Perspectives on Environmental Assessments of Chemicals Used in Consumer Products Bryan W. Brooks

1. Perspectives on Environmental Assessments of Chemicals Used in Consumer Products Bryan W. Brooks Professor and Director Department of Environmental Science Center for Reservoir and Aquatic Systems Research Institute of Biomedical Studies

2. Assessment of Environmental Effects Environmental safety studies generally have a two-fold purpose: 1. Determine whether a chemical produces an effect on a biological system 2. Determine how much of an effect is present Single species laboratory toxicity tests, microcosms/mesocosms, and field studies are often used to determine thresholds at individual, population or community levels

3. Assessment of Environmental Effects: • Prospective and Retrospective • New product safety assessments and environmental quality criteria derivation rely on similar model organisms with survival, growth and reproduction endpoints • Effluent water quality evaluated by whole effluent toxicity tests + + www.cefas.co.uk www.cefas.co.uk fish algae Daphnia

4. What is More Toxic, What is Safer? Hodge and Sterner 1949 De Wolf et al. 2005

5. “Read-Across” approaches are often explored for comparative and relative toxicology studies log KOW Acute Toxicity

6. Uncertainty Uncertainty unknown described Realistic (predictive) High accuracy Conservative Low (protective) accuracy 6 5 4. 4 - Cosm/ Chronic SSD 3. 3 Chronic 2. 2 Acute 1. 1 QSAR 1 2 3 4 5 6 Simple Complex (data poor) (data rich)

7. Ecological Risk Assessment Prospective and Retrospective Problem Formulation Deterministic Approach: [Exposure] / [Effect] > 1 Weight of Evidence Uncertainty RISK Exposure Effects Risk Characterization Risk Management

8. Texas Water Resources www.tpwd.state.tx.us

9. Texas Water Resources www.seco.cpa.state.tx.us

10. Texas Water Resources

11. Texas Water Resources • Wastewater treatment • Five primary types: activated sludge, oxidation ditch, trickling filter, lagoon, rotating biological contactor

12. Uncertainties in ERAs of Consumer Products 1. Ionization and pH Brazos River Watershed Lower pH Generally, higher pH

13. pH Matters: In Streams, In the Lab Uncertainties in ERAs of Consumer Products 1. Ionization and pH Fish Uptake of Diphenhydramine (pKa = 8.9) from Water to Plasma Relationship between pH and DO, Lake Conroe, Texas Brooks et al 2012 Du et al. in prep

14. Uncertainties in ERAs of Consumer Products 1. Ionization and pH Fluoxetine (pKa = 10.1) Sertraline (pKa = 9.4) Nakamura et al. (2008) ↑ nonionized, ↑ BCF • Valenti et al. 2009. ET&C

15. N & P range in standard Lemna media: Uncertainties in ERAs of Consumer Products 2. Nutrient stoichiometry and concentrations affect toxicity , N and P conditions variable, dissimilar from surface waters

16. Uncertainties in ERAs of Consumer Products 2. Nutrient influences on triclosan toxicity • Fulton et al. 2009. ET&C

17. Uncertainties in ERAs of Consumer Products 2. Nutrient influences on triclosan toxicity Day 7 Day 14 • Fulton et al. 2009. ET&C

18. Uncertainties in ERAs of Consumer Products 3. Chirality • Enantiomers can significantly differ in: • Biodegradation • Selectivity for receptors, transporters, and/or enzymes • Type of effect(s) • Potency • Rate of metabolism & structure of metabolites • Rate of uptake and excretion • Introduces Uncertainty in… • EXPOSURE &TOXICITY

19. S-fluoxetine R-fluoxetine Comparative Toxicology and Chirality Feeding rate EC10 R-fluoxetine 16.1µg/L S-fluoxetine 3.7 µg/L Growth EC10 R-fluoxetine 132.9 µg/L S-fluoxetine 14.1 µg/L 5-HT NPY Feeding Growth • Stanley et al 2007 Chemosphere

20. Comparative Toxicology and Chirality Enantiomer-Specific Metabolism Differs from Racemate Rainbow trouth model: S9 substrate depletion kinetics Intrinsic Clearance Rates (mL/hr/mg) Rac-Propranolol 2.89 R-Propranolol 0.66 S-Propranolol 1.91 Connors et al. In prep.

21. Proposed Chiral ERA Decision Tree • Stanley and Brooks. 2009. IEAM

22. Normalized Mean Vitellin (µg organism-1) Model Organism and MOA Matters Uncertainties in ERAs of Consumer Products 4. Mode of Action Multigenerational Daphnia magna Responses to 17α-ethinylestradiol Clubbs & Brooks 2007. EES

23. But High Potency in Fish…. The 17α-ethinylestradiol Example Kidd et al. 2007. PNAS USA

24. “Intelligent” Toxicology Bradbury, Feijtel, van Leeuwen. 2004. ES&T

25. “Intelligent” Ecotoxicology? Ankley et al. 2010 ET&C

26. Some General Research Questions • How can hazard be estimated for compounds with limited exposure data? • How does one select a model for a specific endpoint or chemical class when multiple models exist? • Which chemicals may required future studies of acute and chronic hazards?

27. More Efficient Risk Assessment? Bradbury, Feijtel, van Leeuwen. 2004. ES&T

28. Thresholds of Toxicological Concern • Historically applied to food additives • Oral route only; applications to other routes • of exposure may require additional effort • 1.5 g/person/day considered safe • Some exceptions (e.g., genotoxic carcinogens) • Several previous approaches to TTC • Broad spectrum • Structurally based Kroes et al. 2005. Toxicological Sciences

29. Aquatic Exposure Thresholds of No Concern? “….no evidence suggests that an ETNCaq,MOA1–3 of 0.1 μg/L is an unacceptable value.” De Wolf et al. 2005. ETC

30. 99.99 Criterion concentration or predicted environmental concentration (PEC) 99.9 99 90 Percent rank 70 50 30 Probability of finding a compound ≤ the criterion concentration value or PEC 10 Chemical toxicity distribution (CTD) 5th centile 1st centile 0.1 0.01 0.1 1 10 100 1000 10000 Concentration (log scale) Toxicological benchmark concentration (TBC) Probabilistic Hazard Assessment A Chemical Toxicity Distribution

31. Predicting Toxicity for a Broad Group • Only 5% of drugs predicted to be toxic to fish below • 0.84 mg/L and rodents below 33.5 mg/kg Berninger and Brooks. 2010. Toxicol Lett

32. Predicting Toxicity for a Narrower Group • Only 5% of surfactants predicted to be acutely toxic • to Daphnia magna below 0.354 mg/L • Williams, Berninger and Brooks. 2011. ETC

33. Predicting Toxicity for a Specific Class Parabens: Antimicrobial Agents • Only 5% of parabens predicted to adversely affect fish survival and growth below 0.74 μg/L and 0.37 μg/L, respectively • Dobbins et al. 2009. ETC

34. Predicting Toxicity for a Specific Class Paraben Acute Toxicity MOA: Narcosis? Methylparaben (log P = 1.87) R2 = 0.99 R2 = 0.88 Benzylparaben (log P = 3.64) • Dobbins et al. 2009. ETC

35. Predicting Toxicity for a Specific MOA Acute Toxicity of Acetylcholinesterase Inhibitors • Only 5% of AChEIs predicted to be acutely toxic to Daphnia magna and Pimephales promelas below 0.188 μg/L and 65.07 μg/L, respectively • Williams, Berninger and Brooks. 2011. ETC

36. Using Probabilistic Hazard Approaches to Prioritize Chemical Safety Studies: Application to REACH • Williams, Berninger and Brooks. 2011. ETC

37. Current Challenge: Lack of Safety Data • Lack of safety information for many chemicals • Current approach is retrospective • Can we take prospective approaches?

38. Principles of Green Chemistry 9. Use catalysts Warner, J.; Anastas, P. Green Chemistry: Theory and Practice, 1993.

39. Green Chemistry Principle #4 Chemical products should be designed to preserve efficacy of function while reducing toxicityand other environmental hazards. Chemistry & Engineering Toxicology & Biochemistry Ecology & Env. Science Warner, J.; Anastas, P. Green Chemistry: Theory and Practice, 1993.

40. Sustainable Molecular Design Guidelines?

41. Design Guidelines for Reduced Aquatic Toxicity: Standardized Responses • 70-80% of the compounds that have low acute aquatic toxicity have a defined range of values for octanol-water partition coefficient, logPo/w, and ΔE (LUMO-HOMO energy). • Compounds with logPo/w values < 2 and ΔE > 9 eV are significantly more likely to have low acute aquatic toxicity • These design guidelines closely extend to standardized aquatic chronic/subchronic effects. Voutchkova et al 2011, 2012 Green Chem

42. What if we employed sustainable molecular design for commodity chemicals? • What might be the likelihood of encountering industrial chemicals exceeding established US EPA toxicological categories of concern? • What could be the likelihood of exceeding these toxicological categories if chemical design guidelines were followed in the future?

43. Design Guidelines for Reduced Acute Aquatic Toxicity Japanese medaka Daphnia magna Green algae O. latipes P. subcapitata LC50, 96-h assay EC50, 48-h assay EC50, 72-h 285 chemicals 363 chemicals 300 chemicals Fathead minnow P. promelas LC50, 96-h assay 671 chemicals 4 categories based on EPA toxicological categories LC50/EC50: 0 – 1 mg/L LC50/EC50: 1 – 100 mg/L LC50/EC50: 100 – 500 mg/L LC50/EC50: > 500 mg/L Voutchkova 2011 Green Chem.; Russom 1997 ETC; Japan Ministry of Environment

44. What might be the likelihood of encountering industrial chemicals exceeding established US EPA toxicological categories? All chemicals 14.5 55.1 14.4 16 Percent Rank P. promelas96 hr. LC50 mg/L All chemicals (n=570)

45. What could be the likelihood of exceeding these toxicological categories if chemical design guidelines were followed in the future? All chemicals 14.5 55.1 14.4 16 Percent Rank P. promelas96 hr. LC50 mg/L Chemicals with dE above 9 eV (n=408)

46. What could be the likelihood of exceeding these toxicological categories if chemical design guidelines were followed in the future? All chemicals 14.5 55.1 14.4 16 Percent Rank P. promelas96 hr. LC50 mg/L Chemicals with logP below 2 (n=299)

47. What could be the likelihood of exceeding these toxicological categories if chemical design guidelines were followed in the future? All chemicals 14.5 55.1 14.4 16 Percent Rank Following guidelines 42.7 3.3 % 23.4 30.6 P. promelas96 hr. LC50 mg/L Chemicals with both dE above 9 and logP below 2 (n=233)

48. Extends to other models… P. promelas O. latipes D. magna P. subcapitata

49. Projected Reduction in Chemicals Falling in High Toxicity Category? • Acute • 11.2-20.7% reduction in chemicals classified as “high” acute toxicity • Guidelines are more successful at reducing toxicity in Daphnia than fish species (4.5-9.5%)

50. Ongoing Research • Exploring additional guidelines to understand chemicals remaining in “high” toxicity category • Working to identify sustainable molecular design guidelines for specific MOAs, or other model organisms and responses • Further examine utility of these guidelines may be possible as additional toxicity data becomes available (e.g., REACH)