Monday, January 5, 2009

Brüske-Hohlfeld I. Environmental and occupational risk factors for lung cancer.

The book is indicated in the bottom of the first page (or page 3)..

M. Verma (ed.), Methods of Molecular Biology, Cancer Epidemiology, vol. 472
© 2009 Humana Press, a part of Springer Science + Business Media, Totowa, NJ
Book doi: 10.1007/978-1-60327-492-0

The PMID record is as follows:
Methods Mol Biol. 2009;472:3-23. Links

Environmental and occupational risk factors for lung cancer.

Brüske-Hohlfeld I.
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.

Lung cancer is the world's leading cause of cancer death. It is primarily due to the inhalation of carcinogens and highly accessible to prevention by diminishing exposures to lung carcinogens. Most important will be the complete cessation of exposure to cigarette smoke (first and second hand) and to asbestos. Two environmental exposures--radon in homes and arsenic in drinking water--cannot be totally avoided, but people in certain geographical regions would greatly benefit from a reduction in exposure magnitude. And last but not least, workers all over the world deserve that preventive measures at the workplace are observed with regard to exposures, such as arsenic, beryllium, bis-chloromethyl ether (BCME), cadmium, chromium, polycyclic aromatic hydrocarbons (PAHs), and nickel.
PMID: 19107427 [PubMed - in process]


===========================================
Noreen R. Gonzales, Ph.D.
Staff Scientist, Structure Group
NCBI, NLM, NIH
Bldg 38A, Rm 5N511-J
Tel. (301) 402 3154
===========================================
From: Florence T. Cua [mailto:ftcua8@comcast.net]
Sent: Thursday, January 01, 2009 7:35 AM
To: Gonzales, Noreen (NIH/NLM/NCBI) [E]
Subject: Fwd: [RADONPROFESSIONALS] Environmental and Occupational Risk Factors for Lung Cancer

Dr. Noreen Gonzales McCurdy,

May I ask you to search for this author with this chapter however I do not know the book title?

THANK YOU, DR. NOREEN GONZALES MCCURDY-MY PAASE FRIEND AND COLLEAGUE.










Chapter 1

Environmental and Occupational Risk Factors for Lung Cancer

Irene Br ü ske-Hohlfeld

Abstract
Lung cancer is the world’s leading cause of cancer death. It is primarily due to the inhalation of carcinogens
and highly accessible to prevention by diminishing exposures to lung carcinogens. Most important will
be the complete cessation of exposure to cigarette smoke (first and second hand) and to asbestos. Two
environmental exposures
— radon in homes and arsenic in drinking water
— cannot be totally avoided, but
people in certain geographical regions would greatly benefit from a reduction in exposure magnitude.
And last but not least, workers all over the world deserve that preventive measures at the workplace are
observed with regard to exposures, such as arsenic, beryllium, bis-chloromethyl ether (BCME),
cadmium, chromium, polycyclic aromatic hydrocarbons (PAHs), and nickel.

Key words:
Lung cancer , cigarette smoke ,
asbestos , radon in homes , arsenic in drinking water , beryl-
lium ,
bis-chloromethyl ether (BCME)
,
cadmium , chromium
, nickel, polycyclic aromatic
hydrocarbon
(PAH).

Incidence and mortality rates for lung cancer have risen dramati-
cally since the turn of the last century. In 1878, malignant lung
tumors represented only 1% of all cancers seen at autopsy in the
Institute of Pathology of the University of Dresden in Germany
(1) . By 1918, the percentage had risen to almost 10%, and, in
2004, lung cancer was the most common cause of cancer death
(27% of all cancer deaths) in men in the European community,
resulting in a lifetime risk of dying from lung cancer of 5.5%
(2) .
In the USA, 215,020 new cases and 161,840 deaths from lung
1. Introduction
1. Introduction
1.1. Short Descriptive
Epidemiology
1.1. Short Descriptive
Epidemiology
M. Verma (ed.), Methods of Molecular Biology, Cancer Epidemiology, vol. 472
© 2009 Humana Press, a part of Springer Science + Business Media, Totowa, NJ
Book doi: 10.1007/978-1-60327-492-0
3
4 Brüske-Hohlfeld
cancer are predicted for 2008
1 . Worldwide lung cancer causes the
largest disease burden of all cancers, accounting for more than
1.2 million new cases annually, a figure that is still increasing.
The likelihood of getting lung cancer increases with age.
Only one in ten patients diagnosed with this disease will survive
the following 5 years. While smoking prevalence has declined in
many developed countries, it is increasing in developing countries
and also among women. Throughout the world the incidence
of lung cancer among men exceeds, usually by twofold or more,
that among women. This sex difference is shrinking, however, as
gender differences in smoking have become less pronounced.
Although the causes of lung cancer are almost exclusively envi-
ronmental, it is likely that there is a substantial individual
variation in the susceptibility to respiratory carcinogens. The
risk of the disease can be conceptualized as reflecting the joint
consequences of the interrelationship between exposure to etio-
logic/protective agents and the individual susceptibility to these
agents. A familial aggregation of lung cancer has been described
in numerous studies, including segregation analyses (3) , and a
higher concordance for monozygotic than for dizygotic twins
has been noted
(4) . However, it is still open to what degree the
familial aggregation of lung cancer can be explained by herit-
ability of cancer susceptibility compared with ‘inheritance’ of
smoking behaviour and other factors, such as passive smoking
and eating habits.
The lung consists of two different parts, the airways transport-
ing the air in and out of the lung and the alveoli, which consist
of specialized cells that form millions of tiny, exceptionally thin-
walled air sacs (~200 nm) for gas exchange. Whereas the airways
have a relatively robust barrier of ciliated epithelium and viscous
mucus —
the so-called mucociliary escalator
— the gas exchange
region is only protected by alveolar macrophages. During a typi-
cal day, the average adult inhales about 10,000 L air. All inhaled
gases diffuse from the alveolar air to the blood in the pulmonary
capillaries, as carbon dioxide diffuses in the opposite direction,
from capillary blood to alveolar air. The large surface of the alve-
oli and the intense air blood contact is often illustrated by the
metaphor of one wineglass of blood spread over the surface of a
tennis court. As permeability is the main function of the alveoli,
there are structural and functional limits to act at the same time
as a barrier against inhaled gases and particles, including bacteria
and viruses. The phagocytosis of particles and fibres from the
1.2. The Lung as a
Main Entry Portal
to the Organism
1.2. The Lung as a
Main Entry Portal
to the Organism
1 http://www.cancer.gov/cancertopics/types/lung


Environmental and Occupational Risk Factors for Lung Cancer 5
inhaled gas induces macrophages to release chemokines, cytokines,
reactive oxygen species, and other mediators that can lead to a
sustained inflammation and eventually to fibrotic changes.
Lung cancer develops through a series of progressive pathologi-
cal changes occurring in the respiratory epithelium. According to the
histological appearance of the malignant cells, lung cancer can be
classified into small cell lung cancer and non-small cell lung cancer.
Although this classification based on simple pathomorphological cri-
teria has very important implications for clinical management and
prognosis of the disease, it generally cannot be used to distinguish
between the potential exposures that might have caused it.

What is accepted as a
“ known ” risk factor of lung cancer is judged
differently all over the world, and is heavily influenced by politi-
cal, financial, and industrial interests. Trying to find an objective
point of view, the International Agency for Research on Cancer
(IARC) is considered as an organization adopting such a neu-
tral scientific position. The IARC is an arm of the World Health
Organisation (WHO). It conducts and promotes epidemiological
and laboratory-based research and training, and is most famous
for its series ‘Monographs on the Evaluation of Carcinogenic
Risks to Humans’

2
. Based on animal and human data, interdisci-
plinary working groups of expert scientists
— selected on the basis
of competence and the absence of conflicts of interest — review
published studies and evaluate the weight of the evidence that an
agent can increase the risk of cancer. They assign an agent, mix-
ture, or exposure circumstance to one of five categories:
● Group 1 (agent is carcinogenic to humans)


● Group 2a (agent is probably carcinogenic to humans)

● Group 2b (agent is possibly carcinogenic to humans)

● Group 3 (agent is not classifiable regarding its carcinogenicity)


● Group 4 (agent is agent is probably not carcinogenic to
humans).
The principles, procedures, and scientific criteria that guide
the evaluations are described in the Preamble to the IARC Mon-
ographs
3
. Group 1 pulmonary carcinogens, which will be covered
in this chapter, include arsenic
(5 , 6) , asbestos
(7) , beryllium (8) ,
bis-chloromethyl ether (BCME) (8) , cadmium (8) , chromium
(VI)
(9) , nickel
(9) , radon (10) , silica
(11) , as well as active
(12)
and passive smoking
(13) .
1.3. Risk Factors
of Lung Cancer
1.3. Risk Factors
of Lung Cancer
2 http://monographs.iarc.fr/

3 http://monographs.iarc.fr/ENG/Preamble/index.php


6 Brüske-Hohlfeld

Arsenic is widely distributed throughout the earth’s crust and
is introduced into the groundwater by dissolution of minerals
and ores. Arsenic contamination of groundwater has occurred
in various parts of the world, most notably the Ganges Delta of
Bangladesh and West Bengal, India, but parts of Thailand, Taiwan,
Argentina, Chile, and China have also been affected.
Inorganic arsenic can occur in the environment in several
forms but in natural waters, and thus in drinking water, it is mostly
found as trivalent arsenite, As(III), or pentavalent
arsenate, As
(V). Drinking water poses the greatest threat to public health
from arsenic. Absorption of arsenic through the skin is minimal
and thus hand-washing, bathing, laundry, etc. with water con-
taining arsenic do not pose a human health risk. Organic arsenic
species, abundant in seafood, are very much less harmful to
health, and are readily eliminated by the body.
In Bangladesh, West Bengal (India), and some other areas,
it was common practice to collect drinking water from open dug
wells and ponds. This water was often contaminated with micro-
organisms contributing to transmitting diseases, such as diarrhea,
dysentery, typhoid, cholera, and hepatitis. To prevent morbid-
ity and mortality from gastrointestinal disease in children, the
United Nations Children’s Fund (UNICEF) started a program
to install tube-wells to provide what was then thought to be a
safe source of drinking water
(14) . However, in 1993 it was dis-
covered that about half of these wells contained arsenic levels of
greater than the maximum level of 50
µ g/L permitted in Bang-
ladesh. The WHO recommendations on the acceptability and
safety of levels of arsenic in drinking water are even lower, having
dropped 20-fold, from a concentration of 200 µ g/L in 1958 to
10 µ g/L in the 1993 WHO Drinking Water Guidelines
4 . The
latest statistics indicate that 80% of Bangladesh and an estimated
40 million people are at risk of arsenic poisoning-related diseases,
including lung cancer, because the ground water in these wells is
contaminated with arsenic
(15) .
Long-term exposure to arsenic via drinking water causes skin
changes such as pigmentation changes and thickening (hyper-
keratosis), and, after a latency period, various cancers of the skin,
lungs, urinary bladder, and kidney, liver, and colon. An increased
risk of lung, probably from inhalation of water vapor, has been
2. Environmental
and Occupational
Exposures
2. Environmental
and Occupational
Exposures
2.1. Arsenic
2.1. Arsenic
4 http://www.who.int/mediacentre/factsheets/fs210/en/index.html

Environmental and Occupational Risk Factors for Lung Cancer 7
observed at drinking water arsenic concentrations of 350 –
1140
µ g/L
5
.
According to some estimates, arsenic in drinking
water will cause 200,000
– 270,000 deaths from all cancers in
Bangladesh
(14) .
Arsenic is used in wood preservatives and pesticides, and
industrial emissions may also be significant locally. Occupational
exposure to inorganic arsenic, especially in mining and copper
smelting, has very consistently been associated with an increased
risk of cancer. An almost tenfold increase in the incidence of lung
cancer was found in workers most heavily exposed to arsenic, and
relatively clear dose
— response relationships have been obtained
with regard to cumulative exposure (16) . Other US smelter
worker populations have been shown to have consistent increases
in lung cancer incidence
(17) . A dose — response analysis indi-
cated that the roasters and arsenic departments were risk places
for the development of cancer, especially lung cancer, among
Swedish smelter workers
(18) .
The term asbestos refers to a family of naturally occurring, flexible,
fibrous hydrous silicate minerals. Although many minerals can
crystallize in fibrous, asbestiform habit, only a few have been of
industrial use, like chrysotile, anthophyllite, crocidolite, amosite,
and tremolite. The crystal structure of chrysotile, which repre-
sents 94% of world asbestos consumption, is snakelike (hence also
named
“ serpentine ” ); the others are called amphibole minerals.
Asbestos is of commercial interest because of properties such as
resistance to heat and traction, flexibility and ease of spinning for
textile products, chemical resistance to alkalines, all giving rise to a
startling range of uses
(19) . From the beginning of the 20th cen-
tury, world production of asbestos grew steadily escalating after
World War II in a rush for asbestos cement and textile products,
vinyl asbestos floor tile, friction materials, and spray products to
name just a few. In Western Europe, Scandinavia, North America,
and Australia, the manufacture and use of asbestos products
peaked around 1970 with about 5 million tons/year.
Deposition of inhaled asbestos fibers is diffuse through the
lung and extends to the subpleural lung tissue. Clearance of
asbestos fibers occurs by a variety of pathways, including the
mucociliary escalator, the translocation into the interstitium to
the lymphatic system and the dissolution, degradation and break-
down of the original material. Fibers <3
µ m are phagocytosed and
eliminated via the lymphatics. But, if fibers are longer than 5 µ m,
phagocytosis will be incomplete and they will stay in the tissue
longer. This will initiate and sustain a cascade of events leading
2.2. Asbestos
2.2. Asbestos
5 http://www.who.int/water_sanitation_health/dwq/arsenic2/en/

8 Brüske-Hohlfeld
first to local and later to more diffuse fibrosis, named asbestosis of
the lungs. The relative toxicity of different forms and structures
of asbestos minerals can be linked to their morphology
— long,
thin amphibole fibers are more pathogenic. Asbestos is not a
classic gene mutagen in bacterial systems, but it does have the
capacity to induce chromosomal aberrations and transformation
in mammalian cells.
Problems stemming from the inhalation of asbestos in mill-
ing and manufacturing plants had been observed since the turn of
the century. Early reports (20 – 22) linking asbestos and cancer of
the lung in the 1950
– 1960s laid the foundation for the definitive
investigations of insulation workers in the USA by Irving Selikoff
and his colleagues
(23) . A very good historical overview of the
growing evidence of adverse health effects related to asbestos
exposure is given in the article by the European Environmental
Agency (EEA)
“ Late Lessons from Early Warnings: The Precau-
tionary Principle 1896
– 2000 ” 6 .

Asbestos-induced lung cancer is generally characterized by
a latency period of 20 years or longer between start of expo-
sure and onset of the disease. In a mortality follow-up of 17,800
US and Canadian asbestos insulation workers (24) , there was a
twofold increase of lung cancer during the period 10
– 14 years
after initial employment, reaching nearly sixfold 30
– 34 years
after employment, and declining at longer intervals. Because of
the long latency period, the peak level of lung cancer and meso-
thelioma — a form of cancer that is extremely rare in the general
population and much more specific to asbestos exposure than
lung cancer, as it is not associated with smoking
— has not been
reached yet. Peto et al.
(25) predicted that deaths from mesothe-
lioma among men in Western Europe would increase from just
over 5,000 deaths per year in 1998 to about 9,000 per year in
2018. In Western Europe alone, past asbestos exposure will give
rise to a quarter of a million deaths from mesothelioma over the
next 35 years. The number of lung cancer deaths caused by asbes-
tos is at least equal to the number of deaths from mesothelioma,
but the ratio may be higher.
Worldwide many million of workers have been exposed to
asbestos at the workplace. About 20
– 40% of adult men report
some past occupations and jobs that may have entailed asbestos
exposure at work (26 , 27) . A number of studies have projected
the number of premature deaths that will result from the asbestos
cancer epidemic
(27 – 29) . When the various estimates from these
and other studies are extrapolated to include the world popula-
6 http://reports.eea.europa.eu/environmental_issue_report_2001_22/en/
issue-22-part-05.pdf

Environmental and Occupational Risk Factors for Lung Cancer 9
tion, they project that at least 100,000 workers die each year
from asbestos exposure resulting in cancer
(29) . In this conserva-
tive estimate, it is assumed that asbestos exposures are going to
cease and that the epidemic will run itself out. But the world’s
production of asbestos, which went down by half in 1990s due
to the asbestos ban in many developed countries, seems to have
stabilized now at around 2 million tons/year
(30 , 31) .
By the beginning of 2006, 39 countries in Europe, the
Americas, the Middle East, and Australia had imposed national
bans. With dwindling markets in developed countries, the global
asbestos industry is focusing on emerging markets in developing
countries. Asbestos use in developing countries is increasing at
an annual rate of 7%. Asia has emerged as one of the largest mar-
kets for asbestos consumption, with China, India, Japan, Indo-
nesia, and South Korea among the world’s top ten consumers
in the year 2000
(31) . Asian countries accounted for about 60%
of the global asbestos consumption in the year 2000
(32) . Only
Singapore and recently Japan have adopted a total ban on asbestos.
The only way to assure an end to the asbestos cancer epidemic is
to ban all asbestos mining and manufacture, which will be even
more necessary in developing countries, where enforcement of
health and safety regulations is not a viable alternative. But, even
if exposure to asbestos were to stop soon, somewhere between 5
and 10 million people would ultimately die from asbestos related
diseases
7 .
How much the ubiquitous low-dose exposure to asbestos
fibres in the environment contributes to the burden of lung cancer
in the general population is not known. Camus and co-workers
found no measurable excess of death due to lung cancer among
women in two chrysotile asbestos-mining areas in the province of
Quebec
(33) . However, there is some evidence that family mem-
bers and others living with asbestos workers have an increased
risk of developing mesothelioma. For example, Schneider and
co-workers
(34) described six fatal diseases of pleural mesothelioma:
five wives and one son of asbestos industry workers. The wives
had been exposed to asbestos fibres while cleaning the contami-
nated work clothes and shoes of their husbands at home, and the
son used to visit his father throughout his childhood at the work-
place. Even pet dogs may develop mesothelioma if their owners
are exposed to asbestos
(35) .
Beryllium is most commonly used in high-tech devices where it
is bound into electronic components. Although only a relatively
small number of workers worldwide are potentially exposed to
high levels of beryllium, mainly in the refining and machining of
2.3. Beryllium
2.3. Beryllium
7 http://www.bwint.org/pdfs/chrysotileasbestos.pdf

10 Brüske-Hohlfeld
the metal and in production of beryllium-containing products, a
growing number of workers are potentially exposed to lower levels
of beryllium in the aircraft, aerospace, electronics, and nuclear
industries.
Ward et al. (36) reported the results of a cohort mortality
study of 9,225 workers at seven beryllium plants in the USA,
where a small but significant excess in mortality from lung cancer
was found in the total cohort. The risk of lung cancer was consist-
ently higher in those plants in which there was also excess mortality
from non-malignant respiratory disease. Also, the risk for lung
cancer increased with time since first exposure and was greater in
workers first hired in the period when exposures to beryllium in
the work place were relatively uncontrolled.
The IARC
(8) , the National Toxicology Program, and the
American Conference of Governmental Industrial Hygienists
(ACGIH) have classified beryllium as a human carcinogen, but
only at airborne exposure levels well in excess of the current
occupational exposure limits. The US Environmental Protection
Agency (EPA) classifies beryllium as a probable human carcino-
gen and the European Union states that beryllium may cause
cancer by inhalation.
However, a reanalysis of the original data from the 1992
publication
(36) of a cohort mortality study conducted by the
National Institute of Occupational Safety and Health (NIOSH)
of workers employed in seven plants producing beryllium in the
USA found lower and generally not statistically significant stand-
ard mortality ratios that are not compatible with the interpreta-
tion of a likely causal association
(37) .
In the past, bis-chloromethyl ether (BCME) was used to make
several types of polymers, resins, and textiles. In 1962, suspicion
arose that an excess of lung cancers was developing in a chemi-
cal plant. A prospective cohort study of 125 male workers was
begun, and the group was followed from January 1963 to the
end of 1979. A small epidemic of respiratory cancer evolved,
including 14 cases of lung cancer and 2 cases of laryngeal cancer
among 91 men exposed to chloromethyl ethers (CMEs) in the
17-year period, as compared with 2 cases of lung cancer among
34 unexposed men. The lung cancer epidemic peaked 15
– 19
years after onset of exposure and began to subside thereafter
(38) . Numerous epidemiological studies have demonstrated that
workers exposed to chloromethyl methyl ether and/or BCME
have an increased risk for lung cancer
(39 – 41) . Among heavily
exposed workers, the relative risks (RRs) are tenfold or more.
Risks increase with duration and cumulative exposure and latency
is shortened among workers with heavier exposure. Histological
evaluation indicates that exposure results primarily in lung cancer
of the small cell type.
2.4. Bis-Chloromethyl
Ether and Chloromethyl
Methyl Ether
2.4. Bis-Chloromethyl
Ether and Chloromethyl
Methyl Ether
Environmental and Occupational Risk Factors for Lung Cancer 11
The small quantities that are produced nowadays are only
used in enclosed systems to make other chemicals. Strict controls
have been established to minimize exposure to this chemical
8
in
the USA and worldwide.

Cadmium is used in electroplating for the manufacture of auto-
motive, aircraft, and electronic parts, and marine equipment and
industrial machinery. Cadmium compounds serve as stabilizers
for plastics and as pigments. Cadmium is also widely used in
nickel — cadmium storage batteries and is combined with other
metals in alloys. Most exposure to cadmium and its compounds
occurs in the working environment via inhalation.
Experimentally, cadmium induces lung tumors in rats, but
various epidemiological studies of cadmium-exposed workers did
not show any clear results due to concomitant exposures to other
occupational carcinogens, mainly nickel and arsenic. In a cohort
mortality study conducted at a US plant where cadmium metals
and compounds were processed since 1925, Stayner et al.
(42)
observed an excess in mortality from lung cancer for the entire
cohort. Mortality from lung cancer was greatest among work-
ers in the highest cadmium exposure group, and among workers
with 20 or more years since the first exposure. A statistically sig-
nificant dose — response relationship was evident in nearly all of
the regression models evaluated.

Chromium occurs primarily in the trivalent state, in which it is
unable to enter cells and has a low toxicity. However, hexavalent
chromium, Cr (VI), enters the cell through membrane anionic
transporters. It is a strong oxidizing agent, as well as a skin and
mucous membrane irritant. At the cellular level, Cr exposure may
lead to cell cycle arrest, apoptosis, premature terminal growth
arrest, or neoplastic transformation. Cr-induced DNA
— DNA
interstrand crosslinks (DDC), the tumor suppressor gene p53,
and oxidative processes are some of the major factors that might
play a significant role in determining the cellular outcome in
response to Cr exposure
(43) . The increased risk of lung can-
cer occurs primarily in workers exposed to hexavalent chromium
dust during the refining of chromite ore and the production of
chromate pigments (44 , 45) . Chromium is a human carcinogen
primarily by inhalation exposure in occupational settings (46) ;
little is known about the health risks of environmental exposures
to chromium.

2.5. Cadmium
2.5. Cadmium
2.6. Chromium (VI)
2.6. Chromium (VI)
8 http://www.atsdr.cdc.gov/tfacts128.html

12 Brüske-Hohlfeld
Nickel is used in many industrial and consumer products, includ-
ing stainless steel, magnets, coinage, and special alloys. It is
also used for plating and as a green tint in glass. Nickel is pre-
eminently an alloy metal, and its chief use is in the nickel steels
and nickel cast irons.
A large epidemiologic report on cancer mortality in 10
cohorts of occupationally exposed workers showed (47) that the
mortality from cancers of the lung was associated with exposure
to high levels of oxidic nickel compounds, exposure to sulfidic
nickel in combination with oxidic nickel, and exposure to water-
soluble nickel, alone or together with less soluble compounds.
Grimsrud and co-workers demonstrated a dose-related asso-
ciation between lung cancer and cumulative exposure to water-
soluble nickel compounds
(48) . In a case — control study of
Norwegian nickel refinery workers, the authors examined dose-
related associations between lung cancer and cumulative expo-
sure to four forms of nickel: water soluble, sulfidic, oxidic, and
metallic. A job-exposure matrix was based on personal measure-
ments of total nickel in air and the quantification of the four
forms of nickel in dusts and aerosols. The nickel exposures were
moderately to highly correlated. A clear dose-related effect was
seen for water-soluble nickel (odds ratio, 1.7; 95% confidence
interval (CI], 1.3 – 2.2). A general rise in risk from other types
of nickel could not be excluded, but no further dose-dependent
increase was seen.

Particulate matter (PM) is a complex mixture of airborne solid and
liquid particles including soot, organic material, sulfates, nitrates,
other salts, metals, and biologic material. Many carcinogens, includ-
ing a multitude of polycyclic aromatic hydrocarbons (PAHs), adsorb
to particles and can be deposited throughout the respiratory tract.
Also, combustion of fossil fuels is a source of arsenic in the environ-
ment through disperse atmospheric deposition.
Air pollution may increase lung cancer risk in a number of
ways. Inhalation of fine particles can lead to production of radical
oxygen species that cause DNA damage, which can lead to cancer.
Some of the metals that are found in fine PM are carcinogenic.
Several studies found an association between external measures of
exposure to air pollution and increased levels of DNA adducts,
with an apparent levelling-off of the dose
— response relationship.
The experimental work, combined with the data on frequent oxi-
dative DNA damage in lymphocytes in people exposed to urban
air pollution, suggests 8-oxo-dG as one of the important promuta-
genic lesions
(49) .
In general, ambient levels of PM are characterized as total
suspended matter (TSP), or PM with an effective aerodynamic
diameter of less than 10
µ m (PM
10 ) or 2.5
µ m (PM
2.5 ). Parti-
cles in the sub micrometer ranges, particularly in the size range
2.7. Nickel
2.7. Nickel
2.8. Particulate Air
Pollution
2.8. Particulate Air
Pollution
Environmental and Occupational Risk Factors for Lung Cancer 13
<100 nm, are labelled as ultrafine particles in epidemiology. The
number concentration of these small particles exceeds by far that
of larger ones in the urban area, but their contribution to the total
mass concentration, which is measured on a routinely basis now-
adays in the USA and Europe, is relatively low. Typically, the bio-
logical activity of particles increases as the particle size decreases
and surface area becomes larger. Alveolar deposition is highest
for inhaled ultrafine particles of about 20 nm diameter, higher
than for any other particle size
(50) . Thus, although inhaled mass
concentration of ultrafine particles in urban areas may be low,
numbers of ultrafine particles in the alveolar region of the lung
may be very high. Studies on rodents demonstrate that ultrafine
particles administered to the lung cause greater inflammatory
response than do larger particles per given mass
(51) .
Air pollution has always been an attractive explanation for
the 10
– 40% increase in lung cancer mortality observed in urban
versus rural areas, but confounding from smoking and other fac-
tors has been a great limitation in interpreting geographical com-
parisons
(52) . Two large American cohort studies showed a link
between air pollution and lung cancer: in the Harvard Six Cities
Study — a prospective cohort study — exposure was estimated on
the basis of average levels of pollution over the risk period from
1974 through 1989, assuming residential stability. For 8,111 resi-
dents of six US cities, individual-level information was available
for age, gender, smoking habits, body mass index, and educa-
tion, all confounders or potential effect modifiers. In the cohort,
1,429 deaths occurred, 120 due to lung cancer. The difference
in the long-term average PM concentrations between the most
and least polluted cities was approximately 20 µ g/m 3 and the RR
of lung cancer was increased (RR 1.37). Assuming a linear rela-
tionship between exposure and lung cancer, the RR increased by
approximately 19% per 10
µ g/m
3
increase of PM
(53) .
The second study was the American Cancer Society study that
followed the mortality of approximately 500,000 adult men and
women from 1982 to 1998. Participants were assigned to metro-
politan areas of residence, and mean PM 2.5 concentrations were
compiled for each metropolitan area from several data sources.
Personal information on risk factors (confounders or effect modi-
fiers) was collected by questionnaire at enrolment. The last follow-
up in 2002
(54) indicated a significantly increased mortality risk
ratio for lung cancer (RR 1.14; 95% CI, 1.04 – 1.23) for a differ-
ence of 10 µ g/m
3
of PM 2.5. These results were controlled for
age, gender, race, smoking, education, marital status, body mass,
alcohol consumption, occupational exposure, and diet.
Several recent studies have addressed whether socioeconomic
position modifies the health effects of particulate air pollution
(55) . The majority of studies evaluating individual-level charac-
teristics showed higher effects (in general) among those of lower
14 Brüske-Hohlfeld
socioeconomic position. Low educational attainment seems to be
a particularly consistent indicator of vulnerability in these studies.
Groups with lower socioeconomic position may receive higher
exposure to air pollution at work and at home, living closer to
major roads, and they may experience compromised health sta-
tus due to material deprivation, psychosocial stress, and personal
behaviour. International organizations have identified both air
pollution and poverty as priority areas for public health interven-
tion, as approximately 1 billion people live in poverty (World Bank
2002; http://www.worldbank.org/) and an estimated 1.5 billion
people currently live in polluted urban areas (WHO, 2000).
When interpreting the findings regarding the impact of air
pollution on the general population, it should not be forgotten
that one main component of urban air pollution will always be
diesel motor emissions (DME) coming from a wide variety of
sources, including large trucks, earth-moving equipment, farm
machinery, and diesel-powered cars. Most epidemiological stud-
ies show an association between exposure to DME and lung
cancer risk
(56) . In the light of biological plausibility, making
a causal inference seems to be justified, as DME contain both
highly mutagenic substances
(57) and recognized human car-
cinogens
(58) . Increased levels of human peripheral blood DNA
adducts are associated with occupational exposure to DME
(59) .
Furthermore, DME have been shown to induce lung cancer in
laboratory animals
(60 , 61) .
Radon, as well as polonium-218 and polonium-214, are charac-
terized by alpha radiation, a type of radioactive decay in which an
atom emits an alpha particle (two neutrons and two electrons)
and transforms into an atom with a mass number 4 less and
atomic number 2 less. The range of alpha radiation in the body is
limited to less than 100
µ m, which implies that the skin is a suf-
ficient barrier against alpha radiation, but the alveolar epithelium
is not. When radon gas itself is inhaled, most is exhaled before it
decays. But, if solid decay products are deposited in the lung, they
undergo further radioactive decay, releasing energy in the form of
alpha particles that can either cause double-stranded DNA breaks
or create free radicals that can also damage the DNA and thereby
cause lung cancer. A small part of the inhaled radon and its prog-
eny may be transferred from the lungs to the blood and finally to
other organs, but the corresponding doses and associated cancer
risk are negligible compared with the lung cancer risk.
Originating from the decay of uranium and thorium con-
tained in the crust of the earth, radon gas and its solid decay
products occur naturally in the air worldwide. Its concentration
depends on the highly variable uranium content of the soil. Due
to dilution in the air, outdoor levels of radon are generally low
in comparison with what can be found indoors. Radon gas enters
2.9. Radon
2.9. Radon
Environmental and Occupational Risk Factors for Lung Cancer 15
houses through openings such as cracks at concrete floor — wall
junctions, gaps in the floor, small pores in hollow-block walls,
and through sumps and drains. Exchange of indoor air with the
outside exerts a strong influence on indoor air concentration of
radon and depends on the construction of the house, the sealing
of windows, and the ventilation habits of the inhabitants. Con-
sequently, radon levels are usually higher in basements, cellars,
or other structural areas in contact with soil. Even higher radon
concentrations can be found in places such as mines, caves, and
water treatment facilities.
For a century, it has been known that some underground
miners suffered from higher rates of lung cancer than the general
population. During the past three decades, several epidemiologi-
cal studies (for example, refs.
(62 – 72) ) on uranium miners have
been conducted, all showing an increased risk of lung cancer. The
connection between radon and lung cancer in miners has raised
concern that radon in homes might be causing lung cancer in the
general population. Studies in Europe, North America, and China
have confirmed that radon in homes contributes substantially to
the occurrence of lung cancers worldwide. A recent pooled analysis
of European studies estimated the risk of lung cancer increased by
8.4% (95% CI, 3.0
– 15.8%) per 100 Bq/m 3 increase in measured
radon (
p = 0.0007). This corresponds to an increase of 16% (5 – 31%)
per 100 Bq/m 3 increase in usual radon — that is, after correction
for the dilution caused by random uncertainties in measuring
radon concentrations
(73) . The dose — response relation seems to
be linear without evidence of a threshold.
In 1999, the National Research Council published the BEIR
VI report, which confirms that radon is the second leading cause
of lung cancer in the USA, accounting for 15,000 to 22,000 lung
cancer deaths per year in the USA. One of the most compre-
hensive case
— control epidemiologic radon studies, performed by
Field and colleagues
(74) , demonstrated a 50% increased lung
cancer risk with prolonged radon exposure at the EPA’s action
level of 4 pCi/L. A systematic analysis of pooled data from seven
large-scale case — control studies of residential radon studies was
undertaken to provide a more direct characterization of the pub-
lic health risk posed by prolonged radon exposure. The com-
bined data set included a total of 4,081 cases and 5,281 controls.
Residential radon concentrations were determined primarily by
α-track detectors placed in the living areas of homes of the study
subjects in order to obtain an integrated 1-year average radon
concentration in indoor air. Conditional likelihood regression
was used to estimate the excess risk of lung cancer due to residen-
tial radon exposure, with adjustment for attained age, sex, study,
smoking factors, residential mobility, and completeness of radon
measurements. For subjects who had resided in only one or two
houses in the 5
– 30 exposure time window and who had α-track
16 Brüske-Hohlfeld
radon measurements for at least 20 years of this 25-year period,
the excess odds ratio was 0.18 (0.02, 0.43) per 100 Bq/m 3 .
Recent pooled epidemiologic radon studies by Dan Krewski
et al.
(75 ,
76) have also shown an increased lung cancer risk
from radon below the US EPA’s action level of 4 pCi/L.

The chemical compound silicon dioxide (SiO
2 ), also known as
silica, is one of the most common minerals in the continental
crust. Sand mostly consists of silica, usually in the form of quartz,
but there are many other crystalline forms
— like, for example,
cristobalite and tridymite. Whereas silica in the environment do
not present a public health problem, in occupational settings,
such as mines, stone quarries and granite production, ceramic
and pottery industries, steel production, and sandblasting, silica
can provoke fibrotic changes and cancer of the lung, especially if
inhaled as freshly ground crystalline silica dust.
Several studies have been published on the relation between
occupational silica exposure and lung cancer. In a review of epide-
miological studies between 1996 and 2005
(77) , the pooled RR of
lung cancer, calculated using random effects models, from all cohort
studies was 1.34. The RR was higher, 1.69, in cohort studies of sili-
cotics only. The pooled RR was 1.41 for all case
— control studies.
And, again, the RR was 3.27 in case
— control studies of silicotics
only. In summary, in this re-analysis, the association with lung can-
cer was consistent for silicotics, but less clear for non-silicotics. This
leaves open the question whether silicosis is a surrogate for a more
pronounced exposure relating to higher cancer risk or whether is in
itself a prerequisite in the development of lung cancer.
In a pooled data set of 10 cohort studies, Steenland and co-
workers
(78) examined a total of 65,980 subjects, two thirds of
them miners. There were 1,072 deaths from lung cancer. The
authors found an increasing trend in risk of lung cancer with
cumulative silica exposure: RR 1.0 (95% CI, 0.85
– 1.3); RR 1.3
(95% CI, 1.1
– 1.7); RR 1.5 (95% CI, 1.2 – 1.9); and RR 1.6 (95%
CI, 1.3
– 2.1) compared with the lowest quintile. This dose — risk
relation supports the conclusion of a causal relationship.

Current research indicates that the factor with the greatest impact
on risk of lung cancer is long-term exposure to inhaled tobacco
smoke from cigarettes. But other forms of tobacco smoking,
such as cigars and pipes, also increase risks for cancer of the lung,
cancer of the head and neck, and other cancers. The particulate
phase of the smoke contains most of the 55 carcinogens identified
by the IARC
(12) . Of these, polycyclic aromatic hydrocarbons
and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone are likely to play major roles
(79) . Also,
the alpha-emitting radioisotope polonium-210 has been identified
by the US EPA as a cause of lung cancer in humans when inhaled.
Nicotine itself is not considered to be carcinogenic. Smoking
2.10. Silica
2.10. Silica
2.11. Smoking
2.11. Smoking
Environmental and Occupational Risk Factors for Lung Cancer 17
produces gene mutations and chromosomal abnormalities. Urine
from smokers is mutagenic and tobacco smoke is assessed as geno-
toxic in humans and experimental animals by the IARC.
The US Centers for Disease Control and Prevention describes
tobacco use as
“ the single most important preventable risk to
human health in developed countries and an important cause of
premature death worldwide ” . On average, cigarette smokers die
about 10 years younger than nonsmokers, and stopping at age 60
years, 50 years, 40 years, or 30 years gains, respectively 3, 6, 9, or
10 years of life expectancy
(80) .
Although tobacco smoking accounts for the majority of lung
cancer, approximately 10% of patients with lung cancer in the
USA are lifelong never smokers, women disproportionately more
often than men
(81) .
Second-hand tobacco smoke, also known as environmental tobacco
smoke (ETS), is a mixture of the smoke given off by the burning
end of tobacco products (side stream smoke) and the mainstream
smoke exhaled by smokers. Because side stream smoke is gener-
ated at lower temperatures and under different conditions than
mainstream smoke, it contains higher concentrations of many of
the toxins found in cigarette smoke, such as formaldehyde, lead,
arsenic, benzene, and radioactive polonium-210.
Second-hand smoke was first considered as a possible risk fac-
tor for lung cancer in 1981 when two studies were published
that described increased lung cancer risk among never-smoking
women who were married to smokers. In a case
— control study
from Athens, the odds ratio of lung cancer associated with having
a husband who smokes was 3.4 for nonsmoking women whose
husbands smoked more than one pack of cigarettes per day
(82) .
In a study from Japan 91,540 non-smoking wives aged 40 years
and older were followed up for 14 years (1966
– 1979), and stand-
ardized mortality rates for lung cancer were assessed according
to the smoking habits of their husbands. Wives of heavy smokers
were found to have a higher risk of developing lung cancer and a
dose — response relation was observed
(83) .
More than 50 studies of involuntary smoking and lung cancer
risk in never smokers, especially spouses of smokers, have been
published during the last 25 years. Meta-analyses of those studies
show that there is a statistically significant and consistent associa-
tion between lung cancer risk in spouses of smokers and exposure
to second-hand tobacco smoke from the spouse who smokes. Fur-
thermore, meta-analyses of lung cancer in never smokers exposed
to second-hand tobacco smoke at the workplace have found a
statistically significant increased risk of lung cancer
9 .

2.12. Second-Hand
Tobacco Smoke
2.12. Second-Hand
Tobacco Smoke
9 http://www.cdc.gov/tobacco/data_statistics/Factsheets/LungCancer.
htm
18 Brüske-Hohlfeld
The National Research Council
(84) estimated in 1986 that
almost one fourth of lung cancer cases among non-smokers could
be attributed to passive smoking. In May 2006, the US govern-
ment’s Centers for Disease Control issued its first new study on
second-hand smoke in 20 years. Surgeon General Richard Car-
mona summarized,
“ The health effects of second hand smoke
exposure are more pervasive than we previously thought. The sci-
entific evidence is indisputable: second hand smoke is not a mere
annoyance. It is a serious health hazard that can lead to disease
and premature death in children and non-smoking adults. ” The
study estimated that living or working in a place where smoking
is permitted increases the non-smokers’ risk of developing lung
cancer by 20
– 30%.
The US EPA, the National Institutes of Health National
Toxicology Program, and the IARC have concluded that sec-
ond-hand smoke is a known human carcinogen. If it occurs at
the workplace, it is considered to be an occupational carcinogen
(NIOSH).

Although lung cancer is the world’s leading cause of cancer death,
it is also highly accessible to prevention by diminishing exposure
to known lung carcinogens. So, looking on the bright side, these
are the options for prevention:
Number one on the list is tobacco
smoking . As a response to
the global tobacco epidemic
“ The Tobacco-Free Initiative ” was
established by the WHO in 1998
10 .
The WHO Framework Con-
vention on Tobacco Control (FCTC) was the first public health
treaty negotiated under the auspices of the WHO
11 . It was unani-
mously adopted by the WHO’s 192 Member States in May 2003.
It officially entered into force in 2005 and, by the end of 2006,
the total number of contracting parties had reached 142, covering
more than three quarters of the world’s population. In the end,
the prevention of smoking seems to be on the way.
Less successful has been the call for a global ban on asbestos
sales, though national bans on asbestos exist in most industria-
lized countries. If a substance such as chrysotile is too hazardous
3. Outlook
3. Outlook
10 http://www.who.int/tobacco/resources/publications/TFI%20primer-
English.pdf
11 http://www.who.int/tobacco/framework/download/en/index.html

Environmental and Occupational Risk Factors for Lung Cancer 19
to be used in industrialized countries, it should not be exported;
if it is exported, then full disclosure of the hazards should be made
mandatory. But, the Rotterdam Convention, an international
treaty governing trade in toxic substances, which creates legally
binding obligations for the implementation of the Prior Informed
Consent (PIC) procedure, failed to agree to add chrysotile to a
list of more than 30 substances about which exporting countries
must inform importers before shipping

12
.
While the inclusion of
chrysotile asbestos on the PIC list of the Rotterdam Conven-
tion does not constitute a ban on global sales, it would at least
have enabled developing economies to make informed decisions
on whether they wish to import a chemical that has been found
to be carcinogenic by the International Labor Organization, the
WHO, the IARC, the International Program on Chemical Safety,
the Collegium Ramazzini, and the World Trade Organization.
Current levels of radon in dwellings and other buildings are
of public health concern. The US EPA recommends fixing the
home if radon levels exceed 4 pCi/L
13 . Radon levels less than
4 pCi/L still pose a risk, and in many cases may be reduced. A
person living in an average European house with a radon con-
centration of 50 Bq/m
3
has a lifetime excess lung cancer risk
of 1.5
− 3 × 10 −
3
. A lifetime lung cancer risk below about 1×10

4

cannot be expected to be achievable because the natural concen-
tration of radon in ambient outdoor air is about 10 Bq/m
3
. Nev-
ertheless, the risk can be reduced effectively based on procedures
that include optimization and evaluation of available control
techniques. In general, simple remedial measures should be con-
sidered for buildings with radon progeny concentrations of more
than 100 Bq/m
3
or 2.7 pCi/L equilibrium equivalent radon as
an annual average, with a view to reducing such concentrations
wherever possible
14 .
The scale of the contamination of drinking water by
arsenic in Bangladesh has rightly been called a mass poisoning,
with millions of people exposed. A United Nations Founda-
tion grant was approved in 2000 to enable UNICEF and the
WHO to support a project to provide clean drinking water
alternatives to 1.1 million people in three of the worst-affected
sub-districts in Bangladesh
15 . The project utilizes an inte-
grated approach involving
communication, capacity building
for arsenic mitigation of all stakeholders at subdistrict level and
12 http://www.lkaz.demon.co.uk/chrys_hazard_rott_conv_06.pdf

13 1 pCi/L equals 37 Bq/m
3


14
http://www.euro.who.int/document/e71922.pdf

15 http://www.who.int/mediacentre/factsheets/fs210/en/

20 Brüske-Hohlfeld
below, tube-well testing, patient management, and provision of
alternative water supply options. Urgent requirements include
a large-scale support to the most severely affected populations,
with a simple, reliable, and low-cost equipment for field meas-
urement of arsenic levels in drinking water as well as robust
and affordable technologies for arsenic removal at wells and in
households.
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