Stratifying Risks of Complex Exposures Kendall B. Wallace, Gilman D. Veith & Elisaveta P. Petkova

1. Stratifying Risks of Complex ExposuresKendall B. Wallace, Gilman D. Veith & Elisaveta P. Petkova

2. 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

3. 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)

4. 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

5. Exposure Chemical Reactivity Risk Target Dose Toxicity Physical-chemical determinants - partition constants - electrophilic domains partition electrophilicity

6. 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

7. 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

8. 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

9. 92 chemical entries Illustration of Concept

10. VP>10 mm Hg, 25°C MW<100 n=51 FEMA Chemicalsn=92

11. < 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

12. FEMA List -------------------------------------------------------- n=51 FEMA Chemicalsn=92 Chemical Reactivity Regional dosing is also a function of exposure concentration.

13. 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”

14. 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.

15. 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”

16. 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.