70 ‐ the number of new chemicals registered by the American Chemical Society...
...per hour
McKinney et al. (2007): Environmental Science: Systems and Solutions, p. 377
Mixture toxicity assessment in Europe:
state of the art and the challenges ahead
Thomas Backhaus
University of Gothenburg [email protected]
Number of samples
River Monitoring Data Sweden
Number of pesticides in a sample
Adielsson et al. (2009) Monitoring of pesticides in Swedish rivers. ISSN 0347‐9307. Swedish University of Agricultural Sciences, Uppsala.
Human Monitoring Data France
21.52 pesticides were found in average in each monitored child
Adielsson et al. (2009) Monitoring of pesticides in Swedish rivers. ISSN 0347‐9307. Swedish University of Agricultural Sciences, Uppsala.
Why are mixtures of specific concern?
 Mixture toxicity is higher than the toxicity of each compound at the concentration present in the mixture
 Compliance with individual threshold values (EQS, ADI, TDI, TTC) does not necessarily safeguard against unwanted mixture effects
It adds up…
Faust, M., et al. "Predicting the joint algal toxicity of multi‐component s‐triazine mixtures at low‐effect concentrations of individual toxicants." Aquatic Toxicology 56, no. 1 (2001): 13‐32.
Mixture toxicity concepts
Similarly acting substances: Concentration Addition
ECx( Mix )
 n pi 

  
 i 1 ECxi 
1
ci
ECxi
ECx(Mix)
pi
= Concentration of component i in the mixture
(i = 1...n)
= Concentration of substance i provoking a certain effect x when applied alone
= Predicted total concentration of the mixture, that provokes x% effect.
= relative fraction of component i in the mixture
Dissimilarly acting substances: Independent Action
n
E Mix  1   (1  Ei )
i 1
EMix
Ei
= Effect of the mixture of n compounds
= Effect of substance i, when applied singly
Perspective of a regulator
While REACH considers the effects of single substances, the fact is that we are most commonly exposed to a cocktail of many different substances. This is an area in which important gaps remain in terms of knowledge and assessment. These gaps need to be closed in the coming years.
(Stavros Dimas, EU Commissioner for the Environment, 2009)
Central Documents on Mixture Assessment
 Council Conclusion on Chemical Mixtures (2009)
 Kortenkamp et al. (2009) State of the Art on Mixture Toxicity. Report to the EU Commission
 ECETOC (2011) Report “Development of guidance for assessing the impact of mixtures of chemicals in the aquatic environment”
 Meek et al. (2011) Risk assessment of combined exposure to multiple chemicals: A WHO/IPCS framework, Reg Tox Pharm
 SCHER, SCENIHR, SCCS (2012): Toxicity and Assessment of Chemical Mixtures
 EU Commission COM(2012) 252 final “The combination effects of chemicals”
Opinion of the EU’s Scientific Committees
“It is the opinion of the SCHER that the CA approach may be assumed as a temporary interim method for deriving EQs for mixtures.“
SCHER, Opinion on the Chemicals and the Water Framework Directive: Technical Guidance for Deriving Environmental Quality Standards (2010)
WHO Framework for Human Health Assessment
Meek et al. (2011) Risk assessment of combined exposure to multiple chemicals: A WHO/IPCS framework, Reg Tox Pharm
WHO Framework for Human Health Assessment
Meek et al. (2011) Risk assessment of combined exposure to multiple chemicals: A WHO/IPCS framework, Reg Tox Pharm
Relevant European Provisions
Type of mixture
Is mixture toxicity
taken into account?
• Products:
Mixtures intentionally produced and placed on the EU
market (MCS, UVCBs, Preparations)
In general YES
• Emissions:
Mixtures of chemicals emitted from point sources or
diffusive sources as a result of production processes,
transportation processes, consumption processes,
recycling processes or disposal
In some cases
• Immissions / Multi-Pathway Exposure:
In general NO
NOT intentionally produced complex mixtures,
occurring in environmental media, in food or in humans
as a result of release and emissions from numerous
products and processes
Relevant European Provisions
Type of mixture
Is mixture toxicity
taken into account?
• Products:
Mixtures intentionally produced and placed on the EU
market (MCS, UVCBs, Preparations)
In general YES
• Emissions:
Mixtures of chemicals emitted from point sources or
diffusive sources as a result of production processes,
transportation processes, consumption processes,
recycling processes or disposal
In some cases
• Immissions / Multi-Pathway Exposure:
In general NO
NOT intentionally produced complex mixtures,
occurring in environmental media, in food or in humans
as a result of release and emissions from numerous
products and processes
Recent Regulatory Developments
EU Pesticide Regulation: Specific consideration of mixture toxicity with respect to human health (Regulation ((EC) No 396/2005)
EU Biocide Regulation: Specific consideration of mixture toxicity with respect to human health AND the environment (Regulation 2009/0076 (COD))
Relevant European Provisions
Type of mixture
Is mixture toxicity
taken into account?
• Products:
Mixtures intentionally produced and placed on the EU
market (MCS, UVCBs, Preparations)
In general YES
• Emissions:
Mixtures of chemicals emitted from point sources or
diffusive sources as a result of production processes,
transportation processes, consumption processes,
recycling processes or disposal
In some cases
• Immissions / Multi-Pathway Exposure:
In general NO
NOT intentionally produced complex mixtures,
occurring in environmental media, in food or in humans
as a result of release and emissions from numerous
products and processes
River basin modeling of the expected consequences of chemical mixtures
• Nonylphenol
How?
Sumpter, J., et al. (2006) Modeling Effects of Mixtures of Endocrine Disrupting Chemicals at the River Catchment Scale, Env. Sci. Techn. 40:5478‐5489
River basin modeling of the expected consequences of chemical mixtures
• Nonylphenol
• Natural estrogens (E1, E3), • Pharmaceutical (EE2)
Sumpter, J., et al. (2006) Modeling Effects of Mixtures of Endocrine Disrupting Chemicals at the River Catchment ScaleE, Env. Sci. Techn. 40:5478‐5489
The challenges ahead
The challenges ahead
1. From priority compounds to priority mixtures
Detailed analysis of a sample: contribution of the different compounds
10
sum of risk quotients (MEC/WQS)
9
8
7
6
5
4
3
2
1
0
Detailed analysis of a sample: contribution of the different compounds
10
sum of risk quotients (MEC/WQS)
9
8
7
6
5
4
3
2
1
0
Detailed analysis of a sample: contribution of the different compounds
10
sum of risk quotients (MEC/WQS)
9
8
7
6
5
4
3
2
1
0
The challenges ahead
1. From priority compounds to priority mixtures
2. Driver identification
Synergisms (=higher mixtox than expected)
Christiansen, Sofie, et al. "Synergistic disruption of external male sex organ development by a mixture of four antiandrogens." Environmental Health Perspectives 117.12 (2009): 1839.
The challenges ahead
1. From priority compounds to priority mixtures
2. Driver identification
3. When, why, how often do synergisms occur?
Regulary monitored chemicals in the river Rhine
Regulary monitored chemicals in the river Rhine
1,1,1-Trichloroethane
1,2,3-Trichlorobenzene
4-Chlorotoluene
alpha-Endosulfan
1,2,4-Trichlorobenzene
1,2-Dichlorobenzene
1,3,5-Trichlorobenzene
Ametryn
Anthranilic acid isopropylamide (AIPA)
Atrazine
1,4-Dichlorobenzene
1-Chloro-2-Nitrobenzene
1-Chloro-3-nitrobenzene
Atrazine-desethyl
Azinphos-ethyl
Azinphos-methyl
1-Chloro-4-nitrobenzene
2,4,5-Trichlorophenoxy acetic acid
2,4-DB
Bentazone
beta-Endosulfan
Chloridazon
2,4-Dichlorophenoxy acetic acid
2,6-Dimethylaniline
2-Chloroaniline
Chlorotoluron
DEET (N,N-Diethyl-m-toluamide)
delta-hexachlorocyclohexane
2-Chlorotoluene
2-Nitrotoluene
3,4-Dichloraniline
Desethylterbutylazine
Desisopropylatrazine
Diazinon
3-Chloroaniline
4-chloro-2,6-dimethylaniline
4-Chloroaniline
Dichlorprop
Dichlorvos
Dimethoate
Regulary monitored chemicals in the river Rhine
Dinoseb
Dinoterb
Mecoprop
Metabenzthiazuron
Tetrachloroethene
Tetrachloromethane
Disulfoton
Diuron
DNOC
Metalaxyl
Metazachlor
Methyl-parathion
Tolclophos-methyl
Triadimefon
Triazofos
EDTA
Ethofumesat
Ethyl-parathion
Metolachlor
Metoxuron
Mevinfos
Trichlorethene
Trichloromethane
Trifluralin
Fenitrothion
Fenoprop
Fenthion
Monolinuron
N,N-Dimethylaniline
Nitrobenzene
Vinclozolin
gamma-hexachlorocyclohexane
Hexachlorobutadiene
iso-Chloridazon
NTA
Oxadixyl
Pentachlorophenol (PCP)
Isoproturon
Linuron
Malathion
Propiconazol
Pyrazofos
Simazine
MCPA
MCPB
Terbuthylazine
Terbutryn
88 chemicals
Regulary monitored chemicals in the river Rhine
88 Chemicals
 Pesticides
 Biocides
 Pharmaceuticals
 Industrial Chemicals
 Heavy metals
 Surfactants
 Degradation products
Executive Summary:
“In a study spearheaded by the Environmental Working Group (EWG) in collaboration with Commonweal, researchers at two major laboratories found an average of 200 industrial chemicals and pollutants in umbilical cord blood from 10 babies born in August and September of 2004 in U.S. hospitals. Tests revealed a total of 287 chemicals in the group. The umbilical cord blood of these 10 children, collected by Red Cross after the cord was cut, harbored pesticides, consumer product ingredients, and wastes from burning coal, gasoline, and garbage.”
Jane Houlihan, et al. (2005): Body Burden, the pollution in newborns, The Environmental Group, The challenges ahead
1. From priority compounds to priority mixtures
2. Driver identification
3. When, why, how often do synergisms occur?
4. How should we regulate mixtures with components from different regulatory arenas?
Summary and Conclusions
 Mixtures matter. Summary and Conclusions
 Mixtures matter. They are there and they are toxic.
Summary and Conclusions
 Mixtures matter. They are there and they are toxic.
 Quality standards and risk quotients for individual compounds form the basis, Summary and Conclusions
 Mixtures matter. They are there and they are toxic.
 Quality standards and risk quotients for individual compounds form the basis, but are insufficient alone.
Summary and Conclusions
 Mixtures matter. They are there and they are toxic.
 Quality standards and risk quotients for individual compounds form the basis, but are insufficient alone.
 The science on mixture ecotoxicology provides regulatory tools and options (mainly based on CA, accompanied by error estimations and more advanced modeling approaches).
Regulatory Challenges
 Regulation for coincidental mixtures where compounds from different sectorial regulations are considered
 How to handle a situation in which each individual compound is present at or below its safe level, but the mixture is still toxic?
Mixture toxicity assessment in Europe:
state of the art and the challenges ahead
Thomas Backhaus
University of Gothenburg [email protected]