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The SCHER opinion states:
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 (Cavieres, 2002).
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 exposure to 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., 2007).
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 of chronic 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 benzene, toluene, 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.
Source & ©: SCHER,
3.1.3. Mixture/combined effects, p. 12-14
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