Predicting Chemical Partitioning and Toxicity Using Molecular Interaction Models:

The End of the Age of Octanol

Dominic M. Di Toro

Edward C. Davis Professor of Civil and Environmental Engineering

University of Delaware, Newark, DE

University of HoustonDepartment of Civil and Environmental Engineering's

Beyer Distinguished Lecture SeriesApril 18, 2012

The Problem - Predict Partition Coefficients -

{Physical Chemistry

{EnvironmentalChemistry

EnvironmentalModeling {

Simplifications are difficult to justify…

...Or Improve...

The Age of Octanol- Partitioning -

Karickhoff, S. W., Brown, D. S., & Scott, T. A. (1979). Sorption of hydrophobic pollutants on natural sediments. Wat. Res, 13, 241-248.

Koc ~ Kow

Nguyen TH, Goss K-U, Ball WP. 2005. Environ Sci Technol 39:913-924.

Log

KO

C-K

OW

Reg

ress

ions

The Age of Octanol- Bioaccumulation & Toxicity -

McCarty, L. S., D. Mackay, A.D. Smith, G.W. Ozburn, & Dixon, D. G. (1991). Interpreting aquatic toxicity QSARs: the significance of toxicant body residues at the pharmacologic endpoint. In QSAR In Environmental Toxicology. IV. Amsterdam: Elsevier.

Konemann, H. (1981).. Toxicology, 19, 209-221.

CBB = BCF x LC50

-1-1

+1

Interpretation of Y-Intercept

Target Lipid Model

CBB = BCF × LC50

Di Toro DM, McGrath JA, Hansen DJ. 2000. Technical basis for narcotic chemicals and polycyclic aromatic hydrocarbon criteria. I. Water and tissue. Environ Toxicol Chem 19: 1951-1970

Di Toro DM, McGrath JA. 2000. Technical basis for narcotic chemicals and polycyclic aromatic hydrocarbon criteria. II. Mixtures and sediments. Environ Toxicol Chem 19: 1971-1982.

.

Log KLW = m Log KOW + Chemical Class Corrections (Halogenated, Ketones, PAHs)

Target Lipid ModelTarget Lipid Model

Predicted vs Observed PAH Toxicity

Toxicity of Mixtures

Toxic Units (TU)

Narcosis Additivity

McGrath JA, Di Toro DM. 2009. Validation of the target lipid model for toxicity assessment of residual petroleum constituents: monocyclic and polycyclic aromatic hydrocarbons. Environl Toxicol and Chem 28(6): 1130-1148

Nonpolar and Polar Chemical Toxicity- Octanol -Target Lipid Model

PAH Mixtures

Type I Only

-6

-4

-2

0

2

4

-6 -4 -2 0 2 4

Observed log LC50 (mM)

Pred

icte

d lo

g LC

50 (m

M) Type I & II

-6 -4 -2 0 2 4

Observed log LC50 (mM)

Type I

Type II

Nonpolar and Polar Chemical Toxicity- Octanol -

Di Toro, D.M., J.A. McGrath, and D.J. Hansen, Technical basis for narcotic chemicals and polycyclic aromatic hydrocarbon criteria. I. Water and tissue. Environ.Toxicol.Chem., 2000. 19: p. 1951-1970.

Type II Compounds: Phenols, Amino, Anilines, Nitro, Nitriles, N-heterocycles,

DMPC as Target LipidLC50 vs KOW and KDMPC

Type 1

Type 2

Vaes,HJ, Ramos,EU Verhaar,HJM Hermens,JLM 1997. Acute toxicity of nonpolar versus polar narcosis: Is there a difference? ETC 17:7 pp1380-1384

The Age of Linear Solvation Energy Relationships (LSER/LFER)

Abraham MH, Chadha HS, Whiting GS, Mitchell RC Hydrogen Bonding 32 An analysis of water-octanol and water-alkane partition J. Pharmaceutical Sciences 83(8) 1994

Goss, K., & Schwarzenbach, R. P. (2001). Linear Free Energy Relationships Used To Evaluate Equilibrium Partitioning of Organic Compounds. Environ. Sci. Technol., 35(1), 1-9.

Hydrogen Bonding – Donor

SoluteH-Bond donor (H acidity) = A

SolventH-Bond acceptor = a

Hydrogen Bond

Phenol

Water

Hydrogen Bonding - Acceptor

Water

Phenol

SoluteH-Bond acceptor (H basicitiy) = B

SolventH-Bond Donor = b

Hydrogen Bond

Type I

-6

-4

-2

0

2

4

-6 -4 -2 0 2 4

Observed log LC50 (mM)

Pred

icte

d lo

g LC

50 (m

M)

42 species 527 chemicals 1728 data points

Type II

-6 -4 -2 0 2 4

Observed log LC50 (mM)

Nonpolar and Polar Chemical Toxicity- LSER -

Kipka, U. and D.M. Di Toro, Technical basis for polar and nonpolar narcotic chemicals and PAH criteria. III. A polyparameter model for target lipid partitioning. Environmental Toxicology and Chemistry, 2008. 28(7): p. 1429-1438.

KLW = c + eE +sS + aA + bB + vV

2 phenylphenolTarget Lipid & Octanol - Water Partitioning

log KDOC, observed (L/kg)

2 4 6 8

log

KD

OC, p

redi

cted

(L/k

g)

2

4

6

8

log KOW

2 4 6 8

log

KD

OC, p

redi

cted

(L/k

g)

2

4

6

8

log KPOC, observed (L/kg)

-4 -2 0 2 4 6 8

log

KPO

C, p

redi

cted

(L/k

g)-4

-2

0

2

4

6

8

log KOW, observed

-4 -2 0 2 4 6 8

log

KPO

C, o

bser

ved

-4

-2

0

2

4

6

8

Particulate OCSoils

Sediments

Dissolved OCHumic Acid

LSER

KOWLSER

KOW

Kipka U, Di Toro DM. 2011. A Linear Solvation Energy Relationship Model Of Organic Chemical Partitioning To Particulate Organic Carbon In Soils And Sediments. ETC 30(9): 2013-2022.

The Age of Quantum Chemistry - COSMO-SAC –

Conductor-like Screening Model – Segment Activity Coefficient

Liquid phase DFT/ COSMO

Sta

t. M

echa

nics

Thermodynamic properties COSMO-SAC

Qua

ntum

Mec

hani

csGas phase geometry optimization

Klamt & Schüürmann (1993) J. Chem. Soc. Perkin Trans., 2, 799-805. Lin & Sandler (2002) Ind. Eng. Chem. Res., 41, 899-913.Lin et al. (2004) J. Phys. Chem. A, 108, 7429-7439.

PCB Congener Number

0 20 40 60 80 100 120 140 160 180 200

Expe

rimen

tal H

LC (P

a-m

3 /m

ol)

10-1

100

101

102

103

Dunnivant et al. (1988)Environ. Sci. Technol., 22:448-453 Brunner et al. (1990)Environ. Sci. Technol., 24:1751-1754 Bamford et al. (2000)J. Chem. Eng. Data, 45:1069-1074

Cl Substitution

PCBs: Henry’s Law Constants

Henry’s law constant (HLC)– Equilibrium partitioning between water and air

Lack of reliable measurements for HLC of PCBs

5

COSMO-SAC - Henry’s Law Constant -

Homolog2 3 4 5 6 7 8 9

100

101

102

IUPAC PCB Congener Number0 50 100 150 200

LOESS fit to 31oC Bamford data

LOESS fit to 4oC Bamford data

oC

31

25

18

11

4

Phillips K. L., Sandler S. I., Greene R. W., and Di Toro D. M. (2008) Environmental Science & Technology 42(22), 8412-8418.

Goss et al. (2004) Environ. Sci. Technol., 38, 1626-1628.Bamford et al. (2000) J. Chem. Eng. Data, 45, 1069-1074.Bamford et al. (2002) Environ. Sci. Technol., 36, 4395-4402.Baker et al. (2004) Environ. Sci. Technol., 38, 1629-1632.

Leonardite humic acid Buffle et al., fulvic acid

Chelsea soil humic acid

Stevenson et al., humic acid

Suwannee river fulvic acid

Atalay, Y. B., R. F. Carbonaro, Di Toro DM (2009). "Distribution of Proton Dissociation Constantsfor Model Humic and Fulvic Acid Molecules.“ Environmental Science & Technology 43(10): 3626-3631.

Organic Matter Model Molecules

COSMO-SAC – Predicted KOW & KOCHumic Acid as Solvent

-3 -2 -1 0 1 2 3 4 5 6 7 8 9Measured log KOC

RMSE = 0.83in log KOC

-3

-2

-1

0

1

2

3

4

5

6

7

8

9

-3 -2 -1 0 1 2 3 4 5 6 7 8 9

CO

SMO

-SA

C p

redi

ctio

n

Measured log KOW

RMSE = 0.70in log KOW

LeonarditePredicted KOW Predicted KOC

Phillips KL, Di Toro DM, Sandler SI. 2011. Prediction of Soil Sorption Coefficients using Model Molecular Structures for Organic Matter and the Quantum Mechanical COSMO-SAC Model. Environ Sci & Technol 45(3): 1021-1027.Data: Winget et al. (2000) Environ Sci. Technol. 34, 4733-4740.

COSMO-SACComponents of the Prediction

-2

-1

0

1

2

3

4

5

6

7

8

-1 0 1 2 3 4 5 6 7 8 9 10

CO

SMO

-SA

C lo

g K

OC

COSMO-SAC log ∞i,W

-2 -1 0 1 2COSMO-SAC log ∞i,OM

A B

Phillips KL, Di Toro DM, Sandler SI. 2011. Prediction of Soil Sorption Coefficients using Model Molecular Structures for Organic Matter and the Quantum Mechanical COSMO-SAC Model. Environ Sci & Technol 45(3): 1021-1027.

KOC i,W

i,OM

MWW

MWOCWnC,OM

COSMO-SAC KOC PredictionDifferent OM Molecules

0.0

0.2

0.4

0.6

0.8

1.0

1.2R

MSE

in

log

KO

C

Model for OM

Terrestrial HA Aquatic HA Aquatic FA

Phillips KL, Di Toro DM, Sandler SI. 2011. Prediction of Soil Sorption Coefficients using Model Molecular Structures for Organic Matter and the Quantum Mechanical COSMO-SAC Model. Environ Sci & Technol 45(3): 1021-1027.

AcknowledgementsStudents

Yasemin AtalayDepartment of Civil and Environmental Engineering University of Delaware, Newark, Delaware

Undine KipkaDepartment of Civil and Environmental Engineering University of Delaware, Newark, Delaware

Kathy PhillipsDepartment of Chemical EngineeringUniversity of Delaware, Newark, Delaware

ColleaguesRichard F. Carbonaro

Department of Civil and Environmental EngineeringManhattan College. Riverdale, NY

Stanley I. SandlerDepartment of Chemical EngineeringUniversity of Delaware, Newark, Delaware

Joy McGrathHDR HydroQual

ResearchersPerformed and Reported the Experiments

FundingNational Science FoundationCenter for the Study of Metals in the Environment (EPA)National Institute of Environmental Health Sciences (NIEHS)