Considering mechanistic data to assess mode of action or human relevance

Outline • Assessment of Mode of ActionHuman Relevance in Risk Assessment • Where does this fit? • What data are relevant? – Mechanistic » Such as?? • How is it done? • A Relevant Framework • An Example • Review of Important Aspects • Reading • Introduction of Case Study Exercise Hazard Identification (Is This Toxic?) • Hazard identification is consideration of the intrinsic property of a substance to cause harm – Toxicological, epidemiological study – “Strength” of evidence – Judgment on the reliability of a given data set supporting a toxicological effect • Quality of the studies and methodology

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Considering Mechanistic Data to Assess Mode of Action/Human Relevance

M.E (Bette) Meek McLaughlin Centre University of Ottawa, Ottawa, Canada

Email:bmeek@uottawa.ca

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McLaughlin Centre University of Ottawa

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Outline

• Assessment of Mode of Action/Human

Relevance in Risk Assessment

• Where does this fit?

• What data are relevant?

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Risk Assessment/Management

• Hazard Identification: IS THIS TOXIC?

HUMANS? WHICH ONES? WHICH CONDITIONS?

• Dose-Response Assessment: HOW TOXIC IS IT?

• Exposure Assessment: WHO IS EXPOSED, HOW MUCH, HOW OFTEN, AND FOR HOW LONG EACH TIME?

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Hazard Identification

(Is This Toxic?)

• Hazard identification is consideration of the

intrinsic property of a substance to cause harm

– Toxicological, epidemiological study

– “Strength” of evidence

– Judgment on the reliability of a given data set

supporting a toxicological effect

• Quality of the studies and methodology

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Hazard Identification

(Is this Toxic?)

Epidemiological Studies

Ask the right question

• Examine the right species at the right doses Answer it badly

• Many factors which complicate interpretation (confounders); not very sensitive

Toxicological Studies

Ask the wrong question

• Examine the wrong species at high doses, Answer it well

• Control of Variables

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Hazard Characterization (Is This Toxic to Humans, Which Humans,

Under What Conditions?)

• Hazard characterization is the (qualitative) likelihood of

causing adverse effects in particular subgroups of

humans, based on consideration of results of

toxicological/epidemiological studies and mechanistic

data (mode of action)

• Weight of evidence (WOE) (early, systematic

assimilation)

– Comprehensive, integrated judgment of all

relevant information supporting conclusions

regarding a toxicological effect, including human relevance

• Consistency, specificity, biological plausibility

• Which critical effects for dose-response?

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Implications of Mode of Action for Dose Response Analysis (How Toxic is it?)

• In dose-response analysis, the likelihood of

causing adverse effects in particular subgroups

of humans is quantitatively estimated

• Mechanistic data/Mode of Action (MOA) are

important in selection of approach

– Linear extrapolation or “safe” levels

• reference/tolerable/acceptable intakes

• Also tells us about magnitude of differences

between animals and humans and within

humans

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MOA Implications for Dose Response

PoD = Point of Departure RfD = Reference Dose MoE = Margin of Exposure

Consideration of “Key Events” to

protect human health

RfD = PoD/UFs

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BMC/D - Benchmark dose – modelled estimate of

specified increase in effect

Uncertainty Factor

• Interspecies Differences (x10) (between species)

• Human Variability (x10) (differences within humans)

– interindividual or intraspecies variation

• Other

– Adequacy of database (x1-100)

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Risk Assessment – Qualitative/Quantitative

• Hazard Identification

– Effects seen in animals and/or humans

• Hazard Characterization (qualitative – toxic?)

– Mode of Action/Qualitative Relevance to Humans

• Dose Response Analyses (quantitative – how toxic?)

– Shape of the dose response curve

– Quantitative relevance to humans and in various subgroups

• Differences between experimental species & humans

• Differences within humans

• Exposure Estimation

• Risk Characterization

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Mechanistic Data

Data that inform us about how a chemical induces

adverse effects

• Toxicokinetics: uptake by the body, biotransformation

and distribution and elimination of the substance and

metabolites from the body (absorption, distribution,

metabolism, excretion)

– What does the body do to the chemical?

• Toxicodynamics: interaction with target sites and the

subsequent reactions leading to adverse effects (e.g., biochemical, tissue effects)

– What does the chemical do to the body?

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ANY LOCAL BIOACTIVATION

- not reflected by plasma kinetic measurements CYTOPROTECTIVE MECHANISMS

INTERACTION WITH INTRACELLULAR TARGET(s)

INTRACELLULAR CHANGES

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Examples of Mechanistic Data

(How a Chemical Induces its Effects)

• Information on:

– metabolism

– nature of interaction with biological receptors

• E.g., direct or indirect interaction with genetic material, proteins

– nature of early effects leading to toxicity

• E.g., effects on hormones leading to secondary outcome

• Toxicity leading to cell death and repair

• Physical irritation of chemical precipitates

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How Do Mechanistic Data Help?

They address:

• Are the effects observed in animals relevant to humans?

• Are there subgroups of the human population at special risk?

• E.g., children,

• the elderly?

• What is the risk at the much lower doses to which

humans are exposed?

– High to low dose extrapolations

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Mode vs Mechanism (Toxicokinetics/Toxicodynamics)

• What is Mode of Action (MOA)?

– Key events are not every step in the process,

but rather what is likely to “drive” the process

• How is it different from mechanism of

action?

– All Events at Molecular Level

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Plausible Hypothesis

- Key Events

Detailed Molecular Description

Mode vs Mechanism (Toxicokinetics/Toxicodynamics)

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Key Event

element of the mode of action, or is a

• Examples

– Specific metabolic transformation

– Chemically induced direct and indirect

reaction with genetic material (DNA)

– Cytotoxicity (cell death)

– Hormonal changes

– Increased cell growth and organ weight

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Examples of MOAs

A chain of key events leading to adverse outcome

and Repair (Proliferation)

pathway, leading to male reproductive

malformations

death and repair

repair

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Mode of Action/Human Relevance

(MOA/HR)

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MOA/HR Framework –How

Does it Help?

• designed to organize information

– Guides assessors in considering the extent

of evidence as a basis for decision making

and identifying important data gaps

• i.e., weight of evidence

– Uses established criteria

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IPCS/ILSI MOA/HR (WOE) Framework

Implications of Kinetic & Dynamic

Data forDose– Response

Q1 Is the weight of evidence sufficient to

establish the MoA in animals?

Q2 Fundamental qualitative differences in key events?

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Mode of Action/Human Relevance Framework

Is the weight of evidence sufficient to establish a mode of action (MOA) in animals?

Can human relevance of the MOA

be reasonably excluded on the basis of fundamental, qualitative differences in key events between animals and humans?

Can human relevance of the MOA

be reasonably excluded on the basis of quantitative differences

in either kinetic or dynamic factors between animals and humans?

Implications of kinetic and dynamic data for dose –response

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1.Weight of Evidence for the Mode of Action

in Animals

• Introduction, Postulated Mode(s) of Action (MOAs), Key Events

• Dose-Response/Temporal (Time) Relationships

between Key and End Events

• Consistency, Specificity

– Do all of the observations “line up”?

• Biological Plausibility and Coherence

– Does MOA make sense based on what we know about biology?

• Assessment, Uncertainties

– What do we conclude? What are limitations?

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1.Is the Weight of Evidence – for the Mode of

Action in Animals Sufficient?

• Introduction, Proposed Mode(s) of Action, Key Events

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First Step Possible MOAs (Example)

Possible

Initial Conclusion

Mutagenicity Weight of evidence

Possible

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1.Is the Weight of Evidence – for the Mode of

Action in Animals Sufficient?

• Dose-Response Relationships

events would be compared with one another and with those for endpoints of concern

• Are the key events always observed at doses below or similar to those associated with the toxic outcome?

• Temporal Association (Time)

– Key events and adverse outcomes would be

evaluated to determine if they occur in expected order

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Dose – Response and Temporality

Dose

0.2 (2 ppm)

1 (10 ppm)

4 (40 ppm)

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1.Is the Weight of Evidence – for the Mode of Action in

Animals Sufficient? (Cont’d)

• Strength, Consistency, Specificity

– Is the incidence of the end toxic effect consistent with that for the key events?

• Less than that for the key events

– Is the sequence of events reversible if dosing is

stopped or a key event prevented?

• Biological Plausibility

– Is the pattern of effects across species/strains

consistent with the hypothesized MOA?

– Does the hypothesized mode of action make sense

based on broader knowledge

• E.g biology

• Established MOA?

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1.Is the Weight of Evidence – for the Mode of Action in Animals Sufficient?

(Cont’d)

• Assessment, Uncertainties

strong), given nature and robustness of

data on metabolism, other key events and adverse outcomes

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• Are there similarities or differences

[qualitative (Q.2)/quantitative (Q.3)] in the

occurrence of key events between test

animals and humans?

– Toxicokinetics

– Biochemical, physiological, pathological processes

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Can human relevance be reasonably excluded

on the basis of fundamental qualitative (Q.2)

or quantitative (Q.3) differences?

specific

– e.g.,lack of relevant proteins for binding– Anatomical variations

– Human disease states

• Involves concordance (comparison)

analysis of key events between animals

table key

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Quantitative Concordance Humans

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4 Statement of confidence;

analysis; implications

• Essential output of analysis which indicates that

both qualitative and quantitative considerations

• If not considered relevant to humans:

– degree of confidence in conclusion

• If considered relevant to humans:

– explicit indication of datagaps which, if filled, might permit different conclusion

– presentation of the quantitative considerations

relevant to subsequent dose-response analysis

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How does MOA/HRF impact on Dose

Response?

The information considered as a basis to respond

to Questions #2 and particularly #3 of the

framework is also relevant to dose-response

It determines the relevant approach to

dose-response:

human variability, where data are sufficient (i.e.,

to replace default values of 10x10)

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MOA/HRF Approaches to Dose-Response

effects, there is a dose level below which a

response is unlikely

– mechanisms in the cell protect against toxic effects

cancer/genotoxicity have been assumed to have

a “threshold”

– i.e., a dose below which there is no probability of harm

dose – i.e ,exposure < or >“safe” dose

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Dose-Response Approaches (Non-linear “Thresholded” )

Threshold

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Dose-Response Approaches:

Linear

• For some types of effect, we consider there to

be a probability of harm at all levels of exposure – Often applied in the past to cancer,

Non Threshold

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Mode of Action in Dose Response

• Where we know about mode of action, we can choose the appropriate dose-response model

• Cancer can be induced by “thresholded” modes

– E.g., cytotoxicity, regenerative proliferation

– Receptor mediated modes

• Non-cancer effects can be induced by modes for which there may be a probability of harm at low levels of

exposure (i.e., no thresholds)

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DOSE

00 Threshold

DOSE 00

Non Threshold

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Mode of Action and

Dose-Response (Cont’d)

• Where mode of induction of tumours involves early non-cancer key events (e.g., cell death), can develop a “safe” dose

Measure of Dose-Response

Uncertainty Factor

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Kidney Tumors

Hypothesized Mode of Action for Rat KidneyTumors

Nonlinearity / Threshold

T U M O R S

DOSE 00

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MOA/Key Events Implications for Dose Response

x

Point of Departure

Method of Extrapolation

Consideration of “Key Events” to

protect human health

RfD = PoD/UFs

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DNA Adducts

0 1 2 3 4 5 6 7

Cell Proliferation

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BMC/D - Benchmark dose – modelled estimate of

specified increase in effect

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MOA: Implications for Interspecies Differences and Human Variability: CSAF

InterspeciesDynamics (2.5)

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Assessing Human Relevance of MOA

An Example

M.E (Bette) Meek McLaughlin Centre University of Ottawa, Ottawa, Canada

Email:bmeek@uottawa.ca

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Mode of Action Human Relevance Case Study: Disruption of Thyroid

Homeostasis

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Background

• Herbicide

– to control annual grasses and certain broadleaf

weeds in orange and grapefruit production

• Critical effects

– Thyroid tumours

– Effects on development

• Changes in brain structure and effects on learning

• Similar mode of action hypothesized to lead to cancer and non-cancer effects

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Elimination

T3, T4 TSH

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Thyroid Hyperplasia Rat Thyroid Tumors Health Risk?

Chemical T

Exposure

Hepatic Chemical T Dose

Altered development Developmental Defects

Neuro-Children’s Health Risk

Exposure

Hepatic Clearance

Effects Noncancer Cancer

T4 T3 TSH

Modes of Action and Human Relevance

Altered development Developmental Defects Health Risk?

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Neuro-IPCS/ILSI MOA/HR (WOE) Framework

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• What are potential MoAs?

• What are the key events in the MoA(s)?

Thirdly:

• What is the experimental support? (the data)

– Dose-response, temporal, etc…

• Putting tables together is a valuable exercise!

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reactivity, gene mutations, and chromosomal aberrations

Not likely

Cytotoxic No evidence of cytotoxicty

from 28 and 90-day studies

Not likely

Endocrine Multiple studies showing

hormone changes, hypertrophy and hyperplasia

Possible

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Metabolism & hormone

studies,

& histopathology

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Thyroid Tumors

• Description of Postulated MoA

– Key events

•  clearance from the liver of thyroid hormone

• Decreases in serum hormones

• Increase in thyroid stimulating hormone

• Thyroid hypertrophy (swelling of follicular cells)

• Thyroid hyperplasia (increase in # of cells)

– 2 year study in rats (5 dose levels)

• Standard organ weights and histopathology

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hormone &Thyroid Stimulating Hormone

levels

• 56 day rat study

–  hepatic enzyme activity responsible for clearance–  liver weights

–  clearance of thyroid hormone from blood &

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