12/5/2012
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ACS WEBINARS™ December 6, 2012
Rational Design of Safer Chemicals
Dr. Joseph Fortunak Howard University
Dr. Julie Zimmerman Yale University
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[email protected] Designing Benign Chemistries Julie Beth Zimmerman, PhD Dept. of Chemical and Environmental Engineering School of Forestry and Environmental Studies
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Persistence
Bioaccumulation CDC, 2009 National Report on Human Exposure to Environmental Chemicals: tests the US population for 212 chemicals.
polybrominate d diphenyl ether (flame retardant) found in nearly all participants
dieldrin (pesticide) found in >10% despite ban since 1970
perfluorooctanoic acid hexachlorobenzene (teflon intermediate) (fungicide) found in most found in >50% despite ban since 1984 participants
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2010, Bloomberg News Wegmans stops selling reusable bags after lead tests
2010, Maine Public Broadcasting Network Report: Cosmetic Products Contain High Levels of Toxic Chemicals
2009, BBC News Deet bug repellent 'toxic worry'
2010, NY Times
2009, The Charleston Hydrocarbons in Cereal 2010, The Sun Chronicle Gazette Stoke New Debate Over Study finds food2010, Bloomberg News Food Safety wrapper chemicals in blood Wegmans stops selling reusable bags after lead tests
Toxic Beauty
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Leading to this…
We strive to do the “right things” for human health and environment and our business... But are we…. doing the right things, wrong?
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Unintended Consequences Biofuels that compete with food, feed, and land use
Unintended Consequences
Energy saving compact fluorescent light bulbs reliant on toxic metals
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Net mercury emission reductions from CFL implementation
Eckelman, Zimmerman, Anastas, ES&T, 2008, 42, 8564-8570
energy
biodiversity
climate
toxics
water
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GREEN CHEMISTRY
GREEN ENGINEERING
Green chemistry is the design of chemical Green Engineering is the development and products and processes that reduce or eliminate commercialization of industrial processes that the use and generation of hazardous substances. are economically feasible and reduce the risk to human health and the environment. 12 PRINCIPLES OF GREEN CHEMISTRY 12 PRINCIPLES OF GREEN ENGINEERING • Prevention •Inherent Rather Than Circumstantial • Atom Economy •Prevention Instead of Treatment • Less Hazardous Chemical Syntheses •Design for Separation • Designing Safer Chemicals •Maximize Efficiency • Safer Solvents and Auxiliaries •Output-Pulled Versus Input-Pushed • Design for Energy Efficiency •Conserve Complexity • Use of Renewable Feedstocks •Durability Rather Than Immortality • Reduce Derivatives •Meet Need, Minimize Excess • Catalysis •Minimize Material Diversity • Design for Degradation •Integrate Material and Energy Flows • Real-time analysis for Pollution Prevention •Design for Commercial "Afterlife” • Inherently Safer Chemistry for Accident Prevention •Renewable Rather Than Depleting Anastas, P. T. and Warner, J. C. Green Chemistry: Theory and Practice. Oxford University Press: New York, 1998, p. 30. By permission of Oxford University Press.
Anastas, P.T., and Zimmerman, J.B., "Design through the Twelve Principles of Green Engineering", Env. Sci. Tech. 2003, 37(5), 94A101A.
The Change in Thinking Risk = f(hazard, exposure)
Hazard must be recognized as a design flaw
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Pressure on commercial products
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Green Chemistry Principle #4 Chemical products should be designed to preserve efficacy of function while reducing toxicity and other environmental hazards. Anastas, P. and Warner, J., Green Chemistry: Theory and Practice,Oxford University Press, 1998.
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Strategies for reducing toxicity Prior to commercialization DINCH passed a battery of eco-toxicity and genotoxicity tests covering a variety of species: bacteria, daphnids, zebrafish, earthworms, rats, rabbits, and guinea pigs.
(mixture of isomers) Cost 5M Euro to for testing prior to brining it to the market. Production capacity recently increased to 100000 metric tons/yr.
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Relating biological activity to physicochemical properties = Rational molecular design for reduced toxicity 90% of pharmaceuticals in the market have properties in common:
Lipinski’s Rules for Druglikeness 1. 2. 3. 4. 5. 6. 7. 8.
≤ 5 hydrogen bond donors ≤ 10 hydrogen bond acceptors Molecular weight 160-480 D Octanol-water coefficient (logP) < 5 20-70 atoms Molecular refractivity (polarizability) from 40-130 m3/mol At least one N or O < 6 rings
Hypothesis: a set of rules can be formulated to guide chemists toward non-bioactive, nonhazardous structures
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Data on biological activity EPA ACToR database: 500 public sources, 500k chemicals, 30+ years
Aquatic toxicity Mammalian toxicity
3D semiempirically optimized structure Desalting Corina v.3 Gaussian
Schrodinger’s QikProp Physical properties
Satistical Analysis
SD
2D molecular structure (OpenBabel)
Property calculation
EPA’s Toxic Release Inventory
1D molecular structure
MOL
Toxicity data (MySQL)
SMILES
EPA’s ACToR database
Computational-statistical approach Multivariable optimization
C1CCCCC1
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Relating toxic endpoints to molecular features Acute toxicity
Carcinogenicity
Bioconcentration
Subchronic & chronic toxicity
Neurotoxicity
Degradation & transport
Reproductive toxicity
Immunotoxicity
Aquatic toxicity
Developmental toxicity
Genotoxicity
Terrestrial organism toxicity
Molecular weight
Molecular volume
Dipole moment
Hydrophilic surface area
Hydrophobic surface area
Rotatable bonds
Hydrogen bonds
Ionization potential
Electron affinity
Partition coefficients
Acid/base properties
Polarizability
Why properties to compliment structure?
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EPA’s Toxic Release Registry Chemicals vs all other chemicals
BLUE: Randomly selected chemical products & intermediates RED: EPA’s Toxic Registry Inventory industrial chemicals
Voutchkova, A., Ferris, L., Zimmerman, J., Anastas, P. Tetrahedron 2009.
Case study: ecotoxicity Chemicals from US and Japanese government datasets: bin by “level of concern” Number of compounds EPA Toxicity
LC50 or EC50 in Fathead
Japanese Daphnia
Concern category
mg/L
minnow
medaka
magna
(96-h)
(96-h)
(48-h)
level
1
High
0-1
72
49
123
2
Moderate
1-100
333
231
221
3
Low
100-500
92
5
17
None
500+
73
-
2
Total:
570
285
363
4
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Statistical correlations: single properties
Considering all predicted properties, log P (o/w), LUMO, and DE (HOMOLUMO gap) are most correlated with toxicity
Statistical correlations: pairwise Out of >1000 possible pairwise property combinations, HOMO-LUMO gap and log P (o/w) are most significant
ΔE (eV)
Green = low toxicity (>100 mg/L) Red = high toxicity (9, log P < 2 is the quadrant that captures the least toxic compounds b) This is validated with an additional data set (algae)
Performance of the model Fathead minnow
Japanese medaka
Daphnia magna
% “desirable” compounds captured in logPo/w < 2 and dE >9
88%
75%
92%
% “undesirable” compounds captured in logPo/w < 2 and dE >9
38%
26%
22%
Mean LC50 or EC50 of compounds with logPo/w < 2 and dE >9 (mg/L)
2265
3151
105.2
Mean LC50 or EC50 of all compounds in data set (mg/L)
969
1172
39.7
Median LC50 or EC50 of compounds with logPo/w < 2 and dE >9 (mg/L)
135
47.2
36
Median LC50 or EC50 of all compounds in data set (mg/L)
21.55
14.8
4.1
Criteria
The “desirable” quadrant captures some “undesirable” chemicals, but performs well as a first-tier screening method
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Preliminary Findings • 70-80% of the compounds that have little to no concern for acute aquatic toxicity to four aquatic species have similar range of values of logPo/w and ΔE (LUMO-HOMO) • Limits of logPo/w < 2 and ΔE > 9 eV can significantly improve the probability of identifying, and thus designing, a compound with very low acute aquatic toxicity • It is estimated that this probability is increased 2 to 5fold across a range of model aquatic species
This approach can be applied to • Chemical classes • Toxicity endpoints – Chronic – Acute
• Other hazards – Persistence – Global warming potential
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Extending to chronic aquatic toxicity
Test data from Japanese Ministry of the Environment. Design guidelines are roughly the same as in the acute aquatic toxicity case.
Analysis of outliers
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It’s starting…
Acknowledgements
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References •
•
•
•
•
Kostal, J.; Voutchkova-Kostal, A.; Weeks, B.; Zimmerman, J. B.; Anastas, P. T. "A Free Energy Approach to the Prediction of Olefin and Epoxide Mutagenicity and Carcinogenicity", Chemical Research in Toxicology, in press. Voutchkova-Kostal, A. M.; Kostal, J.; Connors, K. A.; Brooks, B. W.; Anastas, P. T.; Zimmerman, J. B., Towards rational molecular design for reduced chronic aquatic toxicity. Green Chemistry 2012, 14 (4), 1001-1008. Voutchkova, A. M.; Kostal, J.; Steinfeld, J. B.; Emerson, J. W.; Brooks, B. W.; Anastas, P. T.; Zimmerman, J. B., Towards rational molecular design: derivation of property guidelines for reduced acute aquatic toxicity. Green Chemistry 2011, 13 (9), 2373-2379. Voutchkova, A. M.; Ferris, L. A.; Zimmerman, J. B.; Anastas, P. T., Towards Molecular Design for Hazard Reduction - Fundamental Relationships Between Chemical Properties and Toxicity. Tetrahedron 2010, 66 (5), 1031-1039. Voutchkova, A. M.; Osimitz, T. G.; Anastas, P. T., Toward a Comprehensive Molecular Design Framework for Reduced Hazard. Chemical Reviews 2010, 110 (10), 5845-5882.
ACS WEBINARS™ December 6, 2012
Rational Design of Safer Chemicals
Dr. Joseph Fortunak Howard University
Dr. Julie Zimmerman Yale University
Download slides & presentation ONE WEEK after the webinar:
http://acswebinars.org/rational-design Contact ACS Webinars™at
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12/5/2012
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Thursday, December 13, 2012
Chemistry & the Economy Year-end Review Paul Hodges, International eChem Dr. William Carroll, Occidental Chemical Corporation
Thursday, January 10, 2013
A Toast to the Chemistry of Noble Grapes Dr. Susan Ebeler, University of California, Davis Dr. Sara Risch, Popz Europe
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12/5/2012
Gender Bending Science: Impacts of Endocrine Disrupting Chemicals Join Charles Tyler as he explains how these endocrine disrupting chemicals have been shown to affect the sex in fish and implications for humans as well.
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