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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

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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.

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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.

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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.

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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

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2. Fishbein L. Sources, nature and levels of

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pollution and human cancer. New York:

Springer-Verlag; 1990. pp. 9–34.

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3. Environment Canada. State of the

Environment Infobase. Available at: http://

www.ec.gc.ca/soer-ree/English/Indicator_

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4. Editorial Board Respiratory Disease in

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