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Dec 08, 2023 116 likes •208 views

Categorical Default Approaches to Uncertainty Factor Development in y p Chemical Risk Assessment John C. Lipscomb PhD, DABT, F.A.T.S. National Center for Environmental Assessment Assessment, Office of Research and Development, U. S.

SLIDE 1

Categorical Default Approaches to Uncertainty Factor Development in y p Chemical Risk Assessment

John C. Lipscomb PhD, DABT, F.A.T.S. National Center for Environmental Assessment Assessment, Office of Research and Development,

U. S. Environmental Protection Agency,

Ci i ti OH Cincinnati, OH

SLIDE 2

Where Does this Fit in Human Health Risk Assessment? Risk Assessment?

NAS 4-Step Paradigm Hazard Assessment & Characterization & Characterization Exposure Assessment & Characteri ation Dose Response Assessment & Characteri ation Risk Assessment & & Characterization & Characterization Risk Assessment & Characterization

SLIDE 3

Mode Mechanism

Plausible Detailed Plausible Hypothesis with Measured Key Detailed Molecular Description Measured Key Events p

f Causality

Key event: Critical Quantifiable

SLIDE 4

MOA/HR (WOE) Framework

Q1. Is the weight of

evidence sufficient to

I li ti f

establish the MoA in animals?

Implications of Kinetic & Dynamic Data for

Q2. Fundamental qualitative

differences in key events?

Data for Dose– Response

differences in key events? Q3 Fundamental quantitative

Q3. Fundamental quantitative

differences in key events?

SLIDE 5

Default Biologically (MoA) Default

Reference/Acceptable/

(MoA) Based

Reference/Acceptable/ Tolerable Intakes N/LO(A)EL BMC/D = N/LO(A)EL or BMC/D UF U i F Kinetics Dynamics Uncertainty Factor Interspecies Differences ( 10) (x10) Human Variability (x10) Ad f d t b

Adequacy of database (x1-100)

SLIDE 6

The Continuum Default Data-Informed

Default – 10 x 10 Database - Derived - databases of information,

, not group or chemical-specific

Categorical - applies to categories of

substances/species based on their characteristics (BSA substances/species based on their characteristics (BSA correction; RFC - gases/particles)

Chemical Specific Adjustment Factors -

p j

addressing kinetic or dynamic aspects with chemical specific or compound-related information

Fully Data-Derived – biologically-based dose-

Fully Data Derived

biologically based dose response modelling addressing kinetic and dynamic aspects

SLIDE 7

Where Are We Trying to Go in A Ri k C t t? Risk Context?

Greater predictive power

Hi h l

Higher relevance

Moving from default to more biologically

b d based

Relevant pathways

Relevant doses

Relevant doses Relevant species

SLIDE 8

U.S. NRC/NAS Toxicity Testing in the 21st Century

Dose Response

M d f A ti Chemical

Dose Response Assessment

C d Population Based Studies

Mode of Action Characterization

Compounds Assess Biological Perturbation Affected Pathway Dose Response Analysis for Perturbations

f Toxicity

Pathways Calibrating in vitro and human Dosimetry Exposure Guideline Metabolite(s) Perturbation Measures of dose in vitro Human Exposure Data

Hazard Characterization Exposure Assessment Risk Characterization E p u m n

SLIDE 9

Categorical Default Approaches to Uncertainty Factor Development in y p Chemical Risk Assessment

John C. Lipscomb PhD, DABT, F.A.T.S. National Center for Environmental Assessment Assessment, Office of Research and Development,

U. S. Environmental Protection Agency,