras. Son muchos los países en los que está prohibido fumar en el
    trabajo, fundamentalmente por razones de seguridad en cuanto
    incendios/explosiones. Sin embargo, en algunos países no siempre se
    cumple la reglamentación. En varios países recientemente
    industrializados no se han abordado todavía plenamente los problemas de
    salud asociados con el trabajo y muchos empleadores y trabajadores
    desconocen los peligros para la salud de sus actividades. Además, existe
    un amplio "sector extraoficial" de la industria, particularmente en los
    países en desarrollo, en que se trabaja en el hogar y se utilizan
    sustancias químicas (en particular disolventes, resinas y colorantes
    sintéticos), estando expuesta toda la familia, y no hay restricciones
    sobre la exposición a los peligros en el trabajo o al humo.

    Está mucho menos definida la situación en relación con los efectos
    adversos en la salud derivados de la exposición combinada al humo de
    tabaco -- de la corriente principal o del medio ambiente -- y a los
    agentes del entorno doméstico. Sin embargo, la incidencia de cáncer de
    pulmón y la concentración de radón en los hogares tiene una relación
    dosis-respuesta similar a la que se produce entre el cáncer de pulmón y
    la concentración de radón en las minas, y el riesgo es más elevado para
    los fumadores.

    2.  Ejemplos de efectos combinados de la exposición al humo de
        tabaco y a otras sustancias

    Está demostrada la existencia de sinergia en la producción de efectos
    nocivos (cáncer) entre el humo de tabaco y la exposición al arsénico, el
    amianto, el etanol, el silicio y las radiaciones (radón, bomba atómica,
    rayos X). Por otra parte, hay pruebas de antagonismo en el caso del humo
    de tabaco y los clorometiléteres carcinogénicos, es decir, el
    clorometilmetiléter (CMME) y el bis(clorometil)éter (BCME) (Hoffmann y
    Wynder, 1976; CIIC, 1986), el humo de tabaco y la alveolitis alérgica y
    el humo de tabaco y la beriliosis crónica. El humo de tabaco influye en
    el riesgo para la salud  de la exposición en la extracción de carbón, el
    manejo de plaguicidas y las industrias del caucho y el petróleo. Los
    trabajadores de las minas de carbón que fuman tienen un riesgo más
    elevado de contraer bronquitis crónica y enfermedades obstructivas de
    las vías respiratorias, pero no enfisema. El cáncer de pulmón de los
    mineros del carbón se ha atribuido totalmente al humo de tabaco. El humo
    de tabaco puede aumentar el riesgo para salud de la exposición a polvos
    vegetales que producen trastornos respiratorios crónicos, como la
    bisinosis debida al polvo del algodón y el cáncer nasal provocado por el
    polvo de la madera.

    3.  Composición de la hoja del tabaco y del humo de tabaco

    De las hojas de tabaco elaboradas se han aislado más de 3040 compuestos
    químicos (Roberts, 1988). La mayoría son constituyentes de la hoja, pero
    la presencia de algunos depende de las condiciones de cultivo, como el
    suelo y la atmósfera de la zona, mientras que otros se derivan del uso
    de productos químicos agrícolas, de revestimientos, humectantes y
    aromatizantes añadidos a las hojas y de los métodos de curado. Las
    diferentes variedades de tabaco que se cultivan en los distintos países,
    así como las distintas formas de curado y elaboración, ponen de
    manifiesto diversas diferencias. Las proporciones de los distintos
    constituyentes pueden ser diferentes, pero no la composición general.
    Entre los compuestos tóxicos importantes identificados, aparte de la
    nicotina, figuran nitrosaminas carcinogénicas, derivadas de nitritos,
    aminas, proteínas y alcaloides presentes en la hoja, hidro-carburos
    aromáticos policíclicos procedentes del proceso de curado, elementos
    radiactivos absorbidos del suelo y el aire, y cadmio en el tabaco
    cultivado en suelos ricos en este elemento. Cuando se quema tabaco al
    fumar, se forman numerosos productos derivados de la pirólisis y de
    otras reacciones.

    4.  Corriente principal del humo de tabaco

    El humo del tabaco es un aerosol formado por una fase particulada de
    gotitas de líquido dispersas en una fase de gas/vapor. Al fumar un
    cigarrillo se forman numerosos compuestos por la pirólisis del tabaco.
    Éstos pasan a través del cigarrillo en la corriente principal del humo,
    condensándose algunos a corta distancia detrás del cono de combustión,
    o bien se emiten en el aire a partir del extremo que se quema como humo
    lateral. En cada bocanada el humo se hace progresivamente más fuerte,
    porque se le añade material previamente condensado y porque la longitud
    del cigarrillo disponible para la ulterior condensación disminuye. Las
    características fisicoquímicas del humo dependen de la elaboración y la
    combustión del tabaco, la porosidad y el tratamiento del papel en el que
    está envuelto y del tipo de filtro (Hoffman y Hoffman, 1997). En el caso
    de un cigarrillo o "bidi" asiático (tabaco envuelto en hoja vegetal), la
    química del humo se ve afectada por factores tales como las dimensiones,
    la porosidad de la envoltura y los parámetros del volumen, la frecuencia
    y la duración de la bocanada de humo (NIH, 1998). Las variaciones en la
    química del humo se dan fundamentalmente en la proporción entre sus
    constituyentes, más que en la presencia o ausencia de compuestos

    El humo de la corriente principal se genera en una atmósfera con un
    contenido comparativamente bajo de oxígeno a una temperatura de
    combustión de 850-950°C en el cono de combustión. Al principio, las
    partículas presentes en la corriente principal tienen un diámetro
    aerodinámico medio de la masa (MMAD) de 0,2 a 0,3 micras; sin embargo,
    en cuanto llegan al tracto respiratorio, con una humedad del 100%, se
    unen para formar partículas mayores y se comportan como si su MMAD fuera
    del orden de micras. En el tracto respiratorio se puede retener
    alrededor del 50-90% de todas las partículas inhaladas (Wynder y
    Hoffmann, 1967; Hinds et al., 1983). Por lo que se refiere al tamaño, al

    inhalar el humo pueden llegar a los alvéolos las partículas en aerosol,
    los constituyentes de la fase de vapor y los gases permanentes. La
    deposición en el árbol traqueobronquial se ve complicada por el
    comportamiento de los constituyentes hidrofílicos en condiciones de
    humedad elevada, pero el humo llega a todas las partes de las vías

    El humo de la corriente principal contiene cerca de 4000 sustancias
    químicas identificadas y un número desconocido de sustancias químicas
    sin identificar (Roberts, 1988). El humo de la corriente principal se
    puede dividir en una fase de partículas y otra de gas. La fase de
    partículas contiene nicotina, nitrosaminas como la
    4-(metilnitrosamino)-1-(3-piridil)-1-butanona (NNK) y la
     N-nitrosonornicotina (NNN), metales como el cadmio, el níquel, el zinc
    y el polonio-210, hidrocarburos policíclicos y aminas carcinogénicas,
    como el 4-aminobifenilo. La fase de vapor contiene monóxido de carbono,
    anhídrido carbónico, benceno, amoníaco, formaldehído, cianuro de
    hidrógeno,  N-nitrosodimetilamina,  N-nitrosodietilamina y otros
    compuestos. Los compuestos del humo de tabaco se pueden clasificar por
    su actividad biológica como asfixiantes, irritantes, ciliatoxinas,
    mutágenos, carcinógenos, inhibidores de las enzimas, neurotoxinas o
    compuestos farmacológicamente activos. El principal punto de entrada del
    humo del cigarrillo en el organismo es por las vías respiratorias, pero
    muchos constituyentes, en particular del humo de pipa y de cigarro, se
    disuelven en la saliva y se absorben en la cavidad bucal o se ingieren.
    Los fumadores de cigarros y de pipa no suelen inhalar el humo, que
    permanece en la cavidad bucal, se disuelve en la saliva y se absorbe a
    través de las membranas mucosas o se ingiere (NIH, 1998). Las bebidas
    alcohólicas tienen un efecto disolvente de los constituyentes del humo,
    facilitando su absorción.

    5.  Humo de tabaco lateral

    El humo lateral se forma con una temperatura de combustión más baja
    (500-600°C) en una atmósfera reductora. Las partículas del humo lateral
    fresco son prácticamente del mismo tamaño que las de la corriente
    principal, con un diámetro aerodinámico medio de la masa de alrededor de
    0,2 micras. Desde el punto de vista cualitativo, la composición del humo
    lateral es semejante a la del humo de la corriente principal. Algunas
    sustancias químicas se emiten en el humo lateral con una concentración
    mayor por gramo de tabaco quemado que en el humo de la corriente
    principal. Esto es particularmente aplicable a carcinógenos como la
     N-nitrosodimetilamina y la  N-nitrosodietilamina y a metales como el
    níquel o el cadmio. Muchos compuestos carcinógenos están más
    concentrados en el humo lateral que en el principal. En biovaloraciones
    con aplicación a la piel de ratones se ha demostrado que el humo lateral
    condensado es más carcinogénico que el principal (Wynder y Hoffmann,
    1967; US Surgeon General, 1986; NIH, 1998).

    6.  Efectos de la manera de fumar los cigarrillos en la
        toxicidad del humo

    El contenido de nicotina de los distintos cigarrillos varía, y el
    fumador, para satisfacer la necesidad adquirida de nicotina, la ajusta
    mediante la intensidad con la que fuma y la profundidad de la
    inhalación. Por consiguiente, el fumador de cigarrillos con filtro y de
    contenido bajo en nicotina (< 1,2 mg) fuma con mayor intensidad, y esto
    influye en la toxicidad (NIH, 1998).

    7.  Resumen de las conclusiones y recomendaciones

    El consumo de tabaco, en particular el hábito de fumar, representa un
    peligro para la salud pública de la máxima importancia y es una causa
    prevenible importante de morbilidad y mortalidad. Además de los efectos
    adversos del consumo activo de tabaco para la salud, se han demostrado
    efectos adversos derivados de la exposición al humo de tabaco presente
    en el medio ambiente. Los riesgos del hábito de fumar también aumentan
    como consecuencia de las interacciones con ciertos peligros químicos,
    físicos y biológicos existentes en el lugar de trabajo y en el medio
    ambiente general. Hay un pequeño número de casos de interacciones
    antagonistas, pero los riesgos del humo de tabaco para la salud son muy
    superiores a cualquier efecto protector aparente.

    Se deben adoptar todas las medidas posibles para eliminar el consumo de
    tabaco, en particular el hábito de fumar, y se ha de disuadir con
    firmeza de fumar en lugares públicos. A fin de evitar la interacción con
    otros tipos de exposición ocupacional y de eliminar el riesgo de
    exposición al humo de tabaco del medio ambiente, debería prohibirse
    fumar en el lugar de trabajo.

    Con objeto de proteger la salud, en particular la de los niños, se
    debería desalentar con firmeza el hábito de fumar en el hogar. De esta
    manera se previenen posibles interacciones perjudiciales entre el humo
    de tabaco y la exposición a otros peligros en la vivienda. Hay una
    necesidad imperiosa de programas educativos sobre los peligros del
    hábito de fumar para la salud. Los profesionales de la salud deberían
    prestar asistencia para ayudar a los fumadores a dejar este hábito.
    Debido a que el humo puede provocar una alteración de la respuesta a los
    medicamentos y otros tratamientos o una reacción adversa a éstos, los
    médicos deberían estudiar la posibilidad de introducir ajustes
    apropiados de la dosificación y vigilar a los pacientes.

    See Also:
       Toxicological Abbreviations