Atmospheric Environment 43 (2009) 142–152

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Atmospheric Environment
journal homepage: www.elsevier.com/locate/atmosenv

Air pollution and mortality: A history

H.R. Anderson*
Division of Community Health Sciences, St George’s, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom

a b s t r a c t

Keywords: Mortality is the most important health effect of ambient air pollution and has been studied the longest.
Air pollution The earliest evidence relates to fog episodes but with the development of more precise methods of
Mortality investigation it is still possible to discern short-term temporal associations with daily mortality at the
History
historically low levels of air pollution that now exist in most developed countries. Another early
observation was that mortality was higher in more polluted areas. This has been confirmed by modern
cohort studies that account for other potential explanations for such associations. There does not appear
to be a threshold of effect within the ambient range of concentrations. Advances in the understanding of
air pollution and mortality have been driven by the combined development of methods and biomedical
concepts. The most influential methodological developments have been in time-series techniques and
the establishment of large cohort studies, both of which are underpinned by advances in data processing
and statistical analysis. On the biomedical side two important developments can be identified. One has
been the application of the concept of multifactorial disease causation to explaining how air pollution
may affect mortality at low levels and why thresholds are not obvious at the population level. The other
has been an increasing understanding of how air pollution may plausibly have pathophysiological effects
that are remote from the lung interface with ambient air. Together, these advances have had a profound
influence on policies to protect public health. Throughout the history of air pollution epidemiology,
mortality studies have been central and this will continue because of the widespread availability of
mortality data on a large population scale and the weight that mortality carries in estimating impacts for
policy development.
Ó 2008 Elsevier Ltd. All rights reserved.

1. Introduction
Mortality is probably the earliest health outcome to be inves-
tigated by mathematical methods. Using parish records it was
observed in the 17th century that the relationship between age
and mortality could be described by an exponential function and
this gave rise to the idea that human states could be modelled
mathematically much as had been done successfully for physical
phenomena. Modern environmental epidemiology grew out of
a confluence of routine registration of mortality, measurement of
environmental factors and appropriate statistical theory (Lil-
ienfeld, 1980).
Routine recording of mortality in England dates back to the
parish Bills of Mortality, which were first introduced in London in
1532 largely as a response to fear of the plague. Bills of Mortality
were the basis of one of the first quantitative analyses of mortality
(Graunt, 1939). By the middle of the 1800s, following the nation-
wide introduction of civil registration and the census, it became
* Tel.: þ44 20 8725 5419; fax: þ44 20 8725 3584.
E-mail address: r.anderson@sgul.ac.uk
possible to analyse mortality rates. The pioneer of this method was
William Farr, the first Chief Statistician of England’s General
Register Office. Drawing on actuarial techniques he analysed
mortality with the purpose of understanding environmental causes
of mortality (Langmuir, 1976). One example was the finding in
1848–49 of an inverse relationship between elevation above the
high water mark of the Thames river and the risk of death from
cholera (this fitted the current causal theory of miasma). Until the
middle of the 20th century when suitable methods of exposure
measurement and analysis became available, the study of air
pollution and mortality was limited to observations of increased
mortality during fogs. Mortality is now recorded for civil and legal
purposes in most countries and remains the cornerstone of public
health statistics. It has had an especially profound influence on the
growth in our understanding of the health effects of ambient air
pollution and remains important not only as an outcome in
epidemiological investigations, but for the setting of standards and
guidelines (WHO, 2006), health impact assessment (Cohen et al.,
2004) and cost–benefit analysis of policy options (DEFRA, 2007a;
National Research Council, 2002).
Environmental epidemiology aims to understand the relation-
ship between environment and health in human populations, the

1352-2310/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.atmosenv.2008.09.026
 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152
ultimate objective being to use this knowledge to improve public
health. Conceptually, the epidemiological approach comprises two
stages. The first is to establish using statistical methods whether or
not the hazard is associated with health after accounting for chance
and known sources of bias or confounding. The second stage is
causal inference but this is problematic because most epidemio-
logical evidence is of an observational rather than experimental
nature. Causal judgment brings in non-epidemiological evidence,
the most important being that from clinical and laboratory exper-
iments. The epidemiology of air pollution and mortality is further
constrained by the necessity of opportunistically using data about
mortality and air pollution that have been collected for some other
purpose.
The investigation of associations requires data on exposure and
outcome that are heterogeneous. For example, if air pollution data
did not vary from day to day or from place to place, it would not be
possible to investigate the association between pollution and
health outcomes using epidemiological methods. There are two
main types of epidemiological approach to the study of air pollution
and mortality; studies of short-term temporal variability, also
called short-term exposure studies, which include studies of air
pollution episodes and of daily mortality; and studies of spatial
variability, also called long term exposure studies, which compare
mortality across areas varying in air pollution concentrations.
The World Health Organization (WHO) has periodically
reviewed the evidence on air pollution and health and recom-
mended guidelines that it considered would adequately protect
public health. In the late 1970s, WHO concluded that the level of
long term exposure to suspended particulate matter above which
health effects might be observed was around 150 mg m3 (WHO,
1979). After applying a ‘‘safety factor’’ of 2, a possible health based
guideline from 60 to 90 mg m3 was suggested. In 1987 using these
principles, WHO published the first global guidelines for ambient
particulates, sulphur dioxide, nitrogen dioxide and ozone (WHO,
1987). The guidelines for particulate matter (measured as black
smoke with the reflectance method) and sulphur dioxide were
linked. The recommended long term (annual) guidelines were
50 mg m3 and 50 mg m3 respectively, while the 24 h guidelines
were 125 mg m3 and 125 mg m3 respectively. The 24 h guideline
for thoracic particles (the nearest equivalent to PM10) was
70 mg m3. Less than 20 years later, WHO published updated
separate guidelines for particulate matter and sulphur dioxide
(WHO, 2006). The annual and 24 h guidelines for PM10 were low-
ered to 20 and 50 mg m3 respectively. The 24 h sulphur dioxide
guideline was reduced to 20 mg m3 with no annual guideline.
These reductions of more than 50% were based not on a lowest
observed effect to which a safety factor had been applied, as in the
1987 guidelines, but on evidence that health effects were observ-
able across the range of ambient exposures without a discernable
threshold. The most important body of evidence supporting this
radical change in concept came from epidemiological studies of
mortality. This paper traces the historical development of our
understanding of the relationship between ambient air pollution
and mortality and attempts to identify the most important
conceptual and methodological factors responsible for the marked
reduction in the levels of ambient air pollution believed to be
harmful to human populations.
2. Evidence from studies of temporal variability
2.1. Air pollution episodes
Air pollution episodes have no formal definition but usually refer
to obviously high concentrations of air pollution lasting over several
days or weeks (Anderson, 1999). Winter episodes occur during anti-
cyclonic weather conditions associated with temperature inversions
143
in which wind speeds are low and emitted pollutants cannot be
adequately dispersed. Air pollution episodes have occurred in cities
such as London for many centuries and have long been known to be
associated with increases in mortality as recorded by the Bills of
Mortality which showed increases in mortality during ‘‘stinking fogs’’
in the 17th century in London (Brimblecombe, 1987). In England,
increased deaths associated with episodes became easier to identify
following the introduction in 1837 of death registration. Some of the
episodes known to be associated with an increase in mortality in
London since then are summarized in Fig. 1. It is surprising however
that until the 1930s, it was generally believed that the increases in
mortality observed during episodes were mainly due to the, some-
times, extremely cold weather that accompanies winter temperature
inversions, rather than to the accompanying air pollution (Russell,
1926). This position was understandable because at that time, while
temperature was clearly associated with mortality, available statis-
tical techniques were insufficient to identify the smaller independent
effects of air pollution against the background variability of daily
mortality.
An air pollution episode which occurred in 1930 in a small
industrial town in the Meuse Valley, Belgium is an important
landmark in air pollution epidemiology (Firket, 1931, 1936). A large
proportion of the population became acutely affected with respi-
ratory symptoms and in those with chronic cardiorespiratory
problems there was a worsening of their clinical state. There was 10
times the expected number of deaths (60 vs 6). Autopsies showed
acute irritation of the respiratory tract. A similar episode occurred
in Donora PA (population 13,000) in 1948 (Schrenk et al., 1949) in
which there was a 6-fold increase in deaths. As in the Belgian
episode, it occurred during a temperature inversion in a small
industrial town situated in a river valley. These two episodes led to
widespread acceptance that air pollution, at least in very high
concentrations, could increase mortality short-term independently
of the low temperature associated with winter stagnation episodes.
The mechanism was thought to be a toxic inflammation of the
airways. It is notable that in both of these episodes there were
reports of deaths in apparently healthy animals. The effects
observed in these episodes could not plausibly be attributed to
weather conditions alone.
The Belgian and US episodes affected small populations and the
number of excess deaths was small. Further, both had a strong
industrial element suggesting specific toxic chemicals might have
played a role. In a remarkable prediction, Firket, in his paper on the
Meuse episode commented ‘‘A Londres, ou la mortalité journalière
moyenne est de 151.38, on aurait a deplorer 3.179 mort immédi-
ates’’ (Firket, 1931). The risk to public health of air pollution
episodes resulting from non-industrial sources was finally estab-
lished without doubt when London experienced an intense episode
from 5 to 9 December 1952. A prolonged temperature inversion
with little or no wind had enabled the build up of pollutants
emitted mainly from the burning of coal in domestic grates. Smoke
London Administrative County Greater London
4500
Number of deaths
4000
3500
3000
2500
2000
1500
1000
500
0
3
80
82
91
92
48
52
56
57
59
62
75
91
7
18
18
18
18
18
19
19
19
19
19
19
19
19
Fig. 1. Estimated excess deaths in London fogs 1873–1991. Assembled from Brim-
blecombe (1987) and other sources.
144 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152
concentrations measured by the reflectance black smoke method
exceeded 4000 mg m3, with an average level of about 1600 mg m3
at the County Hall over the four days. These concentrations were
about 3–5 times normal for this period. This was the first major
episode in a large city to be investigated intensively and the
ensuing report estimated that in Greater London there had been an
excess of 4000 deaths in the three weeks following the onset of the
episode (Ministry of Health, 1954). This was remarkably close to the
prediction of 3100 by Firket based on the Meuse episode. Mere
inspection of the counts of deaths is sufficient to conclude that an
epidemic of deaths was associated with the episode (Fig. 2).
Statistically, this was not in itself sufficient to clinch the causality of
air pollution because the weather was exceptionally cold at the
same time and there was the additional possibility of a coincident
event such as an influenza epidemic. Influenza was not however
prevalent at the time. The contribution of low temperature was
indicated by comparing events within London with those in other
‘‘Great Towns’’ which were also experiencing cold weather, but
with much less pollution (Fig. 2). The latter showed a not incon-
siderable increase of 15% in mortality during the week of the
London episode, but this was dwarfed by the increase of over 400%
Fig. 2. London October 1952–March 1953. (a) Weekly number of deaths in Greater London compared with those in 140 Great Towns, and with the corresponding period in 1951–
1952. (b) Mean values of sulphur dioxide compared with 1951–1952.
in London strongly suggesting that additional factors were at work,
of which the most likely candidate was air pollution. Interestingly,
as in the Meuse and Donora episodes, deaths of healthy farm
animals (in the city at that time for an agricultural show) were also
reported. One feature of Fig. 2 is that the epidemic appeared to be
biphasic with a second more prolonged increase extending from
the end of December to mid-February amounting to a further 8000
deaths above those predicted from earlier years. The possible
causes of this second wave were considered to be any or all of:
a delayed effect of the air pollution episode; an effect of a further
increase in pollution in January and February; and the coincidence
of an influenza epidemic (Wilkins, 1954). A recent re-examination
of the episode has however cast doubt on whether the second wave
could be blamed entirely on influenza (Bell and Davis, 2001).
Further winter episodes associated with increases in mortality
occurred in London (Fig. 1), as well as in some other large cities such
as New York, until the 1990s (Anderson, 1999).
Air pollution concentrations in London and most other major
western cities have fallen markedly to historically low levels over
the last century. Since 1922, when black smoke began to be
monitored, concentrations have fallen from around 400 mg m3 to
 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152 145

less than 10 mg m3 (Air Quality Expert Group, 2005). In London,
the last winter air pollution episode to cause major public health
concern was in 1991. The city experienced a winter temperature
inversion with air stagnation lasting several days typical of the
conditions previously associated with air pollution episodes. On
this occasion, the pollutants that accumulated were not those
from domestic fuel burning as in 1952, but from mobile sources
with a contribution from space heating using natural gas. The
result was a 5-fold increase in nitrogen dioxide (double the pre-
vailing WHO guidelines – with an hourly peak of 423 ppb), 3.5-
fold increase in black smoke and 2-fold increase in sulphur
dioxide. Although the relative increase in air pollution was quite
similar to that observed in the 1952 episode the absolute levels
were very much lower. Inspection of time-series of daily mortality
revealed only the slightest discernible increase amongst the other
daily variations (Fig. 3). Nevertheless, analysis involving control
years and control areas revealed a 10% increase in mortality
attributable to air pollution (Anderson et al., 1995). This compares
with a greater than 400% increase in mortality observed during
the week of the 1952 fog. This episode occurred during a period
when emissions of oxides of nitrogen had reached their highest
levels in the UK. Now that nitrogen oxide emissions have fallen
due to exhaust treatment and other measures, it is most unlikely
that such an episode could be repeated even under similar
weather conditions. Furthermore, under climate change scenarios,
cold weather with low wind speeds is predicted to become less
common (Department of Health, 2008). Conversely, global
warming will increase the number of hot sunny summer days and,
depending on the presence of precursor pollutants including
oxides of nitrogen, may increase the risk of ozone episodes which
are also associated with increased mortality. In the recent
epidemic of deaths associated with the 2003 European heat wave,
it was estimated that ozone contributed from 2.5% to 85.3% of
excess mortality across 9 French cities (Filleul et al., 2006). Other
ongoing sources of episodes causing a potential increase in
mortality are those due to biomass burning and dust storms, both
of which may increase as a result of climate change.
2.2. Daily time-series studies
Although it was originally believed that the important effects of
air pollution occurred mainly during episodes, it was conjectured
that air pollution might also have effects on mortality at lower
concentrations. In London, for example, while it was observed in
the 1950s that air pollution was correlated with mortality during
non-episode periods, limitations of statistical methods for
controlling for confounding and serial correlation and of data
processing prevented analyses that would convincingly separate
the effects of air pollution from those of confounding factors such
as temperature (Martin and Bradley, 1960). This question was
addressed by the application of time-series techniques to daily time
series of mortality and air pollution which rely on sufficient
heterogeneity between mortality and other factors to separate the
effects of air pollution from those of other factors such as weather,
day of the week, influenza epidemics, season and long term trends.
One of the earliest time-series studies used London data for 1958–
1972 and while this observed an association between Black Smoke
and daily mortality it was concluded that the relative effects were
greater at higher than lower concentrations, this being compatible
with a no-observable-effects level (Mazumdar et al., 1982). Subse-
quently, Ostro (1984), using the same London data, was the first to
show that there was no evidence of a no-observable-effects level
and this was confirmed by Schwartz and Marcus (1990) with the
same data but using different statistical methods. Time-series
studies of morbidity outcomes such as hospital admissions fol-
lowed quickly (Samet et al., 1981).
The relative ease and low cost with which existing mortality and
air pollution data can be obtained and analysed facilitated a rapid
increase in single city studies during the 1990s. This trend reversed
around the turn of the century partly as a result of editorial resis-
tance (Samet, 2002) (Fig. 4). The consistency of positive results has
been remarkable (Pope and Dockery, 2006). As an example, Fig. 5
shows the estimates and 95% confidence intervals extracted from
peer reviewed papers up to 2006 reporting associations between
PM10 and daily cardiovascular mortality (Department of Health
Committee on Medical Effects of Air Pollution, 2006). Nearly all the
estimates are in a positive direction and the majority are statisti-
cally significant. The summary estimate for all cardiovascular
mortality is nearly 1% for a 10 mg m3 increase in PM10. Estimates
for subgroups such as ischaemic heart disease mortality also tend to
be positive. The evidence for other particle metrics, ozone, nitrogen
dioxide and carbon monoxide is similar.
As daily time-series studies grew in number, it became apparent
that although there was a tendency for estimates to be positive, the
effects were small and heterogeneous between studies. The reasons
for heterogeneity were postulated to include variations in exposure
measurement error, toxicity of the pollution and vulnerability of
the population, but the relative contributions of these factors were

All cause mortality

300 Max hourly average NO2 450
35
400
250 Multicity studies
30
350 Single city studies
Numbers of deaths

No of publications

200 300 25
ppb NO2

250 20
150
200
15
100 150

100 10
50
50 5
0 0
0
1

2
9

19 2
19 3
19 4
19 6
19 6
19 7
19 8
19 9
90
19 1
19 2
19 3
19 4
19 5
19 6
97
19 8
20 9
20 0
20 1
20 2
03

20 4
20 5
06
07
19

19

19

19

19

19

19

8
8
8
8
8
8
8
8

9
9
9
9
9
9

9
9
0
0
0

0
0
/

19

19

19

20

20
11

11

11

12

12

01

01
/

/
01

15

29

13

27

10

24

Fig. 4. Annual numbers of peer-reviewed publications with estimates of effect of air

Fig. 3. London November 1991–January 1992. Daily mortality and maximum hourly pollution on daily mortality (Courtesy of Air Pollution Epidemiology Database, St
average nitrogen dioxide concentrations. George’s, University of London.).
146 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152

Cardiovascular mortality and PM10

heart failure, all, Netherlands, Hoek, 2001
dysrhythmias, all, Netherlands, Hoek, 2001
embolism + thrombosis, all, Netherlands, Hoek, 2001
ihd, all, Hong Kong, Wong, 2002
ihd, all, Montreal1, Goldberg, 2001
ihd, all, Montreal, Goldberg, 2001
ihd, all, Netherlands, Hoek, 2001
ami, all, 10 US Cities, Braga, 2001
circulatory, all, Birmingham, UK, Wordley, 1997
circulatory, all, Cook County, Illinois, Ito , 1996

cerebrovascular, all, Maricopa, Moolgavkar, 2000

cerebrovascular, all, Hong Kong, Wong, 2002
cerebrovascular, all, Seoul, Hong, 2002
cerebrovascular, all, Cook, Moolgavkar, 2000
cerebrovascular, all, Netherlands, Hoek, 2001
cerebrovascular, all, Los Angeles, Moolgavkar, 2000

cardiovascular, all, Ogden, Pope , 1999

cardiovascular, all, Palermo, Biggeri, 2001
cardiovascular, all, Huelva, Daponte , 1999
cardiovascular, all, Le Havre, Zeghnoun, 2001
cardiovascular, all, Strasbourg, Zeghnoun, 2001
cardiovascular, all, Mexico City, Castillejos, 2000
cardiovascular, all, Phoenix, Mar, 2000
cardiovascular, all, Utah Valley, Pope III, 1996
cardiovascular, all, Utah County, Pope , 1992
cardiovascular, all, Rome, Biggeri, 2001
cardiovascular, all, Santa Clara County, Fairley, 1999
cardiovascular, all, Provo/Orem, Pope , 1999
cardiovascular, all, Coachella Valley, Ostro, 1999
cardiovascular, all, Bangkok, Ostro, 1999
cardiovascular, all, Florence, Biggeri, 2001
cardiovascular, all, Inchon1, Hong, 1999
cardiovascular, all, Wayne County, Lippmann, 2000
cardiovascular, all, Bologna, Biggeri, 2001
cardiovascular, all, Coachella Valley, Ostro, 2000
cardiovascular, all, 3 Spanish Cities, Ballester, 2002
cardiovascular, all, Rouen, Zeghnoun, 2001
cardiovascular, all, Madrid, Galan, 1999
cardiovascular, all, Montreal, Goldberg, 2001
cardiovascular, all, Paris, Zeghnoun, 2001
cardiovascular, all, Salt Lake City, Pope, 1999
cardiovascular, all, Erfurt, Wichmann, 2000
cardiovascular, all, Santiago, Ostro, 1996
cardiovascular, all, Inchon, Hong, 1999
cardiovascular, all, Turin, Biggeri, 2001
cardiovascular, 65+, Krakow, Szafraniec, 1999
cardiovascular, 65+, Sao Paulo, Gouveia, 2000
cardiovascular, all, London, Bremner , 1999
cardiovascular, all, West Midlands, Anderson, 2001
cardiovascular, all, Milan, Biggeri, 2001
cardiovascular, all, Hong Kong, Wong, 2001
cardiovascular, all, Hong Kong, Wong, 2002
cardiovascular, all, Santiago, Sanhueza, 1999
cardiovascular, all, Netherlands, Hoek, 2000
cardiovascular, all, Netherlands, Hoek, 2001
cardiovascular, 65+, Helsinki, Ponka , 1998
cardiovascular, all, Melbourne, Simpson, 2000
cardiovascular, all, Seville, Ocana-Riola, 1999
cardiovascular random effects estimate

cardiac, all, Maricopa, Moolgavkar, 2000

cardiac, all, Birmingham, Alabama, Schwartz, 1993
cardiac, all, Buffalo, Gwynn, 2000
cardiac, all, Los Angeles, Moolgavkar, 2000
cardiac, all, Lyon, Zmirou, 1996
cardiac, all, 10 US Cities, Braga, 2001
cardiac, all, Cook, Moolgavkar, 2000

-4 -2 0 2 4 6 8
Percentage change 10 unit increase

Fig. 5. Relative risks (95% confidence intervals) for associations between PM10 and daily mortality for cardiovascular disease (Department of Health Committee on Medical Effects of
Air Pollution, 2006, reprinted with permission).

(and still are) poorly understood. Heterogeneity was also likely to
have been affected by differences in the way the exposure and
outcome series had been assembled, analysed and published. An
important aspect of this was choice of the lag. Mortality on
a particular day is likely to be affected by air pollution levels over
a number of prior days but because there was insufficient knowl-
edge about the mechanism connecting exposure to death, it was
not possible to postulate a lag a priori. It is now recognized that
a distributed lag model which captures the combined effect of all
lags is the best approach to this problem (Schwartz, 2000).
However, most early studies reported the results of single day lags
and tended to highlight the ‘‘best’’ one in a positive direction. While
this might have been the closest to the underlying reality, it could
also have been influenced by random variation with a consequent
risk of bias, depending on whether only positive lags were selected.
It is likely that this practice, together with publication bias in favour
of studies with positive results resulted in estimates that could be
inflated by as much as a factor of 2 (Anderson et al., 2005).
The statistical approach to analyzing time series of mortality
has undergone important development since the 1950s (Schwartz,
1994; Katsouyanni et al., 1996; Health Effects Institute, 1995, 1997;
Dominici et al., 2004; Touloumi et al., 2004, 2006; Bell et al., 2004;
Peng et al., 2006). Over the past two decades the most popular
statistical approach has been Poisson regression (outcome is
a daily count, often small in number) with air pollution variables
included as a linear predictors and controlling for time-varying
confounders which are factors that are potentially related both to
mortality and pollution. These are long term time trends, season
and weather. A number of techniques have been to used to model
trends and seasonality in mortality counts, all based upon some
function of time. These functions have included simple dichoto-
mous variables to indicate month of study, parametric cyclical
functions (sine and cosine terms) to model seasonal fluctuations
and more sophisticated parametric and non-parametric tech-
niques such as regression and penalized spline smoothing or local
smoothing based on ‘‘loess’’. Weather factors are connected with
 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152
conditions affecting the dispersion, transport and production of
pollutants and some, such as temperature, are relatively stronger
risk factors for mortality than is air pollution. Especially with daily
data from large cities or multiple cities, regression techniques have
the potential to identify statistically significant relative risks that
are very small, typically less than 1.01% (1% increase) for 10 mg m3
PM10. As experience with regression techniques increased it
quickly became apparent that the results might be sensitive to the
analytic model, especially the way in which time-varying
confounders were controlled (Moolgavkar et al., 1995). These and
other unresolved issues, such as how to measure the independent
effects of individual pollutants, challenged the scientific credibility
and regulatory relevance of time-series evidence. The question of
sensitivity to the statistical approach and the specification of
weather variables was formally addressed by a series of studies
which compared different modelling approaches applied to the
same data sets (e.g. Health Effects Institute, 1995, 1997). The
general conclusion of these studies was that the results of different
methods were in reasonable agreement and were sufficiently
robust to support the case for an association between ambient
particles and daily mortality, at least for policy purposes.
By the late 1990s, the method of choice became Poisson
regression using a generalized additive model (GAM) and non-
parametric smoothing of time-varying confounders but this was
dramatically called into question when it was discovered that
problems with the default convergence criteria used in the S-
plus GAM function could bias estimates upwards. Around the
same time, it was recognized that this method could also
underestimate standard errors. These findings invited further
attacks on time-series results and to clarify the situation,
a formal comparison method with improved methods using the
multicity studies from Europe (APHEA 2), the US (NMMAPS) and
Canada was conducted (Health Effects Institute, 2003). For
NMMAPS, this led to a substantial revision downwards of the
PM10 estimate from 0.44% to 0.22% per 10 mg m3. The effect of
reanalysis on estimates from other studies was however very
small: for the APHEA 2 cities, for example it resulted in
a combined estimate of 0.59%, only 4% less than the previous
estimate of 0.62%. Other approaches to the analysis of time-
series data, based on case-series methods have also been tried
and have obtained results that are similar to those using smooth
function of time to control for seasonality (Neas et al., 1999).
Although progressive refinement of statistical methods has
generally led to smaller estimates than observed in early anal-
yses this has not seriously undermined the consensus that air
pollution does have measurable associations with daily
mortality that cannot be readily explained by other factors.
Recent work using simulated data and multicity mortality data
suggests that there is no single model that will both reduce bias
and maximize prediction and that in sensitivity analyses, the
range of model choice may result in estimates with a 2-fold
range. Nevertheless the lower estimates still exclude zero risk
(Peng et al., 2006; Touloumi et al., 2006).
In order to address issues of bias, small effect size and hetero-
geneity, and to consolidate the evidence generally, the concept of the
planned multicity study was developed. The first of these was
APHEA (Air Pollution and Health, a European Approach) which
involved 15 and 29 European cities in APHEA 1 (Katsouyanni et al.,
1995) and APHEA 2 (Katsouyanni et al., 2001) respectively and this
was followed by the US NMMAPS (National Mortality and Morbidity
Air Pollution Study) (Samet et al., 2000). Up to mid-2008, there were
66 peer reviewed papers based on about 15 studies of from 2 to 92
cities. The results of multicity studies have largely confirmed those
147
of single city studies and enjoy a greater scientific and policy status
on account of their standardized approaches. They also have the
advantage of being more amenable to the investigation of hetero-
geneity (Katsouyanni et al., 2001; Bell and Dominici, 2008).
Despite general acceptance that the association between air
pollution and daily mortality may be causal, the usefulness of the
approach, especially for policy began to be questioned (McMichael
et al., 1998). A particular concern was that time series coefficients
could not be used convincingly to estimate the reduction in life
expectancy, a point that has been elaborated subsequently by
others (Kunzli et al., 2001; Rabl, 2003). More recently, theoretical
arguments have been put forward which integrate time-series and
cohort results and which raise the interesting possibility that
contrary to earlier assumptions, time-series studies may have the
potential to estimate effects on life expectancy (Burnett et al.,
2003). In spite of these unresolved questions, time series studies of
mortality continue to be applied for scientific and policy purposes.
One reason is that many countries, including some with highly
polluted cities, are demanding local evidence rather than relying on
that from western cities and daily mortality studies are the only
feasible method of obtaining this in a reasonable time. Another is
that time-series studies are increasingly being used to study the
relative toxicity of components of the air pollution mixture with the
ultimate aim of informing targeted control policies (Anderson et al.,
2001; Laden et al., 2000). Yet another is the investigation of trends
in time-series effect estimates over time as a method for the
environmental tracking of toxicity and for evaluating trends in
health impact (Burnett et al., 2005; Dominici et al., 2007).
2.3. Intervention studies
Empirical evidence that mortality is reduced when concentra-
tions of air pollutants fall would provide important evidence for the
causality of observational associations reported by temporal and
spatial studies. Such evidence, which is termed ‘‘accountability’’ in
the US, also provides evidence that regulatory interventions result
in health benefits (Health Effects Institute Accountability Working
Group, 2003; National Research Council, 2002). Mostly, annual
trends in air quality occur gradually and it is difficult, if not
impossible, to separate the effects of changes in air pollution from
those of probably more important secular trends in other factors
affecting mortality. For this reason, studies in which decrements in
mortality can be related temporally to the rapid introduction of
abatement measures are of great importance. Two important
examples are the evaluation of the effect on mortality of a ban on
the burning of coal in Dublin (Clancy et al., 2002) and of the over-
night introduction of low sulphur fuel in 1990 in Hong Kong
(Hedley et al., 2002). Both of these studies observed reductions in
mortality and in the case of Hong Kong there was some evidence of
a long term increase in life expectancy. It is notable that in spite of
their importance, these reports were published more than a decade
after the actual intervention.
3. Studies of spatial variability
It had been observed for many centuries that cities tended to be
relatively unhealthy environments, with crowding and lack of
hygiene promoting mortality from respiratory and enteric diseases
and with the availability of vital statistics this was confirmed. Air
pollution was another urban hazard of concern but was difficult to
link convincingly to increased mortality because associations were
likely to be confounded by factors linked both to living in a more
polluted area and to increased mortality. Smoking, crowding,
poverty, occupational hazards and selective migration are exam-
ples. The inferring of associations at an individual level from those
observed at a group level is known as the ‘‘ecological fallacy’’
148 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152
(Morgenstern, 1998). This problem is inherent in air pollution
studies because exposure assessment is mostly at the group rather
than the individual level.
In one of the first spatial studies of air pollution, an analysis of
large towns of England observed a moderate to strong correlation
(above r ¼ 0.5) between smoke emissions, indicated by sales of coal,
and deaths from bronchitis, pneumonia, respiratory tuberculosis,
lung cancer and other causes (Daly, 1959). However, there were also
positive associations between these causes of mortality and lower
social class, overcrowding, population density and lower education
and Daly recognized that these factors were all likely to correlate
with air pollution. It was found however that an association with air
pollution could still be identified after adjusting statistically for
these other factors. In the US similar studies were carried out with
similar results but in all of these studies the potential problem of
ecological confounding remained (Evans et al., 1984; Lave and
Seskin, 1972). More refined approaches of this type are still repor-
ted (Elliott et al., 2007).
The need for better data on exposure and confounding factors at
an individual level led to the development of the cohort approach
which is now regarded as the most influential, both scientifically
and for policy relevance. The essence of a mortality cohort study is
that it compares the incidence of mortality over time in populations
with different levels of long term exposure to air pollution while
controlling at the individual level for confounding factors such as
smoking or educational status. Nevertheless, quantification of
exposure remains a major difficulty because it remains at the group
level and it is difficult, if not impossible, to assess exposure
adequately over the lifetime of the cohort. Some early cohort
studies of smoking and lung cancer did consider the role of the
urban environment, and while concluding that it might have
a small effect were concerned about the likelihood of residual
confounding by smoking (Doll, 1959, 1978). The earliest cohort
study to focus on air pollution compared the risk of death after 14–
16 years in a cohort of over 8000 adults living in 6 US cities. After
adjustment for smoking and other risk factors, mortality in the
most polluted city was 26% higher than in the least polluted city
(Dockery et al., 1993). Although there was adjustment for con-
founding factors at the individual level, the statistical power of this
study was low on account of having only 6 cities and a relatively
low number of participants with which to estimate mortality risks.
On the other hand the exposure assessment was study-directed,
thus reducing the potential for exposure misclassification.
The need for a greater number of cities and a larger sample of
subjects was addressed by a study bolted on to an existing cohort
set up by the American Cancer Association (ACS) to investigate the
effects of smoking and other risk factors on cancer (Pope et al.,
1995). The initial results were based on over half a million subjects
living in 151 US Metropolitan Areas. After controlling for a range of
individual level confounders, such as smoking, there was a 17%
increase in mortality when the area with the lowest concentration
of PM2.5 was compared with the highest. Taken together, the policy
importance of these cohort results was such that there was pres-
sure to reanalyze the data independently but when this was done
the original results were confirmed (Health Effects Institute, 2000).
At the time of writing the number of substantial cohort studies of
adults has increased to about 10, far fewer than the number of
time-series studies. In spite of this, cohort evidence has had a very
strong influence on both science and policy. In part this is because
cohort studies have the important advantage over time-series
studies of being able to provide coefficients, which when combined
with life-tables, can directly estimate the number of life-years lost.
The results of the ACS study have been used by many agencies to
estimate the burden of air pollution mortality (Cohen et al., 2004)
and for cost–benefit analyses of policy options (Commission of the
European Communities, 2007; DEFRA, 2007a).
The earliest cohort studies compared cities using exposure data
from fixed site monitors. More recently, with the development of
more sophisticated spatial modelling techniques, cohort studies
have studied the effects of variations in chronic exposure on
mortality within cities or airsheds. In this design, the analysis is
based on variability in exposure on top of a city or regional back-
ground exposure that is shared by all cohort members. An early
example was from Hamilton in which proximity to major roads was
found to shorten life expectancy (Finkelstein et al., 2004). This was
followed by an analysis of the Los Angeles sub-group of the ACS
cohort (Jerrett et al., 2005). The mortality risks obtained in the
latter study were substantially higher than those obtained in the
main ACS analysis and the favoured explanation for this was that
exposure had been more accurately estimated. The first large
European cohort study of mortality and air pollution was con-
ducted in the Netherlands and found evidence of increased risks
that were to some extent compatible with those of the US ACS
study, thus providing some of the first major European evidence of
its type (Beelen et al., 2008). As with the ACS, this was a cohort set
up to study lifestyle and cancer. Because the Netherlands as a whole
is exposed to a large and fairly homogeneous regional background
of fine particles, heterogeneity of exposure relied mainly on using
traffic data to model spatial variability. What this and similar city or
regional studies cannot show is whether the observed associations
between air pollution and mortality apply also to exposure to the
background concentrations.
4. Causality and mechanisms
The foregoing sections have traced the development of epide-
miological evidence for associations between ambient air pollution
and mortality. While there remains some uncertainty about
unmeasured confounding and various statistical and exposure
measurement issues, it is generally accepted that these associations
are unlikely to be wholly explained by chance, bias or confounding.
However, since the evidence is based on observational studies
using imperfect data and analytic techniques, it is unsafe to infer
that the residual associations are completely explained by a causal
relationship. While the epidemiology of air pollution mortality has
been developing, there have been parallel developments in causal
thinking, which have had an important bearing on the interpreta-
tion of this evidence. Probably the two most important have been
the appreciation of the concept of multifactorial causation and the
development of a framework for making causal judgments.
In the 16th century Paracelsus wrote ‘‘all things are poisons, and
nothing is without poison, only the dose permits something not to
be poisonous’’. He was referring to the fact that the same substance
may be both toxic at high doses and benign or even therapeutic at
low doses. This can be generalized to the concept that many
harmful environmental substances, while toxic in high doses, are
safe in low doses. This concept was and is central to the control of
many occupational and environmental hazards where there is
dependence on the identification of a no-observable-effect level in
recommending a concentration that protects health (WHO, 1987).
This thinking probably governed the early view that air pollution
largely affected populations at times of air pollution episodes and
was not of concern at other times. It explicitly underlay the early
WHO Guidelines for outdoor air pollution which relied consider-
ably on evidence from episodes by recommending guideline values
below which increases in mortality could not be observed. Similar
thinking was current in the US around the same time (Ware et al.,
1981). Thus, in the 1987 guidelines, a level was decided below
which health effects were thought unlikely to occur (around
100 mg m3 annual mean for both smoke and sulphur dioxide) and
a safety factor of 2 was applied. Beginning with the second revision
of WHO guidelines for particulate matter in 2000 (WHO, 2000) and
 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152
continuing with the most recent (WHO, 2006) the concept of a no
observed effects level was abandoned in favour of a model in which
no threshold of adverse effect within the usual ambient range was
assumed. Under this concept, the guideline, while set at a level that
gave reasonable protection for public health, was higher than that
at which effects could be observed. This shift in thinking was
strongly influenced by the accumulating results of time-series
studies of mortality, which tended not to observe a threshold of
effect within the ambient range. An example from the APHEA study
of 29 European cities is shown in Fig. 6 (Samoli et al., 2005). Equally
influential has been that no threshold for cardiopulmonary
mortality was observed in the large multicity ACS cohort study of
chronic exposure and mortality (Pope et al., 2002) (Fig. 7).
The associations between low levels of pollution and mortality
and the absence of a threshold within the ambient range could not
be explained by the single-cause concept that prevailed in earlier
times and which, even now, underlies much lay thinking about
cause. The key to understanding why small exposures can cause
death and why there is a lack of threshold lies in the multifactorial
causal concept (Academy of Medical Sciences Working Group,
2007). A cause of a specific disease event is defined by Rothman and
Greenland (2002) as ‘‘an antecedent event, condition or charac-
teristic that was necessary for the occurrence of that disease at the
moment it occurred, given that other conditions are fixed’’. Nearly
all events are caused by a combination of factors that collectively
constitute ‘‘sufficient cause’’ but individually would not be suffi-
cient or even necessary to cause the event. The causal components
for a ‘‘sufficient cause’’ may vary from person to person and from
population to population. It has been pointed out by Rothman and
Greenland (2002) that the strength of a cause may have great
public health significance while having little biological significance,
depending on the strength of other component causes.
As applied to air pollution and mortality, the argument is that
air pollution acts as an additional stress in persons who are already
in a precarious clinical situation as a result of advanced chronic
disease (such as chronic obstructive lung disease) or a spell of life
threatening acute disease (such as acute pneumonia) (Anderson
et al., 2003). The causes of the conditions that are responsible for
this vulnerability are multifactorial and air pollution adds one
more factor. This is the proposed mechanism by which small
concentrations of air pollution may cause one person to experience
failure of a vital system and die while the vast majority of the
population survive, mostly without any adverse symptoms. At
a population level one reason why we do not generally observe
a threshold is because the population comprises individuals with
varying thresholds. These are theoretical explanations so far sup-
ported by very little direct evidence. Another consequence of
multifactorial causation is that it is vulnerability due to the
Fig. 6. 29 European cities. Exposure response for PM10 and daily mortality (adapted
from Samoli et al., 2005).
149
collective effect of other causal components rather than the air
pollution that largely determines whether or not an individual
experiences a clinical event such as death. Thus is not possible to
identify, say, among deaths from acute myocardial infarction,
which individuals were toppled by air pollution. The policy
implications of the lack of threshold are profound since under this
model the net health benefit is larger with the ‘‘exposure reduc-
tion’’ approach, in which the whole population experiences
a reduction in exposure, than with approaches that concentrate on
reducing exposure below an arbitrary standard in a minority of the
population (DEFRA, 2007a, 2007b).
The appreciation of multifactorial causation is not in itself suffi-
cient to attribute causation to an association. In this respect, an
important advance in causal thinking, which continues to be influ-
ential in the interpretation of associations between air pollution and
health, arose from the need to understand the causal nature of
smoking related health effects (US Department of Health Education
and Welfare, 1964). This was articulated by Hill (1965) who
attempted to determine ‘‘.in what circumstances we can pass from
this observed association to a verdict of causation.’’ The application of
this conceptual framework is preceded by establishing that the
observed associations cannot be explained by chance, bias or con-
founding. Hill described nine ‘‘aspects’’ or ‘‘viewpoints’’ of an asso-
ciation that should be considered in coming to a judgment as to
causality. He emphasized that the purpose of this was to come to
a decision concerning control of the hazard, not to establish scien-
tific proof. These aspects were to ‘‘help us make up our minds on the
fundamental question – is there any other way of explaining the set
of facts before us, is there any other answer equally, or more, likely
than cause and effect’’. This statement is equivalent to the balance of
probabilities concept used in civil law and is appropriate for public
health action. The nine aspects were: strength of association,
consistency of evidence, specificity of effect, temporality, biological
gradient (exposure response), coherence, experiment and analogy.
Of these, only temporality is necessary and none are sufficient. In
interpreting associations between mortality and air pollution some
of these viewpoints are present while others are absent or debatable.
Because the process of deciding causality using this framework
requires judgment (WHO Working Group, 2000), it is not surprising
that a range of interpretations exists, most clearly illustrated by the
different positions taken by environmental activists, governments,
industries, public health authorities and individual scientists and
citizens. The commonest misinterpretation of this approach is to
consider that it is a process of concluding scientific proof rather than,
as intended by Hill, a method of making a decision relating to public
health protection.
While biological plausibility based on known mechanisms is not
a necessary attribute, if it is present it has a strong influence on
causal attribution. Experimental studies of human subjects and of
animals have provided important insights into potential mecha-
nisms by which air pollution might increase mortality, but they do
not tell us whether these mechanisms are in fact responsible. The
history of air pollution epidemiology reveals an unwillingness to
accept epidemiological associations that did not make sense in
terms of known or presumed mechanisms. An important example
of this is the delay in accepting that air pollution may cause effects
beyond the lung, most importantly on the cardiovascular system. In
early air pollution episodes, it was considered that death occurred
as a result of a toxic bronchitis and that cardiovascular deaths were
secondary to respiratory stress. This view persisted until the early
1990s (Bates, 1992). However, the report on the 1952 London fog
episode clearly shows an increase in cardiovascular deaths, which,
while not as great in relative terms as the number of deaths from
respiratory causes, was greater in absolute terms because of
a higher baseline rate (Ministry of Health, 1954). This applied also to
hospital admissions, for which diagnosis is known to be more
150 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152
Fig. 7. American Cancer Society cohort. Exposure response for PM2.5 and mortality by cause (Pope et al., 2002, reproduced with permission).
accurate than death certificates. Furthermore, autopsy evidence
showed that most ischaemic heart disease deaths during the
episode did not show evidence of associated chronic or acute
respiratory disease, thus effectively excluding an effect secondary
to respiratory effects. This cardiovascular dimension to mortality
was ignored, probably because there was no concept to explain it.
However, large numbers of daily time series studies have now
observed short-term associations with cardiovascular mortality
even at low levels compared with episode conditions. Similarly, the
spatial analysis by Daly (1959) did not even consider cardiovascular
disease, presumably because it was not considered plausible. The
ACS cohort study, however, found that the major association was
with cardiovascular rather than pulmonary mortality. Acceptance
of a link with cardiovascular effects increased greatly following the
publication, by Seaton et al. (1995), of a hypothesis to explain how
small particles might cause the release of inflammatory mediators
from lung cells into the systemic circulation. Some of these
substances might affect haemostatic processes and thus trigger
cardiac events or promote atherogenesis. This is a rapidly
expanding field of research and various complex networks of
mechanisms have been proposed, supported in some cases by
evidence (Health Effects Institute, 2002; Brook et al., 2004;
Department of Health Committee on Medical Effects of Air Pollu-
tion, 2006). Most proposed mechanisms depend on pathophysio-
logical changes that originate in the lung but there is also some
evidence that ultrafine particles may even enter the bloodstream
directly. The recognition that particles may have an effect beyond
the respiratory system has opened up the theoretical possibility of
chronic inflammatory effects on virtually any part of the body.
Another finding of the report on the 1952 London fog episode
was an increase in infant mortality but as was the case for cardio-
vascular effects, this was ignored, presumably because it lacked
plausibility. By the end of the 1970s, however, it was clear from
studies of smoking in pregnancy that inhalation of combustion
products could affect foetal growth and increase the risk of sudden
infant death syndrome. This was thought to be due to an intra-
uterine mechanism and at that time there was little appreciation
that postnatal exposure to second hand smoke could be harmful to
the infant. It is now recognized that exposure to second hand
cigarette smoke is an important risk factor for sudden infant death
syndrome and this gave plausibility to early studies associating air
pollution with infant mortality (Bobak and Leon, 1992; Woodruff
et al., 1997). There is now a growing literature on effects on
reproductive and perinatal outcomes (WHO European Centre for
Environment and Health, 2005).
An important causal question that mortality studies have not
satisfactorily addressed is that of the culprit pollutants and sources.
By their nature epidemiological studies investigate complex
mixtures from multiple local and distant sources. Occasionally the
source may be clear, such as in biomass burning or dust storms, but
the exposure of a population such as a city is to pollution from
a range of sources both inside and outside the area and which
together comprise a complex and varying mixture of directly
emitted and secondary components. Those measures available to
epidemiology in the early years (smoke and sulphur dioxide) were
not chosen with toxicology in mind but because they indicated the
main components of the emissions (coal smoke) and these were
until recently the main pollutants measured in many highly polluted
cities, such as in Asia (Health Effects Institute International Over-
sight Committee, 2004). For epidemiology it is an inconvenient fact
that the main measured pollutants (particles, sulphur dioxide,
nitrogen dioxide, ozone and carbon monoxide) are all associated
statistically with daily mortality and that it has proved very difficult,
using statistical methods, to disentangle their independent effects.
The same is true for understanding the effects of respirable particles
differentiated by size, chemistry and source. A recent workshop that
addressed this issue concluded that while it was likely that particle
toxicology varies, it is not possible to quantify this, and that from
a policy perspective, all types need to be considered for regulation
(WHO Regional Office for Europe, 2007). It is now appreciated that
detailed information on the speciation of particles needs to be linked
with feasible epidemiological study designs.
5. From science to policy
In the field of air pollution epidemiology, research has mostly
been driven by policy rather than pure scientific curiosity. The main
research funding has been from responsible government agencies
while science funding sources have tended to be more interested in
basic research into questions raised by epidemiology carried out for
 H.R. Anderson / Atmospheric Environment 43 (2009) 142–152
policy purposes. However, because of the skills required, much of the
research has been done not by government bodies but by academic
scientists in universities and institutes. Early research into the
effects of air pollution on mortality concentrated on identifying
whether or not an effect could be identified in the simple hope that if
this were the case, then the source would be regulated so that ‘‘safe’’
levels could be achieved. However, regulation has economic and
political implications that usually must be based on more than the
mere fact that air pollution is a risk factor for death. At one extreme
authorities in some very polluted cities are still demanding local
evidence of any harm to the population. At the other extreme, more
advanced administrations are demanding data on quantification of
health effects that go beyond just identifying that air pollution is
a hazard. They now require exposure–response relationships and
estimates of health impact, such as life years lost, that can be
incorporated into cost benefit based appraisals of policy options.
6. Conclusions
Thomas Kuhn, in the Theory of Scientific Revolutions, postulated
that major changes in scientific knowledge amount to paradigm
shifts, a paradigm being a set of internally consistent theories and
beliefs (Kuhn, 1962). Paradigm shifts can be attributed to an inter-
action between developments in methods and theoretical concepts.
While this idea is often exemplified by major paradigm shifts such as
from Newtonian to Einsteinian Physics, or from Galenic to modern
pathophysiology, it is a useful tool for thinking about how we have
moved from not regarding even high levels of pollution as
hazardous, through being hazardous only in episodes, through to the
current position which accepts that air pollution increases mortality
at historically low levels and that there is no discernible threshold at
the population level within the ambient range. Some of our advances
in understanding have occurred due to improvements in the tech-
nology for estimating exposure to air pollution and our capacity to
process and analyse with powerful statistical techniques the large
data sets associated with mortality studies. From the biomedical
perspective, the most influential developments have been the
application of the concept of multifactorial causation of disease and
the appreciation that air pollution may cause adverse effects beyond
the lung. These various advances have had major implications for
policies to protect public health. Studies of mortality have been
central throughout and this will continue because of the availability
of mortality data on a large scale and because of the importance of
mortality in estimating health impact.
Acknowledgements
I wish to thank Richard Atkinson and Graziella Favarato in
preparing Fig. 4 from the Air Pollution Epidemiology Database, and
Mary Field-Smith for helping to prepare the manuscript.
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