Historical Perspective

Transcription

1

2 Historical Perspective 1872 drug antagonism (Fraser) 1939 mixture toxicology (Bliss) 1947 synergist piperonyl butoxide discovered 1972 US Clean Water Act Whole Effluent Testing (NPDES) 1986 US EPA human health risk assessment for mixtures 2000 Water Framework Dir - Whole Effluent Assessment 2003 US FQPA cumulative risk assessment for pesticides 2009 State of the Art report to EC (Kortenkamp & co-workers) 1926 drug combinations Käer & Loewe) 1940 pharmacology of mixtures (Gaddum) 1952 Insecticide mode-of-action (Hewlett & Plackett) 1985 principles of chemical combinations (Berenbaum) 1994 dioxin equivalents in wildlife (Giesy et al) 2002 something from nothing in vitro (Silva et al) 2006 EFSA Scientific Colloquium on Cumulative Risk Assessment Refs: Fraser (1872) Brit Med J 2: ; Käer & Loewe (1926) Arch Exp Path Pharmakol 114: ; Bliss (1939) Ann App Biol 26: ; Gaddum (1940) Pharmacology; Finney (1942) Ann App Biol 29:82-94; Hewlett & Plackett (1952) Nature 169: ; Tozzi (1998) history of piperonyl butoxide; Könemann (1981) Toxicol 19: ; Berenbaum (1985) Pharmacol Rev 41: ; Giesy et al (1994) Arch Env Contam Toxicol 27: ; Silva et al (2002) Env Sci Technol 36: ; US EPA (2003) Fed Reg 68 FRL ; WFD and WEA (Whitehouse (2004 )Ecotox 13: ; EFSA (2006) Kortenkamp et al (2009)

3 Historical Perspective 1872 drug antagonism (Fraser) 1939 mixture toxicology (Bliss) 1947 synergist piperonyl butoxide discovered 1972 US Clean Water Act Whole Effluent Testing (NPDES) 1986 US EPA human health risk assessment for mixtures 2000 Water Framework Dir - Whole Effluent Assessment 2003 US FQPA cumulative risk assessment for pesticides 2009 State of the Art report to EC (Kortenkamp & co-workers) 1926 drug combinations Käer & Loewe) 1940 pharmacology of mixtures (Gaddum) 1952 Insecticide mode-of-action (Hewlett & Plackett) 1985 principles of chemical combinations (Berenbaum) 1994 dioxin equivalents in wildlife (Giesy et al) 2002 something from nothing in vitro (Silva et al) 2006 EFSA Scientific Colloquium on Cumulative Risk Assessment 2011 SETAC Special Science Symposium on Mixtures Refs: Fraser (1872) Brit Med J 2: ; Käer & Loewe (1926) Arch Exp Path Pharmakol 114: ; Bliss (1939) Ann App Biol 26: ; Gaddum (1940) Pharmacology; Finney (1942) Ann App Biol 29:82-94; Hewlett & Plackett (1952) Nature 169: ; Tozzi (1998) history of piperonyl butoxide; Könemann (1981) Toxicol 19: ; Berenbaum (1985) Pharmacol Rev 41: ; Giesy et al (1994) Arch Env Contam Toxicol 27: ; Silva et al (2002) Env Sci Technol 36: ; US EPA (2003) Fed Reg 68 FRL ; WFD and WEA (Whitehouse (2004 )Ecotox 13: ; EFSA (2006) Kortenkamp et al (2009)

4

5 Scope From armored combat vehicles to white unicorns

6

7 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)

8 Factors Affecting Biotic Integrity Solubilities Alk/Hardness Land Use Velocity ph D.O. Temp. Organics Chemical Variables Nutrients Metals Turbidity Disease Reproduction Hi/Low Extremes Flow Regime Channelization PPT & Runoff Ground Water 1 o & 2 o Production Seasons Sunlight Energy Source Nutrients Biotic Integrity Predation Feeding Organic Matter Competition Riparian Vegetation Habitat Structure Sinuosity Bank Stability Siltation Canopy Substrate Modified from Karr et al., 1986; Yoder & Rankin, 1993

9

10 Abundance 1e+07 TIC: WER046.D Time-->

11

12 Components Bottom-Up Top-Down Mixture

13 environmental contamination biological analysis chemical analysis confirmation fractionation biological analysis toxicant

14 Mixture toxicity concepts Dissimilarly acting substances: Independent Action E Mix 1 (1 E i ) n i 1 E Mix E i = Effect of the mixture of n compounds = Effect of substance i, when applied singly Similarly acting substances: Concentration Addition ECx ( Mix ) n i 1 pi ECx i 1 c i ECx i 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

15 Power of CA for pesticide mixtures From : Belden et al. IEAM, 2007 MDR= Prediction/Observation

16 ECx (Data & IA S/A Modelled) An example: Cd + diuron in C. elegans Predict ECx values by IA and S/A models and compare to data IA S/A IA Data IA predicted ECx Conclusion - This binary mixture is synergistic

17 Toxicants with different M0A may cause unexpected shifts in species interactions resulting in community level effects that cannot be predicted from laboratory single species tests Hypothesized dose-effect chain ATRAZINE LINDANE Sensitive Phytoplankton +/- (Sensitive) herbivores: Nauplii - Calanoida - Cladocera - Ostracoda - Sensitive detritivores: Amphipoda - Isopoda - Insecta - Insensitive Phytoplankton + Insensitive herbivores and detritivores: Rotifers + Mollusks + Oligochaeta + Harpactoida +

18 IA and CA provide guiding principles The Guide is definitive. Reality is frequently inaccurate. Douglas Adams

19

20 MCR = Hazard Index Largest Hazard Quotient i 1 TUi EC50IA n EC50 max( TU ) CA i i (1,..., n) Junghans et al, Aquatic Toxiology 2006

21 Combination effects of dissimilarly acting chemicals at conc < NOAEL Reference Mixture components Species / Endpoint Individual concentrations Joint effect Hermens et al Ecotoxicol Environ Saf 9: aquatic pollutants from 3 groups with probably different modes of action Fish / Acute mortality 4% of EC50 (assumed to be below NOEC) 50% Payne et al Environ Health Perspect 109: organo-chlorine pesticides exerting effects on cell proliferation in different ways MCF-7 cell proliferation % of NOEC Significant proliferative effect Walter et al Ecotoxicology 11: aquatic priority pollutants selected for structural diversity by chemometric analysis Algae / Reproduction NOEC 64% Faust et al Aquatic Toxicol 63: toxicants known to interact with completely different molecular target sites in algae Algae / Reproduction % of NOEC 18%

22 Safety (Assessment Factors) Do they account for mixture effects? How can we come up with a scientifically sound option?

23 Pareto Principle 20% of the administrative work costs 80% of your time

24 3,096 Surface Water Mixtures 5 to 30 chemicals detected in each mixture 3,064 Samples HI <1 32 Samples HI>1 22 Samples where one or more chemicals have HQs>1 10 Samples No HQ >1 MCR values range from Mean value 1.3 MCR values range from Mean value

25

26 Model or Measure? Effects Modeling Measurement Exposure

27 In God we trust all others have to bring data!

28 Effects Modeling Measurement Exposure Prospective Retrospective

29 Key terms and topics for discussion Safety factors Toxicokinetics, dynamic exposures, pulsed exposure Bioavailability Non-chemical stressors (e.g. hydromorphology) Mode of actions, grouping of chemicals Ecological traits Identification of key toxicants Linking cause and effect Contribution of low doses to mixture effects Regulatory frameworks: REACH, PPP, upcoming biocide regulation, soil directive

30 Seek simplicity - but distrust it. (Alfred North Whitehead, ) cited after: Michael Faust, Bremen University, 1999

31