UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 211
HEALTH EFFECTS OF INTERACTIONS BETWEEN TOBACCO
USE AND EXPOSURE TO OTHER AGENTS
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
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of the policies and activities pursued by the Participating
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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
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CONTENTS
HEALTH EFFECTS OF INTERACTIONS BETWEEN TOBACCO USE AND EXPOSURE TO
OTHER AGENTS
PREAMBLE
ABBREVIATIONS
1. OVERVIEW
1.1. Introduction
1.2. Examples of combined effects of tobacco smoking and other
exposures
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
toxicity
1.7. Summary of conclusions and recommendations
2. EXPOSURE TO TOBACCO PRODUCTS AND HEALTH RISKS FROM TOBACCO USE
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
2.2.1.1 Acute bronchitis
2.2.1.2 Asthma
2.2.2. Chronic responses
2.2.2.1 Chronic obstructive lung
diseases (COLD)
2.2.2.2 Chronic bronchitis
2.2.2.3 Small airways disease
2.2.2.4 Emphysema
2.2.2.5 Pulmonary fibrosis
2.2.2.6 Effects on the immune system
2.2.3. Cancer
2.2.4. Cardiovascular effects
2.2.5. Smoking and occupational accidents, injuries and
absenteeism
2.3. Health risks from smokeless tobacco use
2.3.1. Introduction
2.3.2. Cancer
2.3.3. Cardiovascular disease
3. EFFECTS ON HEALTH OF TOBACCO USE AND EXPOSURE TO OTHER CHEMICALS
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
3.2.1.1 Asbestos and lung cancer
3.2.1.2 Asbestos and pleural
mesothelioma
3.2.1.3 Asbestos and other forms of cancer
3.2.1.4 Asbestosis
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
3.6.1.1 Radon in mines (high linear energy
transfer (LET) alpha-radiation)
3.6.1.2 Environmental radon (high linear
energy transfer (LET) alpha-radiation)
3.6.1.3 Atomic bomb site radiation
(low linear energy transfer (LET)
radiation)
3.6.1.4 Therapeutic X-rays (low linear
energy transfer (LET) radiation)
3.6.1.5 Nuclear plant
3.6.1.6 Summary
3.6.2. Vibration
3.6.3. Noise
3.6.4. Dupuytren's contracture
3.7. Biological agents
3.7.1. Biological (vegetable) dusts
3.7.1.1 Cotton dust
3.7.1.2 Wood dust
3.7.1.3 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
radiation
4. EFFECTS OF EXPOSURE TO TOBACCO SMOKE AND OTHER AGENTS: SEPARATE
EFFECTS OR POSSIBLE INTERACTIONS
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. CONCLUSIONS AND RECOMMENDATIONS
5.1. Conclusions
5.2. Recommendations for protection of human health
6. FURTHER RESEARCH
REFERENCES
SYNOPSIS
PANORAMA GENERAL
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
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Environmental Health Criteria
PREAMBLE
Objectives
In 1973 the WHO Environmental Health Criteria Programme was initiated
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WHO WORKING GROUP ON HEALTH RISKS FROM THE COMBINED EFFECTS OF TOBACCO
SMOKING AND EXPOSURE TO OTHER CHEMICALS
(Geneva, 25-26 April 1966)
Members
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
Secretariat
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
WHO TASK GROUP ON HEALTH EFFECTS OF INTERACTIONS BETWEEN TOBACCO USE
AND EXPOSURE TO OTHER AGENTS
(Geneva, 18-21 February 1997)
Members
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
Netherlands
Observers
Dr G. Minotti, Catholic University of the Sacred Heart, Rome, Italy
( representing the International Union of Pharmaceutical
Societies)
Secretariat
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
HEALTH EFFECTS OF INTERACTIONS BETWEEN TOBACCO USE AND EXPOSURE TO
OTHER AGENTS
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
Kingdom
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.
ABBREVIATIONS
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
workplaces.
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
exposures
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. EXPOSURE TO TOBACCO PRODUCTS AND HEALTH RISKS FROM TOBACCO USE
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.
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
preference.
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.,
1977).
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.
2.2.1.1 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.
2.2.1.2 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
2.2.2.1 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.
2.2.2.2 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.
2.2.2.3 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).
2.2.2.4 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).
2.2.2.5 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.
2.2.2.6 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
carcinogen.
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,
1996).
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.,
1985).
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
absenteeism
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.,
1989).
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. EFFECTS ON HEALTH OF TOBACCO USE AND EXPOSURE TO OTHER CHEMICALS
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
accordingly.
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).
Specifically,
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
industry.
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
particles
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,
1990).
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.
3.2.1.1 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
3.2.1.2 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).
3.2.1.3 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).
3.2.1.4 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
non-smokers.
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 b