Stratifying risks of complex exposures kendall b wallace gilman d veith elisaveta p petkova
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Stratifying Risks of Complex Exposures Kendall B. Wallace, Gilman D. Veith & Elisaveta P. Petkova. Risk. Highly toxic chemicals, But if don’t reach target, No risk. Can flood target with chemical, But if not toxic, No risk. Target Dose. Toxicity. Chemical Toxicity.

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Stratifying risks of complex exposures kendall b wallace gilman d veith elisaveta p petkova
Stratifying Risks of Complex ExposuresKendall B. Wallace, Gilman D. Veith & Elisaveta P. Petkova


Risk

Highly toxic chemicals,

But if don’t reach target,

No risk

Can flood target with chemical,

But if not toxic,

No risk

Target Dose

Toxicity


Chemical toxicity
Chemical Toxicity

  • Biological activityof 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
Chemical Reactivity

  • Electrophilicityis 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


Exposure

Chemical Reactivity

Risk

Target Dose

Toxicity

Physical-chemical determinants

- partition constants

- electrophilic domains

partition

electrophilicity


Model systems
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


Pchem determinants of inhalation exposure

Personal Breathing Zone

Exposure

KHenry = f(Vp/Solw)

Pchem determinants of inhalation exposure

f(temp)

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)

Point Source


LogKow

MAC = f(Kow)

Chemical Reactivity

Differential dosing of the airways from a common exposure

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

Personal Breathing Zone

Exposure

KHenry = f(Vp/Solw)

f(temp)

Point Source


Illustration of concept

92 chemical entries

Illustration of Concept


VP>10 mm Hg, 25°C

MW<100

n=51

FEMA Chemicalsn=92


< C4

small MW

polar

LogKow

> C4

larger MW

non-polar

Chemical Reactivity

VP>10 mm Hg, 25°C

MW<100

n=51

FEMA Chemicalsn=92


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

n=51

FEMA Chemicalsn=92

Chemical Reactivity

Regional dosing is also a function of exposure concentration.


Modeling inhalation toxicology
Modeling inhalation toxicology --------------------------------------------------------

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

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

Toxicity = f([dose]*reactivity)

if chemical reactivity = 1.0

toxicity = dose ……….=> “baseline toxicity”


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.


blood flow --------------------------------------------------------

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

Model Inputs:

Biological -

air flow dynamics

surface area

surface thickness

blood perfusion

Chemical -

Vp

LogPair/tissue

LogPo/w

air flow

diffusion

Assumptions:

Chemical reactivity = 1.0

No chemical interactions

“baseline toxicity”


Summary
Summary --------------------------------------------------------

  • Differential dosing along the airways

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

    • Dose = f(Vp & LogPo/w)

      • John Morris - PBPK

    • Toxicity = f(chemical reactivity)

      • “baseline” v/ “excess/reactive” toxicities

        • Models for chemical reactivities (chemical domains)

        • Multiple molecular initiating events (biological)

    • Inhalation databases (mammalian)

      • UWS

      • Res. Inst. Fragrance Mats.


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