Computational Methods to Address Challenges in Chemical Risk - PowerPoint PPT Presentation

Computational Methods to Address Challenges in Chemical Risk Assessment Bio-Seminar in the Department of Electrical & Computer Engineering at Texas A&M 31 March 2017 Weihsueh A. Chiu, PhD Professor, Veterinary IntegraIve Biosciences College of Veterinary Medicine and Biomedical Sciences 1

Collaborators TAMU-CVM Pacific Northwest NaJonal Laboratory Ivan Rusyn Erin Baker David Threadgill JusJn Teeguarden Postdoctoral associates Nan-hung Hsieh Colorado State University Chimeddulam Dalaijamts Brad Reisfeld Fabian Grimm Sudipto Ghosh TAMU-GERG L'InsJtut naJonal de Tony Knap l'environnement industriel et Terry Wade des risques (INERIS, France) TAMU-EN Frederic Bois Stratos PisJkopoulos TAMU-HSC Tommy McDonald 2

Outline • Overview of chemical risk assessment • Examples of key challenges and role of computaJonal methods • Risk from complex and varied exposures • Addressing populaJon variability • QuanJfying risk and uncertainty • Risk assessment as translaJonal science 3

ScienIfic Components of Risk Assessment Exposure Assessment Source-to-Outcome ConInuum Source/stressor formaIon Fate & Transport Environmental concentraIons Exposure External doses ToxicokineIcs Internal concentraIons Toxicodynamics Biological response measurements Systems dynamics Physiological/health status 4

Transport and transformation of chemicals in the environment Deposition Between Media Advection Diffusion Dispersion Environmental Within Medium Medium Air Deposition Between Media Environmental Medium Resuspension Biota Bioconcentration Deposition Between Media Between Media Advection Diffusion Photolysis Environmental Dispersion Reaction with sunlight Medium Within Medium Soil Hydrolysis Reaction with water Infiltration Environmental Between Media Medium Resuspension Surface Water Deposition Between Media Precipitation Generation of a solid Biodegradation Organic breakdown Biodegradation Dissolution Organic breakdown Formation of a Biodegradation solution in water Organic breakdown Hydrolysis Reaction with water 5

Exposure modeling Storm surge from Hurricane Sediment deposiIon 6

Estimating Human Exposure in the Population Source: SAP SHEDS Overview, 7/14/2010 7

ScienIfic Components of Risk Assessment Exposure Assessment Source-to-Outcome ConInuum Source/stressor formaIon Fate & Transport Environmental concentraIons Exposure External doses PharmacokineIcs/ToxicokineIcs ToxicokineIcs Internal concentraIons Toxicodynamics Biological response measurements Systems dynamics Physiological/health status 8

Toxicokinetics = “Fate and transport within the body” • Exposure alone is not sufficient to elicit toxicity • InteracJon between an exogenous agent and a biological target • What is the agent or toxic moiety? • How does it get to the biological target? • How much of the agent gets there? • How long does it stay there? • ToxicokineIcs is the study of the movement of chemicals in and out of the body (“what the body does to the chemical”) • AbsorpJon • DistribuJon • Metabolism • ExcreJon 9

For pharmaceuticals – mostly use simple empirical models Chemical-specific data Amount Central in gut = Compart- A G ment = A C PredicJons about = + similar scenarios Peripheral Compart- ment = A P in vivo Empirical models 10

More complex models trade off simplicity for predictive power Chemical-specific data Amount Central in gut = Compart- A G ment = A C PredicJons about = + similar scenarios Peripheral Compart- ment = A P in vivo Empirical models (simple & quick) PredicJons about Q p C i C x scenarios with + Q c in vitro different: Q c C a Lung • Exposure routes, C vl Q L Liver = Physiological duraJons, C vf Q f Fat Data levels, pajerns C vr Q r Rapidly perfused (brain, kidney, etc.) + • Species Slowly perfused (muscle, bone, etc.) C vs Q s PBPK models • Individuals (complicated & Ime-consuming) 11

ScienIfic Components of Risk Assessment Exposure Assessment Source-to-Outcome ConInuum Source/stressor formaIon Fate & Transport Environmental concentraIons Exposure Hazard IdenIficaIon and External doses PharmacokineIcs/ToxicokineIcs Dose-Response Assessment ToxicokineIcs Internal concentraIons Toxicodynamics Biological response measurements Systems dynamics Physiological/health status 12

Hazard Identification • DeterminaJon of whether a parJcular chemical is or is not causally linked to parJcular health effects • Increased incidence • Increased severity What adverse effects have been For each adverse effect, what is the evidence observed or are anIcipated? that the agent can cause it in humans? • Human data • Availability of data (absence of evidence ≠ evidence of absence) • Laboratory animal data • Consistency within and across the different • In vitro data types of data. • Physical/chemical/molecular • Biological plausibility / mechanisJc basis property data Recent emphasis has been on applying systemaIc review methods to evaluate evidence of causality (not discussed further today) 13

Dose-Response – Many still ascribe to the principles of Peracelsus … Peracelsus (Phillippus Aureolus Theophrastus Bombastus von Hohenheim) 1493-1541 Known as the ‘ father of toxicology ’ . The saying “ Dosis facit venenum ” (The dose makes the poison) is a?ributed to him. His actual quote translates “ All things are poisons, for there is nothing without poisonous qualiEes...it is only the dose which makes a thing poison. ” toxic therapeutic increasing dose effect effect Slide courtesy of D. Threadgill 14

Traditional interpretation: Existence of a “threshold” below which there are no effects • NOAEL: Greatest concentraJon Percent Incidence of Response or amount of a substance, 100 Magnitude of response found by experiment or observaJon, that causes no LOAEL 75 adverse alteraJon …of the 50 target organism disJnguishable from those observed in normal 25 (control) organisms of the same NOAEL species and strain under the 0 same defined condiJons of Dose Dose exposure.* (Avg. daily dose) • Commonly viewed (incorrectly) as an experimental dose threshold. 15 *WHO definiJon

Implementation: “Safe Human Dose” Established by Use of “Uncertainty” or “Safety” Factors NOAEL Percent Incidence of Response RfD = --------------- 100 Magnitude of response 100 75 50 UF A =10 UF H =10 25 0 UF A-TK =3 UF A-TD =3 UF H-TK =3 UF H-TD =3 Dose Dose (Avg. daily dose) UF H UF A RfD NOAEL 16

ScienIfic Components of Risk Assessment Exposure Assessment Source-to-Outcome ConInuum Source/stressor formaIon Fate & Transport Environmental concentraIons Exposure Hazard IdenIficaIon and External doses Dose-Response Assessment Risk ToxicokineIcs CharacterizaIon Internal concentraIons Toxicodynamics Biological response measurements Systems dynamics Physiological/health status 17

Risk Assessment in the Context of Research & Decision-Making Information Information RISK RISK RESEARCH ASSESSMENT MANAGEMENT • Epidemiology Planning & Scoping D Risk char Ban • Clinical Studies Hazard Identification E More research • Animal Studies C Social Dose-Response Standards : o Species, exposure, etc. I air, water, food • S.A.R. (Structure Activity S Assessment Economic Priorities : I Relationships) research, Exposure Assessment O • Modeling Legal regulation N Research Assessment Needs Needs 18

Multi- and trans-disciplinary nature of risk assessment • Requires data and models from mulJple scienJfic disciplines. • Requires methods and approaches for integraJng diverse informaJon to draw scienJfic conclusions about risk. • Requires consideraJon of not only scienJfic, but also social, economic, and legal factors in order to inform decisions about managing risk. 19

Examples of challenges and computational methods • Complex and varied exposures with incomplete data on chemical risks • Incomplete understanding of populaJon variability in suscepJbility to chemical risks • Inadequate quanJficaJon of chemicals risk and its uncertainJes 20

Example Challenge: Exposure assessment for environmental mixtures Source-to-Outcome ConInuum Storm surge from Hurricane Sediment deposiIon Source/media concentraIons Exposure External doses ToxicokineIcs Usual Approach is to perform “targeted” chemical analyses: “Known unknown” contaminants “Known known” contaminants Internal concentraIons Toxicodynamics Biological response measurements Systems dynamics Physiological/health status • How do you prioriIze “known unknowns” given limited Ime and resources? • What about “unknown unknown” contaminants? 21