Chronic Diseases in Canada
Volume 29 · Supplement 2 · 2010
85 Industry
Inside this issue
86 Cancer risk associated with pulp and
paper mills: a review of occupational and
community epidemiology
Colin L. Soskolne and Lee E. Sieswerda
101 Gold, Nickel and Copper Mining
and Processing
Nancy E. Lightfoot, Michael A. Pacey and Shelley Darling
125 Air
128 Environmental Tobacco Smoke (ETS)
Kenneth C. Johnson
144 Air Pollution
Nhu D. Le, Li Sun and James V. Zidek
EDITORS
The opinions expressed in this publication are those of the authors/researchers and do not necessarily
reflect the views of the Public Health Agency of Canada.
Shirley A. Huchcroft, PhD, Consultant
Epidemiologist, Calgary.
Yang Mao, PhD, Centre for Chronic Disease
Surveillance and Control, Public Health
Agency of Canada.
Robert Semenciw, MSc, Centre for Chronic
Disease Prevention and Control, Public Health
Agency of Canada
CONTRIBUTORS
Kristan J. Aronson, PhD, Department of
Community Health and Epidemiology,
and Division of Cancer Care and
Epidemiology, Cancer Research Institute,
Queen’s University, Kingston.
Chris Bajdik, PhD, Cancer Control Research
Program at the BC Cancer Agency.
Randall J Bissett, MA, MHSc, MD,
Northeastern Ontario Regional Cancer
Centre (NEORCC)
Marilyn Borugian, PhD, Cancer Control
Research Program of the British Columbia
Cancer Agency.
Shelley Darling, MHA, (formerly of)
Epidemiology Research Unit, Regional
Cancer Program, Sudbury Regional Hospital;
(currently at) Planning & Partnerships,
Toronto East General Hospital.
Richard P. Gallagher, MA, FACE,
Cancer Control Research Program at
the British Columbia Cancer Agency.
Lois M. Green, PhD, Ontario Power
Generation, Retired.
Kenneth C. Johnson, PhD, Centre for Chronic
Disease Surveillance and Control, Public
Health Agency of Canada.
Will D. King, PhD, Department of Community
Health and Epidemiology at Queen’s University.
Nhu D. Le, PhD, Cancer Control Research at
the British Columbia Cancer Agency.
Tim Lee, PhD, Cancer Control Research
Program at the BC Cancer Agency.
Nancy E. Lightfoot, PhD, (formerly of)
Epidemiology Research Unit, Regional
Cancer Program, Sudbury Regional Hospital;
(currently at) School of Rural and Northern
Health, Laurentian University.
John R. McLaughlin, PhD, FACE, Cancer
Care Ontario.
Anthony B. Miller, MB, FRCP, Department of
Public Health Sciences, University of Toronto,
Professor Emeritus.
Howard I. Morrison, PhD, Centre for Chronic
Disease Surveillance and Control, Public
Health Agency of Canada.
Michael A. Pacey, BA, (formerly of)
Epidemiology Research Unit, Regional Cancer
Program, Sudbury Regional Hospital.
Lee E. Sieswerda, MSc, Thunder Bay District
Health Unit and Northern Ontario School of
Medicine, Thunder Bay, Ontario.
Colin L. Soskolne, PhD, FACE, Department
of Public Health Sciences, School of Public
Health, University of Alberta.
Li Sun, PhD, (formerly of) Department of
Statistics at the University of British Columbia.
Don Wigle, MD, PhD, MPH, Health Canada,
Retired and the University of Ottawa.
Christy G. Woolcott, PhD, (formerly of)
Department of Community Health and
Epidemiology at Queen’s University in
Kingston; (currently at) Cancer Research
Center of Hawaii, University of Hawaii.
James V. Zidek, PhD, Department of Statistics
at the University of British Columbia, Professor
Emeritus.
Chronic Diseases in Canada (CDIC) is a quarterly
scientific journal focussing on cur rent
evidence relevant to the control and prevention
of chronic (i.e. noncommunicable)
diseases and injuries in Canada. Since 1980
the journal has published a unique blend of
peerreviewed feature articles by authors
from the public and private sectors and
which may include research from such fields
as epidemiology, public/community health,
bio statistics, the behavioural sciences, and
health services or economics. Only feature
articles are peer reviewed. Authors retain
responsibility for the content of their arti cles.
Chronic Diseases in Canada
Public Health Agency of Canada
785 Carling Avenue
Address Locator 6805B
Ottawa, Ontario K1A 0K9
Fax: (613) 9419502
Email: cdicmcc@phacaspc.gc.ca
Indexed in Index Medicus/MEDLINE,
SciSearch® and Journal Citation Reports/
Science Edition
To promote and protect the health of Canadians through leadership, partnership, innovation and action in public health.
— Public Health Agency of Canada
Published by authority of the Minister of Health.
© Her Majesty the Queen in Right of Canada, represented by the Minister of Health, 2010
ISSN 02288699
This publication is also available online at www.publichealth.gc.ca/cdic
Également disponible en français sous le titre : Maladies chroniques au Canada
Industry
Agents of concern in the workplace are
often the same agents of concern to the
community. However, generally speaking –
for both radiation and chemicals – the greatest
exposures (in terms of concen tration and
duration) invariably occur in the workplace,
as opposed to the home and community.
Therefore, studies of exposed workers are
often undertaken before com munity and
general population studies are launched,
under the assumption that if the higher
workplace exposures are not associated with
increased health risks, then it is unlikely that
the lower levels of exposure experienced by
the general population are hazardous. The
assumption here is that the public at large is
equally susceptible, which likely is untrue.
Two industries of particular importance in
Canada – pulp and paper milling and metal
mining and processing – are discussed here.
Both are known to release substances that
can contaminate the environment.
There are pulp and paper mills in every
Canadian jurisdiction except Prince Edward
Island and the territories. 1 The waste water
(effluent) from pulp and paper mill processes
has been known to contain many potentially
hazardous chemicals that have had profound
impacts on the environment. Large volumes of
water are used in pulp production. Depending
upon the type of mill and the processes used,
several chem icals are used to break the wood
down into discrete fibres, to bleach the pulp,
and to achieve the properties required for the
various paper products. For the period of this
review, the most widely used chemical was
chlorine. Dioxins and furans can be formed
from elemental chlorine reacting with the
naturally occurring components of wood.
Effluent quality has vastly improved since
the 1992 Pulp and Paper Effluent Regulations
were promulgated. However, effects on fish
and fish habitat are still being seen and further
monitoring is needed. 2 Canadian mills have
eliminated elemental chlorine bleaching and
moved to either total chlorine free bleaching
(hydrogen peroxide) or elemental chlorine
free bleach ing (hydrogen peroxide and
chlorine dioxide). In addition, effluents are
treated to reduce the levels of any chlorinated
organic compounds before being discharged
to the aquatic environment. Air emissions
from pulp and paper mills include sul phur
dioxide, nitrogen oxides, hydrogen sulphide,
volatile organic compounds and particulate
matter. 3
Large-scale extraction of metals presents
hazardous waste management problems.
Types of contamination can include waste
rock, tailings and slag, contaminated ground
and surface water from leaching and runoff,
and contaminated soil and surface water from
settled air pollutants. Some contaminants of
particular concern are arsenic, nickel and
mercury. In Canada, higher concentrations
of arsenic and nickel have been found near
smelters and gold-mining and ore-roasting
operations. 4 Mercury, of both natural and
industrial origin, is readily transformed into
organomercurials by micro-organisms and
bioaccumulates up the food chain. Other
substances to which workers in the metal
mining and processing industry are exposed
include radon gas, cobalt, asbestos, cadmium,
copper, lead, zinc, cyanide, diesel fuels and
emissions, oil mists, blasting agents, silica
and hydrogen sulphide.
The majority of studies of cancer and
the pulp and paper and metal extraction
industries have involved occupational
rather than community exposures. One
of the challenges of occupational cancer
epidemiology lies in estimating exposure
among workers. In some work environments
(e.g., where radiation is the main
exposure), records from personal monitors
worn by workers throughout their careers
are available. However, in other settings,
exposures must be inferred from job titles.
More recently, job-exposure matrices have
been developed – accompanied by measurements
of specified tasks – with the
objective of more accurately reflecting
actual exposures. Retrospective modelling
of exposures is difficult, as higher exposures
tended to occur before they were
known to be harmful and measurement of
exposures was not done at that time.
As with air pollution, workplace exposure
estimation now makes extensive use of
mathematical modelling. For example,
a study of Canadian nickel workers used a
Bayesian probabilistic framework to esti mate
historical exposures to nickel species
(soluble, oxidic, sulfidic, and metallic),
diesel particulate matter, and silica over a
50-year period from 1950 to 2000. 5 This
sophisticated approach involves several
steps. First, both sparse exposure data and
expert judgement based on plant operating
data and physical modelling are used to
provide exposure estimates. Secondly,
lung burden is estimated as a function of
time from first exposure for each worker
(using a lung deposition model) and pharmacokinetic
data on retention and clearance
of inhaled nickel, diesel, and silica
(found in the published literature).
Thirdly, job-location-year-exposure matrix
information is combined with individual
job histories for all study subjects to
calculate the cumulative exposure metric
(with associated uncertainties) for the
four nickel species, diesel particulate matter,
and silica.
References
1. Environment Canada. Towards More
Innovative Air Quality Management:
Proposal for a Pulp and Paper Air Quality
Forum. National Office of Pollution
Prevention, Environment Canada.
Available at: http://www.ec.gc.ca/nopp/
DOCS/rpt/smartReg/EN/c5.cfm
2. Environment Canada. National Assessment
of Pulp and Paper Environmental Effects
Monitoring Data: A Report Synopsis.
National Water Research Institute,
Burlington, Ontario. NWRI Scientific
Assessment Report Series No. 2; 2003. Cat.
no. En40-237/2-2003E.
3. Bordado JC, Gomes JF. Pollutant
atmospheric emissions from Portuguese
Kraft pulp mills. Sci Total Environ. 1997
Dec 3;208(1-2):139-43.
4. Health Canada. Health and environment:
partners for life. Ottawa: Minister of Public
Works and Government Services Canada;
1997. Cat. No. H49-112/1997E.
5. Ramachandran G. Retrospective exposure
assessment using Bayesian methods.
Ann Occup Hyg. 2001 Nov;45(8):651-67.
85 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Cancer risk associated with pulp and paper mills:
a review of occupational and community epidemiology
Colin L. Soskolne and Lee E. Sieswerda
Pulp and paper mills use a variety of chemical
substances potentially hazardous to human
health. Compounds of both short- and longterm
toxicological significance are found
in workplaces, air emissions, and water
effluent. In this paper we evaluate the body
of published literature on cancer associated
with working in pulp and paper mills as
well as in surrounding communities.
Multiple comparisons, questionable statistical
power, and the absence of individual
exposure assessments have resulted in
non-corroborative findings over the years.
However, a new generation of study
sophistication, international in scale and
coordinated by the International Agency
for Research on Cancer (IARC), has
catalogued tens of thousands of exposure
measurements made at a large number of
work stations within the pulp and paper
industry, allowing for greatly improved
individual-level exposure assessments.
This approach reduces non-differential misclassification
of exposure, increasing the
power of these studies to detect exposure
disease relationships, especially for rarer
cancers.
While the ability to associate specific chemical
exposures with cancer outcomes in the
large IARC multinational cohort may yet
help to resolve the status of some of the many
chemicals not currently classifiable as to
their carcinogenicity by IARC, this effort has,
to date, not added significantly to knowledge.
Of the three studies they have published
to date, one involved a well-established
carcinogen (asbestos) and another involved
a mixture containing probable carcinogens
(volatile organochlorines). While the
asbestos study is somewhat unremarkable
for finding an association with pleural
cancer in the expected direction, the volatile
organochlorine study may be most notable
for failing to find an association between
volatile organochlorine exposure and liver
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
cancer, non-Hodgkin’s lymphoma, or
esophageal cancer, as some previous studies
had found.
Nonetheless, given the known hazards
and the potential for both environmental
and human exposure by any of a number
of pathways, vigilance on the part of
governments for regulation and for ongoing
workplace and environmental monitoring
remains a health imperative.
Introduction
The importance of the pulp and paper
industry in modern life is a result of the
major role of paper and paper products
in every area of human activity. However,
like many industrial processes it has
impacted our environment and our health.
Health concerns include both occupational
hazards and impacts on air, soil, and water
that affect the health of communities in
the vicinity of pulp and paper mills as well
as of those communities downwind or
downstream from mills.
In this paper, we provide some background
on the pulp and paper industry, then
review both the English-language published
literature and accessible unpublished reports
of the epidemiological and toxicological
evidence relating to the contribution of the
pulp and paper industry to cancer risk. The
focus is on studies of cancer risk associated
with having worked in the pulp and paper
industry. In addition, we have reviewed
what information is available on the effects
of these industries on cancer risk in local
communities.
Health implications of work in the pulp
and paper industry were reviewed at the
global level in 1998 in the International
Labour Organization’s Encyclopaedia of
Occupational Health and Safety, prior
to the current crop of studies. 1-5 In sum,
workers have been exposed to mechanical
86
and chemical pulping processes, the latter
mainly split between kraft (or sulphate)
and sulphite processes. Local community
exposures include chlorinated organic
compounds, polychlorinated dibenzodioxins,
and polychlorinated dibenzofurans. In
addition, respirable particles of lime and
sulphates have been found in the ambient
air surrounding pulp mills.
The chemicals used and produced by
pulp and paper mills vary according to
a number of factors, including the wood
species, pulping processes, and bleaching
processes used.
It should be noted that some of the
chemicals to which workers have been
exposed have been reduced or eliminated
in recent years. Asbestos is an example of
a substance that workers were exposed
to in the past, but which is now largely
eliminated in the developed world. Mill
effluent has also been cleaned up in recent
years. In Canada, strict new regulations on
mill effluent came into effect in 1992, with
subsequent reductions in environmental
discharges. 6 However, cancer has a long
latent period, so all of the exposures in the
past century of pulp and paper making are
of interest.
The production context
The component of interest in the manufacture
of pulp and paper is cellulose.
Cellulose is a long-chain carbohydrate
composed of polymerized glucose. It
forms strong fibres that are ideal for
paper-making. To obtain the cellulose
fibres, short-chain carbohydrates called
hemicelluloses (which are combinations
of sugars including glucose, mannose,
galactose, xylose, and arabinose) must
be removed. Compared to cellulose, the
hemicelluloses are easily degraded and
dissolved.
Woody plant materials also contain an
amorphous, highly polymerized substance
called lignin that forms an outer layer
around the fibres and cements them
together. Lignin is also contained within the
fibre. The chemistry of lignin is complex. It
consists primarily of phenyl propane units
linked together in a three-dimensional
structure. The linkages between the
propane side chains and the benzene rings
are broken during chemical pulping to
release cellulose fibres. A number of
additional substances (e.g., resin acids,
fatty acids, turpenoid compounds, and
alcohols) are present in native fibres,
their exact constituents and proportions
depending upon their plant source. Most
of these compounds are soluble in water
or in neutral solvents, and are collectively
called extractives.
Pulp mills extract and process cellulose
fibres from wood, simultaneously removing
unwanted constituents, such as lignin.
The two main types of pulping processes
are mechanical and chemical. Mechanical
pulping uses heat and mechanical forces
Water + fuel
Steam + Na 2 S + NaOH
White
liquor
Causticizer
CaO Ca 2 CO 3
Lime kiln
Green
liquor
TRS
to separate the wood fibres into a lightcoloured
pulp that requires little bleaching.
Chemical pulping uses a mixture of
chemicals to separate the cellulose fibres
from the lignin. The two major chemical
pulping processes are kraft (or sulphate)
and sulphite.
Figure 1 is a simplified process diagram
for a kraft mill. Kraft pulping is carried out
in an alkaline medium and releases fibres
from wood chips by dissolving the lignin
in a caustic solution of sodium hydroxide
and sodium sulphide. Spent digester fluid
is concentrated in evaporators and fed
into the recovery furnace, which recycles
solid sodium sulphide and combusts the
organic component as a source of energy.
A lime kiln recovers calcium oxide for
regeneration of the caustic component of
the digester fluid.
In contrast, the sulphite process is carried
out under acidic conditions and solubilizes
lignin through sulfonation using a solution
of sulphur dioxide and alkaline oxides
such as sodium, magnesium, ammonium
or calcium. The recovery of digester fluid
FIguRe 1
Simplified diagram of the kraft pulping process
Black
liquor
Wood chips
Oxidizing tank,
evaporators,
recovery,
smelt tank
TRS TRS
Air emission
CHCI 3
Chlorine +
chlorine dioxide
Digester Bleaching
Pressing, drying
Pulp
components is accomplished by various
means depending on the alkaline oxide
used. Both chemical processes produce a
relatively dark-coloured pulp that requires
bleaching. The vast majority of the
47 bleached pulp mills operating in Canada
through 1993 used the kraft method. 7
Five mills employed the sulphite process.
The resulting pulp is washed and bleached –
in the past with elemental chlorine, today
with chlorine dioxide and/or hydrogen
peroxide. The washed pulp is rolled
and dried, and the dried pulp is cut and
baled for shipment. Several decades ago,
wastewater from the bleaching process was
typically discharged directly into a nearby
body of water. Since about the 1960s,
mills were required to perform primary
treatment of effluent (i.e., settling out of
large particulates before discharge). Today,
however, Canadian mills are required by
federal regulations to perform secondary
treatment in addition. Most mills in Canada
use aerated stabilization basins or activated
sludge to remove oxygen-consuming materials
and decrease the effluent toxicity, and
this toxicity is monitored. 8
PCDDs
PCDFs
Water effluent
87 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Variations in wood species
Moving across Canada geographically from
west to east, there are four major forest land
formations: the Pacific Coastal Complex,
the Rocky Mountain Complex, the Boreal
Forests, and the Eastern Deciduous Forests.
Depending on the raw material (i.e., tree
species) used in pulp and paper production,
different environmental and occupational
exposures will result.
Botanically, woods are classified into
two main groups: the gymnosperms are
the softwoods, conifers or evergreens; the
angiosperms are the hardwoods – either
deciduous or broad-leaved trees. The
different wood species used in pulping
require different types and quantities
of chemicals, different in-plant processes
and result in different by-products and
product properties.
Generally, hardwoods contain a larger proportion
of cellulose and hemicellulose and
less lignin, as compared to softwoods,
but a greater percentage of extractives.
In addition, hardwood effluent contains
chlorinated syringols. In general, softwood
produces greater quantities of phenolic
compounds than hardwood. Softwood
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
effluent, chlorinated in the bleaching
process, contains chlorophenols, chloroguaiacols
and chlorovanillins.
epidemiological studies of
pulp and paper mill workers
Exposure of pulp and paper mill workers to
potentially hazardous materials may arise at
any stage in the process, from preparation
of the raw wood through the production of
the final pulp or paper product (Table 1).
Wood preparation does not differ substantially
for the several processes, but there
can be significant differences in exposures
in subsequent process steps, including
cooking liquor production, pulp production,
washing, bleaching, recovery, and paper
making.
Most exposure studies in pulp and papermaking
are of gaseous sulphur compounds,
chlorine and chlorine dioxide. Though
they have been shown to have significant
respiratory and cardiovascular effects,
these sulphur compounds have not been
shown to be carcinogenic. In addition,
vapours emanating from pulp may contain
terpenes, sodium hydroxide mist,
methanol, ethanol, sulphuric acid, furfural,
hydroxymethylfurfural, acetic acid, formic
Table 1
Occupational exposures in the pulp and paper industry
Production area/job Potential exposures
Raw wood preparation (i.e., debarking, chipping) Wood volatiles, wood dust, spores, fungi, microbes
88
acid, gluconic acid, hydrogen peroxide
and many other potentially hazardous
compounds. Dusts consisting of lime and
sodium sulphate (among others) are also
present and pose a potential exposure risk
during the chemical recovery process. 9
Long-term exposure to fine particulate
matter (PM 2.5 ) such as this is thought to
cause lung cancer. 10 Pesticides used for
control of slime and algae also constitute
potentially harmful exposures. Exposure to
complex chlorinated organic compounds,
some of which are probable carcinogens,
may occur through contact with slimicides
(e.g., pentachlorophenol), pesticide-treated
wood, or compounds formed during the
bleaching process. Welders are exposed
to hexavalent chromium in stainless steel
welding. Perhaps most importantly from a
cancer risk perspective, in the past workers
(especially maintenance workers) were
commonly exposed to asbestos.
Important challenges in occupational
cancer studies
Workers represent a well-defined group
of people for epidemiological assessment.
The occupational health status of pulp and
paper mill workers has been studied for
a variety of endpoints, including cancer,
pulmonary function, skin diseases, and
Production of cooking liquor Sulphate: ammonia, hydrogen sulphide, sulphur dioxide, mercaptan, chromate and other contaminants
Sulphite: sulphur, sulphur dioxide, calcium carbonate, zinc, sulphuric acid, lead fumes, asbestos,
sulphurous acid
Pulp production, cooking Sulphate: lime, magnesium, wood volatiles
Sulphite: pigments, dyes, wood volatiles
Ground wood: wood volatiles, aniline
Pulp bleaching, bleach plant Chlorine compounds, ozone, hydrogen peroxide, boron compounds, caustic acids
Wet pulp, paper additives Talc, clays, titanium dioxide, urea and melamine formaldehyde, pigments, dyes
Paper rolling, sizing, dying, drying, glazing, coating Urea and melamine formaldehyde, paper dust, coating and pigment dusts
Maintenance General plant exposures, asbestos, welding fumes
Unknown jobs, power, utility General plant exposures, asbestos
Unexposed jobs No significant exposures
hearing impairment. For some endpoints,
such as cancer and respiratory effects,
findings have varied considerably across
studies.
Exposure assessment has been a significant
issue in past studies. Lacking measurement
of exposure to specific chemicals, most
cohort studies have divided workers into at
least three exposure categories: those who
work in a paper mill, a sulphate (kraft) pulp
mill, or a sulphite pulp mill. For simplicity,
workers usually are categorized according
to the last job they held, and exposure is
defined as duration of employment. This
surrogate exposure assessment is crude
and may be problematic if the person has
performed different jobs over his or her
lifetime. Inadequate exposure assessment
and other methodological problems in
the generation of studies prior to about the
mid-1990s, have resulted in controversy
over their interpretation.
Efforts are being made to improve exposure
assessment, 11-15 which would permit more
valid classification of workers for study
purposes. Of particular note is the more
recent large international effort to take
new, detailed measurements of specific
chemicals across the spectrum of jobs
in the pulp and paper industry, and to
integrate them with all known previous
measurements dating back to the 1950s. 13-15
Such detailed measurements have yielded
more comprehensive job-exposure matrices
and more accurate and specific exposure
assessments.
In addition to the ongoing challenge of
exposure assessment, there is another
significant and related challenge that
will become obvious in our review of the
occupational cohort studies in the pulp and
paper industry: choosing an appropriate
comparison group. Most of the cohort
studies that we have reviewed report the
standardized mortality (or incidence) ratio
(SMR or SIR) as their measure of effect.
These measures compare mortality rates (or
disease incidence) in the study cohort to the
general population while simultaneously
accounting for discrepancies in the age
distribution of the two groups. The SMR
and SIR have a number of advantages and
disadvantages, but the chief disadvantage
in the studies we review is its susceptibility
to the healthy worker effect.
The healthy worker effect (HWE) is a form
of bias caused by the fact that people who
become sick or are especially sensitive to
exposures in a particular workplace are
not likely to start or continue employment
at that workplace. Thus, occupational
cohorts tend to be made up of quite
healthy or resistant individuals compared
to the general population. Especially when
studying relatively subtle associations,
the difference in the general robustness
of the workforce compared to the general
population can make it difficult to detect
the effect of toxic exposures on health.
Indeed, in a review of 270 occupational
cohort studies, Meijers et al. 16 found that
most exhibited a HWE (mean SMR: 84)
which had a large influence on the study
findings, tending to turn what might
have been statistically significant positive
findings into negative or equivocal findings.
The effect was especially prominent among
those studies involving chemical exposures.
Unfortunately, the HWE is difficult
to control and is not easily distinguished
from other possible explanations (like
genuine protective effects). Arrighi and
Hertz-Picciotto 17 have reviewed methods
for avoiding or correcting for the HWE,
but these methods were not used in the
older studies we review below. Some of the
newer studies have avoided the problem by
choosing a non-exposed group of workers
(e.g., administrative office workers), rather
than the general population, as the comparison
group.
Another methodological challenge that
arises frequently in occupational cancer
studies is the problem of multiple
comparisons. It is not uncommon for
investigators to search for excess risks
among up to 30 different cancer sites,
frequently over three or more exposure
categories and two or more latency periods.
Thus, many papers essentially involve a
search for statistical significance across
200 or more comparisons. Yet, although
one would expect as many as ten statistically
significant results to occur by chance
alone (at the 95% level of significance),
almost never is a statistical or interpretive
adjustment made for this problem.
89
Case-control and proportional
mortality studies
Thirty-two case-control and proportional
mortality studies have presented some
data on cancer risk among pulp and paper
workers. 18-49 Occupation was usually
abstracted from death certificates or from
cancer registries. The occupational groups
in most of these studies were broad.
The case-control and proportional mortality
studies revealed few statistically significant
associations between cancer and working
in the pulp and paper industry. The casecontrol
studies were generally much
weaker than the cohort studies reviewed
below, largely because most did not attempt
detailed exposure assessment. Most of the
studies referred only to the pulp and paper
industry in general, or to production versus
non-production workers, and did not
separate the workers by process. This is
problematic because the exposures are quite
variable among the different processes.
Lung and pleural cancers have been of
significant interest to researchers of pulp
and paper workers. In a study designed to
avoid the healthy-worker bias, Menck and
Henderson found a significantly increased
risk of lung cancer among paper workers
(SMR= 171, where the denominator
included only working people). 31 In a
relatively weak study design, Harrington et
al. found a statistically elevated risk of lung
cancer (OR = 3.3) in non-urban counties
where pulp and paper was the major
industry. 28 In a death certificate analysis
of counties in Louisiana, Gottlieb et al.
found no increased risk of lung cancer
among either pulp and paper workers or
residents living near pulp and paper mills. 26
Toren et al. found no increased risk of lung
cancer among pulp and paper production
workers, but did find a statistically
significant increased risk (OR = 2.1)
among maintenance workers. 46 Wingren
et al. found no statistically significant
increased risk, except for the poorly
defined group of secondary tumours. 49 In
a study of sulphate mill workers that used
the surrounding communities as referents,
with exposure assessment, Andersson et al.
found a significantly elevated risk for both
pleural and lung cancers (OR = 9.5 and 1.6
respectively). 18 The authors attributed these
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
increases mainly to past asbestos exposure.
This study also found significantly elevated
risks of brain, liver, and biliary tract
cancers, as well as leukemia in the soda
recovery plant, the bleaching plant, and
the digester house. In a case-control study
nested within their ongoing Polish pulp
and paper cohort, Szadkowska-Stanczyk and
Szymczak found a statistically significant,
dose-response relationship between lung
cancer and exposure to inorganic dusts,
even after adjustment for smoking status. 44
They also found an elevated rate of lung
cancer among those exposed to wood
dust (a known carcinogen), but it failed to
achieve statistical significance.
Other cancers of note in case-control studies
have included lymphomas, bladder cancer,
and cancers of the reproductive organs. In
a very early study using death certificates,
Milham and Hesser demonstrated a statistically
increased mortality rate from
Hodgkin’s disease among woodworkers. 32
In a New Zealand cancer registry study,
Pearce et al. could find no statistically
significant association between testicular
cancer and working in the pulp and paper
industry. 38 However, two years later the
same data showed a slightly increased
risk of Hodgkin’s disease. 50 Using British
Columbia (BC) cancer registry data, Band
et al. found a greatly increased risk in the
pulp and paper industry of non-Hodgkin’s
lymphoma (OR = 10), but the risk estimate
was based on only five cases. 19
Also using BC cancer registry data, Teschke
et al. found no significant increases in
either nasal or bladder cancer among pulp
and paper workers. 45 Ugnat et al., in a casecontrol
study of bladder cancer among
chemical workers in Western Canada that
included some pulp and paper workers,
found an elevated, but not statistically
significant, risk of bladder cancer among
pulp and paper workers (OR = 2.33,
95% CI:0.75,7.25, after controlling for
province, age, pack-years of smoking,
education, exposure-years, coffee and tea
consumption). 47 In a recent study, Cocco
et al. examined death certificates in 24 US
states to assess occupational risk factors for
gastric cardia carcinomas. 22 A statistically
significant odds ratio of 2.0 was found for
pulp and paper workers. In one of the few
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
studies of women in the pulp and paper
industry, Langseth and Kjaerheim used a
case-control design to look for an increased
risk of ovarian cancer among (mostly
administrative) workers. 30 No significant
relationships were found between ovarian
cancer and asbestos, talc, or total dust
exposure, which is probably reflective of
the small number of women exposed.
Cohort studies
Cohort studies of pulp and paper workers
have, in general, been more robust than
case-control and proportional mortality
studies. They have benefited from greater
power and heterogeneity of exposure for
comparison purposes. The earlier studies
separated workers into (at least) paper
mill, sulphate pulp, sulphite pulp exposure
categories, while in more recent studies,
chemical-specific exposure assessment by
job classification across process types have
been conducted. Like the case-control and
proportional mortality studies, however,
many of these cohort studies compare
workers to the general population and
therefore are susceptible to the HWE.
Twenty-four cohort studies of cancer among
pulp and paper workers have appeared in
the literature. 51-74 Tables 2 to 4 summarize
the results of the fifteen cohort studies
that provided specific risk estimates and that
presented results according to the three
exposure categories, paper mill, sulphate
pulp, or sulphite pulp. Two of the published
studies were not available in English and
so are not reviewed here. 58,73 Overall, there
were few statistically significant and many
unrepeated results.
Among paper mill workers compared to the
general population, (Table 2) a significant
increase in cancer of the biliary tract was
detected in one study 67 and an increase
in lung cancer was found in another. 62
Smoking habits assessed by questionnaire
did not explain the increase. 75 Two studies,
one of incidence 56 and one of mortality, 57
found significantly fewer than the expected
number of lung cancers. Coggon 57 also found
a significantly more favourable overall
cancer mortality experience among paper
mill workers than the general population.
These findings suggest a HWE. Langseth
and Andersen found no significant cancer
90
excess among paper mill workers, and was
also notable for showing no evidence of
a HWE. 65
Cohort studies of sulphate (kraft) pulp mill
workers found decreased risks of cancer
more often than increased risks (Table 3).
Both Robinson et al. 70 and Matanoski et
al. 68 found significantly reduced overall
cancer mortality among sulphate pulp
workers relative to the general population.
More specifically, Matanoski et al. 68 found
significantly fewer deaths than expected
from cancers of the pharynx, colon, rectum,
pancreas, larynx and lung. However, a
strong HWE appeared to be operating.
Similarly, in 1997, Band et al. found a
significantly decreased risk of mortality for
stomach and pancreatic cancer. 53 A followup
incidence study by Band et al. in 2001
found an excess risk of prostate cancer and
melanoma among kraft mill workers. 54 A
Polish cohort coordinated by Szadkowska-
Stanczyk et al. also showed an elevated
risk of prostate cancer mortality in a cohort
with overall cancer mortality similar to the
general population. 72,76
Cohort studies in sulphite mills also have
shown inconsistent results. Robinson and
colleagues 70 found significantly lower
cancer mortality among sulphite workers
than in the general population (Table 4).
In contrast, the much larger study by Band
et al. in 1997 found an elevated overall
risk of cancer. 53 Specifically, significantly
increased risks of pancreatic, lung, and brain
cancers were detected. The lung and
pancreatic cancer findings were confirmed
in a 2001 incidence study by Band et al.,
and an excess of liver cancer was added to
the positive findings. 54
Langseth and Andersen also found a
statistically significant increase in lung
cancer incidence among sulphite workers. 64
However, the authors suggest that most
of the excess can, in fact, be attributed
to smoking. This explanation cannot be
excluded from Band’s 2001 study either
since he and his colleagues did not have
data on their cohort’s smoking status. 54
Band’s 1997 study found fewer prostate
cancers than expected among sulphite
pulp workers, a finding not confirmed
by his 2001 incidence study. 53 In another
large study, Matanoski et al. found a
significantly decreased risk of cancer. 68
She and her colleagues found fewer colon,
lung, and brain cancer deaths than would
be expected in the general population.
This study seems to have suffered from the
HWE. Henneberger and Lax constructed
a Cox proportional hazards model to
complement the more common SMR
analysis. 61 In their study, an SMR of 95 was
observed for lung cancer. However, after
taking into account age at entry, smoking,
and other factors, a hazard ratio of 2.5
(95% CI 1.3-4.9) was found, based on
35 observations. Henneberger and Lax
stratified this model by length of work and
found a hazard ratio of 1.9 (95% CI 0.8-
4.4) for those with one to ten years of work
experience, and 3.6 (95% CI 1.7-8.0) for
those with more than ten years on the job. 61
Several cohort studies have shown an
increase in cancer among maintenance
workers in pulp and paper mills. Jappinen
et al. found nearly a doubling of risk for
lung cancer among maintenance workers
in paper mills. 62 McLean et al. showed a
significantly increased lung cancer SIR
of 1.44 (based on 36 cases) among nonproduction
workers, but not other workers,
in sulphate mills, suggesting that smoking
was not the main causal factor. 69 The causal
agent is thought to be asbestos, which has
since been largely eliminated from pulp
and paper mills in Canada. A recent study
by Andersson et al. found that testicular
cancer was significantly higher among
maintenance workers than among process
workers employed in both 1960 and 1970
in pulp and paper mills (SIR=4.8, 95% CI:
1.3-12). 52 This is the only study to show
such a finding and it was based on few
cases, so it remains an hypothesis requiring
confirmation.
By the early 1990s, it was becoming
apparent that individual cohort studies
were having difficulty providing clarity
about the risks to pulp and paper workers.
Many of the cancer excesses identified
were found in only one or two studies and
not confirmed by later studies. Indeed, it
could be argued that with the large number
of comparisons being made (owing to
numerous cancer sites), and the small
case numbers, chance could not really be
excluded as an explanation for many of the
excesses. Researchers in the field also came
to realize that estimations of individual
occupational exposure to specific chemicals
should be carried out and used in future
epidemiological studies in the industry. 77
Because of these limitations, in 1991, the
International Agency for Research on
Cancer (IARC) initiated an international
collaboration combining thirteen national
cohorts of pulp and paper workers. The
primary features of this collaboration are
detailed exposure assessment for specific
chemicals and large sample size. Chemicalspecific
exposure assessment allows specific
exposure-outcome hypotheses to be
tested, whereas older studies categorized
exposure only by mill type and job classification.
By establishing a large, standardized
approach to the collection of
data from as many participating centres
around the world as possible, the potential
to provide more definitive answers to the
many questions about health risk would
be increased. Three studies from this collaboration
relating specific exposures
to cancer outcomes have been published to
date. 55,66,78 Because of the detailed exposure
assessment in these studies, they are able
to provide relative risks for the exposed
versus the unexposed, as well as for any
dose-response relationship within those
exposed (Table 5).
As part of this IARC collaborative study,
Carel et al. found that those with a high
probability of ever having been exposed
to asbestos were no more likely to die from
lung cancer than those never exposed, but
were more than twice as likely to die of pleural
cancer (RR = 2.53, 95% CI: 1.03,6.23). 55
A positive dose-response relationship is
suggested by the point estimates for both
cancers, but statistical significance was not
achieved. The relationship found between
asbestos exposure and pleural cancer is not
particularly surprising given that asbestos
is a well-known human carcinogen. 79,80
Another study from this IARC collaboration
by Lee et al. examined the effect of exposure
to sulphur dioxide and cancer
mortality among workers in the pulp and
paper industry. 66 Compared to unexposed
workers, sulphur dioxide-exposed workers
91
were significantly more likely to die from
lung cancer (RR=1.5, 95% CI:1.1,2.0).
This study also found statistically significant
dose-response relationships for all
neoplasms, lung cancer, and non-Hodgkin’s
lymphoma. This study controlled for sex,
age, employment status, calendar year,
country, as well as occupational co-exposure
to asbestos, combustion products and
welding fumes. The authors did not,
however, have information on smoking
status or other lifestyle factors. This lack of
smoking data plagued previous studies
of sulphite mill workers exposed to sulphur
dioxide and limited their interpretability.
Finally, IARC does not currently consider
sulphur dioxide to be a carcinogen, 81 so
this finding will need to be confirmed by
further research.
A third study from this IARC collaboration
by McLean et al. examined the effect of
exposure to organochlorine compounds. 78
Workers exposed to volatile organochlorine
compounds were no more likely to die
from any of the cancers studied compared
to unexposed workers. However, within
the exposed group, the authors noted a
statistically significant dose-response relationship
between volatile organochlorine
compounds and all neoplasms.
To summarize the cohort studies to date,
four major points can be made. First, many
studies show a strong healthy worker
bias, which may be masking potentially
worrisome exposure-disease associations.
Second, a weakness of many of these
cohort studies is the reliance on mortality
data rather than incidence data that
could be obtained from a cancer registry.
Cancer registries became more common
only in the 1960s, and better incidence
studies are beginning to appear. Third,
until recently, exposure assessment has
been weak. Finally, studies usually have
included workers who have worked in
pulp and paper for at least one year, and
very few studies before 2000 considered
length of employment in the analysis.
Henneberger and Lax’s Cox modelling
shows the importance of taking length of
exposure into account. 61 Many of the newer
studies are including length of exposure,
cumulative exposure and/or latency period
in their analyses, 54,55,65,66,69,78 but many have
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Malker et al. 1986 67
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
Table 2
Cohort studies of cancer risk among process workers in paper mills
Carstensen 1987 56
Jappinen et al. 1987 62
Henneberger
et al. 198960 Years of follow-up 20 67 18 25 17 23 40 23 28a 40
Type of risk
estimate
SIR (n) SIR (n) SIR (n) SMR (n) SMR (n) SMR (n) SMR (n) SMR (n) SMR (n) SIRb (n)
All cancers 121 -24 95 -32 85 -40 97 -37 77* -220 58 -10 108 -31
Biliary tract 180* -25
Esophagus 104 -11 239 -1 278 -2
Stomach 171 -5 198 -3 68 -1 68 -16 59 -2
Colon 154 -5 125 -5 275 -4 60 -12 254 -2 110 -44
Rectum 242 -2 70 -8
Pancreas 110 -2 44 -1 132 -15 84 -1
Larynx 86 -2
Lung 67* (?) 197* -12 81 -9 94 -17 57 -5 64* -66 90 -5 166 -16 120 -81
Pleura 160 -3
Skin melanoma 202 -2 310 -1 130 -21
Prostate 81 -2 103 -14
Bladder 108 -1 84 -8 491 -2 270 -2
Kidney 126 -1 80 -1 88 -5
Brain 133 -8 131 -1 174 -2
Non-Hodgkin’s
lymphoma
141 -8
Hodgkin’s disease 57 -1
Multiple myeloma 133 -4
Leukemia 241 -3 60 -1 119 -7 125 -1
Breast 287 -3 64 -7
Cervix 182 -4
Ovary 30 -1
Testis 226 -2
SMR: Standardized mortality ratio
SIR: Standardized incidence ratio
* Significant at 95% level of confidence
a This information was obtained directly from the author in Oct. 2000 and is not explicitly presented in the 1998 paper.
b SIR refers only to “long-term” workers, i.e., those who worked in the pulp and paper industry ≥3 years.
92
Wong et al. 1996 74
Sala-Serra et al. 1996 71
Coggon et al. 1997 57
Szadkowska-Stanczyk
et al. 199772 Szadkowska-Stanczyk
et al. 199876 Langseth &
Anderson 200065
Robinson et al. 1986 70
Table 3
Cohort studies of cancer risk among process workers in sulphate (kraft) pulp mills
Jappinen et al. 1987 62
Sala-Serra
et al. 199671 Band et al. 1997 53
Years of follow-up 18 23 42 22 23 28b 40 42
Type of risk
estimate
SMR (n) SIR (n) SMR (n) SMR (n) SMRa SMR (n) SMR (n) SIR (n) SIR (n)
All cancers 72* -73 92 -54 102 -10 94 -439 82** 80 -20 110 -44 91* -850
Oral cavity/
pharynx
29 -1 82 -11 52** 110 -1 68 -1 75 -25
Esophagus 112 -14 79 64 -8
Stomach 95 -6 87 -7 66* -19 91 60 -2 82 -4 95 -34
Colon 22* -2 192 -4 238 -1 110 -38 64** 120 -6 90 -68
Rectum 72 -12 81** 70 -1 61* -30
Liver 57 -4 112 117 -1 63 -1 105 -8
Pancreas 36 -2 59* -16 79** 64* -16
Peritoneum 1716** -2
Larynx 40** 98 -1 59 -1 57* -13
Lung 83 -25 87 -16 164 -4 100 -151 84** 85 -7 130 -18 140 -12 84* -164
Pleura 251 -4 440 -1 178 -5
Bone 223 -4
Skin melanoma 85 -7 458 -2 230 -4 155* -45
Prostate 119 -8 131 -34 88 854** -4 446** -4 136* -167
Bladder 125 -4 149 -3 119 -12 80 94 -1 73* -41
Kidney 131 -17 95 151 -1 88 -1 84 -26
Brain 80 -17 101 199 -3 99 -23
Non-Hodgkin’s
lymphoma
207 -6 100 -16 118 107 -45
Hodgkin’s disease 119 75 -10
Leukemia 24 -1 97 -19 93 92 -26
Testis 145 323 -1 92 -16
93
Matanoski
et al. 199868 SMR: Standardized mortality ratio
SIR: Standardized incidence ratio
* Significant at 90% level of significance
** Signficant at 95% level of significance
a Cause-specific number of deaths not available; total deaths: 5,378
b This information was obtained directly from the author in Oct. 2000 and is not explicitly presented in the 1998 paper.
Szadkowska-Stanczyk
et al. 199772 Szadkowska-Stanczyk
et al. 199876 Langseth &
Andersen 200065 Band et al. 2001 54
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Robinson et al. 1986 70
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
Table 4
Cohort studies of cancer risk among process workers in sulphite pulp mills
Jappinen et al. 1987 62
Henneberger
et al. 198960 Years of follow-up 18 25 42 25 22 40 42
Type of risk
estimate
SMR (n) SIR (n) SMR (n) SMR (n) SMR (n) SMRa SIR (n) SIR (n)
All cancers 79* -88 105 -33 120 -36 114* -351 108 -123 82** 117* -464
Oral cavity/
pharynx
103 -7 105 91 -11
Esophagus 147 -11 86 126 -7
Stomach 149 -11 129 -6 72 -1 73 -19 78 94 -17
Colon 48 -5 102 -3 83 -21 71** 130 -23 98 -34
Rectum 121 -16 77 124 -27
Liver 199 -8 116 277* -8
Pancreas 32 -2 305 -5 156* -29 185 -11 74 177* -21
Larynx 202 -3 55 133 -12
Lung 81 -26 90 -9 113 -11 132 -121 95 -35 79** 150** -46 132* -112
Pleura 240 -2
Skin melanoma 172 -5 160 -10 139 -10
Prostate 111 -9 104 -3 67* -19 108 111 -78
Bladder 270 -3 72 -7 110 87 -23
Kidney 148 -4 289 -2 143 -11 143 106 -12
Brain 172* -16 34** 153 -10
Non-Hodgkin’s
lymphoma
133 -4 69 -6 89 91 -12
Hodgkin’s disease 159 -4 40
Multiple myeloma 171 -8 103 -5
Leukemia 67 -3 90 -1 51 -6 60 124 -14
Testis 86
SMR: Standardized mortality ratio
SIR: Standardized incidence ratio
* Significant at 90% level of significance
** Signficant at 95% level of significance
a Cause-specific number of deaths not available; total deaths: 1,539
Band et al. 1997 53
94
Henneberger &
Lax 199861 Matanoski et al. 1998 68
Langseth &
Andersen 200065 Band et al. 2001 54
only enough data to dichotomize length of
exposure, and the time periods reported are
inconsistent making comparison difficult.
Of these, only the latest studies by Lee et
al. 66 and McLean et al. 78 had enough power
to show statistically significant increased
risks with increasing cumulative exposure.
The latest generation of cohort studies
from the IARC collaboration are establishing
more specific chemical-disease
relationships. They have moved the focus
away from trying to determine if working in
the pulp and paper industry generally (or
in particular mill types or job classes within
mills) causes cancer. This older approach
left the specific chemical exposure –
disease relationship unspecified. Rather,
the approach of the IARC collaboration
involves measuring the specific chemicals
that workers are exposed to and then
associating the specific chemical exposures
with cancer outcomes. These new exposure
measurements are allowing for larger
studies that combine workers having similar
exposures, both within and across industries,
in order to increase sample size.
This chemical exposure-specific approach
has several advantages. First, knowing the
specific exposure reduces nondifferential
misclassification of exposure, thereby
increasing the power of these studies to
detect exposure-disease relationships.
Second, it is not particularly helpful to
workers or to industry to discover that
simply working in the pulp and paper
industry causes cancer. Rather, specific
exposures need to be identified so that
they can be remediated. Third, the ability
to associate specific chemical exposures
with cancer outcomes in a very large
multinational cohort should help to resolve
the status of some of the large number of
chemicals not currently classifiable as to
their carcinogenicity by IARC. Fourth, and
finally, by being able to make comparisons
both within and across industries (using
relative risks as the measure of association
as opposed to community-based standardized
mortality or incidence ratios), the
influence of any HWE is, for practical
purposes, eliminated.
epidemiological studies
of communities near
pulp and paper mills
Communities near pulp and paper mills
are exposed to a different set of hazardous
chemicals than pulp and paper workers.
Their degree of exposure is, however, much
more difficult to quantify.
Some data exist that quantify particulate
matter in the ambient air surrounding pulp
mills in British Columbia, with documented
respiratory effects in children. 82
Over 250 chlorinated compounds have
been identified in pulp mill effluent. 83 In
comparison with their non-chlorinated
analogues, chlorinated organic compounds
may become more toxic, more lipophilic and
therefore bioaccumulative, less biodegradable,
mutagenic and carcinogenic. 84,85
Polychlorinated dibenzodioxins (dioxins,
PCDDs) and polychlorinated dibenzofurans
(furans, PCDFs) have received a lot of
attention for their persistency and potential
for accumulating in biological tissues. 86,87
One of the PCDDs, 2,3,7,8-tetrachlorobenzopara-dioxin
(TCDD) has been designated
as a definite human carcinogen by the
IARC. 88,p.33 PCDFs are not currently classifiable
as to their carcinogenicity in
humans, but an IARC review noted
incidents in Taiwan and Japan of very high
levels of exposure that may have resulted
in liver cancer. 88,p.345 Both the respiratory
tract and the skin can be routes of exposure
for dioxins and furans. 89
The major chlorinated hydrocarbon emitted
into ambient air from bleached kraft pulp
mills is chloroform, a possible carcinogen. 90
Other halogenated volatile organics that may
become airborne as a result of evaporation
from wastewater include trichloroethylene,
tetrachloroethylene, carbon tetrachloride,
dichloromethane, bromodichloromethane,
and chlorodibromomethane. All of these
compounds are mutagenic; the first five
have tested positive in animal carcinogenicity
bioassays, and some epidemiological
evidence indicates that the first two are
probably human carcinogens.
95
A number of studies in Canada, the USA,
Scandinavia and other parts of the
world have examined the health status
of populations near pulp and paper
mills. 20,21,35,40,91-97 Health endpoints examined
have included acute and chronic
respiratory diseases, cancer, mortality,
hospital admissions, and a variety of
annoyance symptoms (headaches, nausea,
and eye and throat irritation). These studies
implicate odorous pulp mill air emissions
in the genesis of community annoyance
reactions. Without personal exposure data,
objectively determining exposures to various
respiratory irritants is not possible.
Two ecologic studies 20,21 investigated lung
and oral cancer mortality in US counties
according to the proportion of the population
employed in the pulp and paper industry.
In a similar Canadian study, 40 excess allcause
male mortality was observed in six of
21 municipalities studied. Specifically, lung
cancer elevations were noted in four of the
21 municipalities.
In the 1980s and early 1990s, community
concerns in Canada about ambient levels
of pollutants from pulp and paper mills
resulted in two reports. One of these, a
bibliography of related literature, assists
further research in this area; 98 the other called
for environmental regulatory reform. 99
These reports and others were heeded, and
the Canadian government implemented
new guidelines in 1992 to reduce pollution
from pulp and paper mills.
Human health risk assessment
and conclusions
Pulp and paper mills employing chlorine
bleaching use a variety of substances
potentially hazardous to human health.
Compounds of both short- and long-term
toxicological significance are found in the
workplace environment. Air emissions and
water effluent have been largely cleaned up
in Canada since 1992, though surveillance
continues and potential endocrine disrupt
ing chemicals in the effluent need
to be researched further. The presence
of hazardous materials raises inevitable
questions regarding worker health and
safety, as well as the health of the general
population.
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Table 5
Selected relative risks from the latest generation of studies combining cohorts from 13 countries assembled under the auspices of IaRC
[rate ratio (95%CI)]
Study Exposures
studied
Carel et
al. 2002 55
Exposure Categories
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
all Neoplasms
Asbestos Ever vs. Never Exposeda WCE in Ever Exposed
1.0
(1.0,1.1)
lung
1.0
(0.8,1.1)
96
Pleura
2.5
(1.0,6.2)
Stomach
Cancer site
≤ 0.01 f/cc-year Ref Ref
0.02 - 0.09 f/cc-year 1.2 1.2
0.10 - 0.77 f/cc-year 1.4 1.7
≥ 0.78 f/cc-year 1.4 2.4
Test for trend: p = 0.07 p = 0.29
Lee et
al. 200266 Sulphur
Ever vs. Never Exposed
dioxide
b 1.0 1.5
0.7 2.6
2.5
(0.9,1.2) (1.1,2.0)
(0.5,1.1) (1.1,6.1)
c
WCE in Ever Exposed
(1.1,5.5)
< 2.0 ppm-years Ref Ref Ref Ref
2.0 - 5.9 ppm-years 1.0 0.9 1.0 2.6
6.0 - 20.9 ppm-years 1.3 1.6 1.6 5.3
≥ 21.0 ppm-years 1.3 1.5 1.3 4.4
Test for trend: p = 0.001 p = 0.009 p = 0.3 p = 0.03
McLean et
al. 200678 Volatile
Ever vs. Never Exposed
organochlorines
d 0.99 1.1 1.1 0.76 0.79 0.68 0.75 0.95
WCE in Ever Exposed
(0.90,1.1) (0.94,1.4) (0.39,3.3) (0.57,1.0) (0.44,1.4) (0.38,1.2) (0.37,1.5) (0.69,1.3)
< 1 ppm-years Ref Ref Ref Ref Ref Ref Ref
1 - 17 ppm-years 1.1 1.2 1.2 1.2 0.94 1.1 1.1
≥ 18 ppm-years 1.2 1.1 2.5 0.97 0.54 1.5 0.93
Test for trend: p = 0.002 p = 0.39 p = 0.11 p = 0.96 p = 0.29 p = 0.53 p = 0.86
WCE: Weighted cumulative exposure
Ref: Reference group
f/cc-year: Fibres per cubic centimeter-years
ppm-years: Parts per million-years
a Adjusted for country, age, calendar period, employment status
b Adjusted for sex, age, employment status, calendar year, country, exposure to asbestos, combustion products, and welding fumes
c Rate ratio for leukemia only
d Unadjusted model; we calculated the rate ratios using person-years from Table 1 and observed case counts from Table 2 in McLean et al. 2006.
Non-Hodgkin
lymphoma
esophagus
liver
lymphatic and
Hematopoietic
Though recent monitoring reports 8 on pulp
and paper mill effluent in Canada have
been positive in that they show effective
reductions in pollution, surveillance must
continue. Many of the compounds produced
by pulp and paper mills, especially
chlorinated phenolics, dioxins and
furans, are persistent in the environment,
bioaccumulate readily in the food chain,
and can contaminate drinking water.
Studies of pulp and paper mill workers and
nearby communities have produced few
conclusive results to date. Perhaps the most
consistently found increased risk relates
to lung and pleural cancers and asbestos
exposure. Since the pulp and paper industry
no longer uses asbestos, we expect the
risk of lung and pleural cancers, as well
as other respiratory morbidity related to
asbestos exposure, to be eliminated; any
remaining increases in lung cancer per
se would be difficult to disentangle from
smoking histories.
Various methodological limitations exist in
the occupational studies, including potential
ascertainment bias, the ‘healthy-worker
effect’, and spurious correlations arising
from multiple statistical comparisons.
Although a number of occupational studies
have suggested increased risk of cancer
among workers, most have used the popular,
but imprecise, standardized morbidity/
mortality ratio (SMR) as the measure of
effect. In the computation of SMRs, the
standard set of weights is derived from
the exposed population. Because indirect
age-adjusted rates for different studies do
not all use the same weighting factors (as
would be true for directly adjusted rates),
it is technically incorrect to compare SMRs
from two or more studies. Thus, each
indirectly adjusted rate is comparable only
to the standard.
Large cohort and nested case-control studies
with very good exposure assessment to
distinguish exposed from non-exposed
workers should serve to eliminate the
need to use community-based SMRs as the
measure of effect and to reduce the HWE.
And finally, the philosophical and statistical
problem of multiple comparisons is an
issue that needs to be resolved. Because
of the large number of comparisons made
in most of the studies, and the lack of
appropriate statistical adjustment, it is
impossible to distinguish between any
possible real associations and spurious
relationships attributable to chance. This
is unfortunate because methods could be
applied to correct for this problem.
As for epidemiological studies of communities
around pulp and paper mills, the
studies are few and the ecological fallacy
limits the interpretation of results. This bias
may occur because an association observed
between variables on an aggregate level
may not represent the association that
exists at an individual level.
The latest generation of IARC collaboration
studies hold much promise. However, of the
three studies they have published to date,
one involved a well-established carcinogen
(asbestos), another involved a mixture
containing probable carcinogens (volatile
organochlorines), and the third studied
exposure to a substance not classifiable as
a carcinogen (sulphur dioxide). While the
asbestos study is somewhat unremarkable
for finding an association with pleural cancer
in the expected direction, the volatile
organochlorine study may be most notable
for failing to find an association between
volatile organochlorine exposure and liver
cancer, non-Hodgkin’s lymphoma, or
esophageal cancer, as some previous studies
had found. The sulphur dioxide study may
be more significant in that it may influence
IARC’s assessment of sulphur dioxide’s
carcinogenicity. However, perhaps the
greatest impact from the IARC collaborative
studies is that they have now made the
proposition that “cancer is associated
with working in the pulp and paper
industry” almost obsolete. By studying
specific exposures and relating them to the
incidence of specific cancers, the focus has
shifted to the concept of “cancer associated
with a specific exposure.” The fact that the
exposure happens to be in the pulp and
paper industry may be considered peripheral
when one considers new discoveries about
carcinogens. Of course, if such exposures
happen to be an essential part of pulping
and paper-making, then the discovery of
ill-effects would continue to have profound
implications for the industry.
97
As a final note, even with the large IARC
cohort study, some cancers are so rare as to
ensure that any definitive associations with
specific exposures will remain speculative
from an epidemiological perspective. Given
these limitations, it may not be possible
for epidemiological studies to demonstrate
either association or causation. However,
given the known hazards and the potential
for both environmental and human exposure
by any number of pathways, vigilance on
the part of governments for regulation and
ongoing workplace and environmental
monitoring remains a health imperative.
References
1. Keefe A, Teschke K. Paper and pulp industry:
environmental and public health issues.
In: Stellman JM, editor. Encyclopaedia
of occupational health and safety. 4th ed.
Geneva: International Labour Organization
1998:72.17–9.
2. Kennedy S, Toren K. Paper and pulp industry:
injuries and non-malignant diseases. In:
Stellman JM, editor. Encyclopaedia of
occupational health and safety. 4th Ed.
Geneva: International Labour Organization
1998:72.14–5.
3. Teschke K, Astrakianakis G, Anderson J, et
al. Paper and pulp industry: occupational
hazards and controls. In: Stellman JM,
editor. Encyclopaedia of occupational health
and safety. 4th ed. Geneva: International
Labour Organization 1998:72.11–4.
4. Teschke K. Paper and pulp industry:
general profile. In: Stellman JM, editor.
Encyclopaedia of occupational health and
safety. 4th ed. Geneva: International Labour
Organization 1998:72.2–5.
5. Toren K, Teschke K. Paper and pulp
industry: cancer. In: Stellman JM, editor.
Encyclopaedia of occupational health and
safety. 4th ed. Geneva: International Labour
Organization 1998:72.15–7.
6. Haliburton D, Maddison L. Retrospective
Report on Impact of the 1992 Federal
Pulp and Paper Regulatory Framework on
Effluent Quality to 2000. Forest Products
Division, Environment Canada 2003.
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
7. Canadian Environmental Protection Act.
Priority substances list assessment report
No. 2. Effluents from pulp mills using
bleaching. Catalgue No. En 40-215/2E.
Minister of Supply and Services Canada
1991. Available at: http://www.ec.gc.ca/
substances/ese/eng/psap/PSL1_bleached_
pulp_mill_effluents.cfm
8. Environment Canada. National Assessment
of Pulp and Paper Environmental Effects
Monitoring Data: A Report Synopsis. National
Water Research Institute, Burlington,
Ontario. NWRI Scientific Assessment Report
Series No. 2. 2003:28 pages.
9. Pinkerton JE, Blosser RO. Characterization
of kraft pulp mill particulate emissions –
a summary of existing measurements
and observations. Atmos Environ 1981;
15:2071–8.
10. Pope AC, Burnett RT, Thun MJ, et al. Lung
cancer, cardiopulmonary mortality, and
long-term exposure to fine particulate air
pollution. JAMA 2002;287:1132–41.
11. Astrakianakis G, Svirchev L, Tang C, et al.
Industrial hygiene aspects of a sampling
survey at a bleached-kraft pulp mill in
British Columbia. Am Ind Hyg Assoc
J 1998;59:694–705.
12. Bertazzi PA, Pesatori AC, Consonni D, et al.
Cancer incidence in a population accidentally
exposed to 2,3,7,8-tetrachlorodibenzo-paradioxin.
Epidemiology 1993;4:398–406.
13. Kauppinen T, Teschke K, Savela A, et
al. International data base of exposure
measurements in the pulp, paper and paper
product industries. Int Arch Occup Environ
Health 1997;70:119–27.
14. Korhonen K, Liukkonen T, Ahrens W, et al.
Occupational exposure to chemical agents
in the paper industry. Int Arch Occup
Environ Health 2004;77:451-60.
15. Teschke K, Ahrens W, Andersen A, et
al. Occupational exposure to chemical
and biological agents in non-production
departments of pulp, paper, and paper
product mills. Am Ind Hyg Assoc
J 1999;60:73–83.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
16. Meijers JM, Swaen GM, Volovics A, et al.
Occupational cohort studies: the influence of
design characteristics on the healthy worker
effect. Int J Epidemiol 1989;18(4):970-5.
17. Arrighi HM, Hertz-Picciotto I. The evolving
concept of the healthy worker survivor
effect. Epidemiology 1994;5(2):189-96.
18. Andersson E, Hagberg S, Nilsson T, et al.
A case-referent study of cancer mortality
among sulfate mill workers in Sweden.
Occup Environ Med 2001;58:321-4.
19. Band PR, Spinelli JJ, Gallagher RP, et al.
Identification of occupational cancer risks
using a population-based cancer registry.
Recent Results Cancer Res 1990;120:181–9.
20. Blot WJ, Fraumeni JF. Geographic patterns
of oral cancer in the United States: etiologic
implications. J Chron Dis 1977;30:745–57.
21. Blot WJ, Fraumeni JF. Geographic patterns
of lung cancer: industrial correlations. Am
J Epidemiol 1976;103:539–50.
22. Cocco P, Ward MH, Dosemeci M.
Occupational risk factors for cancer of the
gastric cardia. Analysis of death certificates
from 24 US states. J Occup Environ Med
1998;40:855–61.
23. Decoufle P, Stanislawczyk K, Houten L,
et al. A retrospective survey of cancer in
relation to occupation. US DHEW (NIOSH)
1977:77–178.
24. Dubrow R, Wegman DH. Cancer and
occupation in Massachusetts: a death
certificate study. Am J Ind Med 1984;
6:207–30.
25. Gallagher RP, Threlfall WJ. Cancer risk
in wood and pulp workers. In: Stich HF,
editor. Carcinogens and mutagens in the
environment. Boca Raton, Florida: CRC
Press 1985:125–37.
26. Gottlieb MS, Pickle LW, Blot WJ, et al.
Lung cancer in Louisiana: death certificate
analysis. J Natl Cancer Inst 1979;63:1131–7.
27. Guralnick L. Mortality by industry and
cause of death. Vital Statistics, Special
Reports, US DHEW 1963:53.
98
28. Harrington JM, Blok WJ, Hoover RN,
et al. Lung cancer in coastal Georgia: a
death certificate analysis of occupation:
brief communication. J Natl Cancer Inst
1978;60:295–8.
29. Jarvholm B, Malker H, Malker B, et al.
Pleural mesotheliomas and asbestos
exposure in the pulp and paper industries:
a new risk group identified by linkage of
official registries. Am J Ind Med 1988;
13:561–7.
30. Langseth H, Kjaerheim K. Ovarian cancer
and occupational exposure among pulp
and paper employees in Norway. Scand
J Work Environ Health 2004;30(5):356-61.
31. Menck HR, Henderson BE. Occupational
differences in rates of lung cancer. J Occup
Med 1976;18:797–801.
32. Milham S, Hesser JE. Hodgkin’s disease in
woodworkers. Lancet 1967;2:136–7.
33. Milham S, Demers RY. Mortality among
pulp and paper workers. J Occup Med
1984;26:844–6.
34. Milham S. Occupational mortality in
Washington State, 1950–1979. U.S. DHEW
(NIOSH) 1976:76–175.
35. Morton W, Matjanovic D. Leukemia
incidence by occupation in the Portland-
Vancouver metropolitan area. Am J Ind
Med 1984;6:185–205.
36. Nasca PC, Baptiste MS, MacCubbin PA, et
al. An epidemiologic case-control study of
central nervous system tumours in children
and parental occupational exposures. Am
J Epidemiol 1988;128:1256–65.
37. Okubo T, Tsuchiya K. An epidemiologic
study on the cancer mortality in various
industries in Japan. Jap J Ind Health 1974;
16:438–52.
38. Pearce N, Sheppard RA, Howard, et al.
Time trends and occupational differences
in cancer of the testis in New Zealand.
Cancer 1987;59:1677–82.
39. Schwartz E. A proportionate mortality ratio
analysis of pulp and paper mill workers
in New Hampshire. Br J Ind Med 1988;
45:234–8.
40. Serdula J, Semenciw R. Mortality in selected
pulp and paper municipalities, 1984–1990.
Chronic Dis Can 1993;14:16–9.
41. Siemiatycki J. Risk factors for cancer in the
workplace. Boca Raton, Florida: CRC Press
1991:237.
42. Solet D, Zoloth SR, Sullivan C, et al. Patterns
of mortality in pulp and paper workers.
J Occup Med 1989;31:627–30.
43. Svirchev LM, Gallagher RP, Band PR, et
al. Gastric cancer and lymphosarcoma
among wood and pulp workers [letter].
J Occup Med 1986;28:264–5.
44. Szadkowska-Stanczyk I, Szymczak W.
Nested case-control study of lung cancer
among pulp and paper workers in relation
to exposure to dusts. Am J Ind Med
2001;39:547-56.
45. Teschke K, Morgan MS, Checkoway H,
et al. Surveillance of nasal and bladder
cancer to locate sources of exposure to
occupational carcinogens. Occup Environ
Med 1997;54:443–51.
46. Toren K, Sallsten G, Jarvholm B. Mortality
from asthma, chronic obstructive pulmonary
disease, respiratory system cancer,
and stomach cancer among paper mill
workers: A case-referent study. Am J Ind
Med 1991;19:729–37.
47. Ugnat A-M, Luo W, Semenciw R, et al.
Occupational exposure to chemical and
petrochemical industries and bladder cancer
risk in four western Canadian provinces.
Chronic Diseases in Canada 2004;25(2):7-15.
48. Wingren G, Kling J, Axelson O. Gastric
cancer among paper mill workers [letter].
J Occup Med 1985;27:714–5.
49. Wingren G, Persson B, Thoren K, et al.
Mortality pattern among pulp and paper
mill workers in Sweden: A case-referent
study. Am J Ind Med 1991;20:769–74.
50. Kawachi I, Pearce N, Fraser JA. A New
Zealand cancer registry-based study of
cancer in wood workers. Cancer 1989;
64:2609–13.
51. Andersson E, Nilsson R, Toren K. Gliomas
among men employed in the Swedish pulp
and paper industry. Scand J Work Environ
Health 2002;28(5):333-40.
52. Andersson E, Nilsson R, Toren K. Testicular
cancer among Swedish pulp and paper
workers. Am J Ind Med 2003;43:642-6.
53. Band PR, Le ND, Fang R, et al. Cohort
mortality study of pulp and paper mill
workers in British Columbia, Canada. Am
J Epidemiol 1997;146:186–94.
54. Band PR, Le ND, Fang R, et al. Cohort
cancer incidence among pulp and paper
mill workers in British Columbia. Scand
J Work Environ Health 2001;27(2):113-9.
55. Carel R, Boffetta P, Kauppinen T, et al.
Exposure to asbestos and lung and pleural
cancer mortality among pulp and paper
industry workers. J Occup Environ Med
2002;44:579-84.
56. Carstensen J. Occupation, smoking, and
lung cancer [thesis]. Stockholm, Sweden:
Karolinska Institute 1987.
57. Coggon D, Wield G, Pannett B et al.
Mortality in employees of a Scottish paper
mill. Am J Ind Med 1997;32:535–9.
58. Fassa AG, Facchini LA, Dall’Agnol MM. The
Brazilian cohort of pulp and paper workers:
the logistic of a cancer mortality study. Cad
Saude Publica 1998;14(Suppl 3):117–23.
59. Ferris BG, Puleo S, Chen HY. Mortality and
morbidity in a pulp and a paper mill in
the United States: A ten-year follow-up. Br
J Ind Med 1979;36:127–34.
60. Henneberger PK, Ferris BG, Monson RR.
Mortality among pulp and paper workers
in Berlin, New Hampshire. Br J Ind Med
1989;46:658–64.
99
61. Henneberger PK, Lax MB. Lung cancer
mortality in a cohort of older pulp and
paper workers. Int J Occup Environ Health
1998;4:147–54.
62. Jappinen P, Hakulinen T, Pukkala E, et al.
Cancer incidence of workers in the Finnish
pulp and paper industry. Scand J Work
Environ Health 1987;13:197–202.
63. Jappinen P, Pukkala E. Cancer incidence
among pulp and paper workers exposed
to organic chlorinated compounds formed
during chlorine pulp bleaching. Scand
J Work Environ Health 1991;17:356–9.
64. Langseth H, Andersen A. Cancer incidence
among women in the Norwegian pulp
and paper industry. Am J Ind Med 1999;
36:108–13.
65. Langseth H. Andersen A. Cancer incidence
among male pulp and paper workers in
Norway. Scand J Work Environ Health
2000;26(2):99-105.
66. Lee WJ, Teschke K, Kauppinen T, et al.
Mortality from lung cancer in workers
exposed to sulfur dioxide in the pulp and
paper industry. Environ Health Perspect
2002;110:991-5.
67. Malker HS, McLaughlin JK, Malker BK, et
al. Biliary tract cancer and occupation in
Sweden. Br J Ind Med 1986;43:257–62.
68. Matanoski GM, Kanchanaraksa S, Lees PS,
et al. Industry-wide study of mortality of
pulp and paper mill workers. Am J Ind Med
1998;33:354–65.
69. McLean D, Colin D, Boffetta P, et al.
Mortality and cancer incidence in New
Zealand pulp and paper mill workers. NZ
Med J 2002;115:186-90.
70. Robinson CV, Waxweiler RJ, Fowler DP.
Mortality among production workers in
pulp and paper mills. Scand J Work Environ
Health 1986;12:552–60.
71. Sala-Serra M, Sunyer J, Kogevinas M,
et al. Cohort study on cancer mortality
among workers in the pulp and paper
industry in Catalonia, Spain. Am J Ind Med
1996;30:87–92.
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
72. Szadkowska-Stanczyk I, Boffetta P,
Wilczynska U, et al. Cancer mortality
among pulp and paper workers in Poland:
A cohort study. Int J Occup Med Environ
Health 1997;10:19–29.
73. Wild P, Bergeret A, Moulin JJ, et al. Mortality
in the French paper and pulp industry. Rev
Epidemiol Sante Publique 1998;46:85-92.
74. Wong O, Ragland DR, Marcero DH. An
epidemiologic study of employees at seven
pulp and paper mills. Int Arch Occup
Environ Health 1996;68:498–507.
75. Jappinen P, Tola S. Smoking among Finnish
pulp and paper workers’ evaluation of its
confounding effect on lung cancer and
coronary heart disease rates. Scand J Work
Environ Health 1986;12:619–26.
76. Szadkowska-Stanczyk I, Szymczak W,
Szeszenia-Dabrowska N, et al. Cancer risk
in workers in the pulp and paper industry in
Poland. A continued follow-up. Int J Occup
Med Environ Health 1998;11:217–25.
77. Hogstedt C. Cancer epidemiology in the
paper and pulp industry. In: Vainio H,
Sorsa M, McMichael AJ, editors. Complex
mixtures and cancer risk. Lyon: IARC
1990:382–9.
78. McLean D, Pearce N, Langseth H, et al.
Cancer mortality in workers exposed to
organochlorine compounds in the pulp
and paper industry: an international collaborative
study. Environmental Health
Perspectives 2006;114(7):1007-12.
79. International Agency for Research on
Cancer. Monographs programme on the
evaluation of the carcinogenic risks to
humans: Asbestos fibres (Suppl 7). Lyon:
IARC 1987.
80. International Agency for Research on Cancer.
Monographs programme on the evaluation of
the carcinogenic risks to humans: Asbestos
(Vol 14). Lyon: IARC 1977.
81. International Agency for Research on
Cancer. Monographs programme on the
evaluation of the carcinogenic risks to
humans: Sulfur dioxide (Vol 54). Lyon:
IARC 1992.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
82. Vedal S, Petkau J, White R, et al. Acute
effects of ambient inhalable particles in
asthmatic and nonasthmatic children. Am J
Respir Crit Care Med 1998;157(4 Pt 1):1034-43.
83. Sunito LR, Shiu WY, Mackay D. A review
of the nature and properties of chemicals
present in pulp mill effluents. Chemosphere
1988;7:1249–90.
84. McLeay DJ. Aquatic toxicity of pulp and
paper mill effluent : A review. Environment
Canada. Ottawa, Report EPS 4/PF/1,191,
1987.
85. Wong PTS, Chau YK, Ali N, et al. Biochemical
and genotoxic effects in the vicinity of a pulp
mill discharge. Environmental Toxicology
and Water Quality: An International Journal
1994;9:59–70.
86. Berry RM, Luthe CE, Voss RH. Ubiquitous
nature of dioxins: a comparison of the
dioxin content of common everyday
materials with that of pulps and papers.
Environ Sci Tech 1993;27:1164–8.
87. Canadian Environmental Protection Act.
Priority Substances List Assessment Report
No. 1. Polychlorinated Dibenzodioxins and
Polychlorinated Dibenzofurans. Catalogue
No. En 40-215/2E. Minister of Supply
and Services Canada 1990. Available at:
http://www.hc-sc.gc.ca/ewh-semt/pubs/
contaminants/psl1-lsp1/dioxins_furans_
dioxines_furannes/index-eng.php
88. International Agency for Research on
Cancer. Monographs programme on the
evaluation of the carcinogenic risks to
humans: Polychlorinated Dibenzo-para-
Dioxins and Polychlorinated Dibenzofurans
(Vol. 69). Lyon: IARC 1997.
89. Kelada FS. Occupational intake by dermal
exposure to polychlorinated dibenzo-pdioxins
and polychlorinated dibenzofurans
in pulp mill industry. Am Ind Hyg Assoc
J 1990;51:519–21.
90. U.S. Environmental Protection Agency.
Survey of chloroform emission sources.
EPA-450/3-85-026. Research Triangle Park,
NC: EPA 1985.
100
91. Ferris BG, Chen H, Puleo S, et al. Chronic
non-specific respiratory disease in Berlin,
New Hampshire, 1967 to 1973. Am Rev
Respir Dis 1976;113:475–85.
92. Mikaelsson B, Stjernberg N, Wiman LG.
The prevalence of bronchial asthma and
chronic bronchitis in an industrialized
community in northern Sweden. Scand
J Soc Med 1982;10:11–6.
93. Stjernberg N, Eklund A, Nystrom L, et al.
Prevalence of bronchial asthma and chronic
bronchitis in a community in northern
Sweden: relation to environmental and
occupational exposure to sulfur dioxide.
Eur J Respir Dis 1985;67:41–9.
94. Deprez RD. Oliver C. Halteman W.
Variations in respiratory disease morbidity
among pulp and paper mill town residents.
J Occup Med 1986;28:486–91.
95. Stjernberg N, Rosenhall L, Eklund A, et
al. Chronic bronchitis in a community in
northern Sweden: relation to environmental
and occupational exposure to sulphur
dioxide. Eur J Respir Dis 1986;146
(Suppl):153–9.
96. Haahtela T, Martilla O, Vilkka V, et al.
The South Karelia Air Pollution Study:
Acute health effects of malodorous sulfur
air pollutants released by a pulp mill. Am
J Public Health 1992;82:603-5.
97. Jaakkola JJ, Vilkka V, Marttila O, et al. The
South Karelia air pollution study: The effects
of malodorous sulfur compounds from pulp
mills on respiratory and other symptoms.
Am Rev Respir Dis 1990;142:1344–50.
98. Holmberg RG. Pulp mills and the
environment: an annotated bibliography
for northern Alberta. Athabasca University,
Circumpolar Institute and the Environmental
Research Study Centre, University of Alberta
1992. ISBN 0-919737-06-4.
99. Reiter B. The other side of the Canadian
pulp and paper industry: the urgent need
for environmental regulatory reform.
The Pulp, Paper and Woodworkers of
Canada,Vancouver, BC 1990.
gold, Nickel and Copper Mining and Processing
Nancy E. Lightfoot, Michael A. Pacey and Shelley Darling
Ore mining occurs in all Canadian provinces
and territories except Prince Edward Island.
Ores include bauxite, copper, gold, iron,
lead and zinc. Workers in metal mining
and processing are exposed, not only to
the metal of interest, but also to various
other substances prevalent in the industry,
such as diesel emissions, oil mists, blasting
agents, silica, radon, and arsenic. This
chapter examines cancer risk related to the
mining of gold, nickel and copper.
The human carcinogenicity of nickel
depends upon the species of nickel, its
concentration and the route of exposure.
Exposure to nickel or nickel compounds via
routes other than inhalation has not been
shown to increase cancer risk in humans.
As such, cancer sites of concern include the
lung, and the nasal sinus. Evidence comes
from studies of nickel refinery and leaching,
calcining, and sintering workers in the early
half of the 20 th century. There appears to be
little or no detectable risk in most sectors
of the nickel industry at current exposure
levels. The general population risk from the
extremely small concentrations detectable
in ambient air are negligible. Nevertheless,
animal carcinogenesis studies, studies of
nickel carcinogenesis mechanisms, and epidemiological
studies with quantitative exposure
assessment of various nickel species
would enhance our understanding of
human health risks associated with nickel.
Definitive conclusions linking cancer to
exposures in gold and copper mining and
processing are not possible at this time. The
available results appear to demand additional
study of a variety of potential occupational
and non-occupational risk factors.
Introduction
Mining occurs in all Canadian provinces
and territories except Prince Edward
Island. However, it is of most importance
in Ontario, Quebec, British Columbia,
and Saskatchewan. Canadian mines
provide materials for the manufacturing,
construction, automotive, and chemical
industries, and produce important sources
of energy. Canada is a leading mineralproducer
and trader of coal, metals,
structural materials, and non-metallic or
industrial minerals. It is also an important
world producer of zinc, uranium, potash,
nickel, cadmium, selenium, indium,
copper, aluminum, magnesium, titanium,
molybdenum, gypsum, and gold. 1 With
the recent expansion of diamond mining
operations in the north, Canada is now the
third largest producer in the world. 2
This chapter summarizes the history of
mining and the types of ores mined in
Canada, reviews studies of cancer risk
in nickel, gold, and copper mining and
processing workers (excluding those in
metal and alloy fabrication, engineered
products, and metal finishing), and recommends
further cancer-related research
studies relevant to such workers. Studies
of workers are discussed in chronological
order of publication. The selection of
mining and processing operations discussed
is based on metals of high economic value
and the prevalence of currently available
health literature. 2 Uranium merits separate
attention and is therefore excluded from
this discussion, as are other types of metals,
non-metals, structural materials and fuels.
The reader is referred to the Radon section
in the present volume for a treatise of the
relevance of radiation on the development
of cancer.
Canada’s metal industry
History, production and economic value
Canada’s first prospectors and miners, of
First Nations origin, mined copper and
shaped it into tools and artifacts. The
next epoch in Canadian mining history is
documented by evidence of iron mining
in ninth century Viking settlements in
Newfoundland. Then we skip to the early
1600s, when Samuel de Champlain, with
aboriginal assistance, began searching
for mineral occurrences. Iron and silver
discoveries in Nova Scotia resulted in a
few small mining operations subsequently
operated by French and English settlers. 1
Farming, forestry, fishing and the fur
industry dominated Canada’s economic
development until 1849 when the discovery
of placer (i.e., deposits of sand or gravel
that contain valuable metals) 3 gold in
California revived mineral exploration
interest. 1 The Cariboo gold rush in British
Columbia (BC), one of the most colourful
periods in Western Canadian history,
contributed to the construction of the
railway in Canada and launched modern
day prospecting, mining and production.
Subsequent milestones are summarized in
Table 1.
Based on the value of output, the leading
types of Canadian metal production in
2004 were nickel, gold, copper, iron ore,
zinc, uranium, platinum group, silver,
cobalt, and lead (Table 2). 2
Environmental and health
protection strategies
Member companies of The Mining
Association of Canada (MAC) are committed
to sustainable development that
involves, not only a prosperous economy,
but also the protection of human
health and the natural environment.
The MAC is implementing the Towards
Sustainable Mining initiative which
includes an external verification process
and reporting of the industry’s releases
to the environment. Emission reductions
achieved by 2004 compared to the base
year 1988 are given in Table 3 for major
substances commonly released. 5 The
emissions list for the initiative includes
arsenic, cadmium, chromium, cobalt,
copper, cyanides, hydrogen sulphide, lead,
mercury, nickel, silver and zinc, as well
as for sulphur dioxide.
The MAC works with governments, local
communities, and affected stakeholders to
develop, implement, and evaluate the sitespecific
environmental management plans
for each base metal smelter. It monitors
levels of, and reports to the Federal-
Provincial Task Force about emissions of
101 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
dioxins and furans from smelters that have
chlorinated plastics and other chlorinated
substances in their feeds. Companies also
work with other industries, governments,
First Nations communities, and citizens’
groups to minimize adverse effects upon
the environment. 5 The federal/provincial
governments retain ultimate oversight.
Toxicology relevant to metal
mining and processing
Workers in metal mining and processing are
exposed, not only to the metal of interest,
but also to various other substances
prevalent in the industry and not specific to
a particular ore. A wide variety of exposures
could be investigated, including diesel
emissions, oil mists, blasting agents, silica,
radon, and arsenic. The toxicology of some
of these will be discussed, followed by gold,
nickel and copper. It is important to note
that underground and surface exposures
can vary substantially, and exposures can
vary between underground locations.
Arsenic may be present as organic or
inorganic compounds, but inorganic
arsenic is the form of primary toxicological
concern. Trivalent arsenicals are known
human carcinogens. 6 Occupational arsenic
exposure occurs mainly in workers
involved in the processing of copper, gold,
lead, and antimony ores. Other industries
with potential occupational exposures
include those using or producing arsenicals
and arsenic-containing pesticides, burning
arsenic-containing coal in power plants, and
treating wood with arsenic preservatives. 7,8
Data concerning occupational exposure
levels appear limited. The average total daily
intake is approximately 90 µg. 7,9 with about
45 µg from food and 10 µg from drinking
water. 7,10 Absorption of arsenic compounds
can occur through the gastrointestinal tract,
lungs and skin. Excretion occurs primarily
through urination. 7 In smelter workers
inhalation is the primary route of exposure.
Whether inorganic arsenic is responsible
for cancers other than skin or lung remains
unresolved, although there have been
reports of bladder, kidney, liver and colon
cancers. 6,7,11-13 The possible mechanisms
of genotoxicity and carcinogenicity have
not been established. 6 Oxidative stress
and glutathione depletion may be in
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
vitro phenomena evoked by high doses. 6
Inhibition of DNA repair caused by direct
enzyme inhibition or enzyme inhibition via
arsenic-mediated generation of oxidation
products might be more plausible. 6 It has
been suggested that arsenic may act as a
co-carcinogen or tumour promoter. 7 IARC
(International Agency for Research on Cancer)
classifies the group of arsenic and arsenic
compounds as carcinogenic to humans. 14
Silica comprises a substantial part of
the Earth’s crust, is among the most
common minerals on Earth, and exists in
crystalline (or ‘free silica’) and amorphous
forms. 15 It is the crystalline form that is
of concern. 15 Crystalline silica has three
main polymorphs, all of the form (SiO 2 )n,
where n represents the various forms of
the compound: quartz (the most common
form), tridymite, and cristobalite. 15 High
exposures are frequent for foundry workers,
miners (but highly variable depending upon
the silica content of the ore), quarrymen,
and sandblasters. Low exposures are possible
when mixed dusts are inhaled, but
the general population is not exposed to
levels sufficient to cause disease. 15 The
current American Occupational Safety and
Health Administration standard is based
on respirable dust and the percent of silica
in the dust (i.e., [10 mg/m 3 ]/[percent
crystalline silica+2]). 15 The concentration
of particular metals and silica can vary
between deposits of similar type and even
within ore bodies in a deposit.
Inhaled silica can cause fibrosis and lung
cancer in rats. 16 In mice, however, it causes
only fibrosis, and in hamsters it causes
neither. 17 Silica can cause progressive granulomatous
and fibrotic lung disease in
humans. 15 Studies of silica-exposed workers
suggest an increased lung cancer risk,
but are not consistent, nor are exposureresponse
analyses. 15 Steenland concluded
that the weight of evidence suggests that
silica is a human lung carcinogen. 15
Others have proposed that cristobalite and
tridymite, which are more fibrogenic than
quartz, may be even more carcinogenic. 15,18
Still others claim that the evidence for
carcinogenicity of silica is weak in some
occupational cohorts, and absent in others.
Furthermore, rats can display a propensity
for tumour development after exposure
102
to various noncarcinogenic particles. For
example, proteases and oxidants generated
by inflammatory cells in silicotic and
asbestotitic lesions may create a favourable
environment for progression and metastases
of lung cancer by facilitating tumour
cell invasion. Thus the issue of silica
carcinogenicity will only be resolved by
well-controlled epidemiological studies. 19,20
In 1997, IARC concluded that there is
sufficient evidence in humans for the
carcinogenicity of inhaled crystalline silica
in the form of quartz or cristobalite from
occupational sources. 15,16
Radon is a confirmed occupational carcinogen.
It is an inert gas that occurs
naturally as a decay product of radium-226
or uranium-238. Radium-226 and uranium-
238 are present in most soils and rocks
such that radon is continually generated
in the Earth and some atoms could enter
surrounding air and water. Radon has
a half-life of 3.82 days and decays into a
series of solid, short-lived radioisotopes
referred to as radon daughters, radon progeny,
or radon decay products. As inhaled
radon progeny decay, they emit alpha
particles that can damage the DNA of
cells lining airways, and ultimately lung
cancer may ensue. Occupational exposure
to radon progeny is a concern for uranium
and many other types of underground
miners and workers. The radon section
in the present volume provides further
information. Radon progeny also represent
an important cause of lung cancer for the
general population. Radon and its decay
products are invariably present in indoor
environments and, in some extreme cases,
may reach concentrations equivalent to
those in mines. 21
Cobalt and cobalt compounds are considered
by the IARC to be possible human
carcinogens. 14 Others have indicated that,
although cobalt injection (versus ingestion
or inhalation) has proven carcinogenic in
mammals, 22-26 the few studies on humans
have not demonstrated a significant number
of cobalt-induced cancers. 22-24,27 Some
recent data suggest that workers exposed
to cobalt in the hard-metal industry
may be at increased risk of lung cancer
development; 22,28-33 however, the problem
Table 1
Nineteenth and twentieth century metal discoveries in Canada
Time period location Metal 1
Late 1800s Klondike, Yukon gold rush Placer gold, vein gold, silver, lead
Sudbury basin, Ontario Copper, nickel
Late 1890s Rossland, southern BC Gold
Kimberley, southern BC Lead, zinc, silver
1900s Cobalt, northern Ontario Silver
Porcupine and Kirkland Lake, northern Ontario and Hemlo,
northwestern Ontario
Gold
Cadillac, Rouyn-Noranda, and Val d’Or, Quebec Copper-gold4 Flin Flon, northern Manitoba Zinc, copper-nickel
Yellowknife, southern NWT Gold
Great Bear Lake, northern NWT Uranium, radium
Gaspé, Québec Copper
Québec/Labrador Iron
Saskatchewan Potash (1960), uranium (1970s and 1980s)
Thompson, northern Manitoba Copper-nickel
Bathurst, New Brunswick Copper-zinc-lead
Québec and Newfoundland Asbestos
Western and eastern Canada Coal
Table 2
economic value of some Canadian metal production, 2004
Metal 2 estimated value (Canadian dollars in billions)
Nickel $3.3
Gold $2.2
Copper $2.0
Iron ore $1.4
Zinc $1.0
Uranium $0.6
Platinum group metals $0.5
Silver $0.4
Cobalt $0.2
Lead $0.1
Table 3
Reductions in environmental emissions achieved to 2004 (from 1988 levels)
Substance Reduction 5
Arsenic 57%
Copper 67%
Mercury 93%
Zinc 75%
Hydrogen sulphide 69%
Cadmium 79%
Lead 87%
Nickel 74%
Sulphur dioxide 59%
of co-exposure to other metals (e.g., nickel
and arsenic) and small sample sizes 22,24
means there is still insufficient evidence
regarding the occupational carcinogenicity
of cobalt.
Asbestos is known to cause lung cancer
and mesothelioma, and is sometimes
present where other minerals are mined.
Nonasbestiform amphibole minerals have
not been associated with lung cancer,
although they are suspect as a result of
their similarity to asbestiform fibers. 34
Sulphur dioxide (SO 2 ) is listed as unclassifiable
regarding carcinogenicity. 14 SO 2 is
an emission from mining processes associated
with several types of mining. These
exposures are experienced by residents
in neighbouring communities (or even
distant with a bigger smokestack), and not
necessarily just by workers alone.
Gold is considered the most inert of
metals, although it can be sensititizing. 35
Only rarely will the gradual dissolution
at very minute levels by thiol-containing
molecules yield gold complexes which can
generate immunosuppressive and immunostimulative
effects, depending upon the
dose and duration of exposure. 35,36
103 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Nickel is ubiquitous and the respiratory
system (particularly the nasal cavities and
sinuses), the immune system, and the skin
are important routes of nickel exposure. 37
The most acutely toxic nickel compound
is nickel carbonyl which can result in
headache, vertigo, nausea, vomiting,
nephrotoxic effect, and severe pneumonia,
possibly followed by pulmonary fibrosis. 37,38
Excesses of rhinitis, sinusitis, nasal septum
perforations, and bronchial asthma have
been observed in nickel refinery and
nickel plating workers. 37,39 Nickel contact
dermatitis is estimated to affect up to
10% of females and 1% of males in the
general population, and has been observed
frequently in workers exposed to soluble
nickel compounds. 37,39 The IARC classifies
nickel compounds as carcinogenic to
humans, and metallic nickel as a possible
human carcinogen. 38
Oller et al. noted that the epidemiological
literature up to 1990 assumed that all
soluble and insoluble (i.e., oxidic, sulphidic,
and metallic) nickel compounds had the
same carcinogenic mechanism but with
different potencies. 40 However, more recent
in vivo and in vitro studies challenge this
hypothesis and emphasize the importance
of nickel speciation when evaluating
the potential carcinogenicity of nickel
compounds. Based on epidemiological and
animal data, Oller et al. concluded that
three examined nickel compounds had very
different biological behaviours: (1) nickel
subsulphide is likely a human carcinogen;
(2) nickel sulphate hexahydrate, alone, is
not likely a human carcinogen; however,
soluble compounds can cause toxicity and
cell proliferation, such that an enhancing
effect on carcinogenicity of insoluble nickel
compounds is possible and additional
animal studies are required to test this
effect; and (3) green nickel oxide may be
carcinogenic to animals and humans only
at doses high enough to induce chronic
inflammation/cell proliferation; in vitro,
concentrations of green nickel oxide must
be tenfold higher than concentrations of
nickel subsulphide to be equitoxic and to
induce some of the same effects. Oller et al.
integrated the relevant human and animal
data into a general model of lung cancer
development: (1) initiation of tumorgenesis
from genetic or epigenetic events, as
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
a result of direct or indirect actions of
nickel compounds, and (2) promotion
of cell proliferation elicited by certain nickel
compounds. Snow reported that several
studies have indicated that insoluble nickel
compounds are strongly carcinogenic in
vitro and in vivo, 41-45 whereas soluble nickel
compounds are weaker carcinogens.
Nickel is a mutagen in some mammalian
mutagenesis assays 40-42,46 but not in bacterial
assays. 41,42,47 Nickel salts, alone, are not
generally mutagenic, but act synergistically
as co-mutagens. In mammalian cells, in
vitro cellular transformation by nickel is
linked with phagocytic uptake of insoluble
nickel species. 41,43,48 Phagocytosis of nickel
compounds is also associated with the
release of oxygen species by pulmonary
alveolar macrophages. 41,49 Snow indicated
that the mechanisms of genotoxicity were
unclear, likely multifaceted dependent
on the mechanism of nickel uptake, and
related to alterations in DNA-protein
interactions. 41,47
A Nordic group cited the carcinogenic
potency of nickel and relative potency of
different nickel compounds as the most
important problem in nickel toxicology:
Metallic nickel and several nickel
compounds are carcinogenic in experimental
animals after several different
exposure regimes. There is a marked
discrepancy in the carcinogenic
potency of nickel compounds between
animals and humans. In humans,
soluble nickel salts are carcinogenic
but in animals the less soluble nickel
compounds seem to be most potent. 50
Although copper toxicity can occur at
elevated exposure levels, copper is an
essential trace element for human health,
as it is a co-factor for various oxidative
enzymes. 51,52 Acute copper poisoning is
infrequent in humans and largely the
result of ingestion of copper salts. 2 The
effects of copper salts in carcinogenesis
have not received much attention. 53 In
studies of copper and iron effects in Long-
Evans Cinnamon rats, a high spontaneous
incidence of kidney and liver cancer
developed under certain conditions, 53-55
and abnormal copper metabolism was
104
associated with hepatitis and liver cancer. 54
Poirier and Littlefield suggest that this strain
of rats could serve as an excellent model
to study possible common mechanisms of
iron and copper actions, possibly by way
of oxidative damage to DNA. 53
For 2003 threshold limit values (TLVs)
for substances associated with the metal
mining industry, the reader is referred to
the 2003 TLVs and biological exposure
indices (BEIs), published by the American
Conference of Governmental Industrial
Hygienists. 56 The reader is also referred to
this publication for other relevant exposures
to chemical substances and physical agents
that may be of interest. Table 4 presents
some of the TLVs that may be relevant to
this publication. The threshold limit valuetime-weighted
average (TLV-TWA) is the
time-weighted average concentration for
a conventional eight hour work day and
40 hour work week, to which it is thought
that nearly all workers may be repeatedly
exposed, day after day, without adverse
effect. 56
gold
Background
Gold is a soft, malleable, lustrous, highly
valued yellow metal that resists corrosion.
It may represent possibly the most ancient
as well as the most modern pharmaceutical
therapies. 35 Since ancient times, gold has
been used to make jewelry and decorations
and as a cosmetic ingredient. 35 Given that
the pure metal is soft, alloys are needed to
make jewelry, utensils and coins. 57
In Canada, gold is found in a variety of
geological settings and ore deposit types.
Most (60%) is found in gold-only bedrock
sources, which are referred to as lode gold
deposits. These are classified by depth or
temperature (i.e., epithermal, mesothermal,
or hypothermal), by associated mineral
formations (i.e., quartz-carbonate vein or
iron-formation-hosted strata-bound), or by
the composition of the geological matrix
(i.e., disseminated or replacement). 58
In 2003, Canada was the world’s eighth
largest global gold producer, trailing South
Africa, Australia, the United States, China,
Peru, Russia and Indonesia. In 2004, gold
mining was carried out in all provinces
and territories with the exception of Prince
Edward Island. In addition, there were gold
refineries in Quebec and Ontario. While
higher before 1966, employment in Canada’s
gold mines peaked in 1989 at 12,631 workers
and subsequently declined. 2
Studies of gold workers
The South Dakotan Homestake Gold Mine
has operated almost continuously since
1876. 59 The gold-bearing rock consists
of metamorphosed siderite-quartz and
cummingtonite-quartz schists. The gold
ore, therefore, contains large quartz masses
and many quartz veins, along with chlorite,
amphibole, siderite and lesser amounts of
sulfides (pyrrhotite, pyrite, arsenopyrite,
galena, sphalerite and chalcopyrite), calcite,
ankerite, biotite, garnet, fluorite, iron oxides
and gypsum. 59,60 Gillam et al. examined
mortality for a cohort of 440 Homestake
South Dakotan underground gold miners
who were employed in underground
mining for at least 60 months and who
had never mined elsewhere. 61 Follow-up
extended from April 1960 to December 1973.
Of 71 deaths observed (O), 52.9 were
expected (E). The expected number of
deaths is calculated by multiplying the
person-years at risk in the cohort for
each age group by the disease rate in the
reference population for the corresponding
age group and summing, which produces
a non-integer result. Of the 15 cancer
deaths observed, 9.7 were expected.
Ten deaths were from lung cancer, with
2.7 expected (p
23.72 E, p=.018) and for trachea, bronchus
and lung at both Timmins (SMR% 154,
119 O, 77.36 E, p 5µm
b Vapour and aerosol
c Inhalable fraction
d Respirable fraction
e Thoracic fraction
Sulphur dioxide 2 ppm
first. Men with known asbestos exposure
or who had worked in a uranium mine
outside Ontario or in a uranium processing
plant were a separate excluded group. The
two reference populations were the male
population of Ontario matched by age
group and calendar period, and a cohort
of Ontario nickel/copper miners matched
by age group. The cancers examined in the
cohort study were similar to those in Muller
et al.’s previous study. 65 One-sided p-values
were calculated for the SMR%s. Using
the Ontario male reference population, the
SMR% for underground gold miners
was 157 (p=.001, 54 O, 34.5 E, 95%
Confidence Interval (CI) on the observed
deaths 40.6-70.5) for stomach cancer and
140 (p
190 (p
280, 95% CI 113-577, 7 O, 2.50 E) and cancer
of the trachea, bronchus and lung (SMR%
213, 95% CI 148-296, 35 O, 16.44 E).
Workers who had ever been miners displayed
higher mortality rates than nonminers
for cancer of the trachea, bronchus
and lung (SMR% 217, 95% CI 131-339,
19 O, 8.75 E) and Hodgkin’s disease
(SMR% 1176, 95% CI 142-4250, 2 O, 0.17 E).
Refinery workers displayed elevated rates
of mortality from rectal cancer (SMR%
483, 95% CI 194-995, 7 O, 1.45 E) and
cancer of the trachea, bronchus and lung
(SMR% 229, 95% CI 144-347, 22 O, 9.59 E).
Duration of employment was slightly
related to SMR% amongst miners, but not
significantly. However, lung cancer SMR%s
were related to period of employment,
with a pooling of excess in those employed
prior to 1955. The authors noted that there
were major decreases in arsenic and dust
contamination within the mine in 1954.
They concluded that overall mortality risk
from lung cancer was similar in magnitude
for mine and refinery workers. While
no smoking histories were obtained, the
authors felt that the magnitude of risk
excluded smoking as the sole explanation
of lung cancer mortality excess, and
suggested that increased cancer risk may
be due to insoluble arsenic along with
other exposures, such as radon and silica.
The results of this study are somewhat
tempered by the inability to determine
the cause of death in 20.4% of the cohort.
Small samples for some of the mortality
sub-groups and lack of occupational
exposure data, noted by the authors, also
preclude definite conclusions. The study’s
contribution was also minimized by
inadequate consideration of other potential
risk factors.
Steenland, et al. performed a cohort and
nested case-control analysis of lung cancer
among South Dakotan gold miners. 34 This
study used the cohort examined by Brown
et al., 63 and extended the follow-up to
1990. There were 1551 deaths among
3328 gold miners who worked underground
in South Dakota for at least one
year between 1940 and 1965. Cancer
sites examined were digestive system,
peritoneum, respiratory, larynx, lung,
other respiratory, urinary, hematopoietic,
lymphosarcoma/reticulosarcoma, Hodgkin’s
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
disease, leukemia/aleukemia, and other.
The case-control study focussed on mortality
for these sites, with silica and nonasbestiform
amphibole minerals as the
primary exposures of concern. Using United
States mortality reference rates, the cohort
analysis found no statistically significant
SMRs. In comparison to local counties,
however, rates of lung cancer were slightly
elevated among all miners (SMR 1.25, 95%
CI 1.03-1.51, 112 O) and for those with 30 or
more years since first exposure (SMR 1.27,
95% CI 1.02-1.57, 88 O). With all South
Dakota counties as the referent, lung cancer
was again significantly elevated, with rates
higher than those using local counties as
the referent (SMR 1.59, 95% CI 1.31-1.92).
Importantly, no positive exposure-response
trend was found between lung cancer
mortality and cumulative dust exposure,
even when time since last employment
was considered. Unlike other studies
reviewed here, lung cancer mortality was
not elevated by period of hire. However,
a significant trend was observed for non-
Hodgkin’s lymphoma, with a significantly
elevated SMR in the highest dust category
(SMR 3.29, for 48,000+ dust days; dust
day = one day with exposure of one million
particles per cubic foot [mppcf] dust).
In the case-control portion of the study,
Steenland et al. selected 115 lung cancer
deaths. 34 Each case was matched to five
controls, who were the same age as the
case when death occurred, and whose
cumulative exposures were truncated at
the time of death of the case. Smoking
data were historical, extracted from a 1960
survey of the miners. A non-significant
trend in risk of death from lung cancer was
observed in relation to the transformed
log of estimated cumulative exposure, as
well as to duration of estimated exposure.
In the authors’ view, exposure to nonasbestiform
amphiboles or silica were not
likely responsible for lung cancer excesses.
In light of the discrepancies between their
findings and other studies demonstrating
a link between silica and lung cancer, the
authors suggested that all silica may not be
alike, or that studies demonstrating positive
dose-responses to dust may be partially
confounded by radon or arsenic exposures.
Additional potential risk factors may have
108
proved important as well, although they
were not included in this study.
Gold miners in Kalgoorlie, Western
Australia were studied using a proportional
mortality analysis. 70 Follow-up was from
1961 to 1991. De Klerk et al. defined cases
as all deaths from lung cancer (n=98) and
referents as all deaths from other causes
(n=744) excluding tuberculosis, other
respiratory diseases, and cancers of the
larynx and of unknown sites. Using logistic
regression, risks for a range of variables
were determined, including age, smoking,
duration of underground employment, and
presence of bronchitis at the time of survey.
Only smoking displayed a strong effect
on lung cancer risk. Forty years or more
of underground experience also displayed
some effect. The authors stressed that the
results were preliminary, but did indicate a
role for smoking on the relative risk of lung
cancer, and a possible effect of duration
of employment for those with 40 years
or more of underground experience. Other
potential risk factors were not considered.
Another cohort of South African gold
miners in the East/Central/West Rand gold
mines was examined by Reid and Sluis-
Cremer. 71 The cohort included all white
gold miners with birth dates between
January, 1916 and December, 1930 who
had attended compulsory Medical Bureau
of Occupational Diseases examinations in
1969 (n=4925). The miners’ ages ranged
from 39 to 54 at that time. Two thousand,
eight hundred ninety-two miners survived
to 1990. Mortality was higher than expected
(2032 O, 1568 E), with lung cancer mortality
significantly elevated (SMR% 139.8, 95% CI
117.8-164.6, p
lood pressure, Quetelet index, and mining
service (including duration of underground
service and duration of cumulative dust
exposure) were included in the model.
Smoking was the only significant risk
factor (RR 2.41, 95% CI 1.4-4.2); 86%
of the miners had smoked at some time,
averaging 16 to 17 cigarettes per day. Radon
daughter exposure, assessed by number
of underground shifts as a surrogate,
was not related to lung cancer risk. The
authors proposed that more detailed data
on exposure to radiation be part of future
studies. Consideration of other potential
risk factors would also be helpful.
De Klerk and Musk examined silica, silicosis,
and lung cancer mortality in a cohort
of 2297 Kalgoorlie, Western Australia gold
miners. 72 This cohort was derived from
surveys in 1961, 1974, and 1975, and
follow-up was from 1961 to 1993. Two
separate estimates of expected deaths were
calculated. The first (SMR1) assumed that
all workers lost to follow-up were alive on
December 31, 1993 or at age 85, whichever
was earlier. The second estimate (SMR2)
was calculated by censoring subjects by the
date that they were last known to be alive.
Semiquantitative estimates of average and
cumulative exposure to silica were derived
for underground and surface exposure
by combining assigned exposure scores
and employment records. Additionally, a
panel of experts estimated silica exposure
for each occupation. At the time of study,
654 members of the cohort were still alive,
1386 had died and 257 could not be traced.
All-cause mortality in the cohort was
similar to an age, sex and period matched
referent group of Western Australians, but
lung cancer mortality was elevated (SMR1
1.26, 95% CI 1.07-1.59). Censoring the
subjects at date last known alive increased
the significance of the lung cancer ratio
(SMR2 1.49, 95% CI 1.26-1.76).
In a lung cancer case-control study nested
within this cohort, 72 cases were matched
on age to controls who had survived
the cases and had not developed lung
cancer by the year of the cases’ death.
Subjects could be controls for more than
one case, or controls prior to the onset
of a disease which would qualify them
for inclusion as a case. Smoking status
at the time of survey, duration of underground
and surface employment, cumulative
silica exposure score, time-weighted
average of the cumulative silica exposure
divided by duration of employment, time
since first exposure, and decade of first
employment were considered as predictor
variables. Additionally, a worksite variable
was included to differentiate between
underground employment only, underground
and surface, and surface only.
Effect of silicosis by different decades of
diagnosis was also included. Mortality
risk from lung cancer was very strongly
elevated for smokers in this study. There
was an apparent dose-response effect, with
the lowest risk among those who smoked
one to 14 cigarettes per day (RR 19.4, 95%
CI 2.6-143.7), intermediate risk for smokers
of 15 to 24 cigarettes per day (RR 23.0,
Table 5
Stomach cancer mortality in Ontario gold miners, 1955–1986
95% CI
95% CI 3.2-167.6), and highest risk among
those smoking 25 or more cigarettes per
day (RR 32.5, 95% CI 4.4-241.2). Pipe and
cigar smokers also showed higher rates of
lung cancer mortality (RR 9.1, 95% CI 0.82-
101.1). Silicosis (RR 1.59, 95% CI 1.10-2.28)
and bronchitis (RR 1.60, 95% CI 1.09-2.33)
were associated with slightly increased risk
of death from lung cancer. The effect of a
diagnosis of silicosis decayed slightly with
time from diagnosis, but not significantly.
The strongest effect was within one year
of workers’ compensation for silicosis.
Among other considerations, only the log
cumulative exposure to silica, in exposurescore
years, was significantly related to
lung cancer (RR 1.31, 95% CI 1.01-1.70);
however, once silicosis was considered, the
significance of this finding was eliminated
(RR 1.20, 95% CI 0.92-1.56). The authors
concluded that the excess in lung cancer
mortality was restricted to miners who
had received compensation for silicosis.
This may indicate that localized immune
suppression due to silicosis leads to
increased lung cancer risk.
Hnizdo et al. studied a South African
cohort of 2260 white gold miners with an
expanded set of risk factors. 73 The 78 cases
of lung cancer identified during follow-up
between 1970 to 1986 were matched with
386 controls. They found the risk of lung
cancer to be associated with pack years
of cigarette consumption (RR 1.0 for
30 pack years), cumulative dust exposure
(RR 3.19, 95% CI:1.3-7.6 for the highest
exposure group lagged 20 years), duration
of underground mining (RR 3.36, 95% CI:
1.02-10.7 for > 20 years of work, lagged
20 years), and with silicosis (RR 2.45, 95%
CI 1.2-5.2). Since their results could not be
interpreted definitively in terms of causal
association, the authors suggest possible
interpretations for their findings: subjects
with high dust exposure who develop
silicosis are at increased risk of lung cancer,
high levels of exposure to silica dust on its
own is important in the pathogenesis of
lung cancer and silicosis is coincidental,
and high levels of silica dust exposure may
be a surrogate for the exposure to radon
daughters.
In 2003 McGlachan et. al. reported on
cancer incidence using 12.8 million manyears
of follow-up of black men who
worked in South African Gold mines
between 1964 and 1996. 74 Age-standardized
incidence ratios and crude incidence rates
for various cancers were calculated and
compared by ten geographic territories.
Although cancer of the respiratory system
was the most numerous site of cancer in the
cohort, some areas had significantly more
cases while other areas had significantly
less. For example, when compared to the
total mining cohort, the age standardized
incidence ratio (ASIR) for one territory
(Cape) is 148 (p
association between work in gold mining
and stomach cancer mortality, that there is
an association between primary stomach
cancer and place of birth in all Ontario
miners, and that there may be associations
with ethnicity, diet, smoking, alcohol consumption,
social class, socio-economic
status and other non-occupational factors.
Heller recommended: (1) a study of the
Mining Master File separated into cohorts
by year of start of mining (e.g., pre-1945,
1945-1959, 1960-1975, after 1975) to evaluate
the relationship within each cohort of
stomach cancer risk and age, stratified by
place of birth; (2) a separate occupational
hygiene study to ascertain whether a new
carcinogen really exists in Ontario gold
mines; (3) additional study of the Mining
Master File to determine the roles of
occupational and non-occupational factors;
and (4) the adoption of appropriate methods,
including case-control studies and/or
internal direct standardized comparisons,
to account for potential confounding from
non-work related factors.
Nickel
Background
Nickel-copper sulphide deposits occur
towards the base of mafic and/or ultramafic
intrusions or volcanic flows. Usually
they are the simple sulphide, pyrrhotitepentlandite-chalcopyrite,
but subtypes vary
significantly in their geological-tectonic
settings, and in the geometric form and
style of differentiation of the host magmatic
bodies. Subtypes can occur as massive
sulphides, sulphide-matrix breccias, or
disseminations of sulphides. The magmatic
hosts in most subtypes are intrusions, but
in the komatiitic subtype most are volcanic
flows. The ores of the various subtypes
display some differences in composition,
particularly in their nickle to copper
(Ni:Cu) ratios. 78
From the economic perspective, nickel is
of primary interest; copper may be a co- or
by-product, and platinum-group elements
are usual by-products. Gold, silver, cobalt,
sulphur, selenium, and tellerium may also
be recovered since they are associated
with sulphides. 78 Collectively, magmatic
nickel-copper sulphide deposits have generated
much of the world’s past and cur rent
nickel production. However, although
international reserves are large, they are
exceeded by lateritic nickel deposits – the
only other significant nickel source.
In 2003 Canada was the world’s third
leading nickel producer behind Russia and
Australia. In 2004, nickel was mined in the
provinces of Ontario, Manitoba and Quebec,
with smelters in Ontario and Manitoba,
and refineries in Ontario and Alberta. 2
Sudbury, Ontario ores merit some comment
as they represent the world’s largest single
source of nickel and are also an important
economic source of copper. 79 Other than
INCO’s open pit Whistle Mine, all modern
operations in Sudbury are underground. 80
The two major nickel mining companies in
Ontario’s Sudbury Basin are INCO Limited
(now Vale Inco) and Falconbridge Limited
(now Xstrata Nickel). The historical process
of sintering associated with smelting (hightemperature
oxidation) occurred at INCO’s
Copper Cliff and Coniston smelters in
the Sudbury regions and in the leaching,
calcining, and sintering (L,C & S) area
at the Port Colborne, Ontario refinery
which opened in 1918. 80,81 Sintering
was also undertaken at Falconbridge
Limited’s smelter in the Sudbury area.
The sintering processes were similar at
Copper Cliff (which operated from 1948 to
1963), Port Colborne (the 1920s to 1958),
Coniston (1914 to 1972), and Falconbridge
(approximately 1939 to 1978). 80 INCO
refines nickel and copper in Sudbury,
nickel, cobalt, and precious metals in Port
Colborne (nickel discontinued in 1984),
nickel to high purity at Clydach (which
has operated since 1902) in Wales, 82 and
platinum group metals at Acton in London,
England. Falconbridge primarily refines
all ores (i.e., nickel, copper, and cobalt) at
Kristiansand, Norway (which has operated
since 1910). 80,83
Nickel production has occurred in Sudbury
for more than a century. In one period,
open bed roasting formed part of the
Sudbury smelting process, utilized timber
for fuel, and released large quantities
of sulphur dioxide pollution at ground
level. By the late 1920s, this process was
contained within factories, and emissions
were vented through chimneys. In the late
1940s, the use of large magnetic separators
improved pyrrhotite separation. In the
1960s, processing steps to remove some
of the sulphur dioxide were introduced.
In 1972, the newly constructed 387 metre
INCO ‘Superstack’ smelter substantially
improved the Sudbury area air quality and
vegetation. Recent efforts have focussed on
clean-up and ore processing technologies
to enhance productivity and substantially
reduce environmental impact. 80
Studies of nickel workers
Elevated rates of lung and nasal cancers
were observed in workers in nickel refining
and preparation of nickel and copper salts
from 1929 to 1938 at the Clydach refinery
in South Wales. 82,84 This refinery began
operation in 1902 and refined nickel by
the nickel carbonyl process. The increased
rates were attributed to dusty occupations,
and/or drying and powdering of copper
sulphate, and/or exposure to sulphuric acid
which, prior to 1921, contained arsenic. 82
Later, risk was associated with process
steps prior to nickel carbonyl formation.
This risk was reported to have been
eliminated by 1930. 85,86 By 1972, 967 men
were being followed. The relative risk for
nasal sinus cancer deaths increased sharply
with increasing age at first exposure and
remained fairly constant throughout the
follow-up period; however for lung cancer,
risk of death was independent of age at
first exposure and declined sharply with
increasing time since first employment. 87
For those who commenced work at
Clydach before 1920, lung cancer mortality
was between six and 11 times the national
average. 86 This risk declined to 5.2, 2.5,
and 1.5, for those who commenced work
between 1920 and 1924, 1925 and 1929,
and 1930 and 1944, respectively. Nasal
cancer deaths, although rare, were between
300 and 700 times the national average for
those who commenced work before 1920,
about 100 times the national average for
those who started work between 1920 and
1925 and absent thereafter. With follow-up
to 1981, a large excess of lung cancer deaths
was noted in men first exposed prior to
1925, a smaller but significant risk of about
two for those first exposed between 1925
and 1929, and no subsequent excess. 88
During this time, a number of changes
were made in the refinery; arsenical
111 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
impurities were removed and respirator
pads were introduced in 1922; calciners
were altered to reduce dust emission in
1924, and after 1932, the amount of copper
in the raw material was reduced by about
90% and sulphur was almost completely
removed. Further changes in process
chemistry occurred after 1930, including
the installation of new calciners between
1931 and 1936. 87
A study of 2247 Kristiansand, Norway nickel
refinery workers who commenced work
prior to 1966, were alive on January 1 1953,
had been employed for at least three years,
and were followed from 1953 (or the middle
of the year of first employment) to 1979,
revealed an observed/expected ratio of 26.3
for cancer of the nose and nasal cavities
(21 O, 0.8 E) and 3.7 for lung cancer (82 O,
22.0 E). 89 For both cancers, increased risk was
observed for those employed in processing
versus non-processing departments, using
department of longest work to categorize
workers. Both lung and nasal cancer risks
were elevated for workers first employed
before 1960. For both cancers, excess risk
declined with each successive cohort, with
nasal cancer risk much lower for those
first employed near 1960 versus 1930.
A case-control study was conducted on the
island of New Caledonia, where a nickel
refinery is located. 90 Sixty-eight lung cancer
cases (almost all of whom were dead)
were identified from a chart review at a
hospital, and 109 cancer-free controls were
identified through the hospital’s laboratory.
After controlling for age, nickel occupation
(RR 3.0, p
it is unknown which species of nickel the
workers were exposed to. The author noted
that the statistical power of this study was
low due to small sample sizes and there
was a lack of historical measurements
which could have led to misclassification.
Finnish workers with nickel exposure were
studied by Annila et al. 95 One thousand
three hundred and thirty-nine men and
49 women working at the copper/nickel
smelter and refinery between 1960-1985
in Harjavalta, Finland were included in the
study with follow-up to the end of 1995.
Workers were divided according to their
exposure to nickel (employees working
before 1960 would not have been exposed
to nickel as there was no nickel smelting
before that time), job site, and duration
of employment. Overall rates of cancer
incidence were at the expected levels for
workers unexposed and exposed to nickel
with the exception of cancer of the nose and
sinuses in nickel exposed workers, which
was higher than expected (SIR% 879, 2 O,
0.2 E, 95% CI: 106-3170). When examining
a latency of 20 years, nickel exposed
workers again had increased incidence
of cancer of the nose and sinuses (SIR%
1590, 2 O, 0.1 E, 95% CI: 192-5730) and
cancers of the lung and trachea (SIR% 212,
20 O, 9.4 E, 95% CI: 129-327). The only
significant increase in cancer incidence in
nickel exposed smelter workers was lung
and trachea cancer with a 20 year latency
(SIR% 200, 13 O, 6.5 E, 95% CI: 107-342). For
nickel exposed refinery workers, stomach
cancer (SIR% 498, 5 O, 1 E, 95% CI: 162-
1160) and cancers of the nose and sinuses
(SIR% 411, 2 O, 0.05 E, 95% CI: 497-1480)
were elevated and when examining both
5 year and 20 year latency periods, all cancer
sites, stomach, and nose and sinus
cancer were elevated. The authors state
that the refinery workers had exposures
to soluble nickel sulfate while the smelter
workers had only sparingly exposure to
soluble nickel compounds which is the
most likely explanation of the increased
lung and nasal cancers in the refinery
workers. They also suggest that the two
groups would have similar smoking habits
so tobacco exposure could be ruled out as
the reason for the increase in the refinery
workers.
In 2001, Egedahl et al. released the results
of a study that was done on Sherritt
International hydrometallurgical nickel
refinery and fertilizer workers from
Fort Saskatchewan, Alberta. 96 There were
1649 male workers included in the cohort
who worked at least 12 months between
1954 and 1978 with follow-up until the end
of 1995. Work done at this facility between
1954-1976 involved nickel-copper-cobalt
sulfide ore mined from Manitoba. When
compared to the Canadian population, this
group of workers experienced a significantly
lower that expected mortality (SMR% 66,
183 O, 275.6 E, 95% CI: 57-77) and when
examining only the workers who had nickel
exposure (nickel concentrate and metallic
nickel) results were also significantly lower
than the Canadian population (SMR% 57,
59 O, 103.2 E, 95% CI: 43-74). The only
cause of death that was significantly
increased for all workers was cancer of
the pleura (SMR% 1135, 2 O, 0.1E, 95%
CI: 127-4097) and no cause of death was
significantly higher for workers with
nickel exposure. The authors stated that
the decrease in mortality could partially
be explained by the healthy worker effect
and the results from the nickel exposed
workers are consistent with other studies
which examined similar nickel exposures
and workers.
Workers at Clydach nickel refinery were
again studied for cancer incidence and
mortality by Sorahan and Williams. 97
Detailed work histories of 812 men with at
least five years of work experience between
1953-92 were examined by numerous
variables, such as the predominant species
of nickel exposure. For the entire cohort,
there was no significant excess of mortality
for all deaths, for any specific cause of
death, or for cancer mortality. When
period from commencing employment was
analysed, there was a significant increase
of lung cancer mortality in those workers
who had the latest follow-up period of over
30 years (SMR% 186, 16 O, 8.6 E, 95% CI:
106-301). Nickel species exposure analysis
revealed that employees in feed handling
and nickel extraction (oxide/metalic nickel)
had a significantly increased risk of lung
cancer, although there was no significant
heterogeneity in either set of SMRs and
this SMR was not significantly different
from the overall SMR for lung cancer
of 139 (p= 0.18). The smoking status of
417 employees was known and it revealed
a significant increase in lung cancer (SMR%
236, 16 O, 6.8 E, 95% CI: 135-383). From
their analysis, the authors conclude that
patterns of mortality are more likely due
to various selection effects, socioeconomic
gradients, regional effects, and lifestyle
factors than occupational exposures.
A number of studies have been published
by of group of researchers working out
of the Cancer Registry of Norway and
Falconbridge Nikkelverk. 98-100 Grimsrud et.
al. 98 conducted a nested case-control study
from within a cohort of 5389 men who
had been employed at the nickel refinery
in Kristiansand, Norway for at least one
year between 1910 and 1994. Two hundred
and twenty-seven lung cancer cases
were identified by the Cancer Registry of
Norway between 1952 and 1995 (13 did
not participate in the interview) and
525 controls were age-matched from the
cohort. The dose-related associations
between lung cancer and cumulative exposure
to different forms of nickel (soluble,
sulfuric, metallic, and oxidic) were examined
using a job-exposure matrix. Soluble
nickel was found to have the strongest
effect, with an odds ratio of 3.8 (95% CI:
1.6-9.0) for the highest cumulative exposure
category. When they plotted the log
risk by median exposure, it suggested a
curvilinear relation for soluble nickel.
When adjusting for smoking and watersoluble
nickel exposure, other forms of
nickel did not produce significant effects or
relationships, however, there were elevated
odds ratios for sulfidic and oxidic nickel.
The authors noted that there was potential
for misclassification of the exposure data
prior to 1973 as there was no personal
monitoring at that point.
Lung cancer risk by duration of employment
and by exposure to different nickel forms
was again reported by Grimsrud et al.
in 2003. 99 A cohort of 5297 men who
worked at the Norwegian nickel refinery
between 1910 and 1989 and were alive
and residing in Norway after January 1953
were included in the study. Work histories
were examined for employment in selected
groups of departments and for the duration
113 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
of work. A job-exposure matrix was used
to assign nickel exposures. Overall lung
cancer incidence during the period from
1952-2000 was higher than expected (SIR%
260, 267 O, 104 E, 95% CI:230-290), with
those employed between 1910 and 1929
having the highest SIR of 480 (17 0, 3.5 E,
95% CI: 280-760). Men who ever worked
in either copper or nickel electrolysis
departments had an increased SIR% of
350 and 400, workers from the roasting
department had a SIR% of 340 (95% CI:
230-480), smelter workers had a SIR% of
270 (95% CI: 210-360), and maintenance
workers had a SIR of 240 (95% CI: 180-
300). Restricting analysis to 15 years or
more of work experience in a department
resulted in increased SIRs for lung cancer.
Copper and nickel electrolysis workers with
15 years of work experience had an SIR%
of 600 combined (95% CI: 420-830), while
those with more than 15 years of smelter
or roaster employment had a SIR% of 330
(95% CI: 180-560). Increasing cumulative
exposure to water-soluble nickel was found
to increase risk of lung cancer, as well as
increasing cumulative exposure to total nickel.
Many studies have been performed on
nickel workers employed at Sudbury in
northeastern Ontario and at Port Colborne
in southwestern Ontario. Our summary of
this work emphasizes the findings for the
underground component of the workforce,
and where multiple analyses have been conducted
we highlight the most recent results.
Shannon et al. examined multiple causes
of death in a cohort 11,567 nickel workers
who had worked at least six months
at Falconbridge’s Sudbury operations
between 1950 and 1976. 101 The followup
of the cohort extended from 1950 to
1984. Limited occupational hygiene data
were used. Konimeter counts (measuring
dust in particles per cubic centimetre)
were used sporadically before 1960 and
semi-annually from 1960 to 1984. Some
gravimetric sampling data that measured
total dust in milligrams per cubic metre
were available from 1978 onwards. Some
side-by-side sampling was conducted for
comparison purposes. Regression was used
to convert konimeter counts to gravimetric
measures. During periods of limited or
absent data, a best estimate was obtained
by considering work practices, ventilation,
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
and production. It was assumed that nickel
species occurred in respirable dust in the
same proportions as in the material being
handled in the various work areas. Average
nickel concentrations in the mines from
1933 to 1978 by department (worksite)
were very low (0.02 mg/m 3 ); they averaged
0.03 to 0.04 mg/m 3 in the mills and 0.22
mg/m 3 in the sinter plant. Estimated levels
of various nickel species and work history
data were used to calculate cumulative
exposures by multiplying the number of
years at a given exposure level of a nickel
compound by the estimated concentration.
Changes in job or concentration were taken
into account by summing the cumulative
exposures for each worker in the different
jobs.
The cancers studied included: lip, oral
cavity and pharynx; respiratory system;
nasal, etc; larynx; trachea, bronchus and
lung; bone and articular cartilage; male
genitourinary organs; prostate; kidney;
lymphatic and hematopoietic; leukemia;
and cancers of other sites. There were 1398
deaths in the cohort with 1289.3 expected
(SMR% 108, 95% CI 103-114, p
Non-sinter plant workers in the Sudbury
area who had worked 15 or more years
since first exposure displayed a lung cancer
SMR% of 112 (95% CI 103-123, p=.006, 485 O,
433.27 E); the authors considered this
excess to be largely attributable to mining
(SMR% 111, p
employment, and 171 (95% CI 122-233)
for those with 35 or more years duration
of employment.
A sizeable risk of nasal and sinus cancer
was detected in Copper Cliff sinter plant
workers who were first exposed before 1952
and in Port Colborne’s LC&S department.
The overall nasal and sinus SIR% for the
Copper Cliff sinter plant was 2004 (95%
CI 1067-3427, 13 O, 0.649 E) and for
Port Colborne’s LC&S department was
2656 (95% CI 1518-4312, 16 O, 0.603 E).
Statistically significant but less dramatic
risks for nasal and sinus cancer were seen
in INCO smelter workers (SIR% 217, 95%
CI 116-371, 13 O, 5.99 E). Risk among
transportation and maintenance subgroups
was elevated, but not significantly (SIR%
213, 95% CI 92-420, 8 O, 3.75 E), although
this may have resulted from inappropriate
job classification for some workers.
Julian and Muir suggested that additional
research was warranted to provide an
explanation for several excess risks
observed in exploratory analyses. An SIR%
of 157 (95% CI 88-259, 15 O, 9.55 E)
was observed for oral cancer in the Port
Colborne LC&S department. The SIR% for
esophageal cancer risk in the INCO Copper
Cliff copper refinery was 263 (95% CI 136-
460, 12 O, 4.56 E). INCO underground
miners with 30 to 34 years duration of
employment had an SIR% of 161 (95%
CI 120-213, 50 O) for colorectal cancer.
The broadly-defined group of hourly-rated
workers and foremen in INCO mining
transportation and maintenance (including
electrical) displayed an unusual prostate
cancer finding (SIR% 114, 95% CI 89-144,
70 O, 61.61 E); the value was 253 (95% CI
142-417, 15 O, 5.93 E) for those with 25 to
29 years of exposure, and 201 (95% CI 130-
296, 25 O, 12.45 E) for those with at least
25 years of exposure. In the Falconbridge
and Coniston sinter plants, an SIR% of
164 (95% CI 97-259, 18 O, 10.97 E) was
detected for bladder cancer; workers with
10 or more years of exposure had an SIR%
of 389 (95% CI 106-995, 4 O, 1.03 E). In the
INCO copper refinery tankhouse, the SIR%
for brain cancer was 366 (95% CI 158-721,
8 O, 2.19 E) for workers with 10 or more
years since first exposure, and 472 (95% CI
173-1028, 6 O, 1.27 E) for those exposed for
more than one year.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
Julian and Muir indicated that some of the
associations detected in their study were
likely work-related (e.g., in workers with
over 25 years of exposure, the fourfold
risk of laryngeal cancer in millers, and
laryngeal and lung cancer in underground
miners). However, their criteria for determining
work-relatedness were unclear.
The authors acknowledged that, since
historical exposure intensities of specific
contaminants were not used, they could
only speculate as to the specific causes
of increased risks that they considered to
be work-related. In their summary, they
also highlighted the very high risk of nasal
and sinus cancer in the Copper Cliff sinter
plant for workers first exposed before 1952,
and in Port Colborne’s LC&S department.
Some have expressed genuine concern
regarding the combination of the INCO and
Falconbridge cohorts, given the necessary
assumptions made about the similarity
of exposures and working conditions for
similar job titles, departments, and time
periods in the two companies.
Discussion
The International Committee on Nickel
Carcinogenesis in Man, chaired by Sir
Richard Doll, first met in 1985 to clarify
the cancer risk associated with nickel.
In 1989 the Committee prepared a report
summarizing the results from ten nickel
cohorts, of which the Ontario cohorts were
the largest. 104
The committee concluded that, given the
large respiratory cancer excesses primarily
detected in electrolysis workers in the
Kristiansand refinery in Norway, there was
strong evidence that exposure to soluble
nickel was associated with increased
respiratory cancer risk. For the electrolysis
workers, estimated ambient concentrations of
soluble nickel ranged from 1 to 5 mg Ni/m 3 ,
with some concentrations exceeding 5 mg
Ni/m 3 , and small (< 1 mg Ni/m 3 ) airborne
concentrations of oxidic and sulphidic
nickel. Lung cancer risks in nickel refinery
workers were strongly associated with
increasing duration of exposure to soluble
nickel; men with greater than ten years
exposure displayed nearly three times the
lung cancer risk of those without nickel
exposure. At the Clydach refinery, the association
between soluble nickel exposure
116
and lung cancer risk in hydrometallurgy
workers was weaker, but it was felt that
soluble nickel at Clydach had some role in
enhancing risk associated with exposure
to other nickel compounds. Men with high
levels of cumulative exposure to sulphidic
nickel and soluble nickel had higher lung
cancer risks than those exposed to similar
amounts of sulphidic nickel but lower levels
of soluble nickel. The amounts of insoluble
material encountered in the Kristiansand
electrolysis department was considered to
have been seven times greater than at the
Port Colborne refinery, although soluble
nickel levels were probably similar. Results
from men working at the Clydach and
Kristiansand refineries provided evidence
that soluble nickel exposure can lead to
increased nasal cancer risk.
The role of sulphidic nickel exposure
in lung and nasal cancer risk observed
in the refineries was unclear, as high
concentrations of sulphidic nickel were
found in association with high levels of
other nickel species, including oxidic and
soluble nickel. Some of the highest lung
and nasal cancer risks were observed in
Copper Cliff sinter plant workers, Port
Colborne LC& S workers, and Clydach
linear calcining workers, where exposures
to sulphidic nickel were extremely high, but
oxidic nickel levels were also highest and
soluble nickel may also have been present
at high (> 5 mg Ni/m 3 ) concentrations.
The committee indicated that:
Although the miners exposed to low
levels of sulphidic nickel in mineral
form (pentlandite and pyrrhotite) at
the INCO and Falconbridge mines
in Ontario had an increased lung
cancer risk...evidence of increased
lung cancer among other Canadian
hardrock miners with no exposure to
nickel suggests that the risks may not
be attributable to nickel exposure.
Some evidence was presented to indicate
that exposure to oxidic nickel might result
in increased lung and nasal cancer risks.
Kristiansand roasting, smelting, and calcining
workers, thought to have been
exposed mainly to oxidic nickel, displayed
some evidence of increased lung cancer
isk, but the magnitude of the excess
and association between duration of
exposure and risk was not strong. There
was some evidence that lung cancer risks
in the Kristiansand roasting, smelting,
and calcining workers decreased with
reductions in atmospheric oxidic nickel
levels related to refinery process changes.
Men at Clydach with cumulative exposure
to oxidic nickel of > 50 mg/m 3 displayed
elevated lung cancer risks when compared
to those with lower exposures; and those
who worked in the Clydach copper
plant, where oxidic nickel concentrations
were over 10 mg/m 3 , displayed strongly
increased lung and nasal cancer risks.
Whether this was due to oxidic or soluble
nickel, or their combination was unclear.
In addition, there was some evidence of an
association between oxidic nickel exposure
and nasal cancer risks. At Clydach, nasal
cancer occurred in men with greater than
15 years exposure to high levels of oxidic
nickel in furnace operations and less than
one year in other areas with high levels of
sulphidic or soluble nickel. At Kristiansand,
five of seven nasal cancer cases occurred in
long-term roasting, smelting, and calcining
workers with highest (> 90th percentile)
cumulative exposures to oxidic nickel. The
data did not permit separate risk estimation
for nickel-copper-oxide versus oxidic nickel
forms that were copper-free.
Of the studies examined, only the Oak
Ridge Gaseous Diffusion Plant workers
were exposed to metallic nickel alone at
low levels (< one mg Ni/m 3 ) and did not
provide evidence of increased respiratory
cancer risk. In the refinery cohorts, exposure
to metallic nickel was mixed with
exposure to other forms of nickel, but
analyses of lung and nasal cancer mortality
cross-classified by cumulative exposure to
metallic nickel at Clydach and Kristiansand
yielded no evidence of increased lung
or nasal cancer risk with exposure to
metallic nickel.
The International Committee observed that
more than one form of nickel may result in
the development of lung and nasal cancers.
Most of the excess risk of respiratory
cancer observed in refinery workers was
attributed to exposure to a mixture of
oxidic and sulphidic nickel at very high
concentrations, although increased risk
was also associated with exposure to large
concentrations of oxidic nickel without
sulphidic nickel. Soluble nickel exposure
increased the risk of lung and nasal cancers
and might enhance the risk associated
with exposure to less soluble types of
nickel. There was no evidence that metallic
nickel was associated with increased lung
and nasal cancer risk and no substantial
evidence that occupational exposure to
nickel or any of its compounds was likely
to produce cancers other than lung and
nasal cancers. No excesses of any type of
cancer were observed in cohorts that did
not display an excess of lung and nasal
cancers. The preponderance of evidence
for increased lung and nasal cancer risks in
refinery workers exposed to large amounts
of nickel species in processes used in the
past was noted.
The Committee concluded that respiratory
cancer risks are primarily related to exposure
to soluble nickel at concentrations
exceeding 1 mg Ni/m 3 and to exposure to
less soluble forms at concentrations over
10 mg Ni/m 3 . Examination of men exposed
to a variety of nickel species provided no
definitive evidence of increased cancer risk
associated with exposure to metallic nickel,
oxidic nickel or sulphidic nickel (i.e.,
insoluble nickel) at concentrations under
1 mg Ni/m 3 . Soluble nickel concentrations
close to 1 mg Ni/m 3 resulted in increased
lung and possibly increased nasal cancer
risks. Additional research was recommended
to generate quantitative dosespecific
estimates of risk.
The committee also concluded that, as
excess risks were confined to high levels
of exposure coupled with the absence of
hazard from metallic nickel, the general
population risk that would occur at
extremely small concentrations in ambient
air (under 1 µg Ni/m 3 ) would be minute, if
any. The Committee recognized the value
of obtaining additional information, such as
animal carcinogenesis studies and studies
of nickel carcinogenesis mechanisms to
enhance our understanding of human
health risks associated with nickel.
Two other groups have drawn conclusions
from the evidence at hand. The Nordic Expert
Group for Criteria Documentation of Health
Risks from Chemicals concluded that:
Inhalation exposure to soluble nickel
and nickel oxides/sulphides has
caused nasal and pulmonary cancer in
workers in nickel refineries. . . . In nickel
refineries, exposure to approximately
0.1 mg/m 3 soluble nickel salts, and
approximately 1 mg/m 3 nickel oxides/
sulphides seem to involve cancer
hazard, whereas for metallic nickel
dust, there are no convincing data on
carcinogenicity in humans. Exposure
to nickel or nickel compounds via
routes other than inhalation has not
been shown to increase the cancer risk
in humans. 50
This group also recommended further
research, in particular, epidemiological
studies on population groups with defined
qualitative and quantitative exposures, and
basic research into the mechanisms of nickel
carcinogenesis (using experimental systems
of relevance for human carcinogenesis) at
levels of nickel that human cells may have
experienced during occupational exposure.
The World Health Organization concluded
that although some, and possibly all, forms
of nickel may be carcinogenic, there is little
or no detectable risk in most sectors of the
nickel industry at current exposure levels. 39
Some past processes were associated with
very high lung and nasal cancer risks.
Long-term exposure to soluble nickel at
concentrations around 1 mg/m 3 may cause
a marked increase in lung cancer risk, but
the relative risk among workers exposed
to average metallic nickel levels at about
0.5 mg/m 3 is about unity. The cancer risk
at a particular exposure level may be higher
for soluble nickel compounds than for
metallic nickel and perhaps other forms.
The IARC classifies nickel compounds
as carcinogenic to humans, and metallic
nickel as a possible human carcinogen. 38
Copper
Background
The Sudbury nickel-copper ores and numerous
volcanogenic massive sulphide deposits
across the country represent important
sources of Canadian copper. Some aspects
117 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
of nickel-copper-sulphide deposits have
been addressed in the nickel section, above.
Porphyry copper deposits (i.e., deposits of
disseminated copper minerals in or around
a sizeable body of intrusive rock) 3 represent
the world’s most important source of
copper, but less than 50% of Canadian
copper production and about 60% of copper
reserves. 105 Skarn (i.e., metamorphic rocks
surrounding an intrusive where it contacts
a limestone or dolostone formation) 3 and
vein (i.e., a fissure, fault or crack in a rock
filled by minerals that have travelled up
from a deep source) deposits also represent
significant production sources. 105
In 2003, Canada was ranked as the world’s
eighth leading producer of copper, trailing
Chile, the United States, Indonesia, Peru,
Australia, Russia and China. Copper
was mined in New Brunswick, Quebec,
Ontario, Manitoba, Saskatchewan and
British Columbia, with primary smelters
located in Quebec, Ontario and Manitoba,
and with refineries in Quebec, Ontario and
British Columbia. 2
Studies of copper workers
Tokudone and Kuratsune examined cancer
risk in 839 copper smelter workers who
were part of a larger cohort of 2675 Japanese
male smelter workers (both retirees and
current workers employed for at least one
year as of August 1, 1971). 106 Men who
lived outside the study area and those
with less than one year of service before
the end of 1971 were excluded from the
study. The copper smelter workers had
belonged to the copper smelting section for
at least one year, and some also had lead
smelting experience. One hundred fiftyseven
deaths occurred among the copper
smelter workers. Lack of quantitative data
on arsenic and other smelting exposures
led to an approximate categorization of
exposure, which was then used to subdivide
this cohort into a number of subgroups.
Sub-groups were also defined
by length of employment in the smelter.
Comparison cohorts were ferro-nickel
smelting workers (n=268; six deaths),
maintenance and transportation workers
(n=821; 108 deaths), copper or lead
electrolysis or sulphuric acid production
workers (n=389; 22 deaths) and clerical
workers (n=358; 32 deaths).
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
Fifty-five deaths from malignant neoplasms
were observed among the copper smelter
workers, whereas 28.82 were expected
(SMR% 191, p=.01). Excess mortality in
this cohort was seen for large intestine
cancer (except rectum) (SMR% 508, p=.05,
3 O, 0.59 E), liver (primary, secondary
and unspecified) and biliary passage
cancer (SMR% 337, p=.01, 11 O, 3.26 E),
and cancer of the trachea, bronchus and
lung (SMR% 1189, p=.01, 29 O, 2.44 E).
Significantly elevated lung cancer SMR%s
were also observed in all of the copper
smelter sub-cohorts, with a distinct positive
gradient for exposure level, length of
employment and time period of exposure.
Workers exposed for 15 years or more
before 1949 had a much higher mortality
risk than others (SMR% 2048, p=.01, 17 O,
0.83 E). Bearing in mind the small observed
numbers in the sub-groups, mortality risk
among pre-1949 workers was also found to
be closely associated with exposure level,
with risk ratios of 25, 28 and 14 in heavy,
moderate and lightly exposed categories.
The latency period for lung cancer was
37.6 years on average.
After World War II, copper production
dropped, production methods changed,
and the ore came from a source containing
far less arsenic. In the post-1949 group,
mortality was higher for workers with
15 or more years of exposure than for those
with less experience, but did not display
the same mortality gradient with exposure
level. Of the 29 copper smelter workers who
died from lung cancer, 28 began smelting
work before 1949.
The authors concluded that arsenic compounds
and sulphur dioxide were probably
responsible for the excess lung cancer
mortality in copper smelter workers,
although they also noted that polycyclic
aromatic hydrocarbons may have been
involved. The liver and biliary passage
cancers were mainly unspecified, and
without diagnostic validity. Tokudone and
Kuratsune also noted, with some surprise,
the lack of skin cancer deaths, expected to
be higher due to arsenic exposure. They
postulated that the favourable prognosis for
this cancer may have minimized mortality.
118
Ahlman et al. presented the lung cancer
mortality of a male cohort which included a
copper mine and a zinc mine in Finland. 107
An excess was reported for each mine, the
total was statistically significant compared
to Finnish men but not compared to the
regional comparison (10 O, 4.3 E, p
was introduced, and ventilation improved,
reducing the amount of ambient dust. The
authors noted that this may explain the
lower lung cancer risk among those who
mined copper after the 1950s.
Chen et al. considered radiation exposure
an unlikely contributor to the excess lung
cancer mortality in copper miners because
radiation in the sites measured (1.29,
standard deviation 0.55, x 10 11 Curies/
litre) was below accepted thresholds (3 x
10 11 Curies/litre). Secondly, the increase in
the SMR% for lung cancer was restricted
mainly to drilling miners. Given the
excess among drilling miners and miners
employed in the 1950s who were exposed
to more dust, the authors felt that attention
should be concentrated on suspected
human carcinogenic ore components.
Components present in the ore under
study, in decreasing quantity, were silica,
iron, copper, manganese, arsenic, titanium,
and sulphur. Arsenic concentrations were
quite low (0.061%), leading the authors
to exclude it from consideration as an
important lung cancer carcinogen among
these workers; silica and iron were not
ruled out. The possible role of smoking
among these miners was largely discounted,
primarily because of the high prevalence
of smoking in the male population. A
possible interaction between smoking and
other occupational risk factors could not
be excluded, however, and the authors are
considering this in a further case-control
study. 108
Viren and Silvers examined cohort data
from various copper smelter cohorts in
Washington State, Sweden and Montana
to develop unit risk estimates for airborne
arsenic exposure. 109 A pooled estimate was
obtained by combining cumulative exposure
to airborne arsenic and lung cancer
mortality data from all of the studies examined.
Unit risk was defined as the excess
probability of developing lung cancer, given
continuous atmospheric exposure to 1 µg/m 3
of arsenic over a lifetime. This value
represents the best estimate for projecting
excess lung cancer risk in the general
population. The unit risk value for chronic
lifetime exposure to airborne arsenic determined
by Viren and Silvers was 1.43 x 10 -3 .
They emphasized the value of complete
and adequate exposure assessment when
developing quantitative estimates from
epidemiological data. Detailed exposure
reconstruction was considered valuable in
resolving uncertainties in future analyses.
They also advocated clarification of the
association between arsenic levels measured
in workers’ urine and airborne arsenic, in
order to evaluate the relationship between
inorganic arsenic and cancer of other
sites. The roles of other sources of arsenic
exposure and possible confounders could
be examined in future case-control studies.
Lubin et al. updated the analysis of 8014
white male workers employed at a Montana
copper smelter from 1938 to 1989. 110 A
significantly increased SMR was observed
for respiratory cancer (SMR = 1.55, 95%
CI 1.41-1.70). Analyses with an internal
reference group revealed a significant,
linear increase in the excess relative risk of
respiratory cancer with increasing exposure
to inhaled airborne arsenic. The estimate of
the excess relative risk per mg/m 3 -year was
0.21/(mg/m 3 -year) (95% CI 0.10, 0.46).
In an update of an earlier study, Enterline
et al. examined cancer and other types of
mortality in a small cohort of 2802 men in
Washington state who had worked in the
copper smelter for a year or more between
1940 and 1964. 111 The copper smelter had
operated from 1913 to 1984. The followup
period was from 1941 to 1986 for
cancers and from 1960 to 1986 for other
causes of death. In total, there were 1583
deaths, 395 of which were from cancer.
Arsenic exposure was estimated from
departmental measurements of arsenic,
mostly from departments where arsenic
was thought to be problematic. These
data were published in company annual
reports from 1938 onwards. Measurements
of urinary arsenic, offered to all workers,
commenced in 1948. Arsenic air data were
derived from spot and tape samples before
1971 and from personal samples from 1971
onwards. An exposure matrix of arsenic in
air was developed by department and year
from 1938 to 1984. Job histories for each
worker were combined with arsenic data to
calculate cumulative exposure (µg/m 3 /yr)
per worker. This exposure matrix included
categories of
etween airborne arsenic and respiratory
cancer was unusual. In the authors’
estimation, air measurements may not be
adequate measures of biological dose. They
considered that the relation was not likely
due to confounding by factors such as
smoking, however this required additional
investigation. In addition, they indicated
that the bone cancer excess may be
important, since arsenic is stored in bone.
Chen studied various forms of mortality
among 7031 subjects who had worked at a
copper mine in China for at least one year
between January 1, 1969 and June 30, 1985.
The follow-up period was from 1970
to 1992. There were 1121 deaths in the
cohort and 799.81 were expected. All sites,
esophogeal, stomach, liver and lung cancer
were considered. 112 Statistically significant
excesses of cancer mortality were observed
for all cancer sites (SMR% 129, p
from the engineering perspective, as well
as how processes and exposures have
changed over time.
A large number of studies have been
reviewed. The strongest designs are those
with adequate measures of exposure and
those with suitable control populations
or suitable control for smoking and other
carcinogens.
References
1. The Mining Association of Canada. What
metals and minerals mean to Canadians.
Don Mills (Ontario):The Northern Miner;
1997.
2. Natural Resources Canada. Canadian
Minerals Yearbook. Ottawa: Canadian
Government Publishing; 2004. Available at:
http://www.nrcan-rncan.gc.ca/mms-smm/
busi-indu/cmy-amc-eng.htm
3. Whyte J, Brockelbank T, Cooke JS. Mining
explained. Don Mills (Ontario): The
Northern Miner; 1996.
4. Udd, John E. A century of achievement:
the development of Canada’s minerals
industries. Montreal: Canadian Institute of
Mining, Metallurgy and Petroleum; 2000.
5. The Mining Association of Canada. Towards
Sustainable Mining Progress Report 2005.
Available at: http://www.mining.ca/www/
media_lib/TSM_Publications/TSM_Progress_
Report_2005/TSM_05_Report_ENG.pdf
6. Gebel T. Arsenic and antimony: comparative
approach on mechanistic toxicology
[review]. Chem Biol Interact 1997;
107:131–44.
7. Wang Z, Rossman TG. The carcinogenicity of
arsenic. In: Toxicology of metals. Chang KW,
Magos L, Suzuki T, editors. Boca Raton:
CRC Press; 1996. p. 221–9.
8. World Health Organization. Environmental
health criteria. 18. Arsenic. Geneva: World
Health Organization; 1981.
9. Lisella RS, Long KR, Scott HG. Health
aspects of arsenicals in the environment.
J Environ Health 1972;34: 511–8.
10. Strohrer G. Arsenic: opportunity for risk
assessment. Arch Toxicol 1991;65:525–31.
11. Bates MN, Smith AH, Hopenhayn-Rich C.
Arsenic ingestion and internal cancers:
a review. Am J Epidemiol 1992;135:462–76.
12. Chen CJ, Kuo TL, Wu MM. Arsenic and
cancers. Lancet 1988;1:414–5.
13. Tseng WP. Effects and dose-response
relationships of skin cancer and blackfoot
disease with arsenic. Environ Health
Perspect 1977;19:109–19.
14. IARC. 1999. IARC Website: http://
monographs.iarc.fr/ENG/Classification/
index.php
15. Steenland K, Stayner L. Silica, asbestos,
man-made mineral fibres, and cancer.
Cancer Causes Control 1997;8:491–503.
16. International Agency for Research on
Cancer. Silica, Some Silicates, Coal Dust and
para-Aramid Fibrils. In: IARC Monographs
on the evaluation of carcinogenic risks to
humans Vol. 68. Lyon, France: IARC; 1997.
17. Saffioti U. Lung cancer induction by
crystalline silica. In: D’Amato R, Slaga T,
Farland W. et al., editors. Relevance of
animal studies to the evaluation of human
cancer risk. New York (NY): Wiley-Liss;
1992. p. 51–69.
18. McDonald C. Silica, silicosis and lung
cancer, an epidemiologic update. Appl
Occup Environ Hyg 1995;10:1056–63.
19. Gee JB, Mossman BT. Mechanisms of
pathogenicity by crystalline silica. In:
Morgan WKC, Seaton A, editors. Basic
mechanisms in occupational lung diseases
including lung cancer and mesothelioma.
Occupational Lung Diseases. 3rd ed.
Philadelphia: W.B. Saunders Company;
1995. p. 215–6.
20. Davis JMG. In vivo assays to evaluate the
pathogenic effects of minerals in rodents.
In: Guthrie GD, Mossman BT, editors.
Health effects of mineral dusts. Reviews
in Mineralogy. Mineralogical Society of
America, 1993. p. 471–88.
21. Samet JM. Diseases of uranium miners
and other underground miners exposed to
radon. In: Rom WN, editor. Environmental
and occupational medicine. 2nd ed. Toronto:
Little, Brown and Company; 1992.
p. 1085–91.
22. Cohen M, Bowser H, Costa M.
Carcinogenicity and genotoxicity of lead,
beryllium, and other metals. In: Chang LW,
Magos L, Suzuki T, editors. Toxicology
of metals. Boca Raton: CRC Lewis; 1996.
p. 253–84.
23. Kazantzis G. Role of cobalt, iron, lead,
manganese, mercury, platinum, selenium,
and titanium in carcinogenesis. Environ
Health Perspect 1981;40:143–61.
24. Jensen AA, Tuchsen F. Cobalt exposure
and cancer risk. Crit Rev Toxicol 1990;
20:427–37.
25. Steinhoff D, Mohr U. On the question of
a carcinogenic action of cobalt-containing
compounds. Exp Pathol 1991;41:169–74.
26. Domingo JL. Cobalt in the environment and
its toxicological implications. Res Environ
Contam Toxicol 1989;108:105–32.
27. Elinder CG, Friberg L. Cobalt. In: Friberg L,
Nordberg GF, Vouk V, editors. Handbook
on the toxicology of metals. Vol 2, 2nd ed.
Amsterdam: Elsevier; 1986. p. 211–32.
28. Lundgren KD, Ohman H. Pneumoconiose
in der hametallindustrie. Virchows Arch
1954;325:259.
29. Bech AO, Kiplind MD, Heather JC. Hard metal
disease. Br J Ind Med 1962;19:239–52.
30. Alexandersson R, Hogstedt C.
Duosorsaker hos hardmetallarbetare
[abstract]. In: Nordiska Arbetsmiljo Motet
1987;25:27–33.
31. Alexandersson R, Hogstedt C. Dodlighteten
hos manliga harmetalarbetare
Arbetmiljofondens Projekt Nr. 82-0846.
Stockholm: Slutrapport; 1988.
32. Hogstedt C, Alexandersson R. Mortality
among hard-metal workers in Sweden. Scand
J Work Environ Health 1987;13:177–8.
121 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
33. Hogstedt C. Identification of cancer risks
from chemical exposure: an epidemiologic
program at the Swedish National Institute
of Occupational Health. Scand J Work
Environ Health 1988;14 (Suppl 1):17–20.
34. Steenland K, Brown D. Mortality study
of gold miners exposed to silica and
nonasbestiform amphibole minerals: an
update with 14 more years of follow-up.
Am J Ind Med 1995;27:217–29.
35. Merchant B. Gold, the noble metal and
the paradoxes of its toxicology. Biologicals
1988;26:49–59.
36. Rapson WS. Skin contact with gold and gold
alloys. Contact Dermatitis 1985;13:56–65.
37. Gerhardsson L, Skerfving S. Concepts on
biological markers and biomonitoring for
metal toxicity. In: Chang LW, Magos L,
Suzuki T, editors. Toxicology of metals.
Boca Raton: CRC Lewis; 1996. p. 81–107.
38. International Agency for Research on
Cancer. Chromium, nickel and welding.
In: IARC Monographs on the evaluation
of carcinogenic risks to humans. Vol. 49.
Lyon: IARC 1990.
39. World Health Organization. Nickel,
International Program on Chemical Safety
(IPCS). Environmental Health Criteria 108.
Geneva: WHO; 1991.
40. Oller AR, Costa M, Oberdorster G.
Carcinogenicity assessment of selected
nickel compounds. Toxicol Appl Pharmacol
1997;143:152–66.
41. Snow ET. Metal carcinogenesis: mechanistic
implications. Pharmacol Ther 1992;
53:31–65.
42. Coogan TP, Latta DM, Snow ET, et al. Toxicity
and carcinogenicity of nickel compounds.
Crit Rev Toxicol 1989;19:341–84.
43. Costa M. Molecular mechanisms of nickel
carcinogenesis. Annu Rev Pharmacol
Toxicol 1991;31:321–37.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
44. Sunderman FW, Jr. Carcinogenicity of nickel
compounds in animals. In: Sunderman FW,
Jr., editor. Nickel in the human environment.
Lyon: IARC Scientific Publication; 1984.
p. 127–42.
45. USEPA. Health effects documents on
nickel. Vol. 32. Ontario: Ontario Ministry
of Labour; 1986.
46. Julian JA, Muir DCF. A study of cancer
incidence in Ontario nickel workers.
Unpublished final report to Occupational
Diseases Panel, Province of Ontario.
January 15, 1996.
47. Christie NT, Tummolo DM, Klein CB, et al.
Role of Ni(II) in mutation. In: Nieboer E,
Nriagu JO, editors. Nickel and human
health. Current Perspectives. New York:
John Wiley & Sons; 1992. p. 305–17.
48. Miura T, Patierno SR, Sakuramoto T,
et al. Morphological and neoplastic
transformation of C3H/10T1/2 CI 8 mouse
embryo cells by insoluble carcinogenic
nickel compounds. Environ Mol Mutagen
1989;14:65–78.
49. Zhong A, Troll W, Koenig K, et al.
Carcinogenic sulphide salts of nickel and
cadmium induce H O formation by human
2 2
polymorphonuclear leukocytes. Cancer Res
1990;50:7564–70.
50. The Nordic Expert Group (Kristjansson V,
Kristensen P, Lundbert P, et al.) for Criteria
Documentation of Health Risks from
Chemicals. Nickel and nickel compounds.
119. Sverige (Sweden):Arbeslivsintitutet &
forfattarna (National Institute for Working
Life); 1996.
51. Waldron HA, Scott A. Metals. In: Raffle
PAB, Adams PH, Baxter PJ, et al., editors.
Hunter’s diseases of occupations. 8th ed.
London: Edward Arnold; 1994 p. 90–138.
52. Deiss A, Lee GR, Cartwright GE. Hemolytic
anaemia in Wolson’s disease. Ann Intern
Med 1970;73:413–18.
53. Poirier LA, Littlefield NA. Metal interactions
in chemical carcinogenesis. In: Chang LW,
Magos L, Suzuki T, editors. Toxicology of
122
metals. Eds. Boca Raton: CRC Lewis; 1996.
p. 289–98.
54. Izumi K, Kitaura K, Chone Y et al.
Spontaneous kidney tumor in Long-Evans
Cinnamon rats. Proc Am Assoc Cancer Res
1994 35:161.
55. Kato J, Kohgo Y, Sugawara N et al.
Acceleration of hepatic injury by rapid influx
of iron in a mutant strain of Long-Evans
rats developing hepatocellular carcinoma.
Proc Am Assoc Cancer Res 1994;35:130.
56. American Conference of Governmental
Industrial Hygienists. 2003 TLVs and
BEIs. Threshold limit values for chemical
substances and physical agents, biological
exposure indices. Cincinnati (Ohio):
ACGIH; 2003.
57. Van der Voet GB, Wolff RA. Human
exposure to lithium, thallium, antimony,
gold and platinum. In: Chang LW, Magos L,
Suzuki T, editors. Toxicology of metals.
Boca Raton: CRC Lewis; 1996. p. 455–60.
58. Poulsen KH. Lode gold. In: Eckstrand OR,
Sinclair WD, Thorpe RI, editors. Geology
of Canadian mineral deposit types. Ottawa:
Geological Survey of Canada; 1995.
p. 323–82.
59. Ross M, Holan RP, Lamger AM, et al. Health
effects of mineral dusts other than asbestos.
In: Guthrie GD, Mossman BT, editors.
Reviews in minerology: health effects of
mineral dusts. Vol. 28. Washington (D.C.):
Minerological Society of America; 1993.
p. 361–407.
60. Noble JA. Ore mineralization in the
Homestake Gold Mine, Lead, South Dakota.
Geol Soc Amer Bull 1950; 61:221–52.
61. Gillam JD, Dement JM, Lemen RA, et al.
Mortality patterns among hardrock gold
miners exposed to an asbestiform mineral.
Ann NY Acad Sci 1976; 271:336–44.
62. McDonald JC, Gibbs GW, Liddell PDK,
et al. Mortality after long exposure to
cummingtonite-grunerite. Am Rev Respir
Dis 1978;118:271–7.
63. Brown DP, Kaplan SD, Zumwalde RD, et
al. Retrospective cohort mortality study
of underground gold mine workers. In:
Goldsmith DF, Winn DM, Shy CM, editors.
Silica, silicosis, and cancer. New York:
Praeger; 1986. p. 335–50.
64. Armstrong BK, McNulty JC, Levitt LJ, et al.
Mortality in gold and coal miners in western
Australia with special reference to lung
cancer. Br J Ind Med 1979;36:199–205.
65. Muller J, Wheeler WC, Gentleman JF, et al.
Study of mortality of Ontario miners 1955-
1977, Part 1. Toronto and Ottawa: Ontario
Ministry of Labour, Ontario Workers’
Compensation Board, Atomic Energy
Control Board of Canada;1983.
66. Muller J, Kusiak RA, Suranyi G, et al. Study
of mortality of Ontario gold miners. Toronto
and Ottawa: Ontario Ministry of Labour,
Workers’ Compensation Board of Ontario,
University of Toronto, Toronto General
Hospital; 1986.
67. Wyndham CH, Bezuidenhout BN,
Greenacre MJ, et al. Mortality of middle
aged white South African gold miners.
Br J Ind Med 1986;43:677–84.
68. Kusiak RA, Ritchie AC, Springer J, et al.
Mortality from stomach cancer in Ontario
miners. Br J Ind Med 1993;50:117–26.
69. Simonato L, Moulin JJ, Javelaud B, et
al. A retrospective mortality study of
workers exposed to arsenic in a gold mine
and refinery in France. Am J Ind Med
1994;25:625–33.
70. de Klerk NH, Musk AW, Tetlow S.
Preliminary study of lung cancer mortality
among western Australia gold miners
exposed to silica. Scand J Work Environ
Health 1995;21 (Suppl):66–8.
71. Reid PJ, Sluis-Cremer GK. Mortality of white
South African gold miners. Occup Environ
Med 1996;53:11–16.
72. de Klerk NH, Musk AW. Silica, compensated
silicosis, and lung cancer in western
Australian goldminers. Occup Environ Med
1998;55:243–8.
73. Hnizdo E, Murray J, Klempman S. Lung
cancer in relation to exposure to silica
dust, silicosis and uranium production
in South African gold miners. Thorax
1997;52(3):271-5.
74. McGlashan ND, Harington JS, Chelkowska E.
Changes in the geographical and temporal
patterns of cancer incidence among black
gold miners working in South Africa, 1964-
1996. Br J Cancer 2003;88(9):1361-9.
75. Eisler R. Health Risks of Gold Miners: A
Synoptic Review. Environ Geochem Health
2003; 25:325-45.
76. Occupational Disease Panel. Report to the
Workers’ Compensation Board on stomach
cancer in Ontario gold miners. Occupational
Disease Panel; August 1996.
77. Heller JGH Consulting Inc. for The Ontario
Mining Association. February 26, 1997.
Submission to the Workers’ Compensation
Board from The Ontario Mining Association
on ODP Report No. 16. Re: Possible stomach
cancer in Ontario gold miners. 62 p.
78. Eckstrand OR. 1995. 27.1 Nickel-copper
sulphide. Geology of Canadian mineral
deposit types. Eckstrand OR, Sinclair WD,
Thorpe RI, eds. Ottawa, Calgary, Vancouver:
Geological Survey of Canada. p. 584–605.
79. Giblin PE. 1984. Chapter 1. History of
exploration and development, of geological
studies and development of geological
concepts. In: The geology and ore deposits
of the Sudbury structure. Pye EG, Naldrett
AJ, Giblin PE, eds. Ontario Ministry of
Natural Resources: Toronto. p. 3–23.
80. Webb P and The Course Team. Mining, ore
processing and metal extraction. In: Metals 2.
Resource exploitation. Milton Keynes
(England): The Open University; 1996;
p. 56–98.
81. Chovil A, Sutherland RB, Halliday M.
Respiratory cancer in a cohort of nickel
sinter plant workers. Br J Ind Med 1981;
38:327–33.
82. Morgan JG. Some observations on the
incidence of respiratory cancer in nickel
workers. Brit J Ind Med 1958;15:224–34.
83. Pedersen E, Hogetveit AC, Andersen A.
Cancer of respiratory organs among workers
at a nickel refinery in Norway. Int J Cancer
1973;12:32–41.
84. Bradford Hill A. Report to the Mond Nickel
Company (Unpublished). 1939.
85. Doll R, Morgan LG, Speizer FE. Cancers
of the lung and nasal sinuses in nickel
workers. Br J Cancer 1970;4:54–63.
86. Doll R, Mathews JD, Morgan LG. Cancer
of the lung and nasal sinuses in nickel
workers: a reassessment of the period at
risk. Br J Ind Med 1977;34:102–5.
87. Kaldor J, Peto J, Easton D, et al. Models
for respiratory cancer in nickel refinery
workers. J Natl Cancer Inst 1986;77:
841–8.
88. Peto J, Cuckle H, Doll R, et al. Respiratory
cancer mortality of Welsh nickel refinery
workers. In: Sunderman FW, editor.
Nickel in the human environment. Lyon:
IARC Scientific Publications No. 53; 1984.
p. 37–46.
89. Magnus K, Andersen A, Hogetveit AC.
Cancer of respiratory organs among workers
at a nickel refinery in Norway. Int J Cancer
1982;30:681–5.
90. Lessard R, Reed D, Maheux B, et al. Lung
cancer in New Caledonia: a nickel smelting
island. J Occup Med 1978;12:815–7.
91. Goldberg M, Goldberg P, Leclerc A, et al.
A 10-year incidence survey of respiratory
cancer and a case-control study within
a cohort of nickel mining and refining
workers in New Caledonia. Cancer Causes
Control 1994;5:15–25.
92. Enterline PE, Marsh GM. Mortality among
workers in a nickel refinery and alloy
manufacturing plant in West Virginia.
J Natl Cancer Inst 1982;68:925–33.
93. International Nickel Co., Ltd. Nickel and
its organic compounds. Report submitted
to the National Institute for Occupational
Safety and Health. October 1976.
123 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
94. Moulin JJ, Clavel T, Roy D, Dananché B,
Marquis N, Févotte J, Fontana JM. Risk of
lung cancer in workers producing stainless
steel and metallic alloys. Int Arch Occup
Environ Health 2000;73(3):171-80.
95. Anttila A, Pukkala E, Aitio A, Rantanen T,
Karjalainen S. Update of cancer incidence
among workers at a copper/nickel smelter
and nickel refinery. Int Arch Occup Environ
Health 1998; 71(4):245-50.
96. Egedahl R, Carpenter M, Lundell D.
Mortality experience among employees at
a hydrometallurgical nickel refinery and
fertiliser complex in Fort Saskatchewan,
Alberta (1954-95). Occup Environ Med
2001;58(11):711-5.
97. Sorahan T, Williams SP. Mortality of
workers at a nickel carbonyl refinery, 1958-
2000. Occup Environ Med 2005;62(2):80-5.
98. Grimsrud TK, Berge SR, Haldorsen T,
Andersen A. Exposure to Different Forms
of Nickel and Risk of Lung Cancer. Am
J Epidemiol 2002;156(12):1123-32.
99. Grimsrud TK, Berge SR, Marinsen JI,
Andersen A. Lung cancer incidence among
Norwegian nickel-refinery workers 1953-
2000. J Environ Monit 2003;5(2):190-7.
100. Grimsrud TK, Berge SR, Haldorsen T,
Andersen A. Can lung cancer risk among
nickel refinery workers be explained by
occupational exposures other than nickel?
Epidemiology 2005; 16(2):146-54.
101. Shannon HS, Walsh C, Jadon N, et al.
Mortality of 11,500 nickel workers: extended
follow-up and relationship to environmental
factors. Toxicol Ind Health 1991;7:277–94.
102. Roberts RS, Julian JA, Muir DCF, et al. A
study of mortality in workers engaged
in the mining, smelting, and refining of
nickel. II: mortality from cancer of the
respiratory tract and kidney. Toxicol Ind
Health 1989;5:975–93.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
103. Roberts RS, Julian JA, Muir DCF, et al. A
study of mortality in workers engaged in the
mining, smelting, and refining of nickel. I:
methodology and mortality by major cause
groups. Toxicol Ind Health 1989;5:957–74.
104. Report of the International Committee on
Nickel Carcinogenesis in Man. [Review].
Scand J Work Environ Health. 1990;16
(1 Spec No):1–82.
105. Kirkham RV, Sinclair WD. Porphyry copper,
gold, molybdenum, tungsten, tin, silver.
In: Eckstrand OR, Sinclair WD, Thorpe RI,
editors. Geology of Canadian mineral
deposit types. Vol. 19. Ottawa: Geological
Survey of Canada; 1995. p. 421–46.
106. Tokudome S, Kuratsune M. A cohort study
on mortality from cancer and other causes
among workers at a metal refinery. Int
J Cancer 1976;17:310–7.
107. Ahlman K, Koskela RS, Kuikka P, Koponen M,
Annanmaki M. Mortality among sulfide ore
miners. Am J Ind Med. 1991;19(5):603-17.
108. Chen R, Wei L, Huang H. Mortality from
lung cancer among copper miners. Br J Ind
Med 1993;50:505–9.
109. Viren JR, Silvers A. Unit risk estimates
for airborne arsenic exposure: an updated
view based on recent data from two copper
smelter cohorts. Regul Toxicol Pharmacol
1994;20:125–138.
110. Lubin JH, Pottern LM, Stone BJ,
Fraumeni JF. Respiratory cancer in a
cohort of copper smelter workers: results
from more than 50 years of follow-up. Am
J Epidemiol 2000 Mar 15;151(6):554-65.
111. Enterline PE, Day R, Marsh GM. Cancer
related to exposure to arsenic at a copper
smelter.
52:28–32.
Occup Environ Med 1995;
112. Chen R. An analysis program for
occupational cohort mortality and update
of cancer risk in copper miners. Int J Occup
Med Environ Health 1996;9:301–8.
124
113. Pershagen G. Lung cancer mortality among
men living near an arsenic-emitting smelter.
Am J Epidemiol 1985;122:684–94.
114. Marsh GM, Stone RA, Esmen NA, et al. A
case-control study of lung cancer mortality
in four rural Arizona smelter towns. Arch
Environ Health 1998;53:15–28.
115. Mattson ME, Guidotti TL. Health risks
associated with residence near a primary
copper smelter: a preliminary report. Am
J Ind Med 1980;1:365–74.
116. Rice CH. Retrospective exposure assessment:
a review of approaches and directions
for the future. In: Rappaport SM,
Smith TJ, editors. Exposure assessment for
epidemiology and hazard control. Chelsea
(Michigan): Lewis; 1991. p. 185–97.
117. Dosemeci M, Chen J-Q, Hearl F, et al.
Estimating historical exposure to silica
among mine and pottery workers in the
People’s Republic of China. Am J Ind Med
1983;24:55–66.
air
Air contains thousands of natural and
synthetic organic and inorganic chemical
compounds, most of which are present
at very low levels. Many of these are
discussed in the section on chemicals
and are also described in the glossary.
Human exposure to air pollution has been
ubiquitous over time because fire, a major
pollutant source has been used for cooking
and heating. Most air pollutants result from
the combustion of fossil fuels in motor
vehicles, factories, thermal power plants
and home furnaces. 1-2
Air pollutants can be classified into primary
or secondary pollutants. Primary pollutants
are released directly into the air from
specific sources such as industry or motor
vehicles. Some primary pollutants can be
altered by sunlight, heat or other chemicals
to form secondary pollutants.
Substances that pollute air can be solids
(particles and fibres), liquids (droplets)
and vapours or gases. The major pollutants
are particulate matter (PM) and certain
gases. Nitrogen oxides (or NO x ) is a group
of highly reactive gases that are formed
when fuel is burned at high temperatures.
Volatile organic compounds (VOCs) are
compounds having a high vapor and low
water pressure, and are typically industrial
solvents. Nitrogen oxides and VOCs are
organic compounds that convert into vapour
or gas without a chemical reaction, and
key precursor gases which react with other
gases in the presence of sunshine to form
ozone. Ozone is an example of a secondary
pollutant and a major component of smog
which, in turn, is an important type of
air pollution. 3
Sources of PM include fuel combustion
from automobiles, power plants, wood
burning, industrial processes, and diesel
powered vehicles such as buses and trucks. 4
It can also be formed in the atmosphere
when gaseous air pollutants undergo
certain chemical reactions. PM consists of
microscopic particles that vary in size and
chemical makeup. Examples are asbestos,
fibreglass, silica, dusts, heavy metals (e.g.,
mercury and lead), pollen, spores, bacteria,
fungi, cotton and other fibres. The smaller
the particles, the greater their potential
for damage to the human respiratory
tract as they are more easily inhaled and
deposited in the respiratory tract. For
example, particles with an aerodynamic
diameter larger than 10µm are filtered
out of the nose and pharynx, whereas
smaller particles can reach deeper areas
within the lung. Removal of particles from
the upper airways is effective and occurs
within hours, but clearance from the deep
lung by alveolar macrophages may take
days to months. 5 Particles with diameter
of 2.5 µm or less (PM 2.5 ) are the focus of
numerous recent studies and warrant
being singled out since they also have
higher concentrations of nitrates, organic
compounds and transitional metals. 6 A
limited body of work has recently found
some associations, primarily acute effects,
for coarse particulate matter (PM 2.5-10 ). More
recently, several studies have evaluated the
health impacts associated with ultrafine
particles which consists of particles with an
average aerodynamic diamater of less than
0.1 µm. Particulate matter is a combination
of both direct emissions and reactions that
take place in the atmosphere, as therefore,
its’ composition, unlike the common pollutant
gases varies considerably by region.
Commonly studied gaseous air pollutants
include ozone (O 3 ), sulphur dioxide (SO 2 ),
oxides of nitrogen (nitrogen oxide (NO)
and dioxide (NO 2 )) and carbon monoxide
(CO). Because O 3 and NO 2 are less soluble
than other irritant gases, they can reach the
deeper areas of the lung where they cause
inflammation and edema respectively. 5
Pollutants with a carcinogenic potential
include benzo[a]pyrene, benzene, 1,3butadiene,
formaldehyde, chloroform,
chromium, other metals, particulate matter,
especially PM 2.5 , and possibly ozone. 7,8
Indoor air Pollution
Contrary to common perception, indoor
air is a greater source of air pollutants to
Canadians than outdoor air. However,
outdoor air pollution infiltrates buildings,
so the two are not mutually exclusive.
Canadians spend nearly 90% of their
time indoors, 9 usually in airtight, wellinsulated
buildings where the low rate
of air exchange between the outdoor and
indoor environments allows the buildup
of contaminants. For example, (VOCs)
are present at higher concentrations
indoors than outdoors. 10 The importance
of indoor air pollution is heightened for
infants and the elderly who, on average,
spend more time indoors and are typically
more susceptible to harmful effects of
environmental exposures. These individuals
may also be more susceptible to the
effects of air pollution as they may be more
likely to have pre-existing disease, and
children may have less developed immune
systems and growing lungs.
Environmental tobacco smoke (ETS)
has been a major source of indoor air
pollution and adversely affects the health
of both smokers and non-smokers. 11
Cigarette smoke contains more than four
thousand chemical compounds (including
heavy metals such as lead and cadmium,
pesticides and fertilizers) which are
absorbed by tobacco plants from the soil. 12
Nicotine and roughly half of the other
chemical compounds in tobacco smoke are
naturally present in the green tobacco leaves
themselves. The remaining compounds
are produced by chemical reactions when
tobacco is cured and burned. At least 40 of
the compounds present in tobacco smoke
are known to cause or promote cancer. 10
Persons exposed to ETS inhale tar, carbon
monoxide, nicotine, polycyclic aromatic
hydrocarbons (PAHs) and other harmful
compounds. 13
External air, biological contaminants
including fungi and dusts, and combustion
products are also important components
of indoor air pollution. 14 Radon, which has
been shown to increase the risk of lung
cancer, is a naturally occurring radioactive
gas which is discussed in the radiation
section of this monograph. Radon has been
identified as the second leading cause of
lung cancer, after smoking. 15
125 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Outdoor air Pollution
As mentioned earlier, in most areas,
the largest single source of outdoor air
pollution, often visible as smog, is motor
vehicle exhaust. 10 Other major sources
include industrial processes and the
burning of fossil fuels to generate electricity.
Smog is a mixture of ground-level ozone,
particulate matter, acid aerosols, oxides of
sulphur and associated sulphates, oxides
of nitrogen, VOCs and carbon monoxide.
NO 2 , an irritating dark brown gas, gives
smog its characteristic yellowish-brown
colour and, as a surrogate of traffic-related
air pollution, it has been associated with a
modestly increased lung cancer risk. 16-18
There are two types of smog—photochemical
and sulphurous. Photochemical smog is
pollution produced by the action of sunlight
on vehicle exhaust. Ozone levels, an index
for this type of pollution, are highest during
the summer months, with daily peaks
between 12 noon and 6 p.m. Ground-level
ozone concentrations sometimes exceed the
current air quality standards in some areas
of Canada—such as the Windsor-Quebec
City corridor, the Lower Fraser Valley in
British Columbia and the Southern Atlantic
region. 10
Sulphurous smog, with the main ingredient
SO 2 , arises from the combustion of sulphurcontaining
fossil fuels such as coal and
oil. Major outdoor sources include power
plants, smelters and oil refineries (>80%
combined). Sulphurous smog episodes are
more common in winter, possibly from the
higher demand for heat and to atmospheric
inversions associated with fog formation
and higher levels of primary pollutants
such as SO 2 and soot. 5
The burning of fossil fuels is also the major
source of both acid rain and greenhouse
gases. SO 2 , released high into the atmosphere
from stacks, interacts with water, sunlight
and chemical ions to form a variety of
acidic particles (sulphates), which are
important components of both PM and acid
rain. 19 Carbon dioxide, along with methane
and chlorofluorocarbons (other important
by-products of the burning of fossil fuels),
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
reflect radiant infrared energy back to earth
that normally would escape through the
atmosphere back into space. 5
Levels of different contaminants in outdoor
air are influenced by factors such as
population density, the degree of industrialization,
local pollution emission
standards, season, climate and weather
patterns. 10 Air pollutants are carried by
winds and can travel to areas such as the
Arctic that are thousands of miles from
urban and industrial centres.
The following chapters deal with ETS (the
major contributor to indoor PM 2.5 ) 11 and
with outdoor air pollution. The chapter on
outdoor air pollution highlights some of the
difficulties in characterizing exposure, as
well as an examination of the relationship
between outdoor air pollution and cancer.
References
1. Godish T. Air Quality. 4th ed. Boca Raton,
Florida: CRC Press LLC; 2004.
2. Canada-United States Air Quality
Committee. The Canada – United States Air
Quality Agreement: 2004 Progress Report.
Ottawa: Environment Canada; 2004. Cat.
No. En40-388/2004E.
3. Health Canada and Environment Canada.
National ambient air quality objectives for
ground level ozone. Science assessment
document. 1999. ISBN 0-662-29011-9.
Catalogue No: En42-17/7-2-1999E.
Available at: http://www.hc-sc.gc.ca/
ewh-semt/pubs/air/naaqo-onqaa/ground_
level_ozone_tropospherique/summarysommaire/index-eng.php
4. Health Canada – National ambient air
quality objectives for particulate matter –
Part 1 Science Assessment Document.
Minister, Public Works and Government
Services, 1999. ISBN 0-662-63486-1 Cat H46-
2/98-220. Available at: http://www.hc-sc.
gc.ca/ewh-semt/pubs/air/naaqo-onqaa/
particulate_matter_matieres_particulaires/
summary-sommaire/index-eng.php
126
5. Brooks S, Gochfeld M, Herzstein J, et
al. Environmental medicine. St. Louis,
Missouri: Mosby Year Book Inc.; 1995.
6. Pritchard RJ, Ghio AJ, Lehmann JR,
Winsett DW, Tepper JS, Park P. Oxidant
generation and lung injury after particulate
air pollutant exposure increase with the
concentrations of associated metals. Inhal
Toxicol 1996;8:457-77.
7. Cohen AJ, Pope CA. Lung cancer and
air pollution. Environ Health Perspect,
1995;103 (Suppl 8):219–24.
8. Shy CM. Air pollution. In: Schottenfeld D,
Fraumeni JF, editors. Cancer Epidemiology
and Prevention. 2nd ed. Philadelphia: W.B.
Saunders Company; 1996. 407–417.
9. Leech JA, Wilby K, McMullen E, Laporte K.
The Canadian Human Activity Pattern
Survey: report of methods and population
surveyed. Chronic Dis Can 1996;17(3-4):
118-23. Available at: http://www.phac-aspc.
gc.ca/publicat/cdic-mcc/17-3/d_e.html
10. Health Canada. Health and environment:
partners for life. Ottawa: Minister of Public
Works and Government Services Canada;
1997. Cat.: H49-112/1997E.
11. Health Canada. Exposure Guidelines
for Residential Indoor Air Quality.
Environmental Health Directorate, Health
Protection Branch. Ottawa, April 1987. Cat.
H46-2/90-156E.
12. U.S. Department of Health and Human
Services (2005). Report on Carcinogens. 11th Edition. Research Triangle Park, NC: U.S.
Department of Health and Human Services,
Public Health Service, National Toxicology
Program. Available at: http://ntp.niehs.nih.
gov/ntp/roc/toc11.html.
13. National Cancer Institute. Smoking and
Tobacco Control Monograph 10: Health
Effects of Exposure to Environmental
Tobacco Smoke. Bethesda, MD;1999.
Available at: http://cancercontrol.cancer.
gov/tcrb/monographs/10/index.html.
14. Editorial Board Respiratory Disease in
Canada. Health Canada. Ottawa, Canada,
2001. Catalogue no. H35-593/2001E.
15. U.S. Department of Health and Human
Services. Office of the Surgeon General.
Available at: http://www.surgeongeneral.
gov/pressreleases/sg01132005.html
16. Nyberg F, Gustavsson P, Jarup L et al. Urban
air pollution and lung cancer in Stockholm.
Epidemiology 2000;11(5):487-495.
17. Vineis P, Hoek G, Krzyzanowski M, Vigna-
Taglianti F, Veglia F, Airoldi L, Overvad K,
Raaschou-Nielsen O, Clavel-Chapelon F,
Linseisen J, Boeing H, Trichopoulou A, Palli D,
Krogh V, Tumino R, Panico S, Bueno-
De-Mesquita HB, Peeters PH, Lund E E,
Agudo A, Martinez C, Dorronsoro M,
Barricarte A, Cirera L, Quiros JR, Berglund G,
Manjer J, Forsberg B, Day NE, Key TJ,
Kaaks R, Saracci R, Riboli E. Lung cancers
attributable to environmental tobacco
smoke and air pollution in non-smokers in
different European countries: a prospective
study. Environ Health 2007 Feb 15;6:7.
18. Filleul L, Rondeau V, Vandentorren S et al.
Twenty five year mortality and air pollution:
results from the French PAARC survey.
Occup Environ Med 2005 Jul;62(7):453-60.
19. Derwent RG and Malcolm AL. Photochemical
Generation of Secondary Particles in
the United Kingdom. In: Brown LM,
Collings N, Harrison RM, Maynard AD,
Maynard RL, editors. Ultrafine Particles in
the Atmosphere. London: Imperial College
Press; 2003. 103–22.
127 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
environmental Tobacco Smoke (eTS)
Kenneth C. Johnson
Environmental tobacco smoke, also referred
to as second-hand smoke or passive
smoking, has been established as a causal
risk factor for a number of health problems,
principally cardiovascular, respiratory, and
cancer outcomes. ETS is a combination of
sidestream and mainstream cigarette smoke –
sidestream smoke comes from the burning
end of the cigarette, while mainstream
is exhaled from the smoker. More than
50 studies between 1980 and 2005 have
examined the relationship between lung
cancer and exposure to ETS, and over
the last 20 years, at least eight expert
committees have independently concluded
that ETS causes lung cancer in neversmokers.
A recent meta-analysis (systematic
summary) of studies of lung cancer risk in
women who had never smoked, but whose
spouse smoked, estimated a relative risk
(RR) of 1.24 (i.e., a 24% increase in risk
compared to women whose spouses had
never smoked). Recent meta-analyses of
lung cancer risk associated with ETS at
work estimated a 19% and 39% increase
in lung cancer risk for never-smokers
exposed regularly to second-hand smoke
in the workplace. Where ETS exposure has
been examined for combined residential
and workplace exposure, greater exposure
results in higher risks; the summary lung
cancer risk for women never-smokers in the
highest category of combined residential
and occupational lifetime ETS exposure was
estimated at 1.78 (95% Confidence Interval
(CI): 1.49-2.12), and for those women
in the highest category of occupational
exposures the summary risk was 2.25 (95%
CI: 1.81- 2.79).
More recently a literature has developed on
breast cancer and ETS and there are now
more than 20 published studies. A recent
meta-analysis found that regular exposure
to ETS among women who were life-long
non-smokers was associated with increased
breast cancer risk (pooled summary risk
estimate of 1.27 (95% CI: 1.11-1.45)).
The risk estimate for the 5 studies with
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
more complete exposure assessment (quantitative
long-term information on the
three major sources of passive smoke
exposure, childhood, adult residential and
occupational) was 1.90 (95% CI: 1.53-
2.37); while estimates for 14 studies with
less complete ETS exposure measures was
only 1.08 (95% CI: 0.99-1.19). The overall
premenopausal breast cancer risk associated
with ETS was 1.68 (95% CI: 1.33-2.12), and
2.19 (95% CI: 1.68-2.84) for the 5 studies
that incorporated three sources of exposure.
For women who had smoked the breast
cancer risk estimate was 1.53 (95% CI: 1.22-
1.91) when compared to women with neither
active nor regular passive smoke exposure;
2.08 (95% CI: 1.44- 3.01) for more complete
passive exposure assessment. Although the
International Agency for Research on Cancer
(IARC) concluded in 2002 that the collective
evidence on ETS and breast cancer was not
supportive of a causal association, in 2005
the California Environmental Protection
Agency became the first agency concerned
with environmental health to evaluate the
association between premenopausal breast
cancer and ETS as conclusive.
The relation of ETS to other types of cancer
has been less studied. The evidence from the
handful of adult brain cancer studies and
ETS is inconclusive. Studies of childhood
cancer have been equivocal and are likely
subject to important biases from recall,
and participation; and there are limited
numbers of studies of the relationship for
other cancers. ETS may be of particular
relevance to Canadians who, because of the
cold climate, spend much of the year inside
closed spaces with limited ventilation.
Because of the large number of individuals
who have been regularly exposed, even
small increases in individual risk associated
with ETS exposure can impact a substantial
number of Canadians. Compelling evidence
exists to warrant introduction of further
measures to reduce exposure to ETS in
Canada.
128
Introduction
The impact of environmental tobacco
smoke (ETS) on health has been the
subject of a large number of investigations
and several in-depth reviews over the last
25 years. 1,2 ETS has been established as a
causal risk factor for a number of health
problems. The relationship between ETS
and lung cancer has been the focus
of more than 50 studies 3 and a number of
expert panels. 1-5 There are now more than
20 published studies of breast cancer
and ETS, 3 over 30 on childhood cancer and
parental smoking, 3 and a few on brain
cancer. 3 Studies have also been reported for
cancers of the nasal cavity, head and neck,
stomach, cervix, bladder and for adult
leukemia. 3,6,7 For all other cancers, there
is a dearth of information on the possible
relationship with ETS. No association was
noted in one study of bladder cancer and
one study reported mixed results. 8,9
This review begins by examining the
importance of studying the relationship of
ETS to cancer, the cancer risks associated
with active smoking, differences in the
constituents of passive and active smoke,
measurement of individual exposure,
population exposure to passive smoking,
and the special importance of ETS given the
cold Canadian climate. Next the association
of ETS with lung cancer is discussed,
highlighting the difficulties in studying
the relationship, recent meta-analyses of
spousal and of workplace exposure and the
smaller subset of primarily recent studies
that try to enumerate lifetime exposure to
residential and occupational ETS. Third,
breast cancer and ETS are examined in
depth – an area where the accumulating
evidence may prove to be of considerable
public health importance and extend our
understanding of breast cancer etiology.
This is followed by a brief look at the
equivocal research on ETS and childhood
cancer and the limited research on ETS and
adult brain cancer. The chapter concludes
with a brief discussion of public health
efforts to reduce ETS exposure.
Methods and background on
epidemiological studies reviewed
Potential studies for review were identified
through a MEDLINE search (terms:
passive smoking, second-hand smoke,
environmental tobacco smoke and cancer)
to find studies of cancer risks in neversmokers
with lifetime residential and
occupational ETS exposure histories.
There are often challenges in characterizing
large, disparate bodies of epidemiologic
evidence of varying quality. Results
presented here for lung and breast cancer
are based on formal published metaanalyses,
whereas less rigorous, and
more descriptive analyses were available
for other cancer sites. The quality of the
studies included in a meta-analysis will
impact on the quality of the meta-analysis
and in this area of study misclassification
of ETS exposure has been common in the
individual studies and thus impacted
the meta-analyses.
background
Research into ETS and health effects
The first detailed reviews of ETS and health
risks were performed independently in 1986
by the US National Research Council, 1 and
the US Surgeon General. 4 Both concluded
that ETS could cause lung cancer in persons
who had never smoked. In 1993 the United
States Environmental Protection Agency
produced an extensive report 10 with more
than twice the number of studies available
for analysis as available in 1986. In the
next six years, five additional in-depth
reviews were published (by the Australian
National Health and Medical Research
Council, 11 the United Kingdom Department
of Health, 12 the California Environmental
Protection Agency (Cal/EPA), 2 the World
Health Organization, 13 and the United
States National Toxicology Program 14 ). In
2004 the International Agency for Research
on Cancer (IARC) monograph series on
the Evaluation of Carcinogenic Risks to
Humans published Volume 83, Tobacco
Smoke and Involuntary Smoking. 5
In 2005, the Cal/EPA updated their earlier
Health Effects Assessment including
summaries based on a weight of evidence
approach. 3 The review concluded that there
is sufficient evidence that ETS exposure is
causally related to the following non-cancer
health effects:
• developmental effects – reduced fetal
growth, low birth weight, sudden infant
death (SIDS), and pre-term delivery);
• respiratory effects – acute lower respiratory
tract infections in children (e.g.
bronchitis and pneumonia), asthma
induction and exacerbation in children
and adults, chronic respiratory symptoms
in children; eye and nasal irritation
in adults, middle ear infections;
• cardiovascular effects – heart disease
mortality, acute and chronic heart
disease morbidity and alter vascular
properties. 3
The report also concluded that there was
suggestive evidence for other risks including:
spontaneous abortion, intrauterine growth
retardation, adverse impacts on cognition
and behaviour, allergic sensitization, elevated
decreased pulmonary function growth
and adverse effects on fertility or fecundity,
elevated risk of stroke, and chronic
respiratory symptoms in adults. 3
Active smoking and cancer
The interest in ETS and cancer is not
surprising given the demonstrated causal
relationships of active smoking to a number
of cancers. In their 1986 monograph, IARC
identified smoking as causing cancers of
the lung, larynx, oral cavity, pharynx,
oesophagus (squamous cell carcinoma),
pancreas, urinary bladder, and renal
pelvis. 15 Observed relative risks ranged
from about three-fold for pancreatic cancer
to twenty fold for lung cancer. In their
evaluation in 2002, the IARC expert group
concluded that additionally there was now
sufficient evidence for a causal association
between cigarette smoking and cancers
of the nasal cavities and nasal sinuses,
oesophagus (adenocarcinoma), stomach,
liver, kidney (renal-cell carcinoma), uterine
cervix and myeloid leukaemia. Observed
relative risks for these additional cancers
generally were in the two to threefold range. 5
Active smoking is estimated to account
for about 45% of male cancer cases and
22% of female cancer cases in the USA. 16
In 2002, over 36,000 deaths (16.3%) were
attributable to active smoking in Canada. 17
These were primarily deaths from cancer
and coronary heart disease.
Toxicity of second-hand smoke compared
with mainstream smoke
Because the idling cigarette burns at a
much lower temperature (resulting in less
complete combustion) and because more
tobacco is pyrolised during smouldering
than during inhalation (2 second puff
profile versus a 60 second puff interval),
on a per gram basis, the sidestream smoke
from a smoldering cigarette contains higher
amounts of over 40 known carcinogens –
and dozens of possible or probable carcinogens
– than the same volume of
mainstream smoke. For example, on a per
gram basis undiluted sidestream smoke
contains 13 to 30 times as much nickel
as undiluted mainstream smoke from
a non-filter cigarette, up to 50 times as
much formaldehyde, 2.5 to 3.5 times
as much benzo[a]pyrene, 7.2 times as much
cadmium, etc. 10,18 Most Canadians smoke
filtered cigarettes which reduce some of
the carcinogen exposures in mainstream
smoke, but would have no impact on the
quality of the sidestream smoke. Thus
if the comparison was to filtered cigarettes,
the ratios of carcinogens in sidestream to
mainstream smoke would generally be
higher. Furthermore, because about 80%
of the tobacco in a cigarette burns between
puffs, indoor pollution from tobacco smoke
comes mainly from sidestream smoke. 1
However, because sidestream smoke
is diluted by the room air, the actual
concentration and hence exposure to
carcinogens from sidestream smoke is
considerably lower than that from active
smoking. In addition, the concentration of
sidestream smoke in the air is dependent
upon other factors including: room size,
ventilation rates, number of smokers in the
room and the number of cigarettes smoked.
Typically, non-smokers inhale much less
tobacco smoke than smokers and are
exposed to much lower concentrations
because breathing rates are the same but,
smokers inhale 35 ml per puff at a higher
concentration, while passive smokers
inhale about 1 litre per breath at lower
concentrations. Passive smoke exposure in
129 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
non-smokers is estimated to be, on average,
about one percent of the active smoke
exposure that an active smoker receives,
but this is based primarily on the levels of
cotinine (a marker of nicotine exposure)
measured in the urine. 10,19 It is much more
difficult to measure the relative exposure
to carcinogens between smokers and nonsmokers.
For example, a recent study of
the metabolites of 4(methylnitrosamino)-
1-(3-pyridyl)-1-butanone (NNK), a tobacco
specific carcinogen found that passivelyexposed
non-smoking wives of husbands
who smoked, had on average 5.6% of the
levels of the NNK metabolite in their urine
that their husbands had as compared to
0.6% their husband’s levels of cotinine 20
ETS exposure in Canada
ETS may be of particular relevance to
Canadians who, because of the cold
climate, spend much of the year indoors.
The exposure to indoor air contaminants,
such as ETS, is directly affected by the
number of air changes per hour in an
indoor space. 21 Higher air change rates
during cold weather increase heating costs,
so air changes are kept to the minimum
acceptable level, generally limited to
control of humidity and odour. 22
Nearly 5.0 million Canadians aged 15 years
or older (19%) were active smokers in
2005 (16% of women, 22% of men). 23
They smoked an average of 15.7 cigarettes
per day. 23 In addition there were 7.3 million
former smokers (28% of the adult
population). 23 As a result, a large number
of non-smoking Canadians are, or have
until recently, been exposed regularly to
ETS residentially as children or adults,
occupationally and/or socially. Because
of the large number of individuals who
have been regularly exposed, even small
increases in individual risk associated with
ETS exposure can impact a substantial
number of Canadians.
Fewer Canadians are being exposed to ETS
at home and at work. 24 In 1996-97, onethird
of Canadian children under age 12
(nearly 1.6 million children), over 50% of
children in the lowest income families, and
85% of children living with a daily smoker
in the household were being exposed
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
regularly to ETS at home. 25 By 2005, the
percent of Canadian children under age 12
regularly exposed at home to ETS was
down to 9%. 23
Estimates of the percentage of Canadians
that have had regular ETS exposure at
some time in their lives are available from
the National Enhanced Cancer Surveillance
System (NECSS). 26 The NECSS collected
data from a population sample of over
5000 control subjects aged 20 to 74 from
eight Canadian provinces (Newfoundland,
Nova Scotia, Prince Edward Island,
Ontario, Manitoba, Saskatchewan, Alberta
and British Columbia) for the period 1994-
1997. Overall, 50 percent of the women
had actively smoked at some time, while
25% were still smokers at the time of
interview. Of the 50% of women who had
never smoked, 84% reported having lived
with a smoker as a child or adult, or having
worked for at least a year where colleagues
regularly smoked in the immediate work
area. The median number of years of
passive exposure reported among women
who never smoked was 27. 27 The ETS
exposure profile of these participants can
differ to that of the Canadian population
if participation is influenced by some
correlate of smoking behaviour (socioeconomic
status, age, etc).
ETS exposure in various environments
Many studies have examined ETS exposure
levels in different environments, and
several summaries of these studies have
been published. Nearly 100 studies were
examined by Guerin et al. in 1992. 28 ETS
exposure studies have demonstrated
consistently that exposure is particularly
high in bars. 29 Direct measures of specific
air contaminants, such as nicotine,
carbon monoxide and particulates, and
measurements of serum and urinary
cotinine levels in non-smokers who work
in bars all suggest high exposure.
In an analysis summarizing published
studies of passive smoke exposure in the
workplace, Siegel 30 built on the existing
reviews, and found that measured levels of
tobacco smoke in bars were 4.4 to 4.5 times
higher than in residences with at least one
smoker, and 3.9 to 6.1 times higher than in
offices. Each workplace exposure estimate
130
was based on 10 to 22 different studies. A
recent analysis of studies examining mean
nicotine concentrations found that nicotine
levels were generally between 1 and 3 µg/m 3
in homes, between 2 and 6 µg/m 3 in offices,
between 3 and 8 µg/m 3 in restaurants and
between 10 and 40 µg/m 3 in bars. 28 (More
information on ETS exposure is available at
http://www.repace.com/fact_exp.html).
Difficulties in studying ETS and cancer
Several difficulties in studying ETS and
cancer contribute to uncertainty about the
magnitude of risk caused by ETS; these
include sample size, quantifying ETS
exposure, the relatively small increases
in relative risk, misclassification of eversmoking
status, socio-economic differences
between smokers and non-smokers, and
the limited number of studies that collected
data beyond spousal ETS exposure.
Sample size
Inadequate sample size has been a limiting
factor in ETS studies, particularly those
of lung cancer. Among never-smokers,
lung cancer is a rare disease affecting
approximately 12 in 100,000 women per
year. 31 Conversely, 90% of lung cancers
among men and 63% among women
were estimated to be attributable to active
smoking in Canada in 2002. 17 As a result,
obtaining a sample of several hundred neversmokers
who have developed lung cancer
is exceedingly difficult and expensive. First,
over 60% of potential candidates will turn
out to be ineligible but, generally, will
have to be interviewed to establish that.
Second, lung cancer is rapidly fatal, so
cases must be ascertained and approached
without delays and some will have died in
the interim. (The use of proxies is unlikely
to be suitable for describing historic ETS
exposure in the workplace or childhood.)
Third, a very large population base must be
used to be able to complete data collection
within a suitable time frame. The largest
sample size to date was assembled in the
IARC study (650 cases and 1300 controls)
that included 12 study centres in seven
countries. Differences in study design
between centres (e.g., types of controls),
in environment and climate, and in work
practices may reduce the consistency of
the results.
Quantifying eTS exposure
Quantifying ETS exposure is a complex
task dependent on many factors, including
duration of exposure, room size, season,
ventilation, and exposure source.
Researchers have developed questionnaires
that provide valid measures of ETS
exposure 32 that correspond to biomarkers
of tobacco smoke exposure, such as urinary
cotinine levels. The correlation coefficients
for association between the questionnairebased
exposure estimates and the biomarker
levels, however, are low – ranging from 0.19
to 0.29. Historic ETS exposure is difficult to
measure, as there are no biomarkers
available that reflect long term exposure
levels. 32 Most of the studies have depended
upon the simple measure of living with a
spouse who smokes. More sophisticated
studies have evaluated smoking in residential,
social and work environments on
a year-by-year basis from childhood. On
the other hand, because people who smoke
tend to smoke over a long time period and
with a regular pattern (generally a number
of cigarettes everyday at regular intervals),
it may be that simple historic exposure
indices (smoker-years of ETS exposure)
may capture enough information to discern
important risks and differentiate for most
of the population relative differences in
overall exposure.
Small increases in relative risk
Increased relative risks associated with
ETS exposure will typically be modest,
reflecting the lower overall average carcinogen
exposures of ETS relative to
active smoking. With the relative risk
(RR) estimates for ETS and lung cancer
averaging about 1.2 for spousal exposure
among women (nonsmoking women who
lived with a spouse who smoked), 5 there
is concern that even a small bias might
explain the increase. For example, a bias
could be introduced by misclassification
of smoking status.
Misclassification of ever-smoking status
A small percentage of individuals who have
been smokers will report that they never
smoked. Because active smoking carries
a high relative risk for lung cancer, even a
small amount of misclassification of this
sort would increase the risk of lung cancer
among those classified as non-smokers and
hence reduce the difference in risk between
this group and those classified as smokers.
Hackshaw et al. evaluated this and found
that observed levels of misclassification
(1.9% to 7%) would only reduce the
summary odds ratio (OR) from 1.26 to
between 1.19 and 1.21. 33 In addition,
individuals misrepresenting their smoking
status tend to have quit many years prior
and to have been light smokers, 33 both
of which limit the risk that their active
smoking would contribute.
Socio-economic status and eTS
Individuals of lower socio-economic status
have a higher risk of lung cancer 34 and
several surveys have demonstrated higher
ETS exposure in this group as well. 35 If
another correlate of socio-economic status
increased lung cancer risk (for example,
air quality or diet), an association between
lung cancer and ETS could be, at least
partly, the spurious result of the association
of both lung cancer and ETS with socioeconomic
status. A number of studies
have found positive associations between
lung cancer and outdoor levels of air
pollution and measures of traffic density.
Risk of breast cancer, on the other hand, is
positively associated with socio-economic
status; studies which inadequately control
for socio-economic status or reproductive
characteristics may fail to note a true
association. The low SES population has
higher rates of smoking and thus a higher
likelihood of exposure to ETS.
Spousal smoking and cancer
Much of the focus on ETS and cancer has
revolved around the risk associated with
spousal exposure. This choice of focus
for lung cancer and ETS was necessary in
the early days because so few of the early
studies had better exposure measures but
its continued use is unfortunate because:
(1) with a binary exposure measure (spouse
smoked or not), all the “exposed” are put
into one category even though there is a
large gradient of exposure; (2) important
sources of exposures are missed, particularly
parental and workplace ETS exposures,
which may be non-existent, equal to or far
greater than spousal exposure. As a result,
without childhood and workplace exposure
information, many women, who may have
had substantial total ETS exposure, will
be put into the ETS unexposed referent
category for spousal exposure.
eTS and lung cancer
Early studies of ETS and lung cancer
focussed on spousal exposure, in part
because two important early studies, one
in Japan 36 and one in Greece 37 observed
increased lung cancer risk in women with
a husband who smoked. Because Japanese
wives at the time were unlikely to have
been exposed to significant ETS from any
other source, a husband’s smoking history
was a good proxy for a wife’s ETS exposure.
This cohort study found that the rate of
lung cancer death in never-smoking women
whose husbands smoked was 45% higher
when compared to never-smoking women
with nonsmoking husbands.
Following publication of these results,
other researchers with existing lung cancer
datasets quickly used them to conduct
similar analyses. Often the only question
the studies asked about ETS, however, was
whether the husband smoked, even though
the wives may have had substantial ETS
exposure at work or as a child. By 1986,
twelve other analyses had been published;
these were summarized in the metaanalysis
of Wald and colleagues. 38
Between 1981 and 1996, 20 case-control
and three cohort analyses that examined
residential ETS were published. All but
three studies included fewer than 50 non-
smoking cases and most focussed on
spousal smoking only. In 1997, Hackshaw
et al. published a second meta-analysis
which essentially confirmed the results
of the original meta-analysis. 33 This time,
however, there were seven times as many
cases available and the data included
several far more rigorous, in-depth and
larger studies. Fifteen studies met the
three quality criteria for inclusion in the
meta-analysis. Hackshaw et al. calculated
an unadjusted relative risk for women of
1.24 (95% Confidence Interval (CI) 1.13-
1.36) for lifelong non-smokers living with
a spouse who currently smoked compared
with living with a spouse who had never
smoked. An adjusted estimate, taking into
account the possible bias that would be
introduced if any smokers with lung cancer
131 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
eported themselves as non-smokers,
resulted in an estimate of 1.17 (95% CI:
1.05-1.45). Because women may have ETS
exposure other than from their spouse,
misclassification of the true ETS exposure
status of some women will occur. Adjusting
for this, Hackshaw et al. estimated that
the OR would have been 1.42 (95% CI:
1.21-1.66) if spousal exposure alone were
compared to those truly unexposed. 33
A recent Canadian meta-analysis of ETS and
lung cancer found similar risk estimates
to previous meta-analyses and found no
statistically significant differences in the
estimated risks when studies were grouped
by study design. 39 The meta-analysis conducted
for IARC (2004) reported a pooled
relative risk for spousal exposure as 1.24
(95% CI: 1.14-1.34) among women based
on 46 studies and 1.37 (95% CI: 1.02-1.83)
among men based on 11 studies. 5 The report
concluded adult non-smokers exposed to
ETS have a higher risk for lung cancer.
A positive association was found in a large
European cohort study published in 2007
which concluded that ETS caused between
16 and 24% of lung cancers, mainly due to
the contribution of work-related exposure. 40
A meta-analysis of workplace ETS indicated
a 24% increase in lung cancer risk (RR 1.24,
95% CI: 1.18-1.29) among workers exposed
to environmental tobacco smoke. 41
Occupational ETS and lung cancer
By 1994, 14 studies had provided information
on the risks associated with
occupational ETS exposure. Five metaanalyses
of occupational ETS and lung
cancer were published between 1994 and
1996, each reporting on these 14 studies.
In all five, the summary risk estimate for
ever having been exposed to occupational
ETS was close to unity. All five metaanalyses
were conducted by employees
or consultants to the tobacco industry. 42
Several of the 14 studies included in the
meta-analyses had significant study design
deficiencies for addressing occupational
ETS exposure. 42 Some studies had only
current workplace exposure, some relied
heavily on proxy respondents (who likely
would be unable to provide an accurate
long-term occupational ETS exposure history)
and some included ex-smokers in the
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
group being analysed. A more recent metaanalysis
by Wells, 42 established stricter
quality criteria and revisited the weighting
of individual studies in the summary
estimate. Based on five studies meeting
six quality criteria, Wells found a summary
risk estimate of 1.39 (95% CI: 1.15-1.68).
The meta-analysis conducted for IARC
(2004) reported a pooled relative risk for
workplace exposure as 1.19 (95% CI: 1.09-
1.30) among women based on 19 studies
and 1.12 among men (95% CI: 0.80-1.56)
based on 6 studies. 5
Lifetime occupational and residential
ETS exposure and lung cancer risk
Table 1 summarizes recent studies of
lung cancer and ETS among women that
include measures of lifetime residential and
occupational ETS exposure. The Fontham
study 43 is the largest study in the USA, with
detailed exposure measures; the Boffetta
study was a large study conducted in
12 European countries through the IARC 32
and data from several of the other European
studies reported in the table are included
in the Boffetta study.
Where smoking is unrestricted in the
workplace, measured mean concentrations
of nicotine generally exceed those in
residences of smokers and, in some work
environments, the concentrations can be
several times as high as the average levels
in homes. 29 Table 1 contrasts spousal risks
with risks for the highest category (usually
the highest quartile) of occupational and
total ETS exposure. Exposure to spousal
smoking was generally associated with risk
increases of up to 25% in the individual
studies and a summary risk was calculated
as 1.20 (95% CI: 1.01-1.43). In contrast,
the individual study risk estimates for the
highest quartile of combined occupational
and residential exposure – and similarly for
the high occupational exposure estimates –
were often statistically significant and
generally ranged from about a 50% to 200%
increase (ORs of 1.5 to 3.0). Results of a
recent analysis in Canada 44 are consistent
with those of the other reported analyses,
although the study size was relatively small,
making the estimated risks somewhat
unstable. A summary risk estimate based on
the nine studies for women never-smokers
in the highest category of combined
132
residential and occupational lifetime ETS
exposure was 1.78 (95% CI: 1.49-2.12).
For those women in the highest category
of occupational exposure the summary risk
was 2.25 (95% CI: 1.81-2.79).
Observing increased risk primarily in those
subjects likely to have been most highly
exposed is not unexpected. Studies of nonsmokers
suggest that only those within the
top quartile of passive exposure manifest
much increase in urinary cotinine. 45
eTS and breast cancer
Breast cancer is the most commonly diagnosed
cancer among women in Canada,
and incidence rates among women 50 or
more rose gradually between 1975 and
1992, but since 1993 have stabilized. 46
The established potentially-modifiable risk
factors for female breast cancer (primarily
reproductive factors and lack of physical
activity) account for less than half of breast
cancer risk. 47 The published studies of
breast cancer and passive smoking provide
some conflicting evidence regarding the
impact of regular long-term exposure to
ETS on breast cancer risk.
Historically, most studies which looked
at active smoking and breast cancer
have not observed an association; some
have even suggested a reduced risk. 48
Palmer and Rosenberg, 49 in reviewing
19 studies of breast cancer meeting specific
quality criteria related to their ability to
evaluate smoking risk, found that relative
risks ranged from 0.93 to 1.3 for women
smoking at least one pack of cigarettes
per day, compared to never-smokers. They
concluded that “the current evidence
strongly supports the idea that there is no
risk of breast cancer related to smoking.”
However, it has been suggested that the
failure to note an increased risk for active
smoking may lie in the choice of referent
group. 50 In all 19 studies reporting on active
smoking and breast cancer, the referent
group included all never-smokers, many
of whom invariably were exposed to ETS.
Tables 2 to 4 presents a summary of the
published studies of breast cancer and ETS.
The basic study characteristics are given in
Table 2; Table 3 summarizes the exposure
measures, and Table 4, the risk results. The
studies had to meet two basic study quality
criteria: (1) include some quantitative
measure of adult exposure to ETS and (2)
confine the analysis to women who had
never actively smoked. The studies are
briefly described below in historic order,
followed by a summary of a recent metaanalysis
synthesizing the results.
Initial interest in the issue of breast cancer
and ETS arose from a cohort study in
Japan 51 which reported that breast cancer
deaths were elevated by 32% among
women whose husbands smoked. 52 A casecontrol
study in North Carolina, 53 noted a
62% increase in breast cancer risk among
women exposed to ETS, primarily among
premenopausal women. 52 A British casecontrol
study of breast cancer in women
under age 37 found more than a doubling
of risk associated with ETS in the subset
of cases and controls for whom passive
smoking exposure was known. 54
Prompted by these findings, Morabia
mounted a detailed case-control study
in Switzerland to directly evaluate the
impact of ETS on breast cancer. 55 The study
collected detailed year-by-year histories of
passive and active smoking in residential,
workplace and social environments from
244 women with breast cancer and 1032 population
controls. Of these, 126 cases and
620 controls had no exposure to active
smoking. Measurement of cotinine levels
in study subjects’ urine augmented the
validation work. In all four of these earlier
studies, the ORs associated with the highest
levels of exposure were close to or over 2.0.
The Swiss study, which most accurately
assessed the level of ETS exposure and
restricted the passively exposed category
to at least one hour per day for at least
one year found ORs of 3.1 (95% CI: 1.3-
7.5) and 3.2 (95% CI: 1.5-6.5) for less than
50 and greater than 50 hours/day-years of
passive exposure. Wells calculated a fourstudy
combined summary relative risk
of 1.83 (95% CI: 1.40-2.40) for passive
smoking and 2.17 (95% CI: 1.63-2.88) for
ever having actively smoked. 52
Lash and Aschengrau 56 in a case-control
study in Massachusetts of 265 cases and
765 controls, also found a doubling of risk
with passive exposure and with active
smoking. Women exposed to ETS before
age 12 had higher risks. The sample was
primarily postmenopausal. A study by Zhao
et al. 57 in Chengdu, China found more than
a doubling of breast cancer risk for passive
(OR 2.36, 95% CI: 1.66-3.66) and active
smoking (OR 3.54, 95% CI: 1.36-9.18).
Johnson et al. reported the results of a
large Canadian case-control study (805 premenopausal
and 1512 postmenopausal
women with newly diagnosed primary
breast cancer, and 2438 population controls).
27 Among premenopausal women
who were never active smokers, regular
exposure to ETS was associated with an
adjusted breast cancer OR of 2.3 (95%
CI: 1.2-4.6). ETS exposure showed a
strong dose-response trend (test for trend
p < 0.001) with an OR of 2.9 (95% CI:
1.3-6.6) for more than 35 years of ETS
residential and/or occupational exposure.
When premenopausal women who had
ever actively smoked were compared with
women never regularly exposed to passive
or active smoke, the adjusted OR for breast
cancer was also 2.3 (95% CI: 1.2-4.5). At the
same time, a direct comparison of women
who had actively smoked with women who
had never actively smoked, without
controlling for passive smoking, showed
no increase in premenopausal breast cancer
risk, consistent with the active smoking
meta-analysis of Palmer and Rosenberg. 49
Among postmenopausal women who were
never active smokers in the Canadian
study, regular exposure to ETS was
associated with an adjusted breast cancer
OR of 1.2 (95% CI: 0.8-1.8) and an OR of
1.4 (95% CI: 0.9-2.3) for the most highly
exposed quartile of women. The adjusted
OR for postmenopausal breast cancer risk
for women who had ever actively smoked
compared with women never regularly
exposed to passive or active smoke was
1.5 (95% CI: 1.0-2.3). Statistically significant
dose-response relationships were
observed with increasing number of years
of smoking, increasing number of packyears
and decreasing number of years
since quitting. Women with 35 or more
years of smoking had an adjusted OR of
1.7 (95% CI: 1.1-2.7). Passive and active
smoking were associated with a 50% to
90% increase in risk among the younger
half of the postmenopausal women (age
up to 62). Risk was near null for the older
women (age 63 to 75).
A prospective Korean cohort study found
results quite similar to the Canadian study.
The cohort study of 165,000 Korean civil
servants and their spouses included a total
of 138 pre- and postmenopausal breast
cancer cases. Jee et al. found an overall
relative risk of 1.2 for wives of ex-smokers,
1.3 for wives of current smokers, and 1.7
(95% CI: 1.0-2.8) for wives of current
smokers with at least 30 years of smoking. 58
An extended follow up of the cohort now
includes 506 incident breast cancer cases.
Preliminary analyses of these data suggest
that women who lived with men who were
smoking 20 or more cigarettes per day had
a relative risk of 2.1 (95% CI: 1.5-3.0) for
breast cancer under age 50 and 1.6 (95%
CI: 1.0-2.6) for breast cancer at age 50 or
higher. (Personal communication with the
author, July 2000).
Two large American cohort studies,
however, have not found an association
between ETS and breast cancer risk. A
cohort study using the American Cancer
Society’s CPS-II (Cancer Prevention Study 2)
cohort, 59 examined breast cancer in a
12-year follow up of 147,000 never-smoking
wives and found no overall increase in the
risk of death from breast cancer associated
with living with a husband who smoked
(RR=1.0). An analysis of the Nurses Health
Study cohort found a relative risk of breast
cancer for regular passive exposure at work
and at home (in 1982) of 0.90 (95% CI:
0.67-1.22), while the relative risk for active
smoking was 1.04 (95% CI: 0.94-1.15). 60 A
Japanese cohort study also did not observe
any increased risk (RR=0.6). 61
Two case-control studies from North
Carolina reported by Marcus et al. 62 , and by
Millikan et al. 63 did not observe an increased
risk with either adolescent or adult ETS.
However, although childhood exposure
to passive smoking was quantified, these
studies asked only one question on adult
exposure to ETS, namely, had the subjects
lived with a smoker when they were
18 years of age or older.
133 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
Table 1
lung cancer risk associated with spousal, occupational and total passive smoking in female never-smokers –
population studies with at least adult lifetime residential and occupational assessment of eTS exposure
Study Spousal risk
Based on a new set of cases and controls,
Lash and Aschengrau 64 were unable
to replicate their earlier findings of an
increased risk of breast cancer with
exposure to ETS, with no effect observed
with either active smoking (OR 0.72, 95%
CI: 0.55-0.95), or passive smoking (OR
0.85, 95% CI: 0.63-1.1). However, a recent
German case-control study 65 reported an
increased risk for ETS (OR 1.59, 95% CI:
1.06-2.39) and for active smoking (OR
1.45, 95% CI: 0.96-2.19).
Delfino and colleagues 66 examined the issue
of N-acetyltransferase 2 (NAT2) genotype
as it relates to smoking and breast cancer
risk. While finding no evidence that NAT2
was either a risk factor for breast cancer,
or that it altered susceptibility to tobacco
smoke, this study did note modest increases
in risk to women exposed to ETS. The
study by Gammon and colleagues 67 , while
not observing an association between ETS
and breast cancer overall (OR 1.04, 95%
CI: 0.81-1.35), observed a significantly
increased risk for women who lived with
a smoking spouse for more than 27 years
(OR 2.10, 95% CI: 1.47-3.02).
Reynolds et al. (2004) conducted a study of
passive and active smoking in the California
Teachers Study cohort. 68 An elevated risk
for current smokers was reported. Relative
to never-smokers not exposed to household
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
ETS the hazard ratio was 1.25 (95% CI:
1.02-1.53). ETS exposure was limited to the
question of ever having lived with a smoker
as a child or adult. There was no association
reported between ETS exposure and breast
cancer among never-smokers, although a
revised analysis using women age under 50
at diagnosis found a risk of 1.27 (95% CI:
0.84-1.92) for women exposed residentially
both in childhood and as adults. 69
Shrubsole et al. (2004) using casecontrol
data from the population-based
Shanghai Breast Cancer Study reported
no association with spousal smoking. 70
There was some evidence for elevated risk
for ETS exposure in the workplace of five
hours or more per day (OR=1.6, 95% CI:
1.0-2.4) with a significant dose-response
trend (p=0.02). Hanaoka et al. conducted
a study of active and passive smoking in
a cohort of Japanese women ages 40-59
with ten years follow up. 71 An elevated
risk was reported for active and passive
smoking for premenopausal women but not
postmenopausal women. Among women
premenopausal at baseline with a reference
of never-active smokers without ETS exposure,
the RR for ever-smokers was 3.9
(95% CI: 1.5-9.9). Among premenopausal
women at baseline the RR for residential
or occupational/public exposure to ETS
among never-active smokers was 2.6 (95%
CI: 1.3-5.2).
134
Combined residential and
occupational exposure –
high exposure category
Biological Plausibility
High occupational
exposure category
Fontham et al. 1994 (USA) 43 1.23 (0.96–1.57) 1.74 (1.14–2.65) 1.86 (1.24–2.78)
Boffetta et al. 1998 (Europe) 32a 1.11 (0.88–1.39) 1.49 (0.93–2.38) 1.87 (1.10–3.28)
Nyberg et al. 1998 (Sweden) 86 1.05 (0.65–1.68) 2.52 (1.28–4.9) 2.51 (1.28–4.9)
Jockel et al. 1998 (Germany) 45 1.12 (0.54–2.32) 3.24 (1.44–7.32) 3.10 (1.12–8.60)
Zhong et al. 1999 (China) 87 1.1 (0.8–1.5) 1.8 (1.1–2.8) 2.9 (1.8–4.7)
Kreuzer et al. 2000 (Germany) 88 0.96 (0.70–1.33) 1.39 (0.96–2.01) 2.52 (1.12–5.71)
Lee et al. 2000 (Taïwan) 89 2.2 (1.5–3.3) 2.8 (1.6–4.8) Not reported
Wang et al. 2000 (China) 90 Not reported 1.51 (0.9–2.7) 1.93 (1.04–3.58)
Johnson et al. 2001 (Canada) 44 1.21 (0.6–4.0) 1.82 (0.8–4.2) 1.58 (0.6–4.0)
Summary Risk Estimates b 1.20(1.01–1.43) 1.78(1.49–2.12) 2.25 (1.81–2.79)
a The Nyberg, Jockel and earlier Kreuzer data (173 of 292 cases) are included in this 12 centre, 7 country European study.
b Calculated using the method of DerSimonian and Laird 91
It is biologically plausible that cancer
sites not directly in contact with tobacco
smoke can be affected by it. For instance,
pancreatic, cervical and bladder cancers
have higher incidence among smokers. 72
Petrakis et al. 73,74 report cigarette smoke
mutagens in the breast fluid of non-lactating
women, and nicotine has been found in
greater concentrations in the breast fluid
of smokers than in the plasma. 75
Because mutagens in cigarette smoke
accumulate in the breast tissue of nonlactating
women, 73,74 it is biologically plausible
that exposure to tobacco smoke is
related to breast cancer. Compounds similar
to those found in tobacco smoke (e.g., 7,
12-dimethylbenz(a)anthracene (DMBA)) are
powerful breast carcinogens in animals. 76
A number of studies have suggested that
both passive and active smoking were
stronger risk factors for premenopausal
than for postmenopausal breast cancer,
suggesting that there may be a subgroup
of women at increased susceptibility for
breast cancer when exposed to tobacco
smoke (passive or active exposure), who
tend to express their risk after relatively low
exposures (and thus primarily at younger
ages). Recent studies have focussed on the
possibility that N-acetylation phenotype
may affect breast cancer risk. The acetylator
Table 2
Published studies of passive smoking and breast cancer risk
Never-smokers
Study Place Years Study type Outcome age range # of cases # of controls
Hirayama 199251a Japan 65–81 Prospective Death 40+ 115 91,540
Sandler et al. 198553a USA –
North Carolina
79–81 Case/control Diagnosis 15–59 32 177
Smith et al.199454a United Kingdom 85–88 Case/control Diagnosis
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
Table 3
Published studies of passive smoking and breast cancer risk
Passive smoking exposure assessment
Study Summary of exposure measures Childhood exposure
adult residential
exposure
Hirayama 1992a Husband’s smoking history No Husband’s
smoking history
Sandler et al. 1985a Childhood and husband’s history Yes Husband’s
smoking history
136
Occupational
exposure
No
Smith et al.1994a Lifetime residential and occupational Detailed history Detailed history Detailed history
Morabia et al. 1996 Lifetime residential and occupational
and social
Detailed history Detailed history Detailed history Social
Millikan et al. 1998 Residential Years with smoker
at home
Lived with a smoker No
Lash et al.1999 Lifetime residential Yes Yes No
Zhao et al. 1999 Lifetime passive smoking history Yes Yes Yes Yes
Jee et al. 1999 Husband’s smoking history No Husband’s
smoking history
No
Johnson et al. 2000 Lifetime residential and occupational # of smokers in # of smokers in # of smokers in
each residence each residence each job/immediate
work area
Wartenberg et al. 2000 Husband’s smoking history No Husband’s
smoking history
Nob Delfino et al. 2000 Adult residential No Adult residential No No
Marcus et al. 2000 Residential Yes Lived with a smoker No
Nishino et al. 2001 Living with a smoker in 1984 No Living with a smoker
in 1984
No No
Egan et al. 2002 Maternal/paternal smoking, years
as adult living with smoker, current
(1982) work and home exposure
Kropp et al. 2002 Childhood, residential and
occupational history
Lash et al. 2002 Years of exposure; age first lived
with a smoker
Maternal and/or
paternal smoking
Years lived with
smoker, current, 1982
No
Current, in 1982 only No
Detailed history Detailed history Yes No
Yes Years lived with
smoker
No No
Gammon et al. 2004 Parental and spousal exposure Yes Yes No No
Reynolds et al. 2004 Residential Yes Yes No No
Shrubsole et al. 2004 Husband’s smoking history
No Husband’s
Hours per day over No
and occupational
smoking history past 5 years
Hanaoka et al. 2005 Residential and occupational Yes Yes Categorical No
a Risk estimates were obtained by Wells through personal communication with the authors. 52
b For main analysis no occupational exposure
See Table 2 for citation
Other
exposure
Table 4
Published studies of smoking and breast cancer risk
Passive smoking active smoking
Overall exposure Higher exposure category Overall exposure
Study Overall Pre b Post b Overall Pre Post Overall Pre Post
Hirayama 1992 36a 1.32
(0.83–2.09)
Sandler et al. 1985a 1.62
(0.76–3.44)
Smith et al.1994a 2.53
(1.19–5.36)
Morabia et al. 1996 2.3
(1.5–3.7)
Millikan et al. 1998 1.3
(0.9–1.9)
Lash et al.1999 2.0
(1.1–3.7)
Zhao et al. 1999 2.36
(1.66–3.66)
Jee et al. 1999 1.3
(0.9–1.8)
Johnson et al. 2000 1.48
(1.06–2.07)
Wartenberg et al. 2000 1.0
(0.8–1.2)
Delfino et al. 2000 1.78
(0.77–4.11)
Marcus et al. 2000 0.8
(0.6–1.1)
Nishino et al. 2001 0.58
(0.32–1.1)
Egan et al. 2002 1.07
(0.88–1.30)
Kropp et al. 2002 1.61
(1.08–2.39)
Lash et al. 2002 0.85
(0.63–1.10)
Gammon et al. 2004 1.04
(0.81–1.35)
Reynolds et al. 2004c 0.94
(0.82–1.07)
Shrubsole et al. 2004d 1.02
(0.81–1.29)
Hanaoka et al. 2005 1.1
(0.8–1.6)
Blank = Not reported
NA= Not applicable
1.50
(0.5–4.2)
7.1
(1.6–31.3)
2.69
(0.85–9.3)
3.6
(1.6–8.2)
1.5
(0.9–2.8)
2.1
(1.0–4.1)
2.56
(1.63–4.01)
2.3
(1.2–4.6)
1.1
(0.8–1.6)
1.21
(0.78–1.90)
0.93
(0.71–1.22)
1.10
(0.83–1.46)
2.6
(1.3–5.2)
1.0
(0.3–3.6)
1.53
(0.78–3.02)
0.9
(0.4–2.2)
NA NA
2.5
(1.5–4.2)
2.24
(0.75–6.68)
1.2
(0.7–2.2)
2.0
(1.1–3.7)
2.38
(1.66–3.40)
1.2
(0.8–1.8)
0.93
(0.68–1.29)
0.6
(0.4–1.0)
2.1
(1.0–4.1)
1.7
(1.0–2.8)
1.0
(0.8–1.4)
1.03
(0.86–1.24)
1.83
(1.16–2.87)
0.75
(0.47–1.2)
1.22
(0.90–1.66)
a Risk estimates were obtained by Wells through personal communication with the authors. 52
b Pre = Premenopausal, Post = Postmenopausal
c Reynolds et al. 2004 passive smoking higher exposure categories from Reynolds et al. letter (2006). 69
d Shrubsole et al. (2004) combined husband or workplace only and husband and workplace exposure.
See Table 2 for citations
2.9
(1.3–6.6)
1.27
(0.84–1.92)
Age 50–69
1.97
(1.07–3.6)
1.59
(1.01–2.52)
1.21
(0.58–2.51)
NA 2.00
(0.98–4.12)
1.4
(0.9–2.3)
0.87
(0.73–1.03)
3.0
(1.9–4.8)
1.1
(0.7–1.7)
2.0
(1.1–3.6)
3.54
(1.36–9.18)
1.0
(0.8–1.2)
1.25
(0.27–5.82)
1.2
(0.8–1.6)
1.15
(0.98–1.34)
1.45
(0.96–2.19)
0.90
(0.8–1.0)
1.33
(0.97–1.83)
1.25
(1.02–1.53)
3.5
(1.5–7.8)
1.4
(0.8–2.6)
2.3
(1.2–4.5)
0.98
(0.54–1.78)
0.96
(0.55–1.68)
1.7
(1.1–2.6)
1.5
(1.0–2.3)
1.08
(0.72–1.62)
1.21
(0.95–1.54)
137 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
sources of ETS exposure, childhood, adult
residential and occupational), yielded a
higher pooled risk estimate for ETS-exposed
non-smokers of 1.90 (95% CI: 1.53-2.37).
Studies with less complete ETS exposure
measures resulted in little increase in risk
(1.08). For pre-menopausal breast cancer,
the overall risk associated with ETS exposure
was 1.68 (95% CI: 1.33-2.12). Studies
with better exposure measures yielded
a premenopausal risk estimate of 2.19
(95% CI: 1.68-2.84). Figure 1 summarizes
the individual study premenopausal risk
estimates for all exposed women. For
women who had smoked the breast cancer
risk estimate was 1.53 (95% CI: 1.22-1.91)
when smokers were compared to women
who had neither active nor regular passive
smoke exposure; 2.08 (95% CI: 1.44-3.01)
for more complete and 1.15 (95% CI:
0.98-1.35) for less complete ETS exposure
assessment.
Breast Cancer and ETS:
Summary and Conclusions
There is a considerable degree of heterogeneity
in risk estimates amongst the
10
1
0.1
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
studies of breast cancer and ETS. In general,
cohort studies have noted lower risks than
case-control studies. For those studies
which report data according to menopausal
status, relative risks tend to be higher in
pre-menopausal as compared to postmenopausal
women. Studies also varied
in how well confounders were controlled,
and how completely exposure to passive
smoking was assessed.
Prospective cohort studies are generally
seen as methodologically superior to casecontrol
studies, as they are generally free
of concerns of response bias, proxy data
and poor response rates, which are at least
hypothetical problems with case-control
studies. If case subjects were more likely
than control subjects to recall times they
lived or worked with smokers, then this
could create an artificial increase in risk.
The fact that three Asian cohort studies
observed increased risk and dose-response
relationships (where the case-control
concerns do not apply); that both casecontrol
and cohort studies with poorer
exposure measures observe similar (lower)
138
summary risk estimates; that this kind of
bias does not appear to have substantively
impacted on case-control studies of ETS
and lung cancer or heart disease; and that
premenopausal risk is fairly consistently
higher than postmenopausal risk in these
case-control studies all argue against
these case-control specific potential
biases as the explanation for the observed
increases in risks.
An alternate explanation may be the
inability of many cohort studies (and the
case-control studies with poorer exposure
assessment) to adequately identify the
unexposed comparison group. For example,
in the main analysis of the CPS-II American
cohort study, ETS exposure information was
limited to a history of spousal smoking and
workplace and household exposure in 1982
only. The study did not collect information
on the history of workplace, childhood or
non-husband residential ETS exposure for
the women. In a North American study,
missing these ETS exposures is likely to
result in important misclassification of
exposure status. 80 In their dose-response
FIguRe 1
Meta-analysis of passive smoking and premenopausal breast cancer risk among women who never smoked. 79
Individual and summary risk estimates for women ever regularly exposed to passive smoking, stratified by the completeness of the
passive smoking exposure assessment and study design. For Reynolds et al., 2004, new risk estimate from Reynolds et al. letter (2006) 69
presented for women exposed in childhood and adulthood (risk for all exposed women not reported).
Hirayama 1992
Wartenberg et al. 2000
Reynolds et al. 2004
Cohort
Studies likely to have missed important sources
of passive smoking exposure
Hanaoka et al. 2005
Sandler et al. 1985
Millikan et al. 1998
Case-control (All case-control)
Delfino et al. 2000
Shrubsole et al. 2004
Gammon et al. 2004
Studies unlikely to have missed important sources
of passive smoking exposure
Smith et al. 1994
Morabia et al. 1996
Zhao et al. 1999
Relative risk (%95 CI)
Johnson et al. 2000
Kropp et al. 2002
Missed Exposure –
Cohort Studies
Summary estimates
Missed Exposure –
Case-Control
Better Exposure
Assessment
analysis only 50% of women were
categorized as exposed to ETS from their
husbands. 59 Other studies that examined
major sources of ETS exposure, including
residential, workplace and sometimes social
exposure to ETS, have found 80 to 95%
of the women were exposed to ETS. 27,43,56
The Nurses Cohort Study, the second large
American cohort study, also only collected
current workplace exposure in 1982 60 and
the third study on California teachers has
reported only on residential exposure. 68
This misclassification may seriously dilute
risk estimates. 44 The results are particularly
divergent for the women with higher ETS
exposure. 29
The IARC concluded in 2002 that the
collective evidence on ETS and breast
cancer was not supportive of a causal
association. 5 Although four of the ten casecontrol
studies reviewed found significant
increases in risk, prospective studies as a
whole did not report increased risk. The
lack of a positive dose-response relationship
also weighted against an association.
The IARC evaluation was limited to the
15 studies of ETS and breast cancer available
to mid 2002, and therefore didn’t include
several cohort studies published since 2002
that have suggested active smoking risks.
As well, the IARC document presented only
descriptive data on the individual studies
and a non-systematic evaluation of the
quality of each study. No meta-analyses
were performed to try to synthesize the
15 studies or examine the impact of study
characteristics or quality, sub-populations
or menopausal status on observed risk.
In contrast, the California EPA became the
first agency concerned with environmental
health to evaluate the association between
premenopausal breast cancer and ETS as
conclusive, 3 based partly on the metaanalysis
published in 2005 which reported
an overall premenopausal breast cancer
risk for ETS among life-long non-smokers of
1.68 (95% CI 1.33-2.12). 79 One factor was
the additional studies available including
five of ETS and breast cancer. An additional
factor in the California EPA conclusion was
that using a referent population of neversmoking
women not exposed to ETS, while
there continued to be some heterogeneity
in study results, the studies reviewed
provided evidence of a role for active
smoking in causation of breast cancer
and included evidence of a dose-response
relationship. A summary and extension of
the Cal/EPA 2005 review also concluded
ETS was causally related to breast cancer
in premenopausal women. 81 Others have
concluded that the “jury is still out” on the
subject of ETS and breast cancer. 82
A relationship between ETS and breast
cancer has significant public health
implications. Over 90% of the subjects
in the large Canadian population-based
study reported regular exposure to tobacco
smoke at some time. Over 50% had been
regular smokers at some time in their
life, and another 40% of the women
(all never-smokers) had been regularly
exposed in some period of their life to
ETS. Unlike most other established risk
factors for breast cancer, exposure to ETS
is modifiable through public policy. More
study is warranted to clarify the exposure
specifics of the relationship of ETS to breast
cancer.
eTS and brain cancer
Evidence on passive smoking and brain
cancer risk in adults is based on four
studies. The cohort mortality study in Japan
by Hirayama, 36 with only 34 deaths, found
the strongest association, with a more than
threefold increase in brain cancer mortality
among non-smoking wives of husbands
who smoked. Risk varied by the number
of cigarettes the husband smoked per day:
the relative risk was 3.0 (95% CI: 1.1-8.6)
for one to 14 cigarettes per day, 6.3 (95%
CI: 2.0-19.4) for 15 to19 cigarettes, and 4.3
(95% CI: 1.5-12.2) for 20 or more cigarettes.
A case-control study in the United States,
with only 11 non-smoking cases, 53 found
increased risks for some types of cancer,
including a non-significant increase in brain
cancer risk related to husbands’, but not
wives’, smoking. In a case-control study of
intracranial meningioma and smoking in
the United States results for active smoking
were not consistent, but among never
active smokers, passive smoking from a
spouse was associated with increased risk
in both sexes (n=95 cases, 202 controls OR
2.0, 95% CI: 1.1-3.5). 83
The Adelaide Adult Brain Cancer Study 84
was one of ten case-control studies with
a common protocol, coordinated through
IARC and including data on passive
exposure to parental, spousal and co-worker
smoking. It found increased risk estimates
associated with lifetime passive exposure
for meningioma (OR 2.5, 95% CI: 1.0-6.0)
and glioma (OR 1.35, 95% CI: 0.6-2.7).
Unfortunately the study did not separate
smokers from non-smokers, making it
difficult to separate ETS effects in smokers
from those in non-smokers.
eTS and childhood cancer
Over 30 published studies have examined
maternal and/or paternal exposure to
tobacco smoke and childhood cancer. For
a review of these see Chapter 7 of the
California EPA reports. 3 For all cancers
combined the evidence was considered
inconclusive for an association with
maternal smoking and suggestive for
paternal smoking based on relatively
small risks. Findings were considered
inconclusive for childhood leukemia, and
suggestive for childhood lymphomas
and brain cancer, although the suggested
association may be with pre-conceptual
smoking rather than ETS. An earlier metaanalysis
by Boffetta et al. 85 found a small
overall increased risk of childhood cancer
in association with maternal smoking in a
summary of 12 studies (RR 1.10, 95% CI:
1.03-1.19), but not for specific neoplasms.
The summary RR for paternal smoking and
childhood brain cancer from ten studies
was 1.22 (95% CI: 1.02-1.40), and for
lymphoma, the summary risk RR from
four studies was 2.08 (95% CI: 1.08-3.98).
However, there is no clear evidence of doseresponse
relationships. As well, childhood
cancer studies are invariably case-control
in design; such studies have the potential
for recall bias.
Public health efforts to
reduce eTS exposure
Much progress has been made in reducing
exposure to ETS in Canada, the United
States, Australia, and increasingly in
Europe as well (in particular Ireland went
smoke-free for virtually all public places
in March, 2004). Many non-governmental
139 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
organizations have lobbied for smoking
restrictions, and various levels of government
have instigated media campaigns to
raise awareness of the dangers of ETS and
have enacted legislation to restrict smoking
in public places. Smoking restrictions in
larger workplaces and federal buildings
in Canada have existed since the late 1980s.
By 2004, 91% of Canadians reported that
they worked in an environment in which
there were at least some restrictions
on smoking.
In 2000, 27% of children under the age of
18 were regularly exposed to ETS. In 2003,
only 16% were regularly exposed. (http://
www.hc-sc.gc.ca/hl-vs/tobac-tabac/
research-recherche/stat/index-eng.php).
The State of California banned smoking in
all restaurants in 1998 and in bars in 1999.
Massachusetts has eliminated smoking
from restaurants, as has New York City.
(For a short overview of the laws and
impact on restaurant revenues see http://
www.repace.com/fact_rest.html). There
have been a wide variety of restrictions in
local municipalities across Canada. The
nation’s capital, Ottawa, brought in a total
ban in indoor public places in the summer
of 2002. (See Tobacco Control By-laws in
Canada at http://www.hc-sc.gc.ca/hl-vs/
pubs/tobac-tabac/tcbc-rmtc/index_e.html
and Canadian Law and Tobacco at http://
www.cctc.ca/cctc/EN/lawandtobacco).
Provincially, in British Columbia (BC),
through an initiative of the BC Workers
Compensation Board to protect workers,
smoking in bars and restaurants was
banned on January 1st, 2000. In 2001, these
regulations were modified to allow the
construction of smoking rooms which do
not have to be enclosed, and into which staff
may volunteer to serve. An important boost
to smoke-free environments in Canada
occurred on June 1 st 2006, when both
Ontario and Quebec brought in provincewide
bans on smoking in all indoor public
places including bars and restaurants.
Thus, smoking is now banned in these
two provinces in virtually all venues and
there are no provisions for designated
smoking rooms accessible to the public.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
Over 95% of Canadians now live in
communities with 100% protection from
ETS in public places. 92
Conclusions
Over the last 25 years, ETS has been
implicated in delayed childhood development,
childhood respiratory problems,
adverse reproductive outcomes, cardiovascular
disease and cancer. ETS has been
established as a causal agent in lung cancer.
The California EPA has recently become the
first agency concerned with environmental
health to come to the conclusion that there
is a causal relationship between regular
long-term ETS exposure and breast cancer
in younger, primarily premenopausal
women. 3 Our understanding of individual
susceptibility could be refined through
further genetic epidemiological studies,
and the dose-response paradigm of carcinogenicity
for tobacco smoke in relation
to breast cancer may need to be reconsidered
to include thresholds and susceptible
subgroups.
Exposure to tobacco smoke has been
epidemic in many developed countries for
at least the last half century. Fortunately
the landscape is changing rapidly regarding
smoking in public places in North America, in
particular. There has been a major shift
in public attitudes towards the social
acceptability of cigarette smoking in public.
Effective measures to control exposure have
included legislated bans in workplaces
and public places and no smoking policies
where bans have not been implemented
(homes and cars). However, there are still
many children, spouses and workers being
exposed to tobacco smoke daily. In light
of the risks associated with lung cancer,
breast cancer, and nasal cancer, as well as
heart disease and asthma, it is clearly time
to redouble efforts to reduce non-smokers
exposure to ETS in all environments.
References
1. National Research Council. Environmental
tobacco smoke: Measuring exposures and
assessing health effects. 1986. Washington,
D.C., National Academy Press.
140
2. National Institutes of Health. Health
Effects of Exposure to Environmental
Tobacco Smoke: Report of the California
Environmental Protection Agency. 1999.
Washington, U.S.A. NIH Pub No. 994645.
Smoking and Tobacco Control Monograph
Number 10.
3. California Environmental Protection
Agency, Air Resources Board and Office of
Environmental Health Hazard. Proposed
Identification of Environmental Tobacco
Smoke as a Toxic Air Contaminant. Available
at: http://www.arb.ca.gov/regact/ets2006/
ets2006.htm (accessed 21-02-2006). 2005.
4. U.S. Department of Health and Human
Services.Public Health Service.Office of the
Assistant Secretary for Health. The health
consequences of involuntary smoking:
A report of the Surgeon General. 1986.
Washington, D.C., DHHS (PHS).
5. International Agency for Research on Cancer.
IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans, Volume 83,
Tobacco Smoke and Involuntary Smoking.
2004. Lyon.
6. Yuan JM, Wang XL, Xiang YB, Gao YT,
Ross RK, Yu MC. Non-dietary risk factors
for nasopharyngeal carcinoma in Shanghai,
China. Int J Cancer 2000;85:364-369.
7. Kasim K, Levallois P, Abdous B, Auger P,
Johnson KC, Canadian Cancer Registries
Epidemiology Research Group.
Environmental tobacco smoke and risk
of adult leukemia. Epidemiology 2005;
16:672-680.
8. Zeegers MP, Goldbohm RA, van den
Brandt PA. A prospective study on active
and environmental tobacco smoking and
bladder cancer risk (The Netherlands).
Cancer Causes Control 2002;13:83-90.
9. Alberg AJ, Kouzis A, Genkinger JM et al. A
prospective cohort study of bladder cancer
risk in relation to active cigarette smoking
and household exposure to secondhand
cigarette smoke. Am J Epidemiol
2007;165:660-666.
10. National Institutes of Health, National
Cancer Institute, and Environmental
Protection Agency. Respiratory Health
Effects of Passive Smoking: Lung Cancer
and Other Disorders: The Report of the U.S.
Environmental Protection Agency. 933605.
[4]. 1993. Washington, USA., NIH. Smoking
and Tobacco Control Monograph.
11. National Health and Medical Research
Council. The health effects of passive
smoking. 1997. Australia.
12. Department of Health. Report of the
Scientific Committee on Tobacco and
Health. 1998. London, United Kingdom,
The Stationery Office.
13. World Health Organization. International
Consultation on Environmental Tobacco
Smoke (ETS) and Child Health: Consultation
Report. WHO Technical Document. 1-1-
1999.
14. U.S. Department of Health and Human
Services. Public Health Service. National
Toxicology Program. 9th Report on
Carcinogens. 2000. Washington, D.C., U.S.
Department of Health and Human Services.
15. International Agency for Research on Cancer.
IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans, Volume 38,
Tobacco Smoking. 1986. Lyon.
16. Shopland DR, Eyre HJ, Pechacek TF.
Smoking-attributable cancer mortality in
1991: Is lung cancer now the leading cause of
death among smokers in the United States?
J Natl Cancer Inst 1991;83:1142-1148.
17. Baliunas D, Patra J, Rehm J, Popova S,
Kaiserman M, Taylor B. Smokingattributable
mortality and expected years
of life lost in Canada 2002: Conclusions
for prevention and policy. Chronic Dis Can
2007;27:154-162.
18. Kaiserman MJ, Rickert WS. Carcinogens
in Tobacco Smoke: Benzo[a]pyrene from
Canadian Cigarettes and Cigarette Tobacco.
Am J Public Health 1992;82:1023-1026.
19. Thompson SG, Stone R, Nanchahal K,
Wald NJ. Relation of urinary cotinine
concentrations to cigarette smoking and to
exposure to other people’s smoke. Thorax
1990;45:356-361.
20. Anderson KE, Carmella SG, Ye M et al.
Metabolites of a tobacco-specific lung
carcinogen in nonsmoking women exposed
to environmental tobacco smoke. J Natl
Cancer Inst 2001;93:378-381.
21. Repace JL, Jinot J, Bayard S, Emmons K,
Hammond SK. Air nicotine and saliva
cotinine as indicators of workplace passive
smoking exposure and risk. Risk Anal
1998;18:71-83.
22. Reardon JT, Shaw CY, Chown GA.
Ventilation Strategies for Small Buildings.
1990. National Research Council of
Canada.
23. Health Canada. Canadian Tobacco Use
Monitoring Survey (CTUMS). Summary of
Results for 2005 (February to December).
Health Canada website. 2007.
24. Health Canada. Canadian Tobacco Use
Monitoring Survey (CTUMS). Summary of
Results for 2002 (February to December).
Health Canada website. 2006.
25. Stephens, T. Smoking in Canadian homes.
Special Report. 1999. Toronto, ON, Ontario
Tobacco Research Unit.
26. Johnson KC, Mao Y, Argo J et al. The
National Enhanced Cancer Surveillance
System: A case-control approach to
environment-related cancer surveillance in
Canada. Environmetrics 1998;9:495-504.
27. Johnson KC, Hu J, Mao Y, The Canadian
Cancer Registries Epidemiology Research
Group. Passive and active smoking and
breast cancer risk in Canada, 1994-97.
Cancer Causes Control 2000;11:211-221.
28. Guerin MR, Jenkins RA, Tomkins BA. The
chemistry of tobacco smoke: composition
and measurement. Chelsea, MI: Lewis
Publisher; 1992.
29. Hammond SK. Exposure of U.S. workers
to environmental tobacco smoke. Environ
Health Perspect 1999;107 Suppl 2:329-340.
30. Siegel M. Smoking and leukemia: evaluation
of a causal hypothesis. Am J Epidemiol
1993;138:1-9.
31. U.S.Department of Health and Human
Services.Public Health Service. Reducing
the health consequences of smoking:
25 years of progress. A Report of the
Surgeon General. 1989. Washington, D.C.,
DHHS (PHS).
32. Boffetta P, Agudo A, Ahrens W et al.
Multicenter case-control study of exposure
to environmental tobacco smoke and
lung cancer in Europe. J Natl Cancer Inst
1998;90:1440-1450.
33. Hackshaw AK, Law MR, Wald NJ. The
accumulated evidence on lung cancer
and environmental tobacco smoke. BMJ
1997;315:980-988.
34. Epidemiology of lung cancer. (Lung Biology
in Health and Disease; 74). Samet, J. M.
1994. New York, Marcel Dekker.
35. Curtin F, Morabia A, Bernstein MS. Relation
of environmental tobacco smoke to diet
and health habits: variations according
to the site of exposure. J Clin Epidemiol
1999;52:1055-1062.
36. Hirayama T. Cancer mortality in nonsmoking
women with smoking husbands
based on a large scale cohort study in
Japan. Prev Med 1984;13:680-690.
37. Trichopoulos D, Kalandidi A, Sparros L. Lung
cancer and passive smoking: conclusion of
Greek study. Lancet 1983;2(8351):677-678.
38. Wald NJ, Nanchahal K, Thompson SG,
Cuckle HS. Does breathing other people’s
tobacco smoke cause lung cancer? Br J Med
1986;293(6556):1217-1222.
39. Zhong L, Goldberg MS, Parent ME, Hanley JA.
Exposure to environmental tobacco smoke
and the risk of lung cancer: a meta-analysis.
Lung Cancer 2000;27:3-18.
40. Vineis P, Hoek G, Krzyzanowski M et al.
Lung cancers attributable to environmental
141 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
tobacco smoke and air pollution in nonsmokers
in different European countries: a
prospective study. Environ Health 2007;6:7.
41. Stayner L, Bena J, Sasco AJ et al. Lung
cancer risk and workplace exposure to
environmental tobacco smoke. Am J Public
Health 2007;97:545-551.
42. Wells AJ. Lung cancer from passive smoking
at work. Am J Public Health 1998;
88:1025-1029.
43. Fontham ET, Correa P, Reynolds P et al.
Environmental tobacco smoke and lung
cancer in nonsmoking women. A multicenter
study. JAMA 1994;271:1752-1759.
44. Johnson KC, Hu J, Mao Y, Canadian Cancer
Registries Epidemiology Research Group.
Lifetime residential and workplace exposure
to environmental tobacco smoke and lung
cancer in never-smoking women, Canada
1994-97. Int J Cancer 2001;93:902-906.
45. Jockel KH, Pohlabeln H, Ahrens W, Krauss M.
Environmental tobacco smoke and lung
cancer. Epidemiology 1998;9:672-675.
46. Canadian Cancer Society/National Cancer
Institute of Canada. Canadian Cancer
Statistics 2006. 2006. Toronto, Canada.
47. Madigan MP, Ziegler RG, Benichou J,
Byrne C, Hoover RN. Proportion of breast
cancer cases in the United States explained
by well-established risk factors. J Natl
Cancer Inst 1995;87:1681-1685.
48. Gammon MD, Schoenberg JB, Teitelbaum
SL et al. Cigarette smoking and breast cancer
risk among young women (United States).
Cancer Causes Control 1998;9:583-590.
49. Palmer JR, Rosenberg L. Cigarette smoking
and the risk of breast cancer. Epidemiol Rev
1993;15:145-156.
50. Wells AJ. Breast cancer, cigarette smoking,
and passive smoking. Am J Epidemiol
1991;133:208-210.
51. Hirayama, T. Lung cancer and other diseases
related to passive smoking: a large-scale
cohort study. Gupta PC, Hamner III JE, and
Murti PR, eds. Control of tobacco related
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
cancers and other diseases, international
symposium 1990. Bombay: Oxford
University Press, 1992. 129–137. 1992.
52. Wells AJ. Re: “Breast cancer, cigarette smoking,
and passive smoking”. Am J Epidemiol
1998;147:991-992.
53. Sandler DP, Wilcox AJ, Everson RB.
Cumulative effects of lifetime passive
smoking on cancer risk. Lancet 1985;
1(8424):312-315.
54. Smith SJ, Deacon JM, Chilvers CE. Alcohol,
smoking, passive smoking and caffeine
in relation to breast cancer risk in young
women. UK National Case-Control Study
Group. Br J Cancer 1994;70:112-119.
55. Morabia A, Bernstein M, Heritier S,
Khatchatrian N. Relation of breast cancer
with passive and active exposure to tobacco
smoke. Am J Epidemiol 1996;143:918-928.
56. Lash TL, Aschengrau A. Active and passive
cigarette smoking and the occurrence of
breast cancer. Am J Epidemiol 1999;149:5-12.
57. Zhao Y, Shi Z, Liu L. [Matched case-control
study for detecting risk factors of breast
cancer in women living in Chengdu].
Zhonghua Liu Xing Bing Xue Za Zhi
1999;20:91-94.
58. Jee SH, Ohrr H, Kim IS. Effects of husbands’
smoking on the incidence of lung
cancer in Korean women. Int J Epidemiol
1999;28:824-828.
59. Wartenberg D, Calle EE, Thun MJ,
Heath CW, Jr., Lally C, Woodruff T. Passive
smoking exposure and female breast cancer
mortality. J Natl Cancer Inst 2000;92:
1666-1673.
60. Egan KM, Stampfer MJ, Hunter D et al.
Active and passive smoking in breast cancer:
prospective results from the Nurses’
Health Study. Epidemiology 2002;13:138-145.
61. Nishino Y, Tsubono Y, Tsuji I et al. Passive
smoking at home and cancer risk: a
population-based prospective study in
Japanese nonsmoking women. Cancer
Causes Control 2001;12:797-802.
142
62. Marcus PM, Newman B, Millikan RC,
Moorman PG, Baird DD, Qaqish B. The
associations of adolescent cigarette smoking,
alcoholic beverage consumption, environmental
tobacco smoke, and ionizing
radiation with subsequent breast cancer
risk (United States). Cancer Causes Control
2000;11:271-278.
63. Millikan RC, Pittman GS, Newman B et al.
Cigarette smoking, N-acetyltransferases 1
and 2, and breast cancer risk. Cancer
Epidemiol Biomarkers Prev 1998;7:371-378.
64. Lash TL, Aschengrau A. A null association
between active or passive cigarette smoking
and breast cancer risk. Breast Cancer Res
Treat 2002;75:181-184.
65. Kropp S, Chang-Claude J. Active and
passive smoking and risk of breast cancer
by age 50 years among German women.
Am J Epidemiol 2002;156:616-626.
66. Delfino RJ, Smith C, West JG et al. Breast
cancer, passive and active cigarette smoking
and N-acetyltransferase 2 genotype.
Pharmacogenetics 2000;10:461-469.
67. Gammon MD, Eng SM, Teitelbaum SL et al.
Environmental tobacco smoke and breast
cancer incidence. Environ Res 2004;96:
176-185.
68. Reynolds P, Hurley S, Goldberg DE et
al. Active smoking, household passive
smoking, and breast cancer: evidence from
the California Teachers Study. J Natl Cancer
Inst 2004;96:29-37.
69. Reynolds P, Hurley S, Goldberg D.
Accumulating evidence on passive and
active smoking and breast cancer risk. Int
J Cancer 2006;119:239.
70. Shrubsole MJ, Gao YT, Dai Q et al. Passive
smoking and breast cancer risk among
non-smoking Chinese women. Int J Cancer
2004;110:605-609.
71. Hanaoka T, Yamamoto S, Sobue T, Sasaki S,
Tsugane S. Active and passive smoking and
breast cancer risk in middle-aged Japanese
women. Int J Cancer 2005;114:317-322.
72. U.S. Department of Health and Human
Services. Public Health Service. Centres
for Disease Control, Prevention and Health
Promotion Office of Smoking and Health.
The health consequences of smoking:
cancer. A report of the Surgeon General.
1982. Washington, D.C., DHHS (PHS).
73. Petrakis NL, Maack CA, Lee RE, et al.
Mutagenic activity in nipple aspirates of
human breast fluid. (Letter). Cancer Res
1980;40:188-189.
74. Petrakis NL. Nipple aspirate fluid in
epidemiologic studies of breast disease.
Epidemiol Rev 1993;15:188-195.
75. Petrakis NL, Gruenke LD, Beelen TC, et.al.
Nicotine in breast fluid of nonlactating
women. Science 1978;199:303-304.
76. Hollingsworth AB, Lerner MR, Lightfoot
SA et al. Prevention of DMBA-induced
rat mammary carcinomas comparing
leuprolide, oophorectomy, and tamoxifen.
Breast Cancer Treat 1998;47:63-70.
77. Ambrosone CB, Freudenheim JL, Graham S
et al. Cigarette smoking, N-acetyltransferase
2 genetic polymorphisms, and breast cancer
risk. JAMA 1996;276:1494-1501.
78. Koo LC, Kabat GC, Rylander R, Tominaga S,
Kato I, Ho JH. Dietary and lifestyle correlates
of passive smoking in Hong Kong,
Japan, Sweden, and the U.S.A. Soc Sci Med
1997;45:159-169.
79. Johnson KC. Accumulating evidence on
passive and active smoking and breast
cancer risk. Int J Cancer 2005;117:619-628.
80. Johnson KC. Re: Passive smoking exposure
and female breast cancer mortality. J Natl
Cancer Inst 2001;93:719-720.
81. Miller MD, Marty MA, Broadwin R et
al. The association between exposure
to environmental tobacco smoke and
breast cancer: a review by the California
Environmental Protection Agency. Prev
Med 2007;44:93-106.
82. Elwood JM, Burton RC. Passive smoking
and breast cancer: is the evidence for cause
now convincing? Med J Aust 2004;181:
236-237.
83. Phillips LE, Longstreth WJ, Koepsell T,
Custer BS, Kukull WA, van Belle G.
Active and passive cigarette smoking
and risk of intracranial meningioma.
Neuroepidemiology 2005;24:117-122.
84. Ryan P, Lee MW, North B, McMichael AJ.
Risk factors for tumors of the brain and
meninges: results from the Adelaide Adult
Brain Tumor Study. Int J Cancer 1992;51:20-27.
85. Boffetta P, Tredaniel J, Greco A. Risk of
childhood cancer and adult lung cancer
after childhood exposure to passive smoke:
A meta-analysis. Environ Health Perspect
2000;108:73-82.
86. Nyberg F, Agrenius V, Svartengren K,
Svensson C, Pershagen G. Environmental
tobacco smoke and lung cancer in
nonsmokers: does time since exposure play
a role? Epidemiology 1998;9:301-308.
87. Zhong L, Goldberg MS, Gao YT, Jin F. A
case-control study of lung cancer and
environmental tobacco smoke among nonsmoking
women living in Shanghai, China.
Cancer Causes Control 1999;10:607-616.
88. Kreuzer M, Krauss M, Kreienbrock L,
Jockel KH, Wichmann HE. Environmental
tobacco smoke and lung cancer: a casecontrol
study in Germany. Am J Epidemiol
2000;151:241-250.
89. Lee CH, Ko YC, Goggins W et al. Lifetime
environmental exposure to tobacco smoke
and primary lung cancer of non-smoking
Taiwanese women. Int J Epidemiol
2000;29:224-231.
90. Wang L, Lubin JH, Zhang SR et al. Lung
cancer and environmental tobacco smoke
in a non-industrial area of China. Int
J Cancer 2000;88:139-145.
91. DerSimonian R, Laird N. Meta-analysis
in clinical trials. Control Clin Trials 1986;
7:177-188.
92. Physicians for a Smoke-Free Canada.
Newsletter. November 2007. Available at:
http://www.smoke-free.ca/pdf_1/fall2007web.pdf,
http://www.smoke-free.ca/pdf_1/
Q&A-smokefreecommunities.pdf
143 Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
air Pollution
Nhu D. Le, Li Sun and James V. Zidek
Toxic air pollutants are continuously released
into the air supply. Various pollutants come
from chemical facilities and small businesses,
such as automobile service stations
and dry cleaning establishments. Others,
such as nitrogen oxides, carbon monoxide
and other volatile organic chemicals, arise
primarily from the incomplete combustion
of fossil fuels (coal and petroleum) and
are emitted from sources that include car
exhausts, home heating and industrial power
plants. Pollutants in the atmosphere also
result from photochemical transformations;
for example, ozone is formed when molecular
oxygen or nitrogen interacts with
ultraviolet radiation.
An association between air pollution
exposure and lung cancer has been observed
in several studies. The evidence for other
cancers is far less conclusive. Estimates of
the population attributable risk of cancer
has varied substantially over the last
40 years, reflecting the limitations of studies;
these include insufficient information on
confounders, difficulties in characterizing
associations due to a likely lengthy latency
interval, and exposure misclassification.
Although earlier estimates were less than
one percent, recent cohort studies that have
taken into account some confounding factors,
such as smoking and education amongst
others, suggest that approximately 3.6% of
lung cancer in the European Union could be
due to air pollution exposure, particularly to
sulphate and fine particulates. A separate
cohort study estimated 5-7% of lung cancers
in European never smokers and ex-smokers
could be due to air pollution exposure.
Therefore, while cigarette smoking remains
the predominant risk factor, the proportion
of lung cancers attributable to air pollution
may be higher than previously thought.
Overall, major weaknesses in all airpollution-and-cancer
studies to date have
been inadequate characterization of longterm
air pollution exposure and imprecise or
no measurements of covariates. It has only
been in the last decade that measurements to
PM 2.5 become more widely available. A key
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
weakness of many studies is using fixed-site
monitoring data and assuming everyone in
a region had the same exposure. This ignores
spatial variability, and does not take into
account how individuals’ exposures differ
with pollution sources inside, outside, both
at work, home and elsewhere. More recent
efforts to model indicators of vehicular
traffic, and residential distances to major
roads and highway can allow for some of
this spatial variability to be better controlled
for. However, this still does not take into
account differences in activity patterns. If the
effect is small, these biases will compromise
the ability to detect an association. In most
situations, the resulting estimates tend to be
biased toward the null (i.e., no effect). For
misclassification of exposure the inability to
adequately control for confounding variables
may cause bias in either direction. Recent
improvements in statistical methodology use
measurements at fixed sites combined with
residential histories to estimate individuals’
cumulative exposures. They also recognize
measurement errors associated with covariates
in the analysis to improve estimates of
effects. Other challenges include the fact that
measurements of exposure and confounders
can change over time and long term data
are needed due to the anticipated latency
interval between harmful exposures and
development of cancer
Introduction
The London fog episode in 1952 played
a pivotal role in spurring research into
the effects of air pollution. 1 This episode
demonstrated dramatic short-term associations
between very high levels of ambient
particulate pollution and increases in
mortality. Since then, the health impacts
of air pollution have received increasing
attention. This has spanned a large number
of health outcomes and an examination of
several constituents of both indoor and
outdoor air and in workplace settings.
A US Environmental Protection Agency
(EPA) preliminary inventory of toxic release
estimated that about one billion kilograms
144
of toxic air pollutants are released into the
US air supply annually. 2 Various pollutants
come from chemical facilities and small
businesses, such as automobile service
stations and dry cleaning establishments.
Others, such as nitrogen oxides, carbon
monoxide and other volatile organic
chemicals, arise primarily from the
incomplete combustion of fossil fuels
(coal and petroleum) and are emitted
from sources that include car exhausts,
home heating and industrial power plants.
Pollutants in the atmosphere also result
from photochemical transformations; for
example, ozone is formed when molecular
oxygen or nitrogen interacts with ultraviolet
radiation. Table 1 describes commonly
measured pollutants and their sources. A
more detailed discussion on the sources
of several air pollutants can be found in
Fishbein. 2
Annual concentrations of total suspended
particulates (TSP), a measure of ambient
air pollution, are very high in some parts
of the world, much more so than in North
America. For example, in the 1990s, TSP
was higher than 400 µg/m 3 in some Chinese
and Indian cities. 5 The 2005 Air Quality
in Ontario report presents a comparison
of air quality in 39 selected cities world
wide. 6 Since monitoring methods and
locations may vary between cities, the
comparisons were not intended to be used
as a comprehensive ranking.
The Ontario Ambient Air Quality Criteria
(AAQC) one-hour maximum ozone concentration
is 80 parts per billion (ppb)
and the United States National Ambient
Air Quality Standard (NAAQS) is 120 ppb.
Houston, Athens, Hong Kong and Sao Paulo
recorded the highest one-hour maximums
among the selected cities for 2005 at
between 160 and 200 ppb and 9 cities (none
in Canada) had values between 120 and
160 ppb. Windsor, Toronto, Montreal,
and Ottawa had one-hour maximum
concentrations between 80 and 120 ppb.
The United States NAAQS for the annual
mean PM 2.5 , fine particulate matter 2.5
microns and less in diameter, is 15 µg/m 3
and the World Health Organization (WHO)
guideline is 10 µg/m 3 . Five cities, none in
Canada, had annual means for 2005 from
15 to 26 µg/m 3 and the means in Sao Paulo
and Prague were over 20 µg/m 3 . Montreal
had a level of 10 µg/m 3 and the level in
Windsor was slightly higher. Ottawa and
Toronto had levels of approximately 7
and 9 µg/m 3 respectively.
The United States NAAQS for the annual
mean concentrations of NO 2 is 53 ppb and
the WHO guideline is 21 ppb. Eight cities
had means for 2005 from 21 to 36 ppb
including Toronto with a level slightly over
the WHO guideline of 21 ppb. Windsor and
Montreal had annual means of 17-18 ppb.
Levels of several air pollutants, such as
carbon monoxide and nitrogen dioxide, have
dropped markedly since 1990 in Canada
and levels of several others, including
volatile organic compounds, sulphur
dioxide, nitrogen oxide and ground-level
ozone stabilized between the mid 1990s
and 2000. 3 Annual mean concentrations
of PM 2.5 decreased at urban sites across
Canada over the period 1990-1996 and
Pollutant Source
have been relatively steady from 1996 to
2001, while annual mean concentrations of
PM 10 decreased at most urban sites. 7 Using
observations to 2005, a slight increase of
6% for PM 2.5 is projected from 2000-2015. 8
Canadian air pollution data, particularly for
particulate matter, are scant before 1990.
There are several types of air pollution
including: outdoor, indoor air pollution,
occupational, and pollution arising from
industrial point sources. The scope of this
review is outdoor air pollution including
industrial point sources. This chapter
also includes a detailed discussion on the
difficulties in measuring exposure along
with some proposed solutions, as this is
the focus of some of our ongoing research.
However, this subject matter requires a
more advanced mathematical background
than the remainder of the monograph. We
recommend that these sections be skipped
by persons only interested in the review of
outdoor air pollution and cancer.
The relationship between acute and
chronic non-malignant pulmonary diseases
and ambient air pollution is well
studied, but which pollutants and which
components of particulate matter are most
harmful is uncertain. It is recognized that
Table 1
Commonly studied air pollutants and their exposure sources 3,4
145
air pollution increases the incidence of
these conditions (or exacerbates them).
Increases in inhalable particles (airborne
particles with a diameter of no more than
10 µm, commonly known as PM 10 ) in the
atmosphere have been associated with
acute decrements in lung function and other
respiratory adverse effects in children. 9-11
There is evidence that mortality from respiratory
and cardiac causes is associated
with particle concentrations. 12 Increases in
concentrations of ambient ozone have been
associated with reduced lung function,
increased symptoms, increased emergency
room visits and hospitalizations for respiratory
illnesses, and possibly increased
mortality; this extensive literature is
reviewed elsewhere. 13,14 More recent studies
continue to show similar patterns. 15,16 Some
have posited that these increases may be
due to preexisting disease in persons who
are therefore more susceptible to harmful
environmental exposures.
The important limitation of time-series
studies is that they can only look at acutetype
outcomes, not chronic exposures.
Generally speaking, most of the health
impact studies have concentrated on acute
effects, such as emergency room visits, and
the environmental relationships have been
Volatile organic compounds (VOCs) A large proportion of VOCs in Canada are from natural sources. Human sources include gasoline-fuelled
vehicles and gasoline evaporation, solvents including oil-based paint, barbecue starter fluid, household
cleaning products.
Total particulate matter Fine particulate matter (PM 2.5 ) generally arise from combustion of fossil fuels in transportation,
manufacturing, power generation and residential heating. Nitrogen oxides and sulphur dioxide combine
with NH 3 to form secondary airborne particles. Ground-level ozone and over half of PM are produced through
the reaction of precursor gases, two of the key precursor gases are nitrogen oxides and VOCs. Ground-level
ozone and airborne particles are two of the key components of smog.
Nitrogen oxides Nitrogen dioxide, the main component of nitrogen oxides is mainly related to motor vehicle emissions.
Nitrogen oxides (NOx) and VOCs are two of the key precursor gases which react to form ground-level ozone
and PM, sources of precursor gases include motor vehicles, smelters, homes, thermal power plants and
other industries.
Sulphur oxides Non-ferrous smelters and coal-fired power plants are the principal sources of sulphur dioxide.
Sulphur dioxide and nitrogen oxides are the main pollutants forming acid rain.
Carbon monoxide Transportation. CO is an air pollutant closely associated with harmful health effects and in high
concentrations is fatal.
Ozone VOCs react with nitrous oxides in the presence of sunlight to form ground level ozone.
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
identified by correlating the rates of adverse
effects with the levels of environmental
pollution in a geographic region as measured
over a short-term period. Chronic
diseases with a long latency, such as
cancer, generally require the measurement
of chronic, long-term exposures.
As a consequence, air pollution risk has not
been identified as clearly for cancer as for
acute health problems, and the evidence
for cancers other than lung cancer is limited.
Since several excellent literature reviews on
this subject have been published 14,17-23 the
intention here is to discuss key points and
augment them with results from studies
published recently.
evidence of an association
between air pollution and cancer
Biologic mechanisms
It is well-documented that air contains
substances known to transform cells in
culture, 24 and known or suspected to cause
cancer in humans. 2,23 A broad spectrum
of potentially carcinogenic chemicals has
been released into the air. 25-27 Pollutants
with a carcinogenic potential include
benzo[a]pyrene, benzene, inorganic compounds
such as arsenic and chromium,
particulate matter, especially PM 2.5 , and
possibly ozone. 28 PM 2.5 can penetrate deep
into the lungs and are thought to pose a
greater health risk than larger particles.
Reactive oxygen species have been associated
with the toxicological effects of
ultrafine particles. 29 PM 2.5 also has higher
concentrations of sulfates, nitrates, organic
compounds, and transitional metals. 30
Nielsen et al., 31 examining the pattern of a
specific air pollutant – Polycylic Aromatic
Hydrocarbon (PAH) – in a busy street in
Copenhagen, Denmark, identified that the
PAH levels followed the order ‘street > city
background air > suburbs > village >
open air’. The traffic contribution of PAH
to street air was estimated to be 90% on
working days and 60% during weekends.
Its contribution to city background air was
estimated to be 40%.
Lung cancer and urban residence
Some of the first studies of lung cancer and
air pollution showed that lung cancer risks
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
were lower in rural than in urban areas
that, historically, have had higher air pollution
concentrations due to traffic, industrial
sources and home heating. 32 Results
from ecological studies indicate that the
risk of developing lung cancer is greater
in urban than rural areas by a factor of
about 1.3 to 2.0, and generally is higher
in men than women. 33 However, these
studies are of limited value as they lack
information on important confounders
such as smoking and occupational exposures
at an individual level. It is well
documented that smoking is the most
important determinant of lung cancer, and
that the smoking pattern is quite different
between urban and rural populations. 34,35
Smoking has been estimated to cause 87%
of all lung cancers. 36-38 The estimation of air
pollution associated risks for lung cancer
should ideally be adjusted for several
smoking characteristics including the
number of smoking years and the quantity
smoked. Other characteristics may also be
important. For example, Doll discusses the
role that the age a person initiates smoking
may play on subsequent risk, 34 and ETS
also influences subsequent risk. Analytic
epidemiological studies (case-control and
cohort), where confounding factors such
as smoking and occupational exposure,
are taken into account, generally suggest
slightly lower urban/rural risk ratios (1.2
to 1.5). However, it is possible that residual
confounding for smoking may still persist,
the assessment of occupational exposures
are frequently crudely made and no information
on radon exposure is available. It
should be noted that confounding will
only take place if individual-level smoking
behaviours are correlated with the areawide
air pollution measures.
Case-control and cohort studies of
outdoor air pollution and lung cancer
The American Cancer Society (ACS)
and Harvard Six-Cities studies are key
studies in the area, and form an intergral
part of much of the US EPA’s air quality
guidelines. The ACS cohort study enrolled
approximately 1.2 million adults in 1982.
Pope et al. found a 10 μg/m 3 elevation in
fine particulate air pollution was associated
with an 8% increased risk of lung cancer. 39
Measures of the coarse particle fraction
(PM 15-2.5 ) and total suspended particles were
146
not associated with lung cancer mortality.
The Harvard Six City Study included 8,111
adults with prospective follow-up for 14 to
16 years. 40 Elevated lung cancer mortality in
the most polluted city relative to the least
polluted was not statistically significant
(RR=1.37, 95% CI 0.81-2.31), whereas
mortality for cardiopulmonary disease was
significantly elevated.
In the Netherlands, Hoek et al 41 found
no association between lung cancer and
exposure to fine particles (black smoke)
and NO 2 ; however, the study was limited
by a relatively small number of lung
cancer deaths (n=60). Another cohort
study examined the relationship between
air pollution and lung cancer and other
causes of death among 16,209 Norwegian
men. 42 Yearly air pollution levels were
linked with a participant’s home address.
After adjustment for age, smoking and
education, the RR for developing lung
cancer was 1.08 (95% CI=1.02-1.15) for
a 10 μg/m 3 increase in nitrogen oxide. A
Swedish cohort record-linkage study found
an increased risk (RR=1.4) of lung cancer
for those with high exposure to diesel
emission. 43
A study of 14,284 adults who resided
in seven cities in France examined the
relationship between outdoor air pollution
and mortality. 44 The study also collected
information on smoking habits, educational
level and occupational exposures to dust,
gases and fumes. An increase of 10 μg/m 3
was associated with an increased rate
ratio of 1.48 (95% CI=1.05-2.06) of dying
from lung cancer. This risk estimate is
based on a total of 42 lung cancer deaths.
Similar to other cohort studies, confounder
information was collected only at one point
in time, and air pollution exposures were
measured over the course of three years.
Therefore the risk estimates may be biased
by an inability to take into account changes
in the values of these characteristics over
the follow-up interval. A notable strength
of the study was the lengthy follow-up
interval with some subjects followed for
25 years.
A cohort study among 6338 non-smoking
southern California residents was carried
out with lifetime exposure to air pollutants
estimated for each member based on the zip
code centroids of home and work location
histories. 45 For lung cancer mortality the
RR associated with an increase in exposure
equal to the interquartile range (IQR) of
24 μg/m 3 in PM 10 mean concentration
was 3.36 (95% CI=1.57-7.19; 18 deaths)
among men and 1.33 (95% CI=0.60-2.96;
12 deaths) among women. Among men,
ozone was also significantly associated
with lung cancer mortality (RR=4.19, 95%
CI=1.81-9.69), although it was difficult to
separate the effects of PM 10 and O 3 because
of their correlation. For the subset of the
cohort in which coarse and fine PM could
be separated, the associations were best
explained by the PM 2.5 fine fraction. 46
A review has identified ten case-control
studies which included measurements on
one or more of total suspended particulate
matter, SO 2 and NO 2 . 47 Six studies reported
significant associations with increases in
risk of approximately 50%, although for
one of these females had a lower and not
significant RR. One study reported a negative
association and three studies were not
statistically significant. This review included
a recent population-based case-control study
of male residents in Stockholm, Sweden
where the participants’ lifetime exposure
was estimated using residential addresses
and emission data created from road traffic
and heating revealed a 40% increased risk
of lung cancer for the highest relative to the
lowest decile of NO 2 exposure, adjusting
for confounding factors and allowing for a
20-year latency period. 48
Studies of point sources of pollution
and lung cancer
International studies of communities in the
vicinity of large point sources of air pollution
suggest such exposures increase the risk
of developing lung cancer. A relative risk of
around 1.5 to 2.0 was observed for people
living close to arsenic-emitting smelters
versus the reference group at the greatest
distances, after controlling for smoking
and other occupational exposures. 49,50 A
similar RR for lung cancer was associated
with living near multiple industrial sources
in northeast England, although patterns
were different among men and women
and at different ages. 51 Ecological studies
in Scotland have reported increased risks
with residential proximity to steel and
iron foundries even after adjustment for
social class. 52,53 A recent study of people
living in the vicinity of a nonferrous metal
smelter in Sweden found an elevated, but
not statistically significant, risk for men
exposed in the beginning of the operations
(RR=1.51); no overall increased risk was
observed for women. 54 The geographic
pattern of lung cancer incidence near a
coke oven plant in Northern Italy suggested
a role for industrial air pollution as a
risk factor. 55 Results from other studies,
however, have not demonstrated excess
risks. 56,57 Misclassification of exposure may
be more likely in such ecologic studies and
the industrial sites differ.
Molecular epidemiology and toxicology
Molecular epidemiological and toxicological
studies have provided evidence of relationships
between air pollution exposure
and lung cancer. One such study 58 indicated
various dose-response relationships
between biomarkers and environmental
exposures, such as polycyclic aromatic
hydrocarbons and ambient indoor and
workplace air pollution. The biomarkers
included carcinogen-DNA and carcinogenprotein
adducts, gene and chromosomal
mutations, and polymorphisms in putative
susceptibility genes. The study involved
adults, infants and children, including
cancer patients and controls exposed to
varying levels of carcinogens. A cohort
study in Italy found an association between
living in an urban area and anti-benzo[a]
pyrene diol epoxide DNA, a potential
biomarker for lung cancer. 59 Elsewhere, in
a cohort of mothers and newborns living
in an industrialized city in Poland, a doseresponse
relationship between ambient air
pollution and PAH-induced DNA damage
was observed. 60 A recent in vitro study 61
was the first to demonstrate that target cells
of the lungs, when exposed to ambient
particulate matter (a component of air
pollution), initiate a cell signalling cascade
related causally to aberrant cell proliferation
and carcinogenesis. Cislaghi and Nimis 62
studied the associations between cancer
mortality and biodiversity of pollutionsensitive
organisms, using the latter as a
surrogate measure for air pollution. The
results suggest an association between air
pollution and lung cancer, although the
147
weakness of the ecological design should be
noted. These include individuals exposed
in one area moving and developing the
health outcome in another area, an inability
to control for confounding factors, poor
control for the latency period (particularly
for cancer), and assignment of the same
level of exposure over an entire area. The
chapter on epidemiological methods in this
monograph provides further discussion of
the strengths/weaknesses of the different
epidemiological designs (case-control, case-
crossover, cohort, ecologic) and basic concepts
in exposure assessment.
Cancers other than lung
Several epidemiological studies have
included examinations for adult cancers
other than lung. Increases in incidence
and mortality have been observed often in
urban areas for all cancer sites combined,
or for sites other than the respiratory
tract. 20 The observed risks for other cancers
are generally smaller than those for lung
cancer, although some of the associations
seen with childhood leukemia are stronger.
For specific adult cancer sites, the results
are quite inconsistent and below, some of
the key findings are outlined.
A positive but not statistically significant
association between living on roads with
high traffic density and female breast cancer
was reported for one of two counties in
Long Island, New York. 63 In a case-control
study in Erie and Niagara Counties, New
York, total suspended particulates (TSP),
as a proxy for PAH exposure, was investigated
as a risk factor. In postmenopausal
women, exposure to high concentrations
of TSP (>140 microgram/m 3 ) at birth
was associated with an adjusted odds
ratio of 2.42 (95% confidence interval,
0.97-6.09) compared with exposure to
low concentrations (
adverse health effects. 65 Standardized
mortality analysis revealed an increase
in the number of deaths from cancer and
cardiovascular disease in two cities with
nickel refineries when compared to a
control city. 65
In recent years, several studies have examined
the cancer impact of exposure to air
pollution due to motor vehicle emissions,
focussing mainly on children and leukemia.
Taken together the results are equivocal.
Two childhood cancer case-control studies,
one in Denver and one in northern Italy,
found several-fold increased risks for
leukemia in children with high exposure
to traffic emissions. 66,67 Elsewhere, paternal
occupational exposure to exhaust fumes
has been associated with an increase in
childhood cancer in the offspring. 68 Several
studies however have found no association
between living near high traffic areas and
childhood leukemia. 69-72 In one study,
disparate findings were found between
adults and children. Specifically, there was
no association between residence along
main roads and the development of adult
cancers but an association was found with
hematological malignancies in women and
children. 73
Population attributable risks
In summary, strong evidence exists for an
association between air pollution exposure
and lung cancer. The evidence for other
cancers seems far less conclusive, though
additional research is needed. Estimates of
the population attributable risk of cancer has
evolved over the last 40 years, 17,74 reflecting
the limitations of studies, including insufficient
information on confounders and
latency, and misclassification of exposure.
For example, Stocks and Campbell 75 estimated
that urban air pollution adds
about 100 lung cancer deaths per 100,000
persons, while Doll and Peto 35 estimated
that less than one percent of lung cancer
would be due to air pollution. In 1990,
the US EPA estimated that, based on unit
risks from known or suspected carcinogens
found in ambient air, 0.2% of all cancer
and less than one percent of lung cancer
could be attributed to air pollution. 76 In
contrast, the population attributable risks
for smoking and radon are considerably
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
higher. Specifically, an estimated 87% of
lung cancers can be attributed to smoking
and 10-15% to radon. 77
Recent cohort studies, however, reveal that
up to 50% increases in the risk of lung cancer
could be due to air pollution exposure,
particularly associated with indices for
sulphate and fine particulates. 39,40,78 Based
on a conservative estimate of 20% of the
population in the low exposure group (RR
1.1), 4% in the medium exposure group
(RR 1.3) and 1% in the high exposure
group (RR 1.5) approximately 3.6% of
lung cancer deaths in the European Union
could be due to air pollution exposure. 47
An estimated 5-7% of lung cancers among
never and ex-smokers are due to air pollution
in a multi-centre European study
in which exposure to air pollution was
assessed using concentration data from
monitoring stations. 79 Elsewhere, a review
article by Nikic and Stankovic suggests
that the estimate unlikely exceeds 2%
based on applying unit risks of known or
suspected carcinogens found in outdoor
air. 80 These studies suggest that while cigarette
smoking remains the predominant
risk factor, the widely-cited PAR estimates
above may be low. These investigators
used the prospective cohort approach in
their studies in an attempt to overcome
limitations associated with the ecological
designs. Important confounding factors,
such as smoking and education amongst
others, were taken into consideration.
However, most studies have been limited
to using regional or neighbourhood fixed
site exposure estimates which fail to take
into account individual differences in activity
patterns, or adjust for the effects of
indoor radon or air pollution. Changes in
time have largely not been controlled for.
Methodological difficulties
in studying air pollution –
cancer associations
This section on exposure assessment and
measurement errors is included as part
of the air pollution chapter since some of
the methods have been developed as part
of air pollution studies. Although some of
the concepts represent advanced biostatistics,
even a rudimentary understanding of
148
them is helpful in assessing the literature
on the association between cancer and air
pollution.
Overall, a major drawback in all air-pollutionand-cancer
studies to date has been the
inadequate characterization of air pollution
exposure. Generally speaking, air pollution
exposure estimates for all individuals
residing in a local area have been based on
the average or median concentration levels
from fixed monitoring stations in that area;
that is, all individuals in the same area are
assumed to have the same exposure. This is
a limitation particularly given that for some
pollutants associated with traffic (NO 2 and
ultrafine particles) variations within cities
may exceed variations between cities. 81,82
Moreover, even people living adjacent
to each other may experience different
exposures. Air pollution exposures are
dependent on activity patterns, can vary
seasonally, and certain occupations may
be associated with different exposures.
Lifetime residential histories have rarely, if
ever, been taken into account. Also longterm
attempts to characterize exposure
would typically use annual exposure
estimates, which are unable to capture
potentially important long-term effects
associated with very high and short term
increases in exposure. Although individuals
from the same area might have had similar
exposures for a specified period, it is very
likely that their lifetime exposures are
very different due to the mobility of the
population. In Canada, a recent census 83
demonstrated that close to 25% of the
population had changed place of residence
during the previous five years. Personal
monitoring devices are now used for some
studies; however, given the latency involved
for cancer and the need for retrospective
exposure assessment, such methods are
impractical for general population studies.
In this situation, one would need to measure
exposure in a cohort of 20,000 or more
individuals prospectively over several
decades. These devices may have some
utility for occupational exposures. For
studies of cancer, they can be useful for
the purposes of creating retrospectively
based job-exposure matrices; although
such a study would either have to assume
that current exposure were representative
of past exposures, or have some means of
making such an adjustment.
An approach that may become more
widespread in the coming years is the use
of satellite imaging data to estimate PM
and NO 2 levels. This approach can allow
for pollution estimates to be obtained for
rectangular grid areas on a 10 km by 10 km
basis, and hence for all geographical areas
(some better than other), not just areas in
close proximity to fixed site monitoring
stations. 84
These limitations may create substantial
misclassification of exposure and hence
bias the estimated risks. In addition to a
lack of data on other known or suspected
risk factors, an important drawback comes
from treating imprecise measurements
of covariates as if they were measured
accurately. In most situations, exposure
misclassification will tend to bias the risk
estimates towards the null (i.e., no effect)
and model residual variance is increased.
With an appreciable amount of exposure
measurement error, as one might expect
from the large scale of environmental
epidemiological studies, the amount of
bias can be substantial. Thus, an analysis
which does not account for imprecision
in covariates can mask the presence of a
statistically important effect. These limitations
have been recognized by several
investigators. 18,22,28 Measurement error in
other risk factor data can bias the risk estimates
in either direction. The potential for
important sources of bias to arise is possible
given that over a large follow-up interval,
these confounding exposures (e.g., smoking)
can change.
The remainder of this chapter focusses on
methodological developments for estimating
cumulative air pollution exposure using
historical monitoring data and incorporating
measurement errors into the analysis.
The reason for the focus on cumulative
exposure is because of the relevance of
chronic pollution exposures to cancer.
Cumulative exposure assessment
The feasibility of estimating lifetime exposure
to outdoor air pollution depends on
the availability of information on residential
histories of individuals and on historical air
pollution data. These kinds of information
are generally obtainable for residential
history, but historical air pollution data
are limited before 1990. For example, in a
recent large Canada-wide study on environmental
risk factors – initiated by Health
Canada and the provincial partners, and
called the Enhanced Cancer Surveillance
Initiative (ECS) 85 – residential histories
and information on important confounding
factors, such as smoking, diet, and
occupational histories, were collected for
over 20,000 cancer patients and 5,000 controls
from the general population. A
database of potential exposures was also
established. The pollutants modelled
included PM 10 , O 3 , CO, NO, NO 2 , and SO 2 .
Historical air pollution measurements from
fixed monitoring stations are generally
available from government-administered
environmental networks; some stations
have been in operation for over 20 years,
although startup dates vary greatly.
Even with the availability of residential
histories and historical air pollution data,
the difficulties associated with lifetime
exposure estimation remain. Cost prohibits
having air pollution measurements at all
locations of interest, such as residential
locations. Therefore, the basic problem
is to predict the concentration level at an
unmonitored location using the observed
concentrations at the monitoring locations.
The predictions at individual residential
locations can then be aggregated
to estimate the cumulative exposure level.
However, even such methods may not be
accurate as they fail to take into account
differences in the activity patterns, and
hence, can misclassify exposure to outdoor
air pollution at an individual level.
Such so-called spatial interpolation problems
arise in diverse fields, including engineering,
geology, soil science, hydrology
and mining. Analysts commonly tackle
such problems with the well-known
method of Kriging, introduced in the 1960s
by Matheron. 86 The Kriging method predicts
the concentration levels at a location
of interest using a weighted average of
all observed concentration levels at the
monitoring stations where the weights
are proportional to the inverse distances
between the location of interest and the
stations. The predictions have an appealing
optimality, that of being from the best linear
149
unbiased estimator, when the covariance
between the locations (or equivalently the
variogram) is known. Kriging requires a
reasonably dense network of monitoring
stations (10-100), depending on the type of
analysis 87 The method has been extended
to incorporate additional information from
covariables to improve the interpolator.
This is called co-Kriging. 88
These approaches implicitly assume
isotropy for the air pollution field
in the study region; that is, that the closer
the distance between two locations, the
more similar the concentration levels are.
This assumption is generally unrealistic
for environmental data due to potential
differences in geographic setting and
meteorology. For example, the concentration
levels at two locations located on opposite
sites of a mountain may not be very similar
regardless of how geographically close they
are. On the other hand, two locations far
apart may have very similar levels if they
are on the direction of the prevailing wind.
These methods also fail to incorporate
uncertainty about the covariance structure
of the pollution field into their measure of
interpolation error, leading to unwarranted
confidence in the interpolated values.
Several authors have since recognized
these limitations and have proposed modifications
to adjust for them. 89,90 These
modifications, although overcoming the
problems to a certain extent, still assume
isotropy for the pollution field.
Recently, a new theory for the spatial
interpolation of air pollution was developed
that avoids the limitations described
above. 91,92 The approach, which is a Bayesian
alternative to Kriging and co-Kriging, does
not assume either isotropy or a known
covariance structure. The theory permits
temporal and spatial modelling to be done
in a convenient and flexible way. At the
same time, model misclassifications, if
any, can be corrected by additional data –
if and when they become available. The
developed model is hierarchical Bayesian
in character, where the spatial covariance
is left completely unspecified in the first
level. Uncertainty about the covariance
structure is incorporated through the second
level prior, and hence unrealistically
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
small credible regions for the interpolants
are avoided. The covariance structure
is non-parametrically modelled through
the powerful approach of Sampson and
Guttorp, 93 thus avoiding the isotropy
assumption.
This theory has been extended to encompass
not only univariate but also multivariate
responses measured at ambient monitors.
Thus these can be used in predicting
responses at unmeasured sites, e.g., individual
residences. The further extension 94,95
deals with situations where not all monitoring
stations measure the same suite
of pollutants and not all stations started
operation at the same time. The extended
theory allows for the use of all available data
for different pollutants and from different
sources in the estimation process. In other
words, it permits “borrowing strength” to
provide more accurate estimate exposures
to air pollutants. This development is
very relevant for environmental data
where, commonly, over time stations and
pollutants may have been added to or
dropped from the networks due to financial
considerations and additional knowledge.
Validation studies 96 indicate that the
method performs very well. It has been
used successfully in several health impact
studies of air pollution, 97,98 including one
in British Columbia, using the ECS casecontrol
data. In this study, the spatial and
temporal predictive distributions of specific
pollutants were calculated for each month
between 1975 and 1995 using historical
concentration levels. Figure 1 displays
contour levels for the estimated monthly
mean ozone concentration field (June 1985)
over a region.
Through the predictive distributions, the
estimates for monthly concentrations and
their corresponding uncertainties can be
obtained for specific locations in a region.
Thus, for a given residential history, it is
possible to trace the individual locations
of residence through these distributions
and aggregate the corresponding monthly
estimates to get the cumulative exposure
estimates, along with their uncertainties.
Figure 2 displays the estimated monthly
ozone levels from 1975 to 1995 at
three different locations where a study
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
participant resided. It is quite clear that
the exposure patterns and levels vary
substantially, suggesting that cumulative
personal exposure estimates based on
short time periods may not be appropriate.
Furthermore, the observed levels at
the nearest station are quite different
from those estimated at the location of
residence, confirming the need for spatial
interpolation. The new theory is developed
with the assumption that the random
fields follow a gaussian distribution. This
assumption may not be realistic for air
pollutants and so transformations of the
fields are usually required. In some cases,
however, this may not be possible.
Another approach for estimating the
exposure levels at individual residential
locations is to use a dispersion model in
conjunction with emission databases and
the geographical information system.
This approach has been used in a casecontrol
study in Sweden 48 and found to
provide estimates consistent with ambient
measurements for NO 2 at various locations.
99 The emission databases are generally
not readily available and may have
to be constructed for individual studies.
Such constructions could be a major undertaking,
eg. requiring data on the growth of
urban areas, the development of district
heating systems and local industrial
sources, as well as road traffic patterns. 99 It
may also be impossible to construct retrospective
emission estimates.
Land use regression methods are also
increasing in popularity. These methods
predict pollution concentrations at a given
location based on surrounding land use
and traffic characteristics. The pollution
concentrations are modelled as the
dependent variable. These methods have
been used in Europe to model exposures
at an intra-urban level. Jerrett et al. 100
provide background for types of exposure
assessment methods.
Measurement error
Background
The large scale of studies in environmental
epidemiology makes error in the measurement
of individual subject attributes
and exposures inevitable – a fact that
150
has long been recognized. A large body
of work has been developed and much of the
work in occupational exposure assessment
measurement error applies here. In recent
years, advances in computer simulation
have provided some opportunities to
look at the extent of these errors. The
observation that many researchers do not
take account of this pervasive problem may
well derive from complacency inspired by
“… a common perception that the effect of
measurement error is always to attenuate
the line”. 101 That view encourages misplaced
confidence in findings that reject the null
hypothesis on the basis that, if anything, the
measurement error will have “attenuated”
the slope of regression, that is, reduced it
toward the null value. In other words, the
correct p-value would be even smaller if
it were not for the measurement error.
Recent increasing reliance on non-linear
regression models in epidemiology may
have helped kindle interest in the problem.
That reliance can be explained by a combination
of computing technology and
methodological advances like Generalized
Linear models, and GEE (generalized estimating
equations). 102 GEE methods are a
mechanism to adjust for correlations in the
data so that the standard errors are more
accurate (larger errors). The complexity
of the newer models may have challenged
simplistic views borne of simple linear
regression models.
Those same advances may also explain
why investigators have been willing to turn
to the so-called “errors in variable (EIV)”
problem. The errors in variable model differs
from classical regression in that the “true”
explanatory variables are not observed
exactly, but rather are imprecisely measured.
Undoubtedly, Fuller’s fundamental treatise
on the problem 103 stimulated that work,
for it convincingly demonstrated the
truly complex and pernicious character of
measurement error. Since the publication
of Fuller’s book, great advances have
been made by several authors. 101,104 In this
section, a very selective overview of the
problem is given, particularly as it relates
to the authors’ contributions.
Types of measurement error
For exposure variables, measurement
error is generally characterized as either
of “classical” or “Berkson” type, “differential”
or “non-differential”, “structural”
or “functional” (Appendix I). Different
categories of error have seen the development
of different methodological tools.
Some involve errors of mixed type. 105
However, the taxonomy of error is redundant
if error is treated within a Bayesian
framework. All its elements and more
are automatically subsumed by treating
all uncertain quantities (including those
measured with error) as random variables
that can be incorporated in any analysis
through the appropriate joint distribution.
The Bayesian framework is thus natural
for the treatment of measurement error.
Subsequently, in this review the Bayesian
methods developed will be showcased.
In spite of the increasing reliance upon
Bayesian methods in modern statistical
science, much current and recent theory
for treating measurement error has been
developed within the framework of the
repeated sampling paradigm. For completeness,
the developments from that
perspective will also be described.
Error effects and their mitigation
Little of a general qualitative nature is known
about the effects of measurement error,
even though a substantial methodological
base for handling errors exists. By using
that base, the implications of error can be
assessed in particular contexts. However,
some general results are known, and those
are summarized in this subsection.
In the case of binary exposure variables,
Thomas et al 105 showed for analytic
studies that quantities like relative risk
are attenuated by non-differential misclassification.
Analogous results for
matched case-control studies have also
been obtained by Greenland. 106 In fact,
Greenland showed the surprising result
that non-differential misclassification can
have more detrimental effects in matched
than unmatched designs, the size of the
detriment growing with the closeness of
the match. This is of note for investigators
planning a case-control study.
However, these results reverse in clusterbased
i.e., ecological studies. In this case,
the populations are partitioned into groups
and group attribute measures, rather than
those of individuals, enter the analysis; for
example, ecological studies where the group
exposure is measured by the proportion
of those exposed are considered. 107 With
non-differential misclassification, estimates
of rates (slopes) for individuals, based
on group-level analysis, will generally be
inflated rather than deflated (attenuated)
towards the null, as in the case of the
classical error model and simple linear
regression. Thomas et al. 105 noted the
complexities introduced by multi-level
(discrete) exposure variables that make
the effects on ecological estimates quite
unpredictable.
For continuous variables, the classical nondifferential
measurement error model leads,
in simple linear regression, to attenuation
toward the null of the apparent effect of
exposure. This does not occur in the case
of the Berkson error model, however, where
the apparent effect remains unbiased. This
result has recently been proved for more
general settings than just simple linear
regression by Gustafson and Le. 108
In general, ignoring measurement error can
lead to a myriad of problems apart from the
bias resulting from attenuation discussed
above. 109 Further descriptions can be
found in examples given in Appendix II.
In the space available here, it is difficult
to completely survey the array of other
problems attributable to measurement
error. Instead, the reader is referred to
comprehensive surveys available in the
literature. 101,104
Thomas et al. 105 give a good brief survey
of mitigating strategies within the framework
of exposure measurement error,
and Appendix III contains a brief summary
of those most directly relevant to
environmental cancer epidemiology. A
longer general review may be found in
Carroll et al. 101 Comprehensive discussion
on the Bayesian developments for casecontrol
settings can be found in Gustafson 104
and Gustafson et al. 114,115
151
environmental cancer
epidemiology
In this section, an approach to cancer
epidemiology within the context of environmental
health in a general setting is
described. The assessment of environmental
risk in this setting proves challenging.
One expects the relative risks of cancer
from environmental factors to be subtle and
hard to detect. In addition, for some health
conditions, the time between exposure and
disease onset can be lengthy.
To gain realistic power to detect environmental
effects, investigators of environmental
health studies may rely on
quasi-experimental control populations
or “quasi-controls”. In other words, they
target subjects from high as well as low
exposure sub-populations i.e., “clusters”.
These clusters may be determined by
geographic sub-regions, as in the multilevel
longitudinal study of children’s lung
function and disease now being carried out
in southern California by Duncan Thomas
and his co-investigators. 116,117 Here the
exposure of primary interest is air pollution
and the clusters are sub-populations
of school children in a number of regions of
southern California. Some regions with low
air pollution levels, as well as some with
high levels, have been randomly selected
into the study. Salient data on other risk
factor data are collected from both “cases”
and “controls”.
However there is a potential difficulty. The
grading of prospective clusters for level
of exposure must be done largely on a
priori (heuristic) grounds. If subjects are
then followed over time, it may well turn
out that the between-cluster contrasts are
insufficiently large to enable meaningful
comparison. In cancer epidemiology, following
subjects in this manner would not
be realistic, since latency times are typically
long. This forces purely retrospective
analysis. If administrative records are used,
investigators may by forced to incorporate
an ecological component into their design
that comes with it all the difficulties that
can hinder characterizing risk at an individual
level. Paramount among these is
the inability to collect information on the
changes in these risk factors over time.
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
FIguRe 1
Contour levels for the estimated monthly mean ozone concentration field (μg/m 3 ) for June 1985, southern british Columbia
Noting the difficulties associated with
ecological studies, Johnson et al. 85 advocated
instead a case-control study for
trying to elucidate environmental causes of
cancer in a population based sample
of Canadians. Their case-control design
matched cases only rather loosely to
controls (using frequency matching) with
respect to age and area of residence, a desirable
feature in their design if one recalls
the work of Greenland 106 cited above. The
authors give a comprehensive summary
of co-factors (“diet”, “exercise”, “SES”,
“smoking” and “occupation”) for which,
ideally, the analysis needs to be adjusted.
Nevertheless, the case-control design is not
void of limitations, particularly recall bias,
and participation bias. Participation bias
may essentially yield controls that are not
representative of the population that gave
rise to the cases, while recall bias can affect
the risk estimates in instances where cases
and control differ in their remembering past
exposures. These are important limitations
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
that lead some to rely more on findings
derived from prospective (cohort) studies.
Johnson et al. 85 also point to the need to
account for “residential mobility”, since
this is an important factor in determining
environmental exposures. The anticipated
gains from using quasi-control clusters may
well be eroded by uncontrolled variation due
to facts such as subjects moving between
clusters, thereby effectively creating “misclassification
error” in either analytic or
ecological studies. The activity levels for
each individual are also important.
Johnson et al. 85 proposed using the
“Environmental Quality Database” in their
study of the role of environmental factors in
the development of cancer. However, they
provided little discussion on the likely
impact of the inevitable error in the measurement
of exposure. Because of cancer’s
long latency period, and the difficulty in
reconstructing historical exposures, the
size of such error is likely large. In fact,
152
it can be large even in prospective studies
because of the impracticality of measuring
individual, as opposed to ambient,
exposure levels. To yield convincing results,
any statistical analysis must, therefore,
recognize at a fundamental level and
incorporate measurement error. Moreover,
incorporation of that error will entail
backcasting existing space-time series
for environmental hazards for varying
lengths of time, depending how long
individual stations have been monitoring
the environmental factors. Error can arise
not only in the environmental database
that is based on objective determination
of exposure, but in confounding variables
from the reliance on self-reported data
(inaccurate recollection, recall bias, etc).
One statistical strategy for environmental
risk analysis that incorporates measurement
error and concerns a chronic health
outcome such as cancer is described in
Appendix IV. Basically the cumulative
exposures are estimated using the recently
developed Bayesian method 94,95 as outlined
in the previous section. The exposure estimates
come with the associated measure
of uncertainties, including measurement
errors, that can be directly incorporated in
the health impact analysis through the generalized
estimation equation method. 98,102,105
The strategy involves a space-time series
of environmental covariates including the
risk factors. Both individual and ecological
studies are embraced by the abstract
formulation of the problem. This breadth
is achieved by taking “cluster” as the
fundamental building block. The cluster
can represent either a single individual
followed prospectively or retrospectively
over time or a cluster of individuals, each
with an associated series of exposure
meas urements. A more detailed survey
on this statistical strategy can be found
in Zidek. 109
FIguRe 2
estimated monthly ozone levels (μg/m 3 ) from 1975 to 1995 at three different locations where
the study participant resided, southern british Columbia
The vertical dash lines separate the three locations, while the dotted line on the right is the observation series of the monitoring site that is the nearest to location 3.
Concluding remarks
In this chapter, the evidence on the
relationship between cancer and air pollution
is examined. Methodological issues
affecting the precision of the evidence
are reviewed, particularly the inadequate
characterization of air pollution exposures
and the failure to account for their
potential misclassification. The discussion
specifically concerns the association, if
any, between air pollution and cancer,
although it is applicable to general chronic
diseases. Studying the relationship between
risk factors and chronic health outcomes
proves difficult, namely because subjects,
being mobile, will have resided in areas
where pollution levels were unmeasured,
leading to potential measurement error.
The deleterious and unpredictable effects
of such error and the consequent need to
mitigate those effects using predictors
of the unmeasured exposures are discussed.
A new general approach that may be taken
153
in environmental epidemiology to overcome
these difficulties to a certain extent is
described. More research into methods
such as those discussed here is needed
since, in environmental epidemiology, identifying
the risk factors for chronic morbidity
has proven much more challenging than
for acute morbidity. A more detailed
description and recent developments will
be available in the forthcoming book by
Le and Zidek. 127
References
1. Logan WP. Mortality in the London fog
incident, 1952. Lancet 1953;1(7):336-8.
2. Fishbein L. Sources, nature and levels of
air pollutants. In: Tomatis L, editor. Air
pollution and human cancer. New York:
Springer-Verlag; 1990. pp. 9–34.
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
3. Environment Canada. State of the
Environment Infobase. Available at: http://
www.ec.gc.ca/soer-ree/English/Indicator_
series/default.cfm (select urban air quality)
4. Editorial Board Respiratory Disease in
Canada. Health Canada. Ottawa, Canada,
2001. Catalogue no. H35-593/2001E.
5. WHO 2001. Air Quality and Health Air
Management Information Systems AMIS 3.0.
World Health Organization, Geneva.
6. Air Quality in Ontario 2005 Report. Queen’s
Printer for Ontario; 2006. Publication
number 6041e. Available at: http://www.
ene.gov.on.ca/en/publications/air/index.php
7. Environment Canada. National Air Pollution
Surveillance (NAPS) Network, air quality
in Canada : 2001 summary and 1990-2001
trend analysis. Environmental Technology
Advancement Directorate, Environmental
Protection Service, Environment Canada;
May 2004. Cat. no. En84-1/2004E.
8. Environment Canada. Five-year Progress
Report. Canada-wide Standards for
Particulate Matter and Ozone. January 2007.
Available at: http://www.ec.gc.ca/cleanairairpur/caol/pollution_issues/cws/toc_e.cfm
9. Pope CA, Dockery DW. Acute health effects
of PM pollution on symptomatic and
10
asymptomatic children. Am Rev Respir Dis
1992;145:1123–8.
10. Pope CA, Dockery DW, Spengler JD, et al.
Respiratory health and PM pollution: a
10
daily time series analysis. Am Rev Respir
Dis 1991;144:668–74.
11. Yu O, Sheppard L, Lumley T, Koenig JQ,
Shapiro GG. Effects of ambient air pollution
on symptoms of asthma in Seattle-area
children enrolled in the CAMP study.
Environmental Health Perspectives 2001;
108:1209-1214.
12. Schwartz J, Dockery DW. Increased
mortality in Philadelphia associated with
daily air pollution concentrations. Am Rev
Respir Dis 1992 (145):600–4.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
13. Lippman M. Health effects of tropospheric
ozone: review of recent research findings
and their implications to ambient air quality
standards. J Expos Anal Environ Epidemiol
1993;3:103–29.
14. Aunan K. Exposure-response functions
for health effects of air pollutants based
on epidemiological findings. Risk Anal
1996;16:693–709.
15. Willis A, Jerrett M, Burnett RT, Krewski D.
The association between sulfate air pollution
and mortality at the county scale: an
exploration of the impact scale on a longterm
exposure study. J Toxicol Environ
Health 2003; Part A 66:1605-1624.
16. Karakatsani A, Andreadaki S, Katsouyanni K,
Dimitroulis I, Trichopoulos D, Benetou V,
Trichopoulou A. Air pollution in relation
to manifestations of chronic pulmonary
disease: a nested case-control study in
Athens, Greece. Eur J Epidemiol 2003;
18:45-53.
17. Cohen AJ, Pope CA, Speizer FE. Ambient
air pollution as a risk factor for lung cancer.
Salud Publica Mex 1997;39:346–55.
18. Katsouyanni K, Pershagen G. Ambient air
pollution exposure and cancer. Cancer
Causes Control 1997;8:284–91.
19. Moran EM. Environment, cancer and
molecular epidemiology: air pollution.
J Environ Pathol Toxicol Oncol 1996;
15:97–104.
20. Pershagen G. Air pollution and cancer. In:
Vainio H, Sorsa M, McMichael AJ, editors.
Complex mixtures and cancer risk. Lyon:
IARC; 1990. Publication No. 104.
21. Tomatis L. Air Pollution and human cancer.
New York: Springer-Verlag; 1990.
22. Cohen AJ. Outdoor air pollution and lung
cancer. Environ Health Perspect 2000;
108:743-750.
23. Shy CM. Air pollution. In: Schottenfeld D,
Fraumeni JF, editors. Cancer Epidemiology
and Prevention. 2nd ed. Philadelphia: W.B.
Saunders Company; 1996. 407–417.
154
24. Freeman AE, Price PJ, Bryan RJ, et al.
Transformation of rat and hamster embryo
cells by extracts of city smog. Proc Natl
Acad Sci USA 1971;68:445–9.
25. Seinfeld TH. Urban air pollution: state of
the science. Science 1989; 243:745–52.
26. McElroy MB, Salawitch RJ. Changing
composition of the global stratosphere.
Science 1989;243:763–70.
27. Nriagu JO, Pacyna JM. Quantitative
assessment of worldwide contamination of
air, water and soil by trace metals. Nature
1988;333:134–9.
28. Cohen AJ, Pope CA. Lung cancer and air
pollution. Environ Health Perspect 1995;103
(Suppl 8):219–24.
29. Stone V, Shaw J, Brown DM, MacNee W,
Faux SP, Donaldson K. The role of oxidative
stress in the prolonged inhibitory effect
of ultrafine carbon black on epithelial cell
function. Toxicology in vitro 1998;12:649-59.
30. Pritchard RJ, Ghio AJ, Lehmann JR,
Winsett DW, Tepper JS, Park P. Oxident
generation and lung injury after particulate
air pollutant exposure increase with the
concentrations of associated metals. Inhal
Toxicol 1996;8:457-77.
31. Nielsen T, Jorgensen HE, Larsen JC, et al.
City air pollution of polycyclic aromatic
hydrocarbons and other mutagens: occurrence,
sources and health effects. Sci Total
Environ 1996;189–190:41–9.
32. Katsouyanni K, Pershagen G. Ambient air
pollution exposure and cancer. Cancer
Causes Control 1997 May;8(3):284-91.
33. Pershagen G, Simonato L. Epidemiologic
evidence on air pollution and cancer. In: Air
Pollution and Human Cancer. Tomatis L.
(ed.). Berlin: Springer-Verlag;1990. p. 65-74.
34. Doll R. Atmospheric pollution and lung cancer.
Environ Health Perspect 1978;22:23-31.
35. Doll R, Peto R. The causes of cancer:
quantitative estimates of avoidable risks of
cancer in the United States today [review].
J Natl Cancer Inst 1981;66:1191–1308.
36. U.S. Department of Health and Human
Services. Public Health Service. Reducing
the health consequences of smoking:
25 years of progress. A Report of the Surgeon
General. Washington: DHHS (PHS); 1989.
No. 89-8411.
37. U.S. Department of Health and Human
Services. The Health Consequences of
Smoking: A Report of the Surgeon General.
Atlanta, GA: U.S. Department of Health
and Human Services, Centers for Disease
Control and Prevention, National Center
for Chronic Disease Prevention and Health
Promotion, Office on Smoking and Health,
2004. ISBN 0-16-051576-2.
38. Baliunas D, Patra J, Rehm J, Popova S,
Kaiserman M, Taylor B. Smokingattributable
mortality and expected years
of life lost in Canada 2002: Conclusions
for prevention and policy. Chronic Dis Can
2007;27:154-162.
39. Pope CA 3rd , Burnett RT, Thun MJ, Calle EE,
Krewski D, Ito K, Thurston GD. Lung cancer,
cardiopulmonary mortality, and long-term
exposure to fine particulate air pollution.
JAMA 2002 Mar 6;287(9):1132-41.
40. Dockery DW, Pope CA, Xu X, et al. An
association between air pollution and
mortality in six U.S. cities. N Engl J Med
1993;329:1753–9.
41. Hoek G, Brunekreef B, Goldbohm S, Fischer P,
van den Brandt PA. Association between
mortality and indicators of traffic-related air
pollution in the Netherlands: a cohort study.
Lancet 2002 Oct 19;360(9341):1203-9.
42. Nafstad P, Haheim LL, Oftedal B, Gram F,
Holme I, Hjermann I, Leren P. Lung
cancer and air pollution: a 27 year follow
up of 16 209 Norwegian men. Thorax
2003;58(12):1071-6.
43. Boffetta P, Dosemeni M, Gridley G, Bath H,
Moradi T, Silverman D. Occupational exposure
to diesel engine emissions and risk of
cancer in Swedish men and women. Cancer
Causes Control 2001; 12:365-374.
44. Filleul L, Rondeau V, Vandentorren S et al.
Twenty five year mortality and air pollution:
results from the French PAARC survey.
Occup Environ Med 2005 Jul;62(7):453-60.
45. Abbey DE, Nishino N,McDonnell WF,
Burchette RJ, Knutsen SF, Lawrence Beeson W,
et al. Long-term inhalable particles and
other air pollutants related to mortality in
non-smokers. Am J Respir Crit Care Med
1999;159:373-82.
46. McDonnell WF, Nishino-Ishikawa N,
Petersen FF, Chen LH, Abbey DE.
Relationships of mortality with the fine and
coarse fractions of long-term ambient PM10 concentrations in nonsmokers. J Expo Anal
Environ Epidemiol 2000;10:427-36.
47. Boffetta P, Nyberg F. Contribution of
environmental factors to cancer risk.
Br Med Bull 2003;68:71-94.
48. Nyberg F, Gustavsson P, Jarup L, Bellander T,
Berglind N, Jakobsson R, Pershagen G.
Urban air pollution and lung cancer in
Stockholm. Epidemiology 2000; 11: 487-495.
49. Pershagen G. Lung cancer mortality among
men living near an arsenic-emitting smelter.
Am J Epidemiol 1985;122:684–94.
50. Brown LM, Pottern LM, Blot WJ. Lung
cancer in relation to environmental pollutants
emitted from industrial sources.
Environ Res 1984;34:250–61.
51. Bhopal RS, Moffatt S, Pless-Mulloli T,
Phillimore PR, Foy C, Dunn CE, Tate JA. Does
living near a constellation of petrochemical,
steel, and other industries impair health?
Occup Environ Med 1998;55:812-22.
52. Smith GH, Williams FL, Lloyd OL.
Respiratory cancer and air pollution from
iron foundries in a Scottish town: an
epidemiological and environmental study.
Br J Ind Med 1987 Dec;44(12):795-802.
53. Williams FL, Lloyd OL. The epidemic of
respiratory cancer in the town of Armadale:
the use of long-term epidemiological surveillance
to test a causal hypothesis. Public
Health 1988 Nov;102(6):531-8.
155
54. Besso A, Nyberg F, Pershagen G. Air
pollution and lung cancer mortality in the
vicinity of a nonferrous metal smelter in
Sweden. Int J Cancer 2003; 107:448-452.
55. Parodi S, Stagnaro E, Casella C, Puppo A,
Daminelli E, Fontana V, Valerio F, Vercelli M.
Lung cancer in an urban area in Northern
Italy near a coke oven plant. Lung Cancer
2005 Feb;47(2):155-164.
56. Lyon JL, Fillmore JL, Klauber MR. Arsenical
air pollution and lung cancer. Lancet
1977;2:869.
57. Michelozzi P, Fusco D, Forastiere F, Ancona C,
Dell’Orco V, Perucci CA. Small area study
of mortality among people living near
multiple sources of air pollution. Occup
Environ Med 1998; 55:611-615.
58. Perera FP, Mooney LA, Dickey CP, et al.
Molecular epidemiology in environmental
carcinogenesis. Environ Health Perspect
1996;104:441–3.
59. Petruzzelli S, Celi A, Pulera N, et al. Serum
antibodies to benzo(a)pyrene diol epoxide-
DNA adducts in the general population:
effects of air pollution, tobacco smoking,
and family history of lung diseases. Cancer
Res 1998;58:4122–6.
60. Whyatt RM, Santella RM, Jedrychowski W,
et al. Relationship between ambient air
pollution and DNA damage in Polish
mothers and newborns. Environ Health
Perspect 1998;106:821–6.
61. Timblin C, BeruBe K, Churg A, et al. Ambient
particulate matter causes activation of the
c-jun kinase/stress-activated protein kinase
cascade and DNA synthesis in lung epithelial
cells. Cancer Res 1998;58:4543–7.
62. Cislaghi C, Nimis PL. Lichens, air pollution
and lung cancer. Nature 1997;387:463–4.
63. Lewis-Michl EL, Melius JM, Kallenbach LR,
Ju CL, Talbot TO, Orr MF, Lauridsen PE.
Breast cancer risk and residence near
industry or traffic in Nassau and Suffolk
Counties, Long Island, New York. Arch
Environ Health 1996 Jul-Aug;51(4):255-65.
Vol 29, Supplement 2, 2010 – Chronic Diseases in Canada
64. Bonner MR, Han D, Nie J, Rogerson P,
Vena JE, Muti P, Trevisan M, Edge SB,
Freudenheim JL. Breast cancer risk
and exposure in early life to polycyclic
aromatic hydrocarbons using total suspended
particulates as a proxy measure.
Cancer Epidemiol Biomarkers Prev 2005
Jan;14(1):53-60.
65. Norseth T. Environmental pollution around
nickel smelters in the Kola Peninsula
(Russia). Sci Total Environ 1994 Jun 6;
148(2-3):103-8.
66. Pearson RL, Wachtel H, Ebi KL. Distanceweighted
traffic density in proximity to a
home is a risk factor for leukemia and other
childhood cancers. J Air Waste Manag
Assoc 2000; 50:175-180.
67. Crosignani P, Tittarelli A, Borgini A, Codazzi T,
Rovelli A, Porro E, Contiero P, Bianchi N,
Tagliabue G, Fissi R, Rossitto F, Berrino F.
Childhood leukemia and road traffic: A
population-based case-control study. Int
J Cancer 2004; 108:596-599.
68. McKinney PA, Fear NT, Stockton D; UK
Childhood Cancer Study Investigators.
Parental occupation at periconception:
findings from the United Kingdom
Childhood Cancer Study. Occup Environ
Med 2003 Dec;60(12):901-9.
69. Raaschou-Nielsen O, Hertel O, Thomsen BL,
Olsen JH. Air pollution from traffic at the
residence of children with cancer. Am
J Epidemiol 2001; 153(5):433-443.
70. Reynolds P, Von Behren J, Gunier RB,
Goldberg DE, Hertz A. Residential exposure
to traffic in California and childhood cancer.
Epidemiology 2004; 15:6-12.
71. Reynolds P, Von Behren J, Gunier RB,
Goldberg DE, Hertz A, Smith D. Traffic
patterns and childhood cancer incidence
rates in California, United States. Cancer
Causes Control 2002; 13:665-673.
72. Langholz B, Ebi KL, Thomas DC, Peters JM,
London SJ. Traffic density and the risk
of childhood leukemia in a Los Angeles
case-control study. Ann Epidemiol 2002
Oct;12(7):482-7.
Chronic Diseases in Canada – Vol 29, Supplement 2, 2010
73. Visser O, van Wijnen JH, van Leeuwen
FE. Residential traffic density and cancer
incidence in Amsterdam, 1989-1997. Cancer
Causes Control 2004; 15:331-339.
74. Speizer FE. Overview of the risk of respiratory
cancer from airborne contaminations.
Environ Health Perspect 1986;70:9–15.
75. Stocks P, Campbell JM. Lung cancer death
rates among non-smokers and pipe and
cigarette smokers: an evaluation in relation
to air pollution by benzpyrene and other
substances. Br Med J 1955;2:923–39.
76. U.S. Environmental Protection Agency.
Cancer Risk from Outdoor Exposure to
Air Toxics. Vol. I. Final Report. Research
Triangle Park, N.C.: Office of Air Quality
Planning and Standards. September 1990.
EPA-450/1-90-004a.
77. National Academy. Effects of Exposure
to Radon: BEIR VI. Washington, D.C.:
National Academy Press; 1999.
78. Pope CA, Thun MJ, Namboodiri MM, et
al. Particulate air pollution as a predictor
of mortality in a prospective study of
U.S. adults. Am J Respir Crit Care Med
1995;151:669–74.
79. Vineis P, Hoek G, Krzyzanowski M, Vigna-
Taglianti F, Veglia F, Airoldi L, Overvad K,
Raaschou-Nielsen O, Clavel-Chapelon F,
Linseisen J, Boeing H, Trichopoulou A, Palli D,
Krogh V, Tumino R, Panico S, Bueno-
De-Mesquita HB, Peeters PH, Lund E E,
Agudo A, Martinez C, Dorronsoro M,
Barricarte A, Cirera L, Quiros JR, Berglund G,
Manjer J, Forsberg B, Day NE, Key TJ,
Kaaks R, Saracci R, Riboli E. Lung cancers
attributable to environmental tobacco
smoke and air pollution in non-smokers in
different European countries: a prospective
study. Environ Health 2007 Feb:15:6-7.
80. Nikic D and Stankovic A. Air Pollution as
a Risk Factor for Lung Cancer. Arch Oncol
2005;13(2)79-82.
81. Briggs D. Exposure assesssment. In Elliot P,
et al. Spatial Epidemiology: Methods And
Applications. Oxford University Press,
Oxford, 2000. pp.335-359.
156
82. Zhu YF, Hinds WC, Kim S, Shen S, Sioutas C.
Study of ultrafine particles near a major
highway with heavy-duty diesel traffic.
Atmos Environ 2002: 36:4323-4335.
83. Statistics Canada. Mobility and migration.
The Nation Series. 1991 Census of Canada.
1993. Catalogue 93–322.
84. van Donkelaar A, Martin RV, Park RJ.
Estimating ground-level PM with aerosol
2.5
optical depth determined from satellite
remote sensing. J Geophys Res 2006, 111,
D21201, doi:10.1029/2005JD006996. Available
at: http://fizz.phys.dal.ca/~atmos/publications/
vanDonkelaar_2006_JGR.pdf
85. Johnson KC, Mao Y, Argo J, et al., the
Canadian Cancer Registries Epidemiology
Research Group. The National Enhanced
Cancer Surveillance System: a case-control
approach to environmental-related cancer
surveillance in Canada. Environmetrics
1998;9:495–504.
86. Cressie N. Statistics for spatial data. New
York: Wiley; 1991.
87. Jerrett M, et al. A review and evaluation of
intraurban air pollution exposure models.
J Expo Anal Environ Epidemiol 2005
Mar;15(2):185-204.
88. Haas T. Lognormal and moving window
methods of estimating acid deposition.
J Amer Statist Assoc 1990;85:950–63.
89. Handcock MS, Stein ML. A Bayesian analysis
of Kriging. Technometrics 1993;35:403–10.
90. De Oliveria V, Kedem B, Short DA. Bayesian
prediction of transformed Gaussian
random fields. J Amer Statist Assoc 1997;
92:1422–33.
91. Le ND, Zidek JV. Interpolation with
uncertain spatial covariances: a Bayesian
alternative to Kriging. J Multivariate Anal
1992;43:351–74.
92. Brown PJ, Le ND, Zidek JV. Multivariate
spatial interpolation and exposure to air
pollutants. Can J Stat 1994;22:489–510.
93. Sampson PD, Guttorp P. Nonparametric
estimation of nonstationary spatial covariance
structure. J Amer Statist Assoc 1992;
87:108–19.
94. Le ND, Sun W, Zidek JV. Bayesian
multivariate spatial interpolation with data
missing-by-design. J Roy Statist Soc Ser B
1997;59:501–10.
95. Le ND, Sun L, Zidek JV. Spatial prediction
and temporal backcasting for environmental
fields having monotone data patterns. Can
J Stat 2001; 29:516-529.
96. Sun W, Le ND, Zidek JV, et al. Assessment
of a Bayesian Multivariate Interpolation
Approach for Health Impact Studies.
Environmetrics 1998;9:565–86.
97. Duddek C, Le ND, Zidek JV, et al.
Multivariate imputation in cross sectional
analysis of health effects associated with
air pollution. (with discussion). J Environ
Ecol Statist 1995;2:191–2.
98. Zidek JV, White R, Le ND, et al. Imputing
unmeasured explanatory variables in environmental
epidemiology with application
to health impact analysis of air pollution.
J Environ Ecol Statist 1998;2:99–115.
99. Bellander T, Berglind N, Gustavsson P,
Jonson T, Nyberg F, Pershagen G, Jarup L.
Using geographic information systems to
assess individual historical exposure to air
pollution from traffic and house heating in
Stockholm. Environ Health Perspect 2001;
109(6): 633-639.
100. Jerrett M, Burnett R, Goldberg M, Sears M,
Krewski D, Catalan R, Kanaroglou P,
Giovis C, Finkelstein N. Spatial Analysis for
Environmental Health Research: Concepts,
Methods, and Examples. J Toxicol Environ
Health, Part A 2003: 66:1783–1810.
101. Carroll RJ, Ruppert D, Stefanski LA.
Measurement error in nonlinear models.
London: Chapman and Hall; 1995.
102. Liang KY, Zeger SL. Longitudinal data
analysis using generalized linear models.
Biometrika 1986;73:13–22.
103. Fuller W. Measurement error models. New
York: Wiley; 1987.
104. Gustafson P. Measurement Error and
Misclassification in Statistics and
Epidemiology. Chapman & Hall/CRC. 2004.
105. Thomas D, Stram D, Dwyer J. Exposure
measurement error: influence of exposuredisease
relationships and methods of
correction. Annu Rev Public Health
1993;14:69–93.
106. Greenland S. The effect of misclassification
in matched-pair case-control studies.
Am J Epidemiol 1982;116:402–6.
107. Brenner H, Savitz DA, Jockel KH, et
al. Effects of non-differential exposure
misclassification in ecologic studies. Am
J Epidemiol 1992;135:85–95.
108. Gustafson P, Le ND. Comparing the effects
of continuous and discrete covariate
mismeasurement, with emphasis on the
dichtomization of mismeasured predictors.
Biometrics 2002; 58:878-887.
109. Zidek JV. Interpolating air pollution for
health impact assessment. In: Barnett V,
Feridun Turkman K, editors. Statistics
for the environment 3: pollution assessment
and control. New York: Wiley; 1997.
p. 251–68.
110. Zidek JV, Wong H, Le ND, et al. Causality,
measurement error and multicollinearity
in epidemiology. Environmetrics 1996;
7:441–51.
111. Fung K, Krewski D. On measurement error
adjustment methods in Poisson regression.
Environmetrics, 1999;10:213–24.
112. Pierce DA, Stram DO, Vaeth M, et al. The
errors-in-variables problem: considerations
provided by radiation dose-response
analyses of the A-bomb survivor data.
J Amer Statist Assoc 1992;87:351–9.
113. Cook J, Stefanski LA. Simulation extrapolation
method for parametric measurement
error models. J Amer Statist Assoc
1995;89:1314–28.
157
114. Gustafson P, Le ND, Vallee M. A Bayesian
approach to case-control studies with errors
in covariables. Biostatistics 2002; 3:229-243.
115. Gustafson P, Le ND, Saskin R. Casecontrol
analysis with partical knowledge
of exposure misclassification probabilities.
Biometrics 2001; 57:598-609.
116. Peters JM, Avol E, Navidi W, London SJ,
Gauderman WJ, Lurmann F, Linn WS,
Margolis H, Rappaport E, Gong H, Thomas DC.
A study of twelve Southern California
communities with differing levels and types
of air pollution. I. Prevalence of respiratory
morbidity. Am J Respir Crit Care Med 1999
