Brazilian Benzene Seminar

Brasilia, Brazil

December 6, 2012

Rita Schoeny, Ph.D.Senior Science Advisor, Office of Science Policy, Office of Research and Development U.S. EPA

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Low Dose Extrapolation for Low Dose Extrapolation for Carcinogens – U.S. EPA PerspectiveCarcinogens – U.S. EPA Perspective

Disclaimer

The views expressed in this presentation are those do the author and do not represent the policy of the U.S. EPA.

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I am still a Federal employee

04/13/23 3

Cancer Guidelines: What’s Different from 1986? Analyze data before invoking default options. Mode of action is key in decisions Weight-of-evidence narrative replaces the

previous “A-B-C-D-E” classification scheme. Two step dose response assessment

Model in observed range Extrapolate from point of departure

Consider linear and non-linear extrapolation Address differential risks to children

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High dose data – what do they tell us?

Res

pons

e

Dose

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PossibilitiesR

espo

nse

Dose

Interspecies

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Two Step Approach Model data in

the observed range – to a point of departure

Extrapolate below the POD

UF

Dose

Res

pons

e (T

umor

or

Non

tum

or D

ata)

0%

10%

EnvironmentalExposure Levels

of Interest

LED10 ED10

Nonlinear Default

EmpiricalRange of Observation

Range ofExtrapolation

x

x

xx

x

x NOAEL

LOAEL

x

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Extend the Observed Range Using Precursor Data Objective of choosing POD is to set it as

close to environmental levels as Supported by dataAppropriate to model

Cancer Guidelines say precursor data are useful for this

Must have MOA

Section3.2.2

Mode of Action: Bladder Tumors, Key EventsCytotoxicity and Regenerative Hyperplasia

DMAIII

Metabolite

Hyperplasia

UrothelialToxicity

RegenerativeProliferation

Tumor

Sustained BrdU Labeling

Measurable Key Events in Target

Tissue

BrdULabeling

SEM

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Endpoint Duration

Feeding

Duration

Drinking water

10% 1% 10% 1%

BMD (mg/kg/d)

BMDL(mg/kg/d)

BMD(mg/kg/d)

BMDL(mg/kg/d)

BMD(mg/kg/d)

BMDL(mg/kg/d)

BMD(mg/kg/d)

BMDL(mg/kg/d)

Tumor 104 weeks 7.74 5.96 6.80 2.22 104

weeks 1.92 1.21 0.88 0.14

Hyperplasia

10weeks 1.36 1.04 0.42 0.32

104 weeks 1.63 1.04 0.74 0.14

104 weeks 1.97 1.61 0.93 0.66

BrdU labeling

10 weeks 0.65 0.29 0.54 0.07 Not determined. Available data not suitable for modeling.

Cytotoxicity

3 weeks 0.68 0.18 0.31 0.02

No reliable dose-response data available

10 weeks 0.02 0.008 0.002 0.0007

Cacodylic Acid: BMDs and BMDLs

What Else Could Be Used? Pre-neoplastic lesions (e.g. altered

enzyme foci) Mutations? Chromosomal changes? DNA damage?

So Many Models!

UF

Dose

Re

spo

nse

(T

um

or

or

No

ntu

mo

r D

ata

)

0%

10%

EnvironmentalExposure Levels

of Interest

LED10 ED10

Nonlinear Default

EmpiricalRange of Observation

Range ofExtrapolationLinear Default

(Lowest

95%

Confid

ence L

imit

on Dose

)

x

x

(Cen

tral

Est

imat

e)

xx

x

x NOAEL

LOAEL

x

Linear or Non-linear?

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UF

Dose

Re

sp

on

se

(T

um

or

or

No

ntu

mo

r D

ata

)

0%

10%

EnvironmentalExposure Levels

of Interest

LED10 ED10

Nonlinear Default

EmpiricalRange of Observation

Range ofExtrapolation

x

x

xx

x

x NOAEL

LOAEL

x

Two Step Dose Response Process

Another Question First

Is There Something Better?

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Is there too much uncertainty or is critical information lacking? Invoke a

default option*

N

Y

Analyze the available data

Conduct risk assessment

Exposure

Tissue dose

Mode of action

Response

Source

PBPK

BBDR

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Biologically Based Dose Response Model

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BBDR – Based on Knowledge of Key Events

dosimetry Key event B1

Key event B2

Key event A1

Key event A2

Key event A3

Assessment endpoint

Mode of Action

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(PBPK)

AppliedAppliedDose of PhenobarbitalDose of Phenobarbital

Multiple dose-responses

and time-courses

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Reality check (I) There are always data gaps

ArsenicFormaldehydeTCDDphenobarbital

A BBDR model is a description of biological structure with embedded empirical linkages that cover the parts of the overall exposure-dose-response linkage for which data are missing.

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Reality check (II) As research improves our understanding of

the overall exposure-dose-response linkage, the sophistication of the description of the mode of action increases.

Corresponding iteration of the BBDR model leads to more accurate predictions of dose-response and time-course behaviors.

Will always be some degree of residual uncertainty.

But is the default more uncertain?But is the default more uncertain?

And if no BBDR?

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UF

Dose

Re

sp

on

se

(T

um

or

or

No

ntu

mo

r D

ata

)

0%

10%

EnvironmentalExposure Levels

of Interest

LED10 ED10

Nonlinear Default

EmpiricalRange of Observation

Range ofExtrapolation

x

x

xx

x

x NOAEL

LOAEL

x

Two Step Dose Response Process

Linear or Non-linear

Mutagenesis Paradigm

DNA Damaged DNA

Mutagens/Spontaneous

Damage Sensing

Cellular Response

DNA Repair

Repaired DNA

IncorrectRepair/Replication

Mutant DNA

No repair

Dead Cell20

Demarini 70

Threshold? Demonstrated

By inspection of the dose response curve

Fitting models and checking goodness of fit

Statistical tests for one model or another

Based on MOAMutagenic MOA

has been linearBut should consider

biology of mutation

Does mutagenic MOA mean low dose linear?BBDR should be first choice 21

MMS

MNU

2011 EMS Annual Meeting Pottenger 22

In vitro Mutation Dose-Response: MMS & MNUDoak et al., 2007

MMS

MNU

HPRT MF

NOEL = 1 g/ml

No NOEL

Johnson et al., 2009

ENU threshold dose-response (Lutz & Lutz model)

In vitro Mutation Dose-Response: ENU

HPRT MF

Slide from Pottenger 23

UFs Health Canada

IPCS RIVM ATSDR EPA

Interhuman 10 10

(3.16 X 3.16

10 10 1-10

Animal to human

10 10

(2.5 X 4)

10 10 1-10

Subchronic to chronic 1-100 1- 100

10 NA 1-10

LOAEL to NOAEL

10 10 1-10

Incomplete database

NA NA 1-1024

RfV = POD / UF

Example: Inhalation, RfCs – use RfC methodology guidance (U.S. EPA 1994) in determining interspecies UF. (Generally use UF = 3 when dosimetric adjustment of animal data).

Example: Methylmercury PK UF of 3 (based on analyses of interindividual variability) and default PD UF of 3

U.S. EPA Risk Assessment Forum working on Guidance for Data-derived Extrapolation Factors.Divides UFA into toxicokinetic and toxicodynamic

componentsSame for UFH

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Take Home Message

MOA informs dose response assessment

DNA damage is not mutation Mutation is not cancer Some genotoxicity endpoints may be

reasonable biomarkersMay be useful for extending the lower end of

dose response curveUseful in MOA

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NRC 2009 Silver Book 1 Framing questions

and design step. Risk Assessment is

not an end in itself. Characterize

uncertainty and variability

Default before data?

These are strictly my own opinionsThese are strictly my own opinions

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NRC 2009 Silver Book 2 Dose response

Additivity to background is a major theme○ How differentiate between exogenous and

endogenous damage?○ DNA adducts biomarkers, could have major role○ Does this mean linear all the time?

EPA has expressed preference for BBDR○ Low dose data for adduct formation○ Low dose data for mutation○ Low dose data for other markers

Again my own opinionsAgain my own opinions

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CancerCancer

Breaking Down the DichotomyBreaking Down the Dichotomy

Non-ThresholdNon-Threshold IrreversibleIrreversibleRisk valueRisk value

Slope FactorSlope Factor Unit RiskUnit Risk Risk-Specific DoseRisk-Specific Dose

Non-CancerNon-Cancer

ThresholdThresholdReversibleReversibleSafety ValueSafety Value

RfD/RfCRfD/RfC ADI/TDIADI/TDI MRLMRL

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ChloroformCYP2E1

Phosgene

Regenerative Cell Proliferation

Postulated Mode Of Action

MetabolismOxidative

Sustained Toxicity

Tumor Development

Key EventsKey Events

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Postulated Mode Of Action CPCPMetabolismMetabolism

Phosphoramide mustard, PAM

Phosphoramide mustard, PAM

AcroleinAcrolein

DNA damageDNA damage

MutationsMutations

Tumor Tumor DevelopmentDevelopment

Cyt p 450sCyt p 450s