rational design of safer chemicals - american … (96-h) japanese medaka (96-h) daphnia (48-h) 1...
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12/5/2012
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Contact ACS Webinars™at [email protected]
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:
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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.
polybrominated diphenyl ether (flame retardant) found in nearly all participants
dieldrin (pesticide) found in >10% despite ban since 1970
perfluorooctanoic acid (teflon intermediate) found in most participants
hexachlorobenzene (fungicide) found in >50% despite ban since 1984
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2010, Bloomberg News
Wegmans stops selling reusable bags after lead tests
2010, Bloomberg News
Wegmans stops selling reusable bags after lead tests
2010, NY Times
Hydrocarbons in Cereal
Stoke New Debate Over
Food Safety
2010, The Sun Chronicle
Toxic Beauty
2010, Maine Public Broadcasting Network
Report: Cosmetic Products Contain High Levels of Toxic
Chemicals
2009, BBC News
Deet bug repellent
'toxic worry'
2009, The Charleston
Gazette
Study finds food-
wrapper chemicals in
blood
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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
water
toxics climate energy
biodiversity
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GREEN CHEMISTRY
Green chemistry is the design of chemical
products and processes that reduce or eliminate
the use and generation of hazardous substances.
12 PRINCIPLES OF GREEN CHEMISTRY
• Prevention
• Atom Economy
• Less Hazardous Chemical Syntheses
• Designing Safer Chemicals
• Safer Solvents and Auxiliaries
• Design for Energy Efficiency
• Use of Renewable Feedstocks
• Reduce Derivatives
• Catalysis
• Design for Degradation
• Real-time analysis for Pollution Prevention
• Inherently Safer Chemistry for Accident
Prevention
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.
GREEN ENGINEERING
Green Engineering is the development and
commercialization of industrial processes that
are economically feasible and reduce the risk to
human health and the environment.
12 PRINCIPLES OF GREEN ENGINEERING
•Inherent Rather Than Circumstantial
•Prevention Instead of Treatment
•Design for Separation
•Maximize Efficiency
•Output-Pulled Versus Input-Pushed
•Conserve Complexity
•Durability Rather Than Immortality
•Meet Need, Minimize Excess
•Minimize Material Diversity
•Integrate Material and Energy Flows
•Design for Commercial "Afterlife”
•Renewable Rather Than Depleting
Anastas, P.T., and Zimmerman, J.B., "Design
through the Twelve Principles of Green
Engineering", Env. Sci. Tech. 2003, 37(5), 94A-
101A.
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.
Cost 5M Euro to for testing prior to brining it to the market. Production capacity recently increased to 100000 metric tons/yr.
(mixture of isomers)
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Relating biological activity to physicochemical properties
= Rational molecular design for reduced toxicity
Lipinski’s Rules for Druglikeness
1. ≤ 5 hydrogen bond donors
2. ≤ 10 hydrogen bond acceptors
3. Molecular weight 160-480 D
4. Octanol-water coefficient (logP) < 5
5. 20-70 atoms
6. Molecular refractivity (polarizability) from 40-130 m3/mol
7. At least one N or O
8. < 6 rings
90% of
pharmaceuticals
in the market
have properties
in common:
Hypothesis: a set of
rules can be formulated
to guide chemists toward
non-bioactive, non-
hazardous structures
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Data on biological activity EPA ACToR database: 500 public sources, 500k chemicals, 30+ years
EP
A’s
AC
ToR
data
base
Toxicity data (MySQL)
EPA’s Toxic Release Inventory
Aquatic toxicity
Mammalian toxicity
SM
ILE
S
1D molecular structure
MO
L
2D molecular structure (OpenBabel)
SD
3D semi-empirically optimized structure
Desalting
Corina v.3
Gaussian
Pro
pert
y c
alc
ula
tion
Schrodinger’s QikProp
Physical properties
Satistical A
naly
sis
Multivariable optimization
C1CCCCC1
Computational-statistical approach
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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
Voutchkova, A., Ferris, L.,
Zimmerman, J., Anastas, P.
Tetrahedron 2009.
BLUE: Randomly selected chemical
products & intermediates
RED: EPA’s Toxic Registry Inventory
industrial chemicals
Case study: ecotoxicity
Toxicity
category
EPA
Concern
level
LC50 or EC50 in
mg/L
Number of compounds
Fathead
minnow
(96-h)
Japanese
medaka
(96-h)
Daphnia
magna
(48-h)
1 High 0-1 72 49 123
2 Moderate 1-100 333 231 221
3 Low 100-500 92 5 17
4 None 500+ 73 - 2
Total: 570 285 363
Chemicals from US and Japanese government
datasets: bin by “level of concern”
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Statistical correlations: single properties
Considering all predicted
properties, log P (o/w),
LUMO, and DE (HOMO-
LUMO 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
log p(o/w)
Green = low toxicity (>100 mg/L)
Red = high toxicity (<100 mg/L)
Narcosis: known to be affected by bioavailability of the chemical (log P)
Reactive endpoints: often “softness” is important (HOMO-LUMO gap)
ΔE
(e
V)
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Testing the design guidelines
a) Combined data sets show DE >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 Criteria
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
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 5-
fold 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.
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Rational Design of Safer Chemicals
Dr. Joseph Fortunak
Howard University Dr. Julie Zimmerman
Yale University
Download slides & presentation ONE WEEK after the webinar:
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Gender Bending Science:
Impacts of Endocrine Disrupting Chemicals
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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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