Stratifying Risks of Complex Exposures

Kendall B. Wallace, Gilman D. Veith & Elisaveta P. Petkova

RiskRisk

ToxicityToxicityTarget DoseTarget Dose

Highly toxic chemicals,But if don’t reach target,No risk

Can flood target with chemical,But if not toxic,

No risk

Chemical Toxicity

Biological activity of a chemical substance can be expressed as a function of a partition coefficient (“dose”) and a chemical reactivity descriptor (“toxicity”)

For a chemical to express its toxicity it must

be transported from its site of administration to its site of

action (partition)

bind or react with a receptor or target molecule (reactivity)

Chemical Reactivity

Electrophilicity is one of the primary chemical reactivity descriptors successfully employed in describing toxicity of diverse classes of chemicals

Electrophilicity Domains Michael Acceptors SN-Ar Electrophiles SN-2 Electrophiles Schiff base formers Acrylating agents

RiskRisk

ToxicityToxicityTarget DoseTarget Dose

ExposureExposure Chemical ReactivityChemical Reactivity

Physical-chemical determinants - partition constants - electrophilic domains

partition electrophilicity

Model Systems

The application of these principles to the prediction of the partition and toxicity of complex mixtures can be achieved in a number of different models covering a wide range of complexity

read across between chemicals with similar

chemical/toxicological functionality

large computerized chemical databases containing 2D and 3D

structural descriptors

knowledge based expert systems for toxicological modeling

KHenry = f(Vp/Solw)

Personal Breathing Zone

Exposure

f(temp)

Pchem determinants of inhalation exposure

Point Source

Exposure (PBZ) composition is determined by, but much different from point source, and changes with temperature.

Exp(PBZ) = f(point source)(Vp*T/sol)Sol = f(LogPair/source solvent)

Personal Breathing Zone

Exposure

Chemical Reactivity

LogK

ow

KHenry = f(Vp/Solw)

f(temp)

MAC = f(Kow)

Point Source

“toxicity” occurs at all levels of the airways - from nasopharyngeal irritation to occlusion of the terminal conducting airways and destruction of the alveolar sacs

Differential dosing of the airways from a common exposure

Illustration of Concept

45% 55%

with PELswithout PELs

92 chemical entries

FEMA Chemicals n=92

VP>10 mm Hg, 25°C

MW<100

n=51

Chemical Reactivity

LogK

ow

> C4

larger MW

non-polar

< C4

small MW

polar

VP>10 mm Hg, 25°C

MW<100

FEMA Chemicals n=92

n=51

Chemical Reactivity

FEMA Chemicals n=92

n=51

CAS Name PEL, ppm PEL, mg/m3 Smiles7783064 Hydrogen sulfide S

64186 Formic Acid 5 9 C(=O)O64197 Acetic acid 10 25 C(C)(=O)O

109944 Ethyl formate 100 300 C(=O)OCC79209 Methyl acetate 200 610 C(C)(=O)OC108214 Isopropyl acetate 250 950 C(C)(=O)OC(C)C

64175 Ethyl alcohol 1000 1900 C(C)O67630 Isopropyl alcohol 400 980 C(C)(C)O

75070 Acetaldehyde 200 360 C(C)=O

67641 Acetone 1000 2400 C(C)(C)=O431038 2,3-Butanedione C(C)(=O)C(C)=O

75503 Trimethylamine CN(C)C

CAS Name PEL, ppm PEL, mg/m3 Smiles74460905 Sulfur dioxide O=S=O624920 Dimethyl disulfide CSSC107039 Propanethiol C(S)CC624895 Methyl ethyl sulfide C(C)SC870235 Allyl mercaptan C(=C)CS

140885 Ethyl acrylate 25 100 C(=O)(C=C)OCC110190 Isobutyl acetate 150 700 C(C)(=O)OCC(C)C80626 Methyl methacrylate 100 410 C(=O)(C(=C)C)OC

110623 Valeraldehyde C(=O)CCCC

108101 4-Methyl-2-pentanone 100 410 C(C)(=O)CC(C)C

107857 Isopentylamine C(C)(C)CCN

5724812 1-Pyrroline C1CCCN=1

Regional dosing is also a function of exposure concentration.

FEMA List --------------------------------------------------------

Exp(PBZ) = f([point source]*Vp(t)/sol)

Dose = f([exposure]/(Vp*LogPo/w))

Toxicity = f([dose]*reactivity)if chemical reactivity = 1.0toxicity = dose ……….=> “baseline toxicity”

Modeling inhalation toxicology

L C 5 0 ( m o u s e ) = 0 . 5 7 * V P + 2 . 0 8

R

2

= 0 . 7 4 n = 2 8

L C 5 0 ( r a t ) = 0 . 6 9 * V P + 1 . 5 4

R

2

= 0 . 9 1 n = 3 7

0

1

2

3

4

5

- 1 0 1 2 3 4

V a p o r P r e s s u r e , m m H g

LC50, mmol/m3 .

L C 5 0 R a t 4 o r 8 h r s

L C 5 0 M o u s e 1 5 m i n

L i n e a r ( L C 5 0 M o u s e 1 5 m i n )

L i n e a r ( L C 5 0 R a t 4 o r 8 h r s )

A baseline inhalation toxicity model for narcosis in mammals.Veith GD, Petkova EP, Wallace KB.

SAR QSAR Environ Res. 2009 Jul;20(5-6):567-78.

A PBPK MODEL FOR INSPIRED VAPOR UPTAKE IN THE HUMAN AND ITS APPLICATION TO DIACETYL DOSIMETRY.J. B. Morris. Toxicology Program, University of Connecticut, Storrs, CT.Society of Toxicology, March 7-11, 2010, Salt lake City

diff

usio

n

blo

od

flo

w Model Inputs: Biological - air flow dynamics surface area surface thickness blood perfusion

Chemical - Vp LogPair/tissue LogPo/w

Assumptions: Chemical reactivity = 1.0 No chemical interactions

air

flow

“baseline toxicity”

Summary

• Differential dosing along the airways

• QSAR-based strategies for estimating risks is a two-component model:

1. Dose = f(Vp & LogPo/w)• John Morris - PBPK

2. Toxicity = f(chemical reactivity)• “baseline” v/ “excess/reactive” toxicities

– Models for chemical reactivities (chemical domains)

– Multiple molecular initiating events (biological)

3. Inhalation databases (mammalian)• UWS

• Res. Inst. Fragrance Mats.