Better health and environmental protection from harmful chemical mixtures
Submitting InstitutionBrunel University
Unit of AssessmentEarth Systems and Environmental Sciences
Summary Impact TypeEnvironmental
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Public Health and Health Services
Summary of the impact
Hundreds of synthetic chemicals contaminate our food and water. Brunel's research shows harmful
cumulative cocktail effects of low levels of contaminants in food and water, previously thought to be
safe. The active translation of these results into European chemicals legislation also ensured a
sound basis for including multiple chemical exposures in risk assessment. By working with the
European Food Safety Authority, we demonstrated a viable approach to grouping chemicals for
mixtures risk assessment. Based on our research, a totally new approach to grouping chemicals
for mixtures risk assessment has been decided. This will influence maximum residue levels for
toxic pesticides in food in Europe leading to better protection of consumers against the increased
risks of harm due to multiple pesticide residues present in the majority of food items.
Although chemical exposures of human populations and of wildlife are not to single substances,
but to large numbers of chemicals simultaneously, the combined effects of such exposures had
rarely been studied. In 1999, Professors Sumpter and Tyler (then at Brunel) recognized this
major limitation and began to develop experimental strategies (Thorpe 2001, 2003) for assessing
the joint toxicity of chemical mixtures in ecotoxicology. In 2001, Sumpter began to collaborate on
chemical cocktails with Drs Andreas Kortenkamp and Martin Scholze, at the School of
Pharmacy, University of London in an EU-funded project, ACE (Analysing combination effects of
mixtures of estrogenic chemicals in marine and freshwater organisms), led by Professor Sumpter.
The ACE project helped create a sound conceptual basis for the assessment of multi-component
mixtures using mathematical algorithms to derive prediction curves for combinations which could
be used as a benchmark against which synergisms and antagonisms could be evaluated.
Subsequently, many observations confirming the predictability of multi-component mixtures were
made with in vitro assays, but information about mixtures of chemicals in entire organisms was
needed to make these ideas more credible in the arena of risk assessment. These concepts and
methodologies were further developed in an EU-funded project awarded to Kortenkamp (Eden) in
which Sumpter participated. In 2005, Prof Sumpter, and Dr Jayne Brian published a landmark
paper on the effects of five chemicals in fish, showing that the variability normally encountered in
an in vivo system is no hindrance to predicting mixture effects accurately (Brian et al. 2005). It also
demonstrated that taking account of mixture effects provided consistently higher risk estimates
than approaches which do not consider combination effects. As a direct result, the idea that
mixture effects should be taken into account during chemical risk assessment gained credibility,
however, the practicalities of doing so had to be worked out.
A key issue was which chemicals should be grouped together for chemical risk assessment
and which criteria should be used for grouping?
Established practice was to group together chemicals with very similar structural features and
mechanisms. For example, the US EPA currently considers organophosphate pesticides and
carbonate pesticides in separate groups, although both types of pesticides essentially work
through the same mechanisms, inhibition of acetylcholine esterase. In several key scientific papers
and reports, Prof Kortenkamp's team (who joined Brunel in July 2011 with Silva, Martin, Evans,
Orton, Ermler and Scholze) showed that these criteria are too narrow and might lead to
underestimations of risks by leaving out chemicals that in reality also contribute to a mixture effect.
Several pesticides affecting male sexual development by totally different mechanisms were shown
to act together and result in significant mixture effects despite their enormous chemical and
mechanistic diversity (Evans et al. 2012, Kortenkamp et al. 2012, Orton et al. 2012, Christiansen et
al., 2012). This research was conducted as part of the EU-funded CONTAMED project headed by
Kortenkamp and had a profound impact on the thinking about grouping criteria for predicting the
effects of mixtures of pesticides found in food and water. It led to the realization that grouping
according to chemical structural features and mechanisms would lead to underestimations of risk
by ignoring chemicals that in reality also contribute to combination effects.
References to the research
Thorpe, K. L., Hutchinson, T. H., Hetheridge, M. J., Scholze, M., Sumpter, J. P., & Tyler,
C. R. 2001, "Assessing the biological potency of binary mixtures of environmental
estrogens using vitellogenin induction in juvenile rainbow trout (Oncorhynchus mykiss)"
Environmental Science and Technology 35; 2476-2481. http://dx.doi.org/10.1021/es001767u (155
Thorpe, K. L., Cummings, R. I., Hutchinson, T. H., Scholze, M., Brighty, G., Sumpter, J.
P., & Tyler, C. R. 2003, "Relative potencies and combination effects of steroidalestrogens in fish",
Environmental Science and Technology 37; 1142-1149. http://dx.doi.org/10.1021/es0201348 (260
Brian, JV., Harris, CA., Scholze, M., Backhaus, T., Booy, P., Lamoree, M., Pojana, G., Jonkers, N.,
Runnalls, T., Bonfà, A., Marcomini, A. and Sumpter, JP., 2005, "Accurate prediction of the
response of freshwater fish to a mixture of estrogenic chemicals", Environmental Health
Perspectives 113; 721- 728. http://dx.doi.org/10.1021/es0201348 (180 citations)
Christiansen, S., Kortenkamp, A., Axelstad, M., Boberg, J., Scholze, M., Rosenskjold Jacobsen, P.,
Faust, M., Lichtensteiger, W., Schlumpf, M., Burdorf, A., Hass, U. (2012) "Mixtures of endocrine
disrupting contaminants modelled on human high end exposures — an exploratory study in rats."
International Journal of Andrology 35; 303-316 http://dx.doi.org/10.1111/j.1365-2605.2011.01242.x
Evans, R., Scholze, M., Kortenkamp, A. (2012) "Additive mixture effects of estrogenic chemicals in
human cell-based assays can be influenced by inclusion of chemicals with differing effect profiles"
PloS 7 (8) e43606 http://dx.doi.org/10.1371/journal.pone.0043606 Published: AUG 17 2012 (2
Kortenkamp A, Evans R, Faust M, Kalberlah F, Scholze M, Schumacher-Wolz U (2012).
"Investigation of the state of the science on combined actions of chemicals in food through
dissimilar modes of action and proposal for science-based approach for performing related
cumulative risk assessment". Supporting publications 2012:EN-232.
Orton, F., Rosivatz, E., Scholze, M., Kortenkamp, A. (2012) "Competitive androgen receptor
antagonism as a factor determining the predictability of mixture effects of widely used pesticides."
Environmental Health Perspectives 120; 1578-1584. http://dx.doi.org/10.1289/ehp.1205391 (0
Details of the impact
Although the experimental mixtures work conducted by Kortenkamp, Sumpter and co-workers
raised the profile of the topic, the scientific findings in and of themselves could not open up
avenues for improvements of chemical risk assessment and regulation. To achieve this,
translational work in the appropriate political context in the European Union was necessary.
Kortenkamp was actively involved in this translation and a State of the Art report on Mixture
Toxicology for the European Commission (published whilst Kortenkamp was at the London School
of Pharmacy) had considerable impact. It cited the work carried out by Sumpter, Brian, Tyler and
Thorpe (Brunel staff and students at the time the research was carried out) as "Ecotoxicology that
has played an important role in advancing mixture toxicology, with human and mammalian
toxicology slowly catching up" (Kortenkamp et al, 2009). Several recent pieces of European
chemicals legislation now require consideration of mixture effects, including the Plant Protection
Product Regulation, PPPR (1107/2009) and the Biocidal Products Regulation (EU 528/2012),
REACH, the Water Framework Directive, and the Cosmetics Directive. In the Water Framework
Directive, it states that mixtures can be considered when their qualitative and quantitative
composition is well described and that the concentration addition concept defined by Brunel's
researchers can be used as a default for setting quality standards. Indeed, it is now unanimously
agreed that for chemical mixtures, a classical tiered approach should be used and that the concept
of concentration addition (CA) described by Brunel researchers is a suitable approach for the first
Implementation of legislation is a separate step, requiring a framework and a methodology, that
has still not been taken for the Water Framework Directive, the PPPR, the Biocidal Products
Regulation or REACH, albeit there have been many calls for action. For pesticides and biocides,
the European Commission mandated the European Food Safety Authority (EFSA) with working out
the details for considering combination effects during the setting of maximum residue levels in food
To this end, the EFSA Plant Protection Product Regulation (PPR) Panel instituted a working
group which Kortenkamp was called to join as an external expert. The task of this group was
to draft a Scientific Opinion of EFSA which was to be adopted by the EFSA PPR Panel. The EFSA
working group began by deciding which chemicals should be considered together in mixtures risk
assessment, in so-called common assessment groups usually made on the basis of specific
criteria regarding common chemical structures and common toxicological mechanisms.
The EFSA working group, however, developed a novel grouping strategy that began not with
considerations of mechanisms, but instead using common adverse outcomes as the starting point
for creating common assessment groups. Novel grouping criteria, based on the concept of shared
toxicity and common adverse outcomes, irrespective of mechanisms, were developed for
application to the regulatory framework. With this new grouping approach, all pesticides that affect
e.g. the thyroid gland are considered together. The resulting large groupings (around 100
pesticides in the case of the thyroid) can then be broken down into finer groupings, according to
additional mechanistic criteria, as and when they become available.
This strategy was chosen with explicit reference to work conducted by Kortenkamp and
collaborators (Christiansen et al. 2012, Orton et al. 2012) showing that cocktail effects of
chemicals could occur independently of chemical and mechanistic similarity between the
ingredients of the cocktail. In June 2013, the EFSA PPR Panel adopted this Scientific Opinion
(EFSA 2013, published in July). The adoption process involved rigorous reviews to which Dr
Daniel Pickford of Brunel's IfE contributed substantially as an EFSA PPR Panel member.
Some of the proposed new assessment groups consist of nearly 100 active pesticidal substances.
This marks a radical departure from practice in the USA, where up to now a maximum of 5
pesticides are included in the same assessment group. The novel approach taken by EFSA will set
a precedent internationally, not only for pesticides regulation, but for the regulation of chemicals in
The Scientific Opinion (EFSA 2013) is shaping profoundly the way in which maximum
residue levels for pesticides in food items are set. For the first time, these decisions will be
made by taking account of combination effects of pesticides. In certain cases, maximum residue
levels may have to be lowered and this will lead to better protection of consumers from
pesticide residues. In turn, this will reduce total health impacts from pesticide use in Europe
(currently estimated at around 2000 disability adjusted life years lost per year) and reduce EU
consumer concern regarding pesticide residues (currently the EU barometer states 72% of EU
consumers are worried about exposure to pesticide residues). The "knock on" effects
internationally, will also lower general public and occupational allowable exposures to pesticides in
other countries, such as the USA and Japan.
Sources to corroborate the impact
1) Plant Protection Product Regulation, PPPR (1107/2009)
2) Biocidal Products Regulation (EU 528/2012
3) REACH European Regulation (No 1907/2006)
4) The Water Framework Directive (No 2000/60/EC)
5) Cosmetics Directive (No 76/768/EEC)
6) EFSA (2013) Scientific opinion on the identification of pesticides to be included in cumulative
assessment groups on the basis of their toxicological profile. EFSA Journal;
7) Fantke, P., Rainer, F and Jolliet, O. 2012. Health impact and damage cost assessment of
pesticides in Europe Environment International 49 (2012) 9-17
- Scientific Officer in the European Food Safety Authority (EFSA) Pesticide Unit, Secretary to
the Working Group of the Plant Protection Products and their Residues (PPR) Panel that
drafted the EFSA (2013) Scientific Opinion
- Toxicologist working for the Danish Environmental Protection Agency, Vice Chair of EFSA's
PPR Panel and Chair of the working group that drafted the EFSA (2013) Scientific Opinion.
Both can corroborate the role Kortenkamp played in drafting the Scientific Opinion, as well as the
impact of Brunel University's research on the opinion.