Tools and perspectives for assessing chemical mixtures and multiple stressors
Introduction
Chemical risk assessment has traditionally focused on single stressors. This can partly be explained by the fact that the acute pollution problems of the 20th century were caused by a limited number of chemicals that were emitted in relatively large quantities by a limited number of well-defined sources. Consequently, risk assessments focused on particular substances or sources. The main questions addressed were “Can this substance cause adverse effects?” or “Can this production plant cause adverse effects?” These assessments typically try to capture the chain of events that starts with the emission of a substance into the environment and ends with the emergence of adverse health effects. This approach has been very effective in reducing environmental problems that are caused by single stressors and/or sources, e.g. lead, asbestos and chlorinated insecticides.
Now the overt pollution problems have largely been solved, awareness is growing that exposure to single chemicals is the exception rather than the rule. In everyday life, humans and other living organisms are rarely exposed to single stressors, but to a mixture of different stressors; either concurrently, sequentially, or both. Although researchers and risk assessors have always recognized the need to address this problem, progress has been slow because of lacking knowledge, experimental limitations, and scarce funding (Callahan and Sexton, 2007).
One of the reasons for the growing interest in mixtures and cumulative risks is that some health problems are on the rise without an obvious explanation. It is estimated that 7.4% of the married women in the USA between 15 and 44 years of age are infertile (Chandra et al., 2005). The diagnoses of autism, attention deficit and hyperactivity disorders (ADD and ADHD) and the prevalence of childhood brain cancer and acute lymphocytic leukemia have all increased over the past 30 years (Jahnke et al., 2005, Trasande and Landrigan, 2004). Air pollution and early life exposure to environmental pollutants are commonly cited as possible causes. Furthermore, a range of health issues is suspected to be related to cumulative stress. For example, neuro-developmental disorders can be caused by heavy metals, dioxins, PCBs and pesticides (Brent, 2004); childhood cancer could be related to a number of physical, chemical and biological agents (e.g. parental tobacco smoke, parental occupational exposure to solvents; Trasande and Landrigan, 2004). As a consequence, several national and international institutions have recognized the need to evaluate risks from mixtures and multiple stressors (NRC, 1994, PCCRARM, 1997, Mileson et al., 1999, US EPA, 2000, US EPA, 2003, ATSDR, 2004, WHO, 2009, European Scientific Committees, 2011).
Cumulative risk assessment can be defined as “an analysis, characterization, and possible quantification of the combined risks to health or the environment from multiple agents or stressors” (US EPA, 2003). The conventional methods for risk assessment of single stressors need to be adapted and extended to deal with the specific challenges posed by mixtures and multiple stressors. This requires new knowledge, e.g. about the complex exposure patterns of individuals and populations, and about the potential interactions between stressors. Novel exposure tools are required that focus on the exposed individual or population, instead of the traditional tools that focus on single substances or pollution sources (Loos et al., 2010a). Measurement data on exposures to mixtures and multiple stressors need to be combined with data on the prevalence of adverse health effects in populations and ecosystems in order to identify potential causal relationships (Rappaport, 2011). Furthermore, methods are needed to predict the effects of concurrent or sequential exposures to mixtures and multiple stressors, preferably based on data from single compounds because these are widely available. We need to understand how and why stressors interact because it is not feasible to test all possible combinations of stressors in the laboratory. Those tests that are necessary need to be performed according to intelligent testing strategies to optimize the use of resources and limit the use of laboratory animals. Collaboration between human and ecological experts in toxicology and risk assessment is desirable because both fields struggle with similar issues and can benefit from each other's strengths (Ragas et al., 2011a). In addition to interactions between chemicals, there are possible interactions with other stressors, such as climate variables (Schlink et al., 2002, Leitte et al., 2009), which need to be addressed.
In November 2004, the EU research project NoMiracle was launched (http://www.nomiracle.jrc.ec.europa.eu). The main aim of the project was to gather new knowledge for the improvement of current risk assessment methods and the development of novel methods for cumulative risk assessment. The work was conducted until 30 October 2009. Thirty eight institutions from 17 European countries participated in the project. The consortium consisted of scientists with expertise in human toxicology, epidemiology, aquatic and terrestrial ecotoxicology, risk assessment, environmental chemistry, biochemistry, toxicogenomics, physics, mathematical modeling, geographical informatics, and social and economic sciences. Box 1 shows the main goals of the NoMiracle project. The themes of NoMiracle were rather broad, allowing for interdisciplinary collaboration.
The project resulted in more than 200 scientific reports and 200 peer-reviewed papers covering a large diversity of topics such as the identification of exposure scenarios, sorption behavior of substances, environmental degradation, analytical methods, fate modeling, toxicokinetics, mixture toxicity, effects of multiple stressors, in vitro test systems, probabilistic risk assessment methods, exposure modeling, risk perception and risk visualization. Six open international workshops and conferences were held. An international workshop on mixture toxicity was organized together with the Society of Environmental Toxicology and Chemistry (SETAC) and resulted in a book on mixture toxicity (Van Gestel et al., 2010). The main results of the NoMiracle project were published as a special issue of Science of the Total Environment (Løkke et al., 2010). The new methods and models that were developed are publicly available in the NoMiracle Tool Box (http://www.nomiracle.jrc.ec.europa.eu/Lists/Toolbox/).
The present paper summarizes the most important insights and findings of the EU NoMiracle project within three major fields of the project, namely: (1) risk assessment of chemical mixtures, (2) combinations of chemical and natural stressors, and (3) the receptor-oriented approach in cumulative risk assessment. The results of the NoMiracle project are discussed in the light of recent developments in risk assessment of mixtures and multiple stressors. The paper concludes with an outlook for the future and a number of research and policy recommendations.
Section snippets
Mixture experiments
The NoMiracle consortium set up a series of (eco)toxicity tests with chemical mixtures. The chemicals were taken from a priority list that focused on metals, polyaromatic hydrocarbons (PAHs) and specifically acting pesticides (e.g. organophosphate and neonicotinamide pesticides). Species used for testing included the Vibrio fischeri Microtox™ system, Tubifex tubifex, chironomidae, Danio rerio, Daphnia magna, Mytilus galloprovincialis, Lumbricus rubellus, Folsomia candida, Caenorhabditis elegans
Combinations of chemical and natural stressors
In real-world environments it is not unusual for organisms and humans to be exposed to several stressful factors of natural origin besides those of polluting chemicals. These natural factors may in aquatic ecosystems include anoxia and pH changes which have serious consequences for many species (Hoegh-Guldberg et al., 2007). In the terrestrial environment extreme climatic conditions, such as heat waves, drought, flooding or extreme cold are also important stressors. With current concerns over
The receptor-oriented approach
Risk management aims to control events that can result in adverse effects in humans or ecosystems. In the case of single chemicals, these events can be presented by a single chain, starting with the production and emission of the chemical of concern and ending with the adverse effects (Fig. 3). When the relationships between the links of the chain are known, data and measures relating to one link can be translated relatively easily into implications for other links. This explains why
Discussion
The NoMiracle project covered a broad field. In this review we have focused on three important topics for the assessment of risks associated with multiple stressors, namely the need for novel tools for (1) risk assessment of chemical mixtures, (2) combinations of chemical and natural stressors, and (3) the receptor-oriented approach in cumulative risk assessment.
Within the risk assessment of chemical mixtures, there is much discussion on the occurrence and frequency of nonadditive effects,
Conflict of interest
None.
Funding source
EU FP6 integrated project NoMiracle Contract No. 003956.
Acknowledgements
The studies were supported by the EU 6th Framework program for Research and Technological Development under the Integrated Project NoMiracle (Novel Methods for Integrated Risk assessment of Cumulative Stressors in Europe; http://nomiracle.jrc.it), Contract No. 003956.
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