3.1.3. Mixture/combined effects
The SCHER was asked to
consider the practicality of a
risk assessment which
takes into account combined exposure and cumulative effects of
specific air pollutants. Within this opinion, the SCHER
interprets the combined effects as the total effects caused by
exposure to all chemical and biological
(allergens and microbes)
stressors present in indoor air.
At present the (quantitative) risk characterization must
mostly be done on a single chemical basis because there are
seldom relevant data and established methods to evaluate mixture
effects. In indoor environment, exposures are always to complex
mixtures of substances from different sources which may jointly
contribute to the toxic
effects. Due to the complexity of indoor air pollution and its
variability with time, estimation of risk associated with
exposure of the complex mixture as such and then generalize the
obtained results is rarely feasible. This approach has only been
used in few cases, when sensory irritation was the end-point
(Hempel-Jørgensen et al., 1999, Nielsen et al., 2007b).
The majority of toxicology data refer to exposures to single
chemicals. Such data can be used directly if chemicals in a
mixture act independently with different endpoints, i.e. the
effect of each component of the mixture is not influenced by the
presence of the other components (‘dissimilar joint action’).
The single chemical approach is supported by the results of some
studies, which indicate that interactions were unlikely to occur
at environmentally relevant concentrations (which often are well
below the NOAEL values). Interactive effects giving rise to
possible health concern have been reported, starting from
concentrations around the LOAEL (Cassee et al, 1998).
However, the single chemical approach is not applicable when
the components affect each others response. Such combined
effects may be additive (a ‘similar joint action’; similar
endpoints, similar mechanism of action and /or toxicokinetics
properties) or there may be interactions (antagonistic or
synergistic effects). Combined effects have been demonstrated
e.g. by mixtures of
pesticides when potentially
harmful effects were observed at concentrations of each single
component below or approaching the individual NOAEL value
Models to evaluate
toxicity of chemical
mixtures have focused primarily on quantifying dose addition, as
in the EPA assessment of health risk at hazardous waste sites
(US EPA, 1986). The methods for dose addition which have been
most frequently used are the Relative Potency Factor (RPF), the
Toxic Equivalent Factor
(TEF) and the Hazard Index (HI). When extensive mechanistic
information is not available, the HI is the preferred approach.
HI is a dimensionless figure, corresponding to the sum of the
ratios between the exposure level and the reference dose (RfD)
of each component, representing the relative potency. When HI
for the whole mixture is equal to 1, it is supposed that the
exposure correspond to the RfD of the mixture; when values are
higher than 1, potential health concerns should be considered.
HI derivation can be revised in order to be able to incorporate
interaction data, when available, introducing a weight of
evidence evaluation and an adjustment factor for the relative
potency of each component (US EPA, 2001b).
With respect to indoor air pollution, a number of studies have
dealt with the combined effects of indoor air pollutants,
including effects of
fine particles and gases in
ambient air. The results have suggested that e.g. particles may
behave as carriers for the toxicant into the lungs and that
particulate matter may
facilitate airway sensitisation in susceptible individuals (e.g.
Hamada et al, 2000). NO2 has increased the
inflammatory effect of
aeroallergen exposure in
asthmatics (Barck et al.,
2005) whereas formaldehyde
has not modified the aeroallergen airway effect (Ezratty et al.,
An additive approach has been considered useful for evaluation
of mixtures of airborne sensory irritants above the threshold
level (e.g. Cometto-Muñiz and Hernãndez 1990; Hempel-Jørgensen
et al. 1999) and may be assumed as a first approximation of
sensory irritation effects of mixtures based on animal and human
studies (Nielsen et al., 2007b).
Some efforts have also been made to evaluate combined effects
of a larger group of indoor air pollutants. The Committee of the
Health Council in the Netherlands tentatively evaluated the
health impact of
volatile organic compounds
(VOCs) from building materials (HCN, 2000). The Dutch committee
considered the air quality guidelines developed by the WHO for
outdoor air (WHO, 2000) and estimated the maximum tolerable
pollution of indoor air by VOCs to be between 0.2 and 3.0
mg/m3, giving as recommended cumulative limit value
of 0.2 mg/m3 for VOCs not showing carcinogenic,
reprotoxic or sensitizing properties. However, because the
composition of total VOCs varies from place to place, this may
only be used as a very general indicator of indoor air quality.
Moreover, the compounds of highest concentrations are not
necessarily those with offending effects in indoor air (Wolkoff
and Nielsen, 2001).
The main problems encountered in applying the combined effect
approach is that few data are available on interactions among
more than two chemicals and they usually do not address issues
toxicity at concentrations
representative of actual human exposure. The use of PBPK and
PBPD modelling may help (ATSDR, 2002, De Rosa et al, 2004). The
use of mechanistic data derived from testing with binary
mixtures may be extrapolated to more complex mixtures by means
of PBPK models, as demonstrated with a mixture of
ethylbenzene and xylene (BTEX) (Haddad, 2000) and may be very
useful for the evaluation of metabolic interactions. In general,
the issue of toxicity due to chemical mixture or multiple
exposures suffers of the lack of both experimental data on the
mode/mechanisms of actions and a generally accepted strategy for
the related risk evaluation (McCarty and Borgert, 2006).
At present at the EU level there is not a general recommended
approach to conduct the
risk assessment for
chemical mixtures or for combined effects due to concomitant
exposure to different chemicals through different routes.
Altogether, the SCHER
considers that the
risk assessment which
takes into account the combined exposure and cumulative effects
of the pollutants in indoor environment is seldom possible.
Mostly, there are not enough relevant data and the available
methods may not fit the case. However, the SCHER recommends that
the possibility of combined effects is considered in the risk
assessment and they are evaluated on a case-by-case approach.
Interactions between chemicals and other factors such as
microbes are insufficiently known to provide guidance.