 4.3
Is there new scientific evidence to justify
reconsideration of the current WHO Guidelines
for NO2?
"Answer:
The current WHO guideline
values for NO2 are a 1-hour
level of 200 µg/m3 and
an annual average of 40 µg/m3.
Since the previous review, only a small
number of additional human exposure studies
have been carried out. These do not support
the need to change the 1-hour guideline
value. With regard to the annual average,
there have been some new epidemiological
studies reporting associations of longer-term
exposure with lung
function and respiratory symptoms.
The former group that proposed the annual
guideline value of 40 µg/m3
acknowledged that “although there
is no particular set of studies that clearly
support the selection of a specific numerical
value for an annual average guideline
the database nevertheless indicates a
need to protect the public from chronic
nitrogen
dioxide exposures”. Because
of a lack of evidence, the former group
selected a value from a prior WHO review.
The new evidence does not provide sufficient
information to justify a change in the
guideline value. Given the role of NO2
as a precursor of other pollutants and
as a marker of traffic related pollution,
there should be public health benefits
from meeting the current guidelines. Thus
the present working group did not find
sufficient evidence to reconsider the
current 1-hour and annual WHO guidelines
for NO2.
Rationale:
Ambient
air NO2 is in large part derived
from the oxidation of NO, the major source
of which is combustion emissions, mainly
from vehicles. NO2 is therefore
a clear indicator for road traffic. NO2
is also subject to extensive further atmospheric
transformations that lead to the formation
of O3
and other strong oxidants that participate
in the conversion of NO2 to
nitric acid and SO2 to sulphuric
acid and subsequent conversions to their
ammonium neutralization salts. Thus, through
the photochemical
reactions sequence initiated by solar-radiation-induced
activation of NO2, the newly
generated pollutants formed are an important
source of nitrate, sulphate
and organic aerosols that can contribute
significantly to total PM10
or PM2.5
mass. For these reasons, NO2
is a key precursor for a range of secondary
pollutants whose effects on human health
are well documented.
Short-term chamber studies
with humans (384, 385) as well as in animal
exposure studies continue to support the
view that at the levels encountered in
the ambient
outdoor air, direct effects of NO2
alone on the lungs (or any other system)
are minimal or undetectable. At NO2
concentrations in excess of those achieved
in outdoor air (with the possible exception
of road tunnels), mild airway inflammation
occurs (386). Human chamber studies have
shown that in allergic subjects NO2
can enhance the effect of allergens (387,
388, 389). Bronchial reactivity also was
increased in the presence of NO2
(390). These studies show effects at levels
twice or more of the current guideline
value and therefore do not provide evidence
to justify a change.
The number of time-series
studies using peak hourly concentrations
and/or daily mean concentrations of NO2
as air pollution indicators has grown
substantially over the past five years.
Overall, these studies have supported
associations between ambient
NO2 concentrations and a range
of adverse health effects. A meta-analysis
on mortality showed consistent associations
with NO2 (391). Hospital admissions
for respiratory disease were shown to
increase with increasing levels of NO2
in some areas (357). While such studies
have supported an association between
ambient NO2 concentrations
in relation to multiple respiratory and
cardiovascular health outcome measures,
these cannot establish causality for an
NO2 effect. It is likely that
many health effects observed occur as
a result of exposure to confounding traffic
related pollutants and/or secondary pollutants
that include O3,
acid aerosol and particles. In a significant
proportion of the epidemiological studies
increased risks of adverse health outcomes
diminish considerably or become non-significant
when other pollutants are considered in
the statistical models. In others, however,
NO2 enhances the magnitude
of effects observed with other pollutants
(29, 349).
Recent epidemiological
studies have shown consistent associations
between long term exposure to NO2
and lung
function in children (22, 23, 236)
as well as with lung function and respiratory
symptoms in adults. These effects cannot
be attributed to NO2 exposure
per se. Few studies have attempted (or
had the data) to evaluate the relative
contribution of particulate
matter and NO2 on the health
outcomes described. Those who were able
to do this show a separate but smaller
contribution of NO2 (392).
The importance of NO2
as a key component for the rise of secondary
toxic pollutant concentrations in ambient
air and its potential in mixtures to enhance
the effects of other environmental pollutants
including allergens, warrants a guideline
that limits the resulting health effects.
Indeed, some additional emphasis might
be given to NO2 for the very
reason that it is a good indicator of
traffic-related air pollution and an important
source of a range of more toxic pollutants
that probably act in combination to produce
adverse health effects."
Source
& © : WHO
Regional Office for Europe  "Health
Aspects of Air Pollution" (2003),
Chapter 7 Nitrogen dioxide, Section 7.2
Answers and rationales, Question 1
"What is the basis for maintaining
the WHO NO2 annual specific
guideline value of 40 µg/m3?
Answer:
There is evidence from
toxicological studies that long-term exposure
to NO2 at concentrations higher
than current ambient
concentrations has adverse effects.
Uncertainty remains over
the significance of NO2 as
a pollutant with a direct impact on human
health at current ambient air concentrations
in the European Union, and there is still
no firm basis for selecting a particular
concentration as a long-term guideline
for NO2. NO2 is
an important constituent of combustion
generated air pollution. In recent epidemiological
studies of the effects of combustion-related
(mainly traffic generated) air pollution,
NO2 has been associated with
adverse health effects even when the annual
average NO2 concentration is
within a range that includes 40 µg/m3,
the current guideline value. However,
we are unable to establish an alternative
NO2 guideline from these studies.
We therefore recommend that the WHO annual
specific guideline value of 40 µg/m3
should be retained or lowered.
Rationale:
The WHO Air Quality Guideline
value of 40 µg/m3 as
annual mean was based on limited but suggestive
evidence from indoor studies that long-term
exposure to combustion products from indoor
gas appliances including NO2
had a deleterious effect on health. The
figure of 40 µg/m3 was
adopted from the International Programme
on Chemical Safety (IPCS; Environmental
Health Criteria 188) and reflected the
association between indoor exposure to
combustion products from indoor gas appliances
including NO2 and lower respiratory
tract illnesses in children. There
was some uncertainty over the appropriate
numerical value for the guideline, as
NO2 was not directly measured
in all studies. It was also noted that
outdoor epidemiological studies had shown
associations between outdoor concentrations
of NO2 and small reductions
in lung
function and a slightly increased
prevalence of asthma.
Since the current WHO
Air Quality Guidelines were established
(WHO, 2000) the evidence regarding the
long-term effects of NO2 as
a single pollutant and adverse human health
has increased a little. There is new evidence
from human and animal studies in vivo
(Pamanathan et al., 2003; Blombert et
al., 1997; van Bree et al., 2000) and
from limited in vitro (Devalia et al.,
1993; Bayram et al., 1999) studies that
short-term exposure to NO2
can be toxic to airway and alveolar epithelial
cells. This is a result of its oxidant
capacity to cause tissue damage (Persinger
et al., 2002). This lends plausibility
to the possibility that there could be
long-term effects. There are no human
studies of long-term exposure to pure
NO2; studies have only been
performed with short-term exposure to
concentrations higher than common ambient
concentrations and not at the low levels
that might be causing long-term effects
(e.g. Chitano et al., 1995; Hyde et al.,
1978; Wegmann et al., 2003). There are
also studies showing lung damage following
long-term exposure to nitrogen
dioxide in animals. Again the concentrations
used are above common ambient concentrations.
Epidemiological studies
of short-term changes in NO2
concentrations suggest that these may
be associated with ill health at common
ambient concentrations. This may have
implications for long-term effects. None
of these studies, however, provides a
significantly improved basis for the long-term
guideline of 40 µg/m3
as annual average for NO2 as
a single toxic pollutant gas.
We have been asked to
comment on our confidence in this guideline.
Our reply is that it remains difficult
to provide solid scientific support for
the numerical value of the guideline.
There still is no robust basis for setting
an annual average guideline value for
NO2 through any direct toxic
effect. However, new epidemiological evidence
has emerged that increases our concern
over health effects associated with outdoor
air pollution mixtures that are apparently
well characterized by NO2.
We refer to evidence supporting effects
of a mixture of NO2 and derived
pollutants including nitrate rich particles
and nitric acid vapour at mean NO2
concentrations in a range that includes
40 µg/m3 (range 8–75
µg/m3) (McConnell et
al., 2003). This study demonstrated an
association between bronchitis symptoms
among children with asthma and the yearly
variability of NO2 concentrations
in southern Californian communities. We
note that the highest 4 year average concentration
of NO2 in the communities studied
was 75 µg/m3. Of interest
is the high correlation between NO2
and Organic Carbon (OC) in this study
(0.69). In two-pollutant models, adjusting
for O3,
PM10,
PM2.5,
coarse
particles, inorganic acid and elemental
carbon, OC was the pollutant that retained
most of its significance. PM2.5
and NO2 also had fairly robust
associations with symptoms; PM2.5,
NO2 and OC all lost their significance
in all two-pollutant models including
combinations of these, showing that either
was representing a gas-particle mixture
most likely dominated by traffic emissions.
In the same study, Gauderman et al. (2000)
reported an association between annual
average PM10,
PM2.5,
inorganic acid and NO2 concentrations
and a reduction in lung growth in fourth
grade children. In this study, the highest
concentration of NO2 recorded
was about 45 ppb (80 µg/m3)
while in 6 of the 12 communities studied
the annual average concentrations was
less than 40 µg/m3. Again,
there were significant correlations between
these pollutants (up to 0.87 for NO2
and inorganic acid), and all of the associations
lost significance in two-pollutant models
including any combination between the
four. A further study from this cohort
(Gauderman et al., 2002) included more
detailed measurements of acid vapours
and of elemental and organic carbon. In
this study acid vapour (sum of nitric,
formic and acetic acid) was the clearest
determinant of reduced lung function growth,
and again, acid, NO2 and particle
metrics mostly lost significance in two-
pollutant models. In this second study,
however, NO2 coefficients reduced
less after adjustment for PM2.5
or PM10
than vice versa. What these studies point
towards is that NO2 is serving
as an indicator of a complex mixture,
and that its indicator value is reduced,
but not removed by adjustment for PM2.5
and other particle metrics.
In Europe, a negative
association between the development of
lung function and ambient
NO2 concentrations (Schindler
et al., 1998) has been reported, where
the highest ambient annual mean concentration
of NO2 in the communities studied
was 57.5 µg/m3. In this
study, the role of co- pollutants was
not examined
A recent series of European
studies has used Geographic Information
Systems (GIS) to generate exposure distributions
for traffic-related pollutants, primarily
NO2, “soot”
(measured as reflectance of particle filters)
and PM2.5.
These studies were conducted over annual
average NO2 ranges of 25–84
µg/m3 (Carr et al., 2002;
Nicolai et al., 2003), 15–67 µg/m3
(Hoek et al., 2001; Hoek et al., 2002),
27–44 µg/m3 (Janssen
et al., 2001; Janssen et al., 2003), 20–67
µg/m3 (Gehring et al.,
2002) and 13–58 µg/m3
(Brauer et al., 2002). In all of these,
the correlation between the two or three
metrics of exposure was high, so that
they could not be separated. In all studies,
there were positive associations between
NO2 and health endpoints
such as respiratory symptoms and mortality
indicating that over these low ranges
of exposure, NO2 as marker
of traffic-related pollution is clearly
associated with adverse effects on health.
In a European study of lung cancer, NO2
(calculated from NOx) was used explicitly
as a marker of road traffic exhaust levels,
since historical road maps and traffic
flow estimates, and dispersion models,
were used to map the road traffic contribution
to ambient
NO2. These geographical estimates
produced an individual average in the
range 4–51 µg/m3
for the first decade of the study (Bellander
et al., 2001). In a similar recent European
study total residential NOx
(mainly from vehicles) was historically
assessed by dispersion modelling, showing
a five year individual average in the
range 1–170 µg/m3
(Nafstad et al., 2003). Residential road
traffic exhaust levels corresponding to
over 30 µg/m3 NO2
or NOx were found to increase
the lung cancer risk by about 40% 10–30
years later in the two studies (Nyberg
et al., 2000, Nafstad et al., 2003). A
point worthy of note is that associations
of ambient NO2 concentrations
with health effects is manifest in a much
smaller geographical scale than has previously
reported (Cohen, 2003).
The current annual average
NO2 guideline value of 40 µg/m3
is within the exposure ranges reported
in these investigations, and one being
conducted almost entirely over a range
below the current annual average guideline
concentration value. These recently published
studies document that NO2,
as marker of a complex mixture or traffic-related
pollution, is consistently associated
with adverse effects on health at relatively
low levels of long-term average exposure.
They also show that these associations
cannot be completely explained by co-exposure
to PM2.5,
but that other components in the mixture
(such as organic carbon and acid vapour)
might explain part of the association.
As such components have not been routinely
measured, and as there is much information
on NO2 concentrations in ambient
air, it seems reasonable to propose to
CAFE that a prudent annual average limit
value for NO2 be set, acknowledging
that this takes account of any direct
toxic effect that NO2 might
exert and to control complex mixtures
of combustion-related pollution (mainly
from road traffic).
There are some limitations
to using NO2 purely as an indicator
for combustion-related air pollution,
since the mixture will vary in different
places and change with time. However,
this limitation would also apply for,
e.g. PM2.5
since it is not known what aspects or
components of particulate air pollution
are responsible for the adverse health
effects observed. When more information
on the relationship between different
aspects of combustion-related air pollution
and health is available, it is possible
that more efficient protection against
the health effects of these complex gas-particle
mixtures will be obtained by regulating
another metric than NO2 alone
or in combination (Seaton & Dennekamp,
2003). Such candidates include black smoke,
elemental and organic carbon, measures
of acidity, NOx and particulate
number concentration.
Research should be undertaken
to determine whether NO2 at
concentrations achieved in the outdoor
environment, has any detectable toxicity
on the human lung using a range of outcome
measures. Research is also urgently needed
to determine which aspects or components
of combustion mixtures are responsible
for the adverse health effects observed
in epidemiological studies."
Source
& © : WHO
Regional Office for Europe Health
Aspects of Air Pollution
- answers to follow-up questions from
CAFE (2004), Question 7
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