Applying 21 st Century Toxicology to Green Chemical and Material Design: Bridging the Gaps

Transcription

1 Applying 21 st Century Toxicology to Green Chemical and Material Design: Bridging the Gaps Thomas G. Osimitz, Ph.D., D.A.B.T. Science Strategies, LLC SciVera, LLC

2 Agenda Challenges Scientific Cultural Consideration of Toxicology in the Context of other Attributes of Greenness

3 Challenges Scientific Data vs. understanding Old to new toxicology Research Regulatory applications Identification of a test or battery to indicate greenness Bright lines Implies more precision that truly exists Continuous improvement and directional change Cultural Chemists and toxicologists Scientists and business people Hazard vs. Risk

4 Scientific Challenges Data are not information, Information is not knowledge, Knowledge is not understanding, Understanding is not wisdom. (Cliff Stoll & Gary Schubert)

5 Data Unprecedented amount of data available Rapidly produced at low cost Making sense out of it? Zen and the Art of ComplexBiology - Practicing Zen Biology the art of quieting biological noise allows important, even subtle, changes to rise above the fray and be more easily noticed. - (Posted by: Amy Palmer on: July 5, 2011, blog.ingenuity.com)

6 NIH National Chemical Genomics Center Enzymatic assays Receptor binding assays GTPγSbinding Assays Tissue culture assays Cell-based Elisa and Western Blots (for quantitative antigen detection ) FLIPR Assays (GPCR and ion channel targets) Various reporter based assays

7 NIEHS High Throughput Screens Apoptosis Assays Caspase-Glo 3/7 Assay Caspase-Glo 9 Assay Caspase-Glo 8 Assay Cytotoxicity Assays CellTiter-Glo Luminescent Cell Viability Assay (measures ATP levels Cytotox-ONE HomogeneousMembrane Integrity Assay (measures release of lactate dehydrogenase from membrane-damaged cells P-glycoprotein (Pgp) ATPase Assay (aka MDR1 or ABCB1) Pgp-Glo Assay

8 EPA s ToxCast TM Program

9 Currie and Goodman, 2011

10 Information How do the gene changes relate to the specific pathways effected?

11 Currie and Goodman, 2011

12 Currie and Goodman, 2011

13 Currie and Goodman, 2011

14 Knowledge About the relative effects of the chemical on various pathways operating at the same time

15 Currie and Goodman, 2011

16 Understanding The relationship between changes in gene expression in pathways and toxicity in whole animals A great challenge

17 Wisdom Use of the data for decision-making about use of chemicals Uncertainty acknowledged Directional indications Continuous improvement and iterations

18 EPA, 2005

19 Scientific Challenges Defining what is green Battery and framework is needed Careful of ascribing too much precision in numbers Traditional toxicology Uncertainty factors for animal studies Use of single data point from complex studies» NOAEL and acceptable exposures New toxicology nomics

20 Scientific Challenges Old to New Toxicology Research Advancing rapidly Still diverging, will be converging Regulatory Applications Needs to increase Lags scientific advances

21 Scientific Challenges Incorporation of toxicology (hazard) findings into overall assessment of greenness Important, but not always paramount Utility of risk as a means of prioritizing more later

22 Cultural Challenges Toxicologists and chemists should be friends Precedent in history The farmer and the cowman should be friends. Oh, the farmer and the cowman should be friends. One man likes to push a plough, the other likes to chase a cow, But that's no reason why they cain'tbe friends. Territory folks should stick together, Territory folks should all be pals. Cowboys dance with farmer's daughters, Farmers dance with the ranchers' gals. (Rogers and Hammerstein)

23 Cultural Challenges Responsibilities of Toxicologists Befriend a smart chemist Become familiar with existing design rules Maximize the value of every study you run In vitro assays Short term or high throughput assays evaluate analogs (by structure and property) to aid development of design rules In vivo studies (Almost) never, ever run repeated dose studies without considering internal dose measurement» Aids in extrapolation across route and species (human) Go beyond simple determination od NOAEL, consider Benchmark dose

24 Cultural Challenges Responsibilities of Chemists Befriend a smart toxicologist Become familiar with existing design rules Take a short course in toxicology Collaborate with a toxicologist to consider chemical analogs that you can synthesize and that you would predict will have reduced hazard (and/or potency)

25 Cultural Challenges Risk versus Hazard Letting the perfect being the enemy of the good Damaging to continuous improvement Must be addressed and acknowledged Proposal to use risk to prioritize Consider both hazard and potency (dose-response) Add exposure estimates Modeled Based on intended use

26 Cultural Challenges Making the business case Not as easy as it looks Long term pay off Especially if moving beyond eco-efficiency Uncertain competitive advantage Many assumptions Requires commitment from the top CEO and Board, shareholders

27 Integrating Toxicology into other Measures of Greenness Essential for a holistic consideration of alternatives Many schemes possible can also include efficacy and economy Incorporation of toxicology (hazard) findings into overall assessment of greenness Important, but not always paramount Utility of risk as a means of prioritizing

28 Judson, EPA, 2011 Pharmacodynamics Adverse Effect MOA Key Events Pharmacokinetics Dose-to-Concentration Scaling Function (C ss /DR) Probability Distribution Toxicity Pathway BPADL HTS Assays Probability Distribution for Dose that Activates Biological Pathway PK Model Populations Biological Pathway Activating Concentration (BPAC) Probability Distribution 28 Intrinsic Clearance Plasma Protein Binding

29 Combining in vitro activity and dosimetry Range of in vitro AC50 values converted to human in vivo daily dose Pyrithiobac-sodium Triclosan log (mg/kg/day) LargeOverlap Judson, EPA, 2011 Safety margin Actual Exposure (est. max.) Rotroff, et al. Tox.Sci2010 Etoxazole Emamectin Buprofezin Dibutyl phthalate Pyraclostrobin Parathion Isoxaben Pryrithiobac-sodium Bentazone Propetamphos 2,4-D S-Bioallethrin MGK Atrazine Bromacil Fenoxycarb Forchlorfenuron Methyl Parathion Triclosan Rotenone Cyprodinil Isoxaflutole Acetamiprid Zoxamide Diuron Bensulide Vinclozolin Oxytetracycline DH Dicrotophos Metribuzin Triadimefon Thiazopyr Fenamiphos Clothianidin Bisphenol-A Alachlor Acetochlor Diazoxon Dichlorvos Chlorpyriphos-oxon 29

30 The Ideal Result Greggs, GMA, 2011

31 The More Likely Result Greggs, GMA, 2011

32 Perspective Remember: Essentially, all models are wrong, but some are useful George Box The same applies to scoring and weighting schemes

33 In Closing The Golden Age of Toxicology is Now Nomics, systems biology, modeling Challenge: To use the datacarefully to develop informationand knowledgethat helps us to understandthe likelihood of adverse effects in whole animals (people) and the environment so that we can made wise decisions with respect to the assessment and design of chemicals

34 Acknowledgements Paul Anastas Bob Boethling Steve DeVito Adelina Voutchova Julie Zimmerman

35 Resources Designing Safer Chemicals (Eds. Boethling, R.; Voutchkova, A.; Anastas, P.) To be published this year Handbook of Green Chemistry (Anastasand Warner) Voutchkova, A.M., Osimitz, T.G., and Anastas, P.; Chem Rev, 2010, 110, Voutchkova, A. M.; Ferris, L. A.; Zimmerman, J.B.; Anastas, P. T. Tetrahedron, 2010, 66,