Guidelines for

Carcinogen

Risk

Assessment

Risk

Assessment

Forum

U.S. Environmental

Protection

Agency

Washington,

DC

EPAJ63

O/P-03/OO

iF

March

2005

---

DISCLAIMER

This

document

has been reviewed

in

accordance

with

U.S.

Environmental

Protection

Agency

policy and

approved

for publication.

Mention

of trade

names

or

commercial

products

does

not constitute

endorsement

or

recommendation

for use.

---

CONTENTS

1.

iNTRODUCTION

.

1-1

1.1.

PURPOSE

AND

SCOPE

OF

THE

GUIDELiNES

1-1

1.2.

ORGANIZATION

AND

APPLICATION

OF

THE

GUIDELiNES

1-3

1.2.1.

Organization

1-3

1.2.2.

Application

1-5

1.3.

KEY

FEATURES

OF

THE

CANCER

GUIDELINES

1-7

1.3.1.

Critical

Analysis

of

Available

Information

as

the

Starting

Point

for

Evaluation

1-7

1.3.2.

Mode

of

Action

1-10

1.3.3.

Weight

of

Evidence

Narrative

1-11

1.3.4.

Dose-response

Assessment

1-12

1.3.5.

Susceptible

Populations

and

Lifestages

1-13

1.3.6.

Evaluating

Risks

from

Childhood

Exposures

1-15

1.3.7.

Emphasis

on

Characterization

1-21

2.

HAZARD

ASSESSMENT

2-1

2.1.

OVERVIEW

OF

HAZARD

ASSESSMENT

AND

CHARACTERIZATION

...

2-1

2.1.1.

Analyses

of

Data

2-1

2.1.2.

Presentation

of

Results

2-1

2.2.

ANALYSIS

OF

TUMOR

DATA

2-2

2.2.1.

Human

Data

2-3

2.2.1.1.

Assessment

of

evidence

of

carcinogenicity

from

human

data

2-4

2.2.1.2.

Types

of

studies

2-5

2.2.1.3.

Exposure

issues

2-6

2.2.1.4.

Biological

markers

2-7

2.2.1.5.

Confounding

actors

2-8

2.2.1.6.

Statistical

considerations

2-9

2.2.1.6.1.

Likelihood

of

observing

an

effect

2-9

2.2.1.6.2.

Sampling

and

other

bias

issues

2-10

2.2.1.6.3.

Combining

statistical

evidence

across

studies

.

...

2-11

2.2.1.7.

Evidence

for

Causality

2-11

2.2.2.

Animal

Data

2-15

2.2.2.1.

Long-term

Carcinogenicity

Studies

2-15

2.2.2.1.1.

Dosing

issues

2-16

2.2.2.1.2.

Statistical

considerations

2-19

2.2.2.1.3.

Concurrent

and

historical

controls

2-20

2.2.2.1.4.

Assessment

of

evidence

of

carcinogenicity

from

long

term

animal

studies

2-21

2.2.2.1.5.

Site

concordance

2-22

2.2.2.2.

Perinatal

Carcinogenicity

Studies

2-22

2.2.2.3.

Other

Studies

2-24

2.2.3.

Structural

Analogue

Data

2-25

2.3.

ANALYSIS

OF

OTHER

KEY

DATA

2-25

---

2.3.1.

Physicochemical Properties

.

2-25

2.3.2.

Structure-Activity

Relationships

2-26

2.3.3.

Comparative

Metabolism

and

Toxicokinetics

2-27

2.3.4.

Toxicological

and

Clinical

Findings

2-29

2.3.5.

Events

Relevant

to Mode

of Carcinogenic

Action

2-30

2.3.5.1.

Direct

DNA-Reactive

Effects

2-31

2.3.5.2.

Indirect

DNA

Effects

or

Other

Effects

on Genes/Gene

Expression

2-32

2.3.5.3.

Precursor

Events

and Biomarker

Information

2-34

2.3.5.4.

Judging

Data

2-36

2.4.

MODE

OF

ACTION—GENERAL

CONSIDERATIONS

AND

FRAMEWORK

FOR

ANALYSIS

2-36

2.4.1.

General

Considerations

2-36

2.4.2.

Evaluating a Hypothesized

Mode

of Action

2-40

2.4.2.1.

Peer

Review

2-40

2.4.2.2.

Use of

the

Framework

2-40

2.4.3. Framework

for

Evaluating

Each

Hypothesized

Carcinogenic

Mode

of

Action

2-41

2.4.3.1.

Description

of the

Hypothesized

Mode

of

Action

2-43

2.4.3.2.

Discussion

of the

Experimental

Support

for the

Hypothesized

Mode

of

Action

2-44

2.4.3.3.

Consideration

of

the

Possibility

of

Other

Modes

of Action

. 2-46

2.4.3.4.

Conclusions

About

the Hypothesized

Mode

of

Action

2-47

2.4.4. Evolution

with

Experience

2-49

2.5.

WEIGHT

OF EVIDENCE NARRATIVE

2-49

2.6.

HAZARD

CHARACTERIZATION

2-59

3.

DOSE-RESPONSE

ASSESSMENT

3-1

3.1.

ANALYSIS

OF

DOSE

3-3

3.1.1.

Standardizing Different

Experimental

Dosing

Regimens

3-4

3.1.2.

Toxicokinetic

Data

and

Modeling

3-5

3.1.3.

Cross-species Scaling

Procedures

3-6

3.1.3.1.

Oral

Exposures

3-6

3.1.3.2.

Inhalation

Exposures

3-8

3.1.4.

Route

Extrapolation

3-9

3.2.

ANALYSIS

IN

THE RANGE

OF OBSERVATION

3-11

3.2.1.

Epidemiologic

Studies

3-11

3.2.2.

Toxicodynamic

(“Biologically

Based”)

Modeling

3-13

3.2.3.

Empirical

Modeling

(“Curve

Fitting”)

3-14

3.2.4.

Point

of Departure

(POD)

3-16

3.2.5.

Characterizing

the

POD:

The

POD

Narrative

3-18

3.2.6.

Relative

Potency

Factors

3-20

3.3.

EXTRAPOLATION TO

LOWER

DOSES

3-20

3.3.1.

Choosing

an

Extrapolation

Approach

3-21

3.3.2.

Extrapolation

Using

a

Toxicodynamic

Model

3-21

---

3.3.3.

Extrapolation

Using

a

Low-dose

Linear

Model

3-23

3.3.4.

Nonlinear

Extrapolation

to

Lower

Doses

3-23

3.3.5.

Comparing

and

Combining Multiple

Extrapolations

3-24

3.4.

EXTRAPOLATION

TO

DIFFERENT

HUMAN

EXPOSURE

SCENARIOS

3-26

3.5.

EXTRAPOLATION

TO

SUSCEPTIBLE

POPULATIONS

AND

LIFESTAGES

3-29

3.6.

UNCERTAINTY

3-29

3.7.

DOSE-RESPONSE

CHARACTERIZATION

3-32

4.

EXPOSURE

ASSESSMENT

4-i

4.1.

DEFINING

THE

ASSESSMENT

QUESTIONS

4-1

4.2.

SELECTING

OR

DEVELOPING

THE

CONCEPTUAL

AND

MATHEMATICAL

MODELS

4-3

4.3.

COLLECTING

DATA

OR SELECTING

AND

EVALUATING

AVAILABLE

DATA

4-3

4.3.1.

Adjusting

Unit

Risks

for

Highly

Exposed

Populations

and

Lifestages

. 4-4

4.4. EXPOSURE

CHARACTERIZATION

4-5

5. RISK

CHARACTERIZATION

5-1

5.1.

PURPOSE

5-1

5.2.

APPLICATION

5-4

5.3.

PRESENTATION

OF

THE

RISK

CHARACTERIZATION

SUMMARY

5-5

5.4. CONTENT

OF THE

RISK

CHARACTERIZATION

SUMMARY

5-6

APPENDIX:

MAJOR

DEFAULT

OPTIONS

A-i

APPENDIX B:

EPA’s

GUIDANCE

FOR

DATA

QUALITY

ASSESSMENT

B-i

REFERENCES

R-l

LIST

OF

FIGURES

Figure

1-1.

Flow

chart

for

early-life

risk

assessment

using

mode

of

action

framework

....

1-23

Figure

3-1.

Compatibility

of

Alternative

Points

of

Departure

with

Observed

and

Modeled

Tumor

Incidences

3.35

Figure

3-2.

Crossing

between

10%

and

1% Dose-Response

Curves

for Bladder

Carcinomas

and

Liver

Carcinomas

Induced

by

2-AAF

3-35

---

1.

INTRODUCTION

1.1.

PURPOSE

AND

SCOPE

OF

THE

GUIDELINES

These

guidelines

revise

and

replace

the

U.S.

Environmental

Protection

Agency’s

(EPA’s,

or

the

Agency’s)

Guidelines

for

Carcinogen

Risk Assessmen4

published

in

51

FR

33992,

September

24,

1986

(U.S.

EPA,

1986a)

and

the 1999

interim

final

guidelines

(U.S. EPA,

1999a;

see

U.S.

EPA

2001b).

They

provide

EPA

staff with

guidance

for

developing

and using

risk

assessments.

They

also

provide

basic

information

to the

public

about

the Agency’s

risk

assessment

methods.

These

cancer

guidelines

are used

with

other

risk assessment

guidelines,

such

as

the

Guidelines

for

Mutagenicity

Risk

Assessment

(U.S.

EPA,

1986b)

and the

Guidelines

for

Exposure

Assessment

(U.S.

EPA,

1 992a).

Consideration

of other

Agency

guidance

documents

is

also

important

in

assessing

cancer

risks

where procedures

for

evaluating

specific

target

organ

effects

have

been developed

(e.g.,

assessment

of

thyroid

follicular

cell tumors,

U.S. EPA,

1998a).

All of EPA’s

guidelines

should

be

consulted

when

conducting

a risk

assessment

in

order

to

ensure

that information

from

studies

on

carcinogenesis

and

other

health

effects

are

considered

together

in the

overall

characterization

of

risk.

This

is particularly

true

in

the

case in

which

a

precursor

effect

for a tumor

is

also

a precursor

or

endpoint

of

other health

effects

or when

there

is

a concern

for a

particular

susceptible

life-stage

for

which

the

Agency

has

developed

guidance,

for

example,

Guidelines

for Developmental

Toxicity

RiskAssessment

(U.S.

EPA,

1991a).

The

developmental

guidelines

discuss

hazards

to children

that

may

result

from exposures

during

preconception and prenatal

or

postnatal

development

to sexual

maturity.

Similar

guidelines

exist

for

reproductive

toxicant

risk

assessments

(U.S.

EPA,

1 996a)

and

for neurotoxicity

risk

assessment

(U.S.

EPA,

1

998b).

The

overall

characterization

of

risk is

conducted

within

the

context

of

broader

policies

and guidance

such

as

Executive

Order

13045,

“Protection

of

Children

From

Environmental

Health

Risks

and Safety

Risks”(

Executive

Order

13045,

1997)

which

is

the

primary

directive

to federal

agencies

and

departments

to identifi

and

assess environmental

health

risks and

safety

risks

that may

disproportionately

affect

children.

1—1

---

The

cancer

guidelines

encourage

both

consistency

in the

procedures

that

support

scientific

components

of

Agency

decision

making

and

flexibility

to

allow

incorporation

of

innovations and

contemporaneous

scientific

concepts.

In

balancing

these

goals,

the

Agency

relies

on

established

scientific

peer

review

processes

(U.S.

EPA,

2000a;

0MB

2004).

The

cancer

guidelines

incorporate

basic

principles

and

science

policies

based

on

evaluation

of the

currently

available

information.

The Agency

intends

to revise

these

cancer

guidelines

when

substantial

changes

are necessary.

As

more

information

about

carcinogenesis

develops,

the

need

may

arise

to

make

appropriate

changes

in

risk

assessment

guidance.

In

the

interim,

the

Agency

intends

to

issue

special

reports,

after

appropriate

peer

review,

to

supplement

and

update

guidance

on

single

topics

(e.g.,

U.S.

EPA,

1991b).

One

such

guidance document,

Supplemental

Guidance

for

Assessing

Susceptibilityfrom

Early-Lfe

Exposure

to

Carcinogens

(“Supplemental

Guidance”),

was

developed

in

conjunction

with

these

cancer

guidelines

(U.S.

EPA.,

2005).

Because

both

the

methodology

and

the data

in

the

Supplemental

Guidance

(see Section

1.3.6)

are

expected

to

evolve

more

rapidly

than

the

issues

addressed

in

these

cancer

guidelines,

the

two

were

developed

as separate

documents.

The Supplemental

Guidance,

however,

as

well

as

any

other

relevant

(including

subsequent) guidance

documents,

should

be

considered

along

with

these

cancer

guidelines

as risk

assessments

for

carcinogens

are

generated.

The

use

of supplemental

guidance,

such

as

the

Supplemental

Guidance

for

Assessing

Cancer

Susceptibility

from

Early-life

Exposure

to

Carcinogens,

has

the

advantage

of

allowing

the Supplemental

Guidance

to be

modified

as

more

data become available.

Thus,

the

consideration

of

new,

peer-reviewed

scientific

understanding and

data

in

an

assessment

can

always

be

consistent

with

the purposes

of

these

cancer

guidelines.

These

cancer

guidelines

are

intended

as

guidance

only.

They

do not

establish

any

substantive “rules”

under

the

Administrative

Procedure

Act

or any

other

law

and have

no binding

effect

on

EPA

or any

regulated

entity,

but instead

represent

a non-binding

statement

of policy.

EPA

believes

that

the cancer

guidelines

represent

a

sound

and

up-to-date

approach

to

cancer

risk

assessment,

and

the

cancer

guidelines

enhance

the

application

of

the

best available

science

in

EPA’s

risk

assessments. However,

EPA

cancer

risk

assessments

may

be

conducted

differently

than

envisioned in the

cancer

guidelines

for

many

reasons,

including

(but

not limited

to)

new

1-2

---

information,

new scientific

understanding,

or new

science

policy

judgment.

The

science

of

risk

assessment

continues

to

develop

rapidly,

and

specific

components

of

the

cancer

guidelines

may

become

outdated

or may

otherwise

require

modification

in individual

settings.

Use

of

the cancer

guidelines

in

future

risk

assessments will

be based

on

decisions

by

EPA

that

the

approaches

are

suitable

and

appropriate

in the

context

of those

particular

risk

assessments.

These

judgments

will

be

tested

through

peer

review,

and

risk

assessments

will

be modified

to

use different

approaches

if appropriate.

1.2.

ORGANIZATION

AND

APPLICATION

OF

THE

CANCER

GUIDELINES

1.2.1.

Organization

Publications

by

the Office

of

Science

and

Technology

(OSTP,

1985)

and

the National

Research

Council

(NRC)

(NRC,

1983,

1994)

provide

information

and

general

principles

about

risk

assessment.

Risk

assessment

uses

available

scientific

information

on

the

properties

of an

agent’

and

its

effects

in

biological

systems to

provide

an

evaluation

of the

potential

for

harm

as

a

consequence

of

environmental

exposure. The

1983

and

1994

NRC

documents

organize

risk

assessment

information

into

four

areas:

hazard

identification,

dose-response

assessment,

exposure assessment,

and risk

characterization.

This

structure

appears

in these

cancer

guidelines,

with

additional

emphasis

placed

on

characterization

of

evidence

and

conclusions

in

each

area

of

the assessment.

In

particular,

the

cancer

guidelines

adopt

the

approach

of the

NRC’s

1994

report

in

adding

a

dimension

of

characterization

to the

hazard

identification

step:

an evaluation

of the

conditions under

which

its

expression

is

anticipated.

Risk

assessment

questions

addressed

in

these

cancer

guidelines

are

as follows.

•

For

hazard—Can

the

identified

agent

present

a carcinogenic

hazard

to

humans

and,

if

so, under

what

circumstances?

•

For

dose

response—At

what

levels

of

exposure

might

effects

occur?

The

term “agent”

refers

generally

to any

chemical

substance,

mixture,

or

physical

or biological

entity

being

assessed,

unless

otherwise

noted

(See

Section

1.2.2

for

a note

on

radiation.).

1-3

---

•

For

exposure—What

are

the

conditions

of

human

exposure?

•

For

risk—What

is the

character

of the

risk?

How

well

do

data

support

conclusions

about

the

nature

and extent

of the

risk

from

various

exposures?

The

risk

characterization

process

first

summarizes

findings

on

hazard,

dose

response,

and

exposure

characterizations

and

then

develops

an integrative

analysis

of the

whole

risk

case.

It

ends

in the

writing

of

a technical

risk characterization.

Other

documents,

such

as

summaries

for

the

risk

managers

and

the

public,

reflecting

the

key points

of the

risk

characterization

are

usually

written.

A

summary

for

managers

is a

presentation

for those

who

may

or

may

not be

familiar

with

the scientific details

of cancer

assessment.

It

also

provides

information

for other

interested

readers.

The

initial

steps

in

the risk

characterization

process

are

to make

building

blocks

in

the

form

of

characterizations

of the

assessments

of hazard,

dose

response,

and

exposure.

The

individual

assessments

and

characterizations

are then

integrated

to

arrive

at

risk

estimates

for

exposure

scenarios

of

interest.

As part

of the

characterization

process,

explicit

evaluations

are

made

of the

hazard

and

risk potential

for

susceptible

lifestages,

including

children

(U.S.

EPA,

1995,

2000b).

The

1994

NRC

document

also

explicitly

called

attention

to the

role

of

the risk

assessment

process

in

identifying

scientific

uncertainties

that,

if addressed,

could

serve

to

reduce

their

uncertainty

in

future

iterations

of

the

risk assessment.

NRC

recommended

that

when

the

Agency

“reports

estimates

of risk

to decisions-makers

and the

public,

it

should

present

not

only

point

estimates

of

risk,

but

also the

sources

and

magnitudes

of

uncertainty

associated

with these

estimates”

(p.

15). Thus,

the identified

uncertainties

serve

as a feedback

loop

to

the

research

community

and

decisionmakers,

specifying

areas

and

types

of

information

that

would

be

particularly

useful.

There

are

several

reasons

for individually

characterizing

the

hazard,

dose

response,

and

exposure

assessments.

One

is that

they

are

often

done

by

different

people

than

those

who

do

the

integrative

analyses.

The

second

is that

there

is

very

often

a lapse

of

time

between

the

conduct

of

hazard

and

dose-response analyses

and

the

conduct

of

exposure

assessment

and

integrative

1-4

---

analysis.

Thus,

it

is important

to capture

characterizations

of assessments

as

the

assessments

are

done to avoid

the

need

to

go

back and

reconstruct

them.

Finally, frequently

a single

hazard

assessment

is

used

by several

programs

for several

different

exposure

scenarios.

There

may

be

one or several

documents

involved.

“Integrative

analysis”

is

a generic

term; and many

documents

that

have other titles

may

contain

integrative analyses.

In

the

following

sections,

the

elements

of these

characterizations

are discussed.

1.2.2.

Application

The cancer

guidelines

apply within

the

framework

of policies

provided

by

applicable

EPA statutes

and

do

not alter

such

policies.

•

The cancer

guidelines

cover the assessment

of

available

data. They

do not

imply

that

one

kind of data

or

another

is prerequisite

for regulatory

action concerning

any

agent.

It is

important

that, when

evaluating

and

considering

the use

of any data,

EPA analysts

incorporate

the basic standards

of

quality,

as defined

by the

EPA

Information

Quality

Guidelines

(U.S.

EPA,

2002a

see Appendix

B) and

other

Agency guidance

on

data

quality

such as

the EPA Quality

Manual

for

Environmental

Programs

(U.S.

EPA,

2000e),

as well

as 0MB

Guidelines

for

Ensuring

and

Maximizing

the

Quality,

Utility, and

Integrity

of

Information

Disseminated

by

Federal

Agencies

(0MB,

2002).

It is very

important

that

all analyses

consider

the

basic

standards

of

quality,

including

objectivity,

utility,

and

integrity. A

summary

of the factors

and

considerations

generally

used

by

the

Agency

when

evaluating

and

considering

the use

of scientific

and

technical

infonnation

is

contained

in

EPA’s

A Summary

of General

Assessment

Factorsfor

Evaluating

the

Quality

ofScientific

and Technical

Information

(U.S.

EPA, 2003).

•

Risk

management

applies

directives

in

statutes,

which

may

require

consideration

of

potential

risk

or

solely

hazard

or exposure

potential,

along with

social,

economic,

technical,

and other

factors

in decision

making.

Risk assessments

may

be used

to

support

1-5

---

decisions,

but

in order

to

maintain

their

integrity

as

decision-making

tools,

they

are

not

influenced

by

consideration

of

the

social

or

economic

consequences

of

regulatory

action.

The

assessment

of

risk

from

radiation

sources

is

informed

by

the continuing

examination

of human

data

by the

National

Academy

of

Sciences/NRC

in its

series

of numbered

reports:

“Biological

Effects

of

Ionizing

Radiation.”

Although

some

of the

general

principles

of

these

cancer

guidelines

may

also

apply

to radiation

risk

assessments,

some

of

the details

of

their

risk

assessment

procedures

may

not,

as they

are

most

focused

on

other

kinds

of agents.

Therefore,

these

cancer

guidelines

are

not

intended

to

provide

the

primary

source

of, or

guidance

for,

the

Agency’s

evaluation

of

the

carcinogenic

risks

of radiation.

Not

every

EPA

assessment

has

the

same

scope

or

depth,

a

factor

recognized

by

the

National

Academy

of

Sciences

(NRC,

1996).

For

example,

EPA’s

Information

Quality

Guidelines

(U.S.

EPA,

2002a,

see Appendix

B)

discuss

influential

information

that

“will

have

or

does

have

a clear

and

substantial

impact

... on

important

public

policies

or

private

sector

decisions ... that

should

adhere

to a rigorous

standard

of quality.”

It is

often

difficult

to

know

a

priori

how

the results

of a

risk

assessment

are

likely

to

be

used

by

the

Agency.

Some

risk

assessments

may

be

used

by

Agency

economists

and

policy

analysts,

and

the

necessary

information

for such

analyses,

as discussed

in

detail

later in

this

document,

should

be

included

when

practicable

(U.S.

EPA,

2002a).

On the

other

hand,

Agency

staff

often

conduct

screening-

level

assessments

for

priority

setting

or separate

assessments

of

hazard

or

exposure

for

ranking

purposes

or

to

decide

whether

to invest

resources

in collecting

data

for a

full

assessment.

Moreover,

a

given

assessment

of

hazard

and

dose

response

may

be

used

with

more

than

one

exposure

assessment

that

may

be

conducted

separately

and

at different

times

as

the need

arises

in

studying

environmental

problems

related

to various

exposure

media.

The

cancer

guidelines

apply

to

these

various

situations

in

appropriate

detail,

given

the scope

and

depth

of

the

particular

assessment.

For

example,

a screening

assessment

may

be

based

almost

entirely

on

structure

activity

relationships

(SARs)

and

default

options,

when

other

data

are

not

readily

available.

When

more

data and

resources

are readily

available,

assessments

can

use

a critical

analysis

of all

of

the

available

data

as the

starting

point

of

the risk

assessment.

Under

these

conditions,

default

1-6

---

options

would

only

be

used

to address

uncertainties

or the

absence

of

critical

data.

Default

options

are inferences

based

on

general

scientific

knowledge

of the

phenomena

in

question

and

are also

matters

of

policy

concerning

the

appropriate

way

to bridge

uncertainties

that

concern

potential

risk

to human

health.

These

cancer

guidelines

do

not

suggest

that

all

of the

kinds

of

data

covered

here

will

need

to be

available

or used

for

either

assessment

or

decision

making.

The

level

of

detail

of an

assessment

is

a matter

of

Agency

management discretion

regarding

applicable

decision-making

needs.

The Agency

generally

presumes that

key

cancer

information

(e.g.,

assessments

contained

in

the

Agency’s

Integrated

risk

Information

System)

is

“influential

information”

as defined

by

the

EPA

Information

Quality

Guidelines

and

“highly

influential”

as

defined

by

OMB’s

Information

Quality

Bulletin

for Peer

Review

(0MB

2004).

1.3.

KEY

FEATURES

OF

THE

CANCER

GUIDELINES

1.3.1.

Critical

Analysis

of

Available

Information

as

the

Starting

Point

for

Evaluation

As

an increasing understanding

of

carcinogenesis

is becoming

available,

these

cancer

guidelines

adopt

a view

of

default

options

that

is

consistent

with

EPA’s

mission

to

protect

human

health

while

adhering

to the

tenets

of

sound

science. Rather

than

viewing

default

options

as the

starting

point

from

which

departures

may

be

justified

by

new

scientific

information,

these

cancer

guidelines

view

a

critical

analysis

of

all

of

the available

information

that

is relevant

to

assessing

the

carcinogenic

risk

as

the

starting

point

from which

a

default

option

may

be

invoked

if

needed

to

address

uncertainty

or

the

absence

of

critical

information.

Preference

is

given

to using

information that

has

been

peer reviewed,

e.g.,

reported

in

peer-reviewed

scientific

journals.

The

primary

goal

of EPA

actions

is

protection

of human

health;

accordingly,

as an

Agency

policy,

risk

assessment

procedures,

including

default

options

that

are

used

in

the

absence

of

scientific

data

to

the

contrary,

should

be

health

protective

(U.S.

EPA,

1 999b).

Use

of health

protective

risk

assessment

procedures

as described

in

these

cancer

guidelines

means

that

estimates,

while

uncertain,

are

more

likely

to

overstate

than

understate

hazard

and/or

risk.

NRC

(1994)

reaffirmed

the

use

of

default

options

as

“a

reasonable

way

to

cope

with

uncertainty

about

the choice

of

appropriate

models

or

theory”

(p.

104).

NRC

saw

the

1-7

---

need

to

treat

uncertainty

in

a

predictable

way

that

is

“scientifically

defensible,

consistent

with

the

agency’s

statutory

mission,

and

responsive

to

the

needs

of

decision-makers”

(p.

86).

The

extent

of

health

protection

provided

to

the

public

ultimately

depends

upon

what

risk

managers

decide

is

the

appropriate

course

of

regulatory

action.

When

risk

assessments

are

performed

using

only

one

set

of

procedures,

it

may

be

difficult

for

risk

managers

to

determine

how

much

health

protectiveness

is

built

into

a

particular

hazard

determination

or

risk

characterization.

When

there

are

alternative

procedures

having

significant

biological

support,

the

Agency

encourages

assessments

to

be

performed

using

these

alternative

procedures,

if

feasible,

in

order

to

shed

light

on

the

uncertainties

in

the

assessment,

recognizing

that

the

Agency

may

decide

to

give

greater

weight

to

one

set

of

procedures

than

another

in

a

specific

assessment

or

management

decision.

Encouraging

risk

assessors

to

be

receptive

to

new

scientific

information,

NRC

discussed

the

need

for

departures

from

default

options

when

a

“sufficient

showing”

is

made.

It

called

on

EPA

to

articulate

clearly

its

criteria

for

a

departure

so

that

decisions

to

depart

from

default

options

would

be

“scientifically

credible

and

receive

public

acceptance”

(p.

91).

It

was

concerned

that

ad

hoc

departures

would

undercut

the

scientific

credibility

of

a

risk

assessment.

NRC

envisioned

that

principles

for

choosing

and

departing

from

default

options

would

balance

several

objectives,

including

“protecting

the

public

health,

ensuring

scientific

validity,

minimizing

serious

errors

in

estimating

risks,

maximizing

incentives

for

research,

creating

an

orderly

and

predictable

process,

and

fostering

openness

and

trustworthiness”

(p.

81).

Appendices

N-i

and

N-2

of

NRC

(1994)

discussed

two

competing

standards

for

choosing

default

options

articulated

by

members

of

the

committee.

One

suggested

approach

would

evaluate

a

departure

in

terms

of

whether

“it

is

scientifically

plausible”

and

whether

it

“tends

to

protect

public

health

in

the

face

of

scientific

uncertainty”

(p.

601).

An

alternative

approach

“emphasizes

scientific

plausibility

with

regard

to

the

use

of

alternative

models”

(p.

631).

Reaching

no

consensus

on

a

single

approach,

NRC

recognized

that

developing

criteria

for

departures

is

an

EPA

policy

matter.

The

basis

for

invoking

a

default

option

depends

on

the

circumstances.

Generally,

if

a

gap

in

basic

understanding

exists

or

if

agent-specific

information

is

missing,

a

default

option

may

be

used.

If

agent-specific

information

is

present

but

critical

analysis

reveals

inadequacies,

a

default

1-8

---

option

may

also

be

used. If

critical analysis

of

agent-specific

information

is

consistent

with

one

or more biologically

based models

as well

as

with the

default

option,

the

alternative

models

and

the default

option

are both carried

through

the

assessment

and

characterized

for

the risk

manager.

In this case,

the default

model not

only

fits

the

data,

but also serves

as

a

benchmark

for

comparison

with

other

analyses.

This

case

also highlights

the importance

of extensive

experimentation

to

support

a conclusion

about mode

of action,

including

addressing

the

issue

of

whether alternative

modes

of action

are

also

plausible.

Section

2.4

provides

a

framework

for

critical analysis

of

mode

of action

information

to address

the extent

to

which

the available

information

supports

the hypothesized

mode

of

action,

whether

alternative

modes

of action

are

also

plausible,

and

whether

there

is confidence

that

the

same

inferences

can be

extended

to

populations

and

lifestages

that are not

represented

among

the experimental

data.

Generally,

cancer

risk decisions

strive

to be

“scientifically

defensible,

consistent

with

the

agency’s

statutory

mission,

and

responsive

to

the needs

of decision-makers”

(NRC,

1994).

Scientific

defensibility

would

be evaluated

through

use of EPA’s

Science

Advisory

Board,

EPA’s

Office

of Pesticide

Programs’

Scientific

Advisory

Panel,

or

other

independent

expert

peer

review

panels

to determine

whether

a consensus

among scientific

experts

exists.

Consistency

with

the

Agency’s

statutory

mission

would

consider

whether

the

risk assessment

overall

supports

EPA’s

mission

to protect

human health

and safeguard

the natural

environment.

Responsiveness

to

the

needs of

decisionmakers

would

take

into

account pragmatic

considerations

such

as the nature

of

the decision;

the

required

depth

of

analysis;

the

utility,

time, and

cost of

generating

new

scientific

data; and

the time,

personnel,

and resources

allotted to

the risk

assessment.

With

a

multitude

of

types of data,

analyses,

and risk

assessments,

as well

as

the

diversity

of needs of

decisionmakers,

it is neither

possible

nor desirable

to specif’

step-by-step

criteria

for

decisions

to

invoke a default

option.

A

discussion

of major

default

options

appears

in the

Appendix.

Screening-level

assessments

may

more readily

use

default parameters,

even

worst

case assumptions,

that would

not be appropriate

in a full-scale

assessment.

On

the

other

hand,

significant

risk management

decisions

will

often

benefit

from

a more comprehensive

assessment,

including

alternative

risk models

having

significant

biological

support.

To

the extent

practicable,

such

assessments

should

provide

central

estimates

of

potential

risks

in conjunction

with lower

1-9

---

and

upper

bounds

(e.g., confidence

limits)

and

a

clear

statement

of the

uncertainty

associated

with

these

estimates.

In

the

absence

of

sufficient

data

or

understanding

to develop

of

a robust,

biologically

based model,

an

appropriate

policy

choice

is to have

a single

preferred

curve-fitting

model

for

each

type

of data

set. Many

different

curve-fitting

models

have

been

developed,

and those

that

fit

the observed

data reasonably

well may

lead

to several-fold

differences

in estimated

risk

at the

lower

end of

the

observed

range.

In

addition,

goodness-of-fit

to the

experimental

observations

is

not

by itself

an

effective

means

of discriminating

among

models

that

adequately

fit

the

data

(OSTP,

1985). To

provide

some

measure

of consistency

across

different

carcinogen

assessments,

EPA

uses

a standard

curve-fitting

procedure

for tumor

incidence

data.

Assessments

that include

a

different

approach

should

provide

an

adequate

justification

and compare

their

results

with

those

from

the

standard

procedure.

Application

of

models

to data

should

be

conducted

in an

open

and

transparent

manner.

1.3.2.

Mode

of

Action

The

use

of mode

of action

2

in the

assessment

of potential

carcinogens

is a main

focus

of

these

cancer

guidelines.

This

area

of emphasis

arose

because

of the

significant

scientific

advances

that

have

developed

concerning

the

causes

of cancer

induction.

Elucidation

of a

mode

of

action

for a

particular

cancer

response

in

animals

or

humans

is a data-rich

determination.

Significant

information

should

be

developed

to

ensure

that a

scientifically

justifiable

mode

of

action

underlies

the process

leading

to cancer

at

a

given

site.

In

the

absence

of

sufficiently,

scientifically

justifiable

mode

of

action

information,

EPA

generally

takes

public

health-

protective,

default

positions

regarding

the

interpretation

of toxicologic

and

epidemiologic

data:

2

The

term

“mode

ofaction”

is defined

as a

sequence

of key

events

and processes,

starting with

interaction

of an agent

with a

cell,

proceeding

through

operational

and anatomical

changes,

and

resulting

in

cancer

formation.

A

“key

event”

is

an

empirically

observable

precursor

step that

is itself a

necessary

element

of the

mode

of action

or

is

a

biologically

based

marker

for

such an element.

Mode

of action

is

contrasted

with

“mechanism

of

action,”

which

implies

a more

detailed

understanding

and description

of

events,

often

at the molecular

level,

than is

meant

by

mode

of

action.

The

toxicokinetic

processes

that

lead

to formation

or distribution

of the

active

agent

to the target

tissue

are

considered

in

estimating

dose

but

are

not

part

of

the mode

of

action

as the term

is

used

here.

There

are many

examples

of possible

modes

of

carcinogenic

action, such

as mutagenicity,

mitogenesis,

inhibition

of cell

death,

cytotoxicity

with

reparative

cell

proliferation,

and

immune

suppression.

1-10

---

animal

tumor

findings

are judged

to

be relevant

to

humans,

and

cancer

risks

are

assumed

to

conform

with

low dose

linearity.

Understanding

of

mode

of

action

can

be a key

to identifying

processes

that

may

cause

chemical

exposures

to

differentially

affect

a

particular

population

segment

or

lifestage.

Some

modes

of action

are

anticipated

to be

mutagenic

and

are assessed

with

a linear

approach.

This

is

the mode

of

action

of

radiation

and

several

other

agents

that

are

known

carcinogens.

Other

modes

of

action

may

be modeled

with

either

linear

or

nonlinear

3

approaches

after

a

rigorous

analysis

of

available

data

under

the guidance

provided

in the

framework

for mode

of

action

analysis

(see

Section

2.4.3).

1.3.3.

Weight

of

Evidence

Narrative

The

cancer

guidelines

emphasize

the

importance

of weighing

all of

the

evidence

in

reaching

conclusions about

the

human

carcinogenic

potential

of agents.

This

is

accomplished

in

a single

integrative

step

after

assessing

all

of

the

individual

lines

of

evidence,

which

is

in

contrast

to

the step-wise

approach

in

the

1986 cancer

guidelines.

Evidence

considered

includes

tumor

findings,

or

lack thereof

in

humans

and

laboratory

animals;

an

agent’s

chemical

and

physical

properties;

its

structure-activity

relationships

(SARs)

as compared

with

other

carcinogenic

agents;

and

studies

addressing

potential

carcinogenic

processes

and

mode(s)

of action,

either

in

vivo

or

in

vitro.

Data

from

epidemiologic

studies

are

generally

preferred

for

characterizing

human

cancer

hazard

and

risk.

However,

all

of

the

information

discussed

above

could

provide

valuable

insights

into

the

possible

mode(s)

of

action

and

likelihood

of human

cancer

hazard

and

risk.

The

cancer

guidelines

recognize

the

growing

sophistication

of

research

methods,

3

The

term

“nonlinear”

is used

here

in a narrower

sense

than its

usual

meaning

in the

field

of

mathematical

modeling.

In

these

cancer

guidelines,

the

term

“nonlinear”

refers

to

threshold

models

(which

show

no

response

over

a range

of

low

doses

that include

zero)

and

some

nonthreshold

models

(e.g.,

a quadractic

model,

which

shows

some

response

at

all

doses

above

zero).

In these

cancer

guidelines,

a nonlinear

model

is one whose

slope

is

zero

at

(and

perhaps

above)

a dose

of zero.

A

low-dose-linear

model

is

one

whose

slope

is

greater

than

zero

at a dose

of zero.

A

low-dose-linear model

approximates

a straight

line only

at

very

low

doses;

at

higher

doses

near

the

observed

data,

a

low-dose-linear model

can

display

curvature.

The

term

“low-dose-linear”

is

often abbreviated

“linear,”

although

a

low-dose-linear model

is

not linear

at all

doses.

Use

of nonlinear

approaches

does

not imply

a

biological

threshold

dose

below

which

the

response

is zero.

Estimating

thresholds

can

be problematic;

for

example,

a response

that

is not

statistically

significant

can be

consistent

with a

small

risk that

falls

below

an

experiment’s

power

of

detection.

1—11

---

particularly

in their

ability

to

reveal

the

modes

of action

of carcinogenic

agents

at cellular

and

subcellular

levels

as

well

as toxicokinetic

processes.

Weighing

of the

evidence

includes

addressing not

only

the

likelihood

of

human

carcinogenic

effects

of

the

agent

but

also the

conditions

under

which

such

effects

may

be

expressed,

to

the

extent

that

these

are revealed

in the

toxicological

and

other

biologically

important

features

of

the agent.

The

weight

of

evidence

narrative

to characterize

hazard

summarizes

the results

of

the

hazard

assessment

and

provides

a

conclusion

with

regard

to human

carcinogenic

potential.

The

narrative

explains

the

kinds

of evidence

available

and how

they

fit

together

in

drawing

conclusions,

and

it points

out significant

issues/strengths/limitations

of

the

data and

conclusions.

Because

the narrative

also

summarizes

the

mode

of action

information,

it sets

the

stage

for

the

discussion

of

the

rationale

underlying

a

recommended

approach

to

dose-response

assessment.

In

order

to

provide

some

measure

of clarity

and consistency

in

an

otherwise

free-form,

narrative

characterization,

standard

descriptors

are used

as

part

of

the hazard

narrative

to

express

the

conclusion

regarding

the

weight

of

evidence

for

carcinogenic

hazard

potential.

There

are

five

recommended

standard

hazard

descriptors:

“Carcinogenic

to Humans,”

“Likely

to

Be

Carcinogenic to

Humans,”

“Suggestive

Evidence

of Carcinogenic Potential,”

“Inadequate

Information

to

Assess

Carcinogenic

Potential,”

and “Not

Likely

to

Be Carcinogenic

to

Humans.”

Each

standard

descriptor

may

be applicable

to

a wide

variety

of data

sets

and weights

of

evidence

and

is presented only in

the

context

of

a

weight

of

evidence

narrative.

Furthermore,

as

described

in

Section

2.5

of these

cancer

guidelines,

more

than

one

conclusion

may

be

reached

for

an

agent.

1.3.4.

Dose-response

Assessment

Dose-response

assessment evaluates

potential

risks

to humans

at

particular

exposure

levels.

The

approach

to

dose-response

assessment

for

a particular

agent

is

based

on the

conclusion reached

as

to its

potential

mode(s)

of

action

for each

tumor

type.

Because

an

agent

may

induce

multiple

tumor

types,

the dose-response

assessment

includes

an analysis

of all

tumor

types,

followed

by an

overall

synthesis

that includes

a

characterization

of the

risk estimates

across

tumor

types,

the

strength

of the

mode

of

action

information

of

each

tumor

type,

and

the

1-12

---

anticipated

relevance

of each

tumor type

to

humans,

including

susceptible

populations

and

lifestages

(e.g.,

childhood).

Dose-response

assessment

for

each

tumor

type

is

performed

in two

steps:

assessment

of

observed

data

to derive

a

point

of

departure

(POD),

4

followed

by extrapolation

to

lower

exposures

to

the

extent

that is

necessary.

Data

from

epidemiologic

studies,

of sufficient

quality,

are generally

preferred

for estimating

risks.

When

animal studies

are

the

basis

of the

analysis,

the estimation

of a

human-equivalent

dose

should

utilize

toxic

okinetic

data

to

inform

cross

species

dose

scaling

if appropriate

and if

adequate

data

are

available.

Otherwise,

default

procedures

should

be applied.

For

oral

dose,

based

on

current

science,

an

appropriate

default

option

is to

scale

daily

applied

doses experienced

for

a lifetime

in

proportion

to

body

weight

raised

to the

3/4

power

(U.S.

EPA, 1

992b).

For inhalation

dose,

based

on

current

science,

an

appropriate

default

methodology

estimates

respiratory

deposition

of

particles

and

gases

and

estimates

internal

doses

of gases

with different

absorption

characteristics.

When

toxicokinetic

modeling

(see

Section

3.1.2)

is used

without

toxicodynamic

modeling

(see

Section

3.2.2),

the

dose-response

assessment

develops

and

supports

an

approach

for

addressing

toxicodynamic

equivalence,

perhaps

by

retaining

some

of the

cross-species

scaling

factor

(see Section

3.1.3).

Guidance

is

also provided

for

adjustment

of dose

from

adults

to

children

(see

Section

4.3.1).

Response

data on

effects

of the

agent on

carcinogenic

processes

are analyzed

(nontumor

data)

in

addition

to

data on

tumor

incidence.

If

appropriate,

the analyses

of data

on tumor

incidence

and

on

precursor

effects

may

be

used in

combination.

To

the

extent the

relationship

between

precursor

effects

and

tumor

incidence

are

known,

precursor

data

may

be used

to

estimate

a

dose-response

function

below

the observable

tumor

data.

Study

of the

dose-response

function

for

effects

believed

to

be

part

of the

carcinogenic

process

influenced

by

the agent

may

also

assist

in

evaluating

the

relationship

of exposure

and response

in

the range

of observation

and

at

exposure

levels

below

the

range

of

observation.

‘

A

“point

of

departure”

(POD)

marks

the

beginning

of extrapolation

to

lower

doses.

The

POD

is an

estimated

dose

(usually

expressed

in

human-equivalent

terms)

near

the

lower end

of

the

observed

range,

without

significant

extrapolation

to lower

doses.

1-13

---

The

first step

of

dose-response

assessment

is

evaluation

within

the

range

of

observation.

Approaches

to

analysis

of

the

range

of

observation

of

epidemiologic

studies

are

determined

by

the

type

of

study

and

how

dose

and

response

are

measured

in the

study.

In

the

absence

of

adequate

human

data

for dose-response analysis,

animal

data

are

generally

used.

If there

are

sufficient

quantitative

data

and

adequate

understanding

of

the carcinogenic

process,

a

biologically

based

model

may

be

developed

to

relate

dose

and

response

data

on an

agent-specific

basis.

Otherwise,

as a

default

procedure,

a standard

model

can be

used

to curve-fit

the

data.

The

POD

for

extrapolating

the

relationship

to

environmental

exposure

levels

of

interest,

when

the latter

are

outside

the

range

of

observed

data,

is

generally

the

lower

95% confidence

limit

on

the

lowest

dose

level

that

can

be

supported

for

modeling

by

the data.

SAB

(1997)

suggested

that,

“it may

be

appropriate

to

emphasize

lower

statistical

bounds

in

screening

analyses

and

in

activities

designed

to develop

an

appropriate

human

exposure

value,

since

such

activities

require

accounting

for

various

types

of uncertainties

and a

lower

bound

on

the

central

estimate

is

a scientifically-based

approach

accounting

for

the

uncertainty

in

the

true

value

of

the

ED

10

[or

central

estimate].”

However,

the

consensus

of

the

SAB

(1997)

was

that,

“both

point

estimates

and

statistical

bounds

can

be

useful

in

different

circumstances,

and

recommended

that the

Agency

routinely

calculate

and

present

the

point

estimate

of

the

ED

10

[or

central

estimate]

and

the

corresponding

upper

and

lower

95%

statistical

bounds.”

For example,

it may

be

appropriate

to emphasize the central

estimate

in

activities

that

involve

formal

uncertainty

analysis

that

are

required

by

0MB

Circular

A-4

(0MB,

2003)

as

well

as ranking

agents

as

to their

carcinogenic

hazard.

Thus,

risk assessors should

calculate,

to

the

extent

practicable,

and

present

the

central

estimate

and

the corresponding

upper

and

lower

statistical

bounds

(such

as

confidence

limits)

to

inform

decisiomiiakers.

The

second

step

of

dose-response

assessment

is

extrapolation

to

lower

dose

levels,

if

needed.

This

extrapolation

is based

on

extension

of a

biologically

based

model

if supported

by

substantial data

(see Section

3.3.2).

Otherwise,

default

approaches

can be

applied

that are

consistent

with

current

understanding

of

mode(s)

of

action

of the

agent,

including

approaches

that

assume

linearity

or

nonlinearity

of the

dose-response

relationship,

or

both.

A

default

approach

for

linearity

extends

a

straight

line

from

the

POD

to

zero

dose/zero

response

(see

1-14

---

Section

3.3.3).

The

linear

approach

is used

when:

(1) there

is

an absence

of

sufficient

information

on

modes

of

action

or (2)

the mode

of

action

information

indicates

that

the

dose-

response

curve

at

low dose

is

or is

expected

to

be linear.

Where

alternative

approaches

have

significant

biological

support,

and

no

scientific

consensus

favors

a single

approach,

an

assessment

may

present

results

using

alternative

approaches.

A

nonlinear

approach

can

be

used

to develop

a

reference

dose

or

a reference

concentration

(see

Section

3.3.4).

1.3.5.

Susceptible Populations

and

Lifestages

An important

use

of mode

of

action

information

is

to identify

susceptible

populations

and

lifestages.

It

is rare

to

have

epidemiologic

studies

or

animal

bioassays

conducted

in

susceptible

individuals.

This

information

need

can

be

filled

by

identifying

the

key

events

of

the

mode

of

action

and

then

identifying

risk

factors,

such

as

differences

due

to

genetic

polymorphisms,

disease,

altered

organ

function,

lifestyle,

and

lifestage,

that

can augment

these

key

events.

To

do

this,

the information

about

the

key

precursor

events

is

reviewed

to

identify

particular

populations

or

lifestages

that

can

be particularly

susceptible

to

their

occurrence

(see

Section

2.4.3.4).

Any

information

suggesting

quantitative

differences

between

populations

or lifestages is

flagged

for

consideration in

the dose-response

assessment

(see

Section

3.5

and

U.S.

EPA

2002b).

1.3.6.

Evaluating

Risks

from

Childhood

Exposures

NRC

(1994)

recommended

that

“EPA

should

assess

risks

to

infants

and

children

whenever

it

appears

that

their

risks

might

be

greater

than

those

of

adults.”

Executive

Order

13045

(1997)

requires

that

“each

Federal

Agency

shall

make

it

a high

priority

to

identify

and

assess

environmental

health

and

safety

risks

that

may

disproportionately

affect

children,

and

shall

ensure

that

their

policies,

programs,

and

standards

address

disproportionate

risks

that

result

from

environmental health

risks

or safety

risks.”

In assessing

risks

to children,

EPA

considers

both

effects

manifest

during

childhood

and

early-life

exposures

that

can

contribute

to

effects

at any

time

later

in

life.

These

cancer

guidelines

view

childhood

as a

sequence

of

lifestages

rather

than

viewing

children

as

a

subpopulation, the distinction

being

that

a subpopulation

refers

to a portion

of

the

1-15

---

population,

whereas

a lifestage

is inclusive

of the

entire

population.

Exposures

that are

of

concern

extend

from

conception

through

adolescence

and

also

include

pre-conception

exposures

of

both

parents.

These

cancer

guidelines

use

the

term

“childhood”

in

this

more

inclusive

sense.

Rarely

are

there

studies

that

directly

evaluate

risks

following

early-life

exposure.

Epidemiologic

studies

of

early-life

exposure

to

environmental

agents

are

seldom

available.

Standard

animal

bioassays

generally

begin

dosing

after

the

animals

are several

weeks

old,

when

many

organ

systems

are

mature.

This

could

lead

to an

understatement

of

risk,

because

an

accepted

concept

in

the

science

of

carcinogenesis

is that

young

animals

are

usually

more

susceptible

to the

carcinogenic

activity

of

a chemical

than

are mature

animals

(McConnell,

1992).

At

this time,

there

is

some

evidence

of higher

cancer

risks

following

early-life

exposure.

For

radiation

carcinogenesis,

data

indicate

that

risks

for

several

forms

of cancer

are

highest

following

childhood exposure

(NRC,

1990;

Miller,

1995;

U.S.

EPA,

1999c).

These

human

results

are

supported

by

the

few

animal

bioassays

that

include

perinatal

(prenatal

or

early

posthatal)

exposure.

Perinatal

exposure

to some

agents

can

induce

higher

incidences

of

the

tumors

seen

in

standard

bioassays;

some

examples

include

vinyl

chloride

(Maltoni

et al.,

1981),

diethylnitrosamine

(Peto

et

al.,

1984),

benzidine,

DDT,

dieldrin,

and

safrole

(Vesselinovitch

et

al.,

1979).

Moreover,

perinatal

exposure

to

some

agents,

including

vinyl

chloride

(Maltoni

et

al.,

1981)

and

saccharin

(Cohen,

1995;

Whysner

and

Williams,

1996),

can

induce

different

tumors

that are

not

seen

in

standard

bioassays.

Surveys

comparing

perinatal

carcinogenesis

bioassays

with

standard

bioassays

for

a limited

number

of chemicals

(McConnell,

1992;

U.S.

EPA,

1

996b)

have

concluded

that

•

the

same

tumor

sites

are

usually

observed

following

either

perinatal

or

adult

exposure,

and

•

perinatal exposure

in

conjunction

with

adult

exposure

usually

increases

the

incidence

of

tumors

or

reduces

the

latent

period

before

tumors

are

observed.

1-16

---

The

risk attributable

to early-life

exposure

often

appears

modest

compared

with

the

risk

from

lifetime

exposure,

but

it can be

about

10-fold

higher than

the

risk

from

an

exposure

of

similar

duration

occurring

later in

life (Ginsberg,

2003).

Further

research

is

warranted

to

investigate

the

extent

to which

these

findings

apply to

specific

agents,

chemical

classes,

and

modes

of

action

or in

general.

These

empirical

results

are

consistent

with

current

understanding

of the

biological

processes

involved

in

carcinogenesis,

which

leads to

a reasonable

expectation

that

children

can

be

more

susceptible

to many

carcinogenic

agents

(Anderson

et al.,

2000; Birnbaum

and

Fenton,

2003;

Ginsberg,

2003;

Miller

et

al., 2002;

Scheuplein

et al.,

2002).

Some

aspects

potentially

leading

to

childhood

susceptibility

are listed

below.

•

Differences

in the

capacity

to metabolize

and clear

chemicals

can

result

in larger

or

smaller

internal

doses of

the active

agent(s).

•

More

frequent

cell

division

during

development

can

result

in

enhanced

expression

of

mutations

due to

the

reduced

time

available

for repair

of

DNA lesions

(Slikker

et

al.,

2004).

•

Some

embryonic

cells,

such

as brain

cells,

lack key

DNA

repair

enzymes.

•

More

frequent

cell

division

during

development

can

result

in

clonal

expansion

of

cells

with mutations

from

prior

unrepaired

DNA damage

(Slikker

et

al.,

2004).

•

Some

components

of

the

immune

system

are not

fully functional

during

development

(Holladay

and Smialowicz,

2000;

Holsapple

et al.,

2003).

•

Hormonal

systems

operate

at

different

levels

during

different

lifestages.

1-17

---

Induction

of

developmental

abnormalities

can

result

in

a predisposition

to

carcinogenic effects

later

in

life

(Anderson

et

al., 2000;

Bimbaum

and

Fenton,

2003;

Fenton

and

Davis,

2002).

To

evaluate

risks

from

early-life exposure,

these

cancer

guidelines

emphasize

the

role

of

toxicokinetic

information

to estimate

levels

of the

active

agent

in

children

and toxicodynamic

information

to identify

whether

any

key

events

of the

mode

of

action

are

of increased

concern

early

in life.

Developmental

toxicity

studies

can

provide

information

on

critical

periods

of

exposure

for

particular targets

of

toxicity.

An

approach

to

assessing

risks

from

early-life

exposure

is

presented

in

Figure

1-1.

In the

hazard

assessment,

when

there

are

mode

of

action

data,

the

assessment

considers

whether

these

data

have

special

relevance

during

childhood,

considering

the

various

aspects

of

development

listed

above.

Examples

of

such

data include

toxicokinetics

that

predict

a

sufficiently

large

internal

dose

in children

or a

mode

of

action

where

a

key

precursor

event

is

more

likely

to

occur

during

childhood.

There

is no

recommended

default

to settle

the question

of

whether

tumors

arising

through

a

mode

of

action

are

relevant

during

childhood;

and

adequate

understanding

the

mode

of

action

implies

that

there

are sufficient

data

(on

either

the specific

agent

or

the

general

mode

of action)

to

form

a

confident

conclusion

about

relevance

during

childhood

(see

Section

2.4.3.4).

In the

dose-response

assessment,

the

potential

for

susceptibility

during

childhood

warrants

explicit

consideration

in each

assessment.

These

cancer

guidelines

encourage

developing

separate

risk

estimates

for children

according

to a

tiered

approach

that

considers

what

pertinent

data

are

available

(see Section

3.5).

Childhood

may

be a

susceptible

period;

moreover,

exposures

during

childhood

generally

are not

equivalent

to

exposures

at other

times

and

may

be

treated

differently

from

exposures

occurring

later

in

life

(see

Section

3.5).

In

addition,

adjustment

of

unit risk

estimates

may

be

warranted

when

used

to

estimate

risks

from

childhood

exposure

(see

Section

4.4).

At this

time,

several

limitations

preclude

a full

assessment

of

children’s

risk.

There

are

no

generally

used

testing

protocols

to

identify

potential

environmental

causes

of

cancers

that

are

1-18

---

unique

to

children,

including

several

forms

of childhood

cancer

and

cancers

that

develop

from

parental

exposures,

and cases

where

developmental

exposure

may alter

susceptibility

to

carcinogen

exposure

in

the adult

(Bimbaum

and

Fenton,

2003).

Dose-response

assessment

is

limited

by

an

inability

to observe

how

developmental

exposure

can

modif’

incidence

and

latency

and

an inability

to estimate

the

ultimate

tumor

response

resulting

from

induced

susceptibility

to

later

carcinogen

exposures.

To partially

address

the

limitations

identified

above,

EPA

developed

in conjunction

with

these

cancer

guidelines,

Supplemental

Guidance

for

Assessing

Susceptibility

from

Early-Lfe

Exposure

to Carcinogens (“Supplemental

Guidance”).

The Supplemental

Guidance

addresses

a

number

of

issues

pertaining

to

cancer

risks

associated

with

early-life

exposures

generally,

but

provides

specific

guidance

on

procedures

for

adjusting

cancer

potency

estimates

only

for

carcinogens

acting

through

a

mutagenic

mode

of

action.

This Supplemental

Guidance

recommends,

for such

chemicals

when

no

chemical-specific

data

exist,

a default

approach

using

estimates

from

chronic

studies

(i.e., cancer

slope

factors)

with

appropriate

modifications

to

address

the

potential

for

differential

risk

of early-lifestage

exposure.

The

Agency

considered

both the

advantages

and

disadvantages

to extending

the

recormnended,

age

dependent

adjustment

factors

for

carcinogenic

potency

to carcinogenic

agents

for

which

the mode

of action

remains

unknown.

EPA decided

to recommend

these

factors

only

for carcinogens

acting

through

a

mutagenic

mode

of

action

based

on a combination

of

analysis

of

available

data

and

long-standing

science

policy

positions

which

govern

the

Agency’s

overall

approach

to

carcinogen

risk

assessment.

In

general,

the Agency

prefers

to rely

on

analyses

of

data, rather

than

general

defaults.

When

data

are

available

for

a sensitive

lifestage,

they

would

be

used directly

to

evaluate

risks

for

that

chemical

and

that

lifestage

on a case-by-case

basis.

In

the

case

of

nonmutagenic

carcinogens,

when

the

mode

of action

is unknown,

the

data were

judged

by

EPA

to be

too

limited

and

the

modes

of

action too

diverse

to use

this

as

a

category

for which

a

general

default

adjustment

factor

approach

can

be

applied.

In this

situation,

a

linear

low-dose

extrapolation

methodology

(without

further

adjustment)

is recommended.

It is

the

Agency’s

long-standing

science

policy

position

that

use

of the

linear

low-dose

extrapolation

approach

1-19

---

provides

adequate

public

health

conservatism

in the

absence

of

chemical-specific

data

indicating

differential

early-life

sensitivity

or when

the

mode

of

action

is not

mutagenic.

The

Agency

expects

to

produce

additional

supplemental

guidance

for other

modes

of

action,

as

data

from

new

research

and

toxicity

testing

indicate

it is

warranted.

EPA

intends

to

focus

its research,

and

work

collaboratively

with

its

federal

partners,

to improve

understanding

of

the implications

of

early

life

exposure

to

carcinogens.

Development

of

guidance

for

estrogenic

agents

and chemicals

acting

through

other

processes

resulting

in

endocrine

disruption

and

subsequent

carcinogenesis,

for

example,

might

be

a

reasonable

priority

in light

of

the human

experience

with

diethylstilbesterol

and

the

existing

early

life animal

studies.

It

is

worth

noting

that

each

mode

of

action

for

endocrine

disruption

will probably

require

separate

analysis.

As

the

Agency

examines

additional

carcinogenic

agents,

the

age

groupings

may

differ

from

those

recommended for assessing

cancer

risks

from

early-life

exposure

to

chemicals

with

a

mutagenic

mode

of action.

Puberty

and

its associated

biological

changes,

for

example,

involve

many

biological

processes

that

could

lead

to

changes

in

sensitivity

to the

effects

of

some

carcinogens,

depending

on

their

mode

of

action.

The

Agency

is interested

in identifying

lifestages

that

may

be

particularly

sensitive

or refractory

for carcinogenesis,

and believes

that

the

mode

of

action

framework

described

in

these

cancer

guidelines

is an appropriate

mechanism

for

elucidating

these

lifestages. For each

additional

mode

of

action

evaluated,

the

various

age

groupings

determined

to

be at

differential

risk may

differ

from

those

proposed

in

the

Supplemental Guidance.

For

example,

the

age

groupings

selected

for

the

age-dependent

adjustments

for

carcinogens

acting

through

a

mutagenic

mode

of

action

were

initially

selected

based

on the

available

data,

i.e.,

for

the laboratory

animal

age

range

representative

of

birth

to

<

2

years

in

humans.

More

limited

data

and

information

on human

biology

were

used

to

determine

a

science-informed

policy

regarding

2

to

<

16 years.

Data

were

not

available

to

refine

the

latter

age group.

If

more

data

become

available

regarding

carcinogens

with

a

mutagenic

mode

of

action,

consideration

may

be

given

to

further

refinement

of

these

age

groups.

1-20

---

1.3.7.

Emphasis

on

Characterization

The cancer

guidelines

emphasize

the

importance

of

a

clear

and

useful

characterization

narrative

that

summarizes

the

analyses

of

hazard,

dose-response,

and

exposure

assessment.

These

characterizations

summarize

the

assessments

to explain

the

extent

and weight

of

evidence,

major

points

of

interpretation

and

rationale

for

their

selection,

strengths

and

wealcnesses

of

the

evidence

and

the

analysis,

and

discuss

alternative

conclusions

and uncertainties

that

deserve

serious

consideration

(U.S.

EPA,

2000b).

They

serve

as starting

materials

for the

overall

risk

characterization

process

that

completes

the

risk assessment.

1-21

---

Figure 1-1.

Flow

chart for

early-life

risk assessment

using

mode

of

action

framework.

Use

linear

extmpolatinn

as

a default.

No

further

analys

of

tumo is.

Model

using

MOA or

use

REYRfC

method

as

default.

Adjuments

for

suseeptible

lifeages

or populatons

are pert

ofthe

process.

Use

the

same

linear

extrapolation

for

all

lifestages,

unless

have

c hemical

specific

information

on lifeages

or

populations

Use

framework

in Cancer

Guidelines

to

establish

MOA(s)

MOA

sufficiently

supported

in animals?

MOA

can

not

be

determined

Yes

MOA

relevant

to

humans?

No

Yes

Flag

lifestage(s)

orpopulation(s)

that

could

be susceptibè

(based

on

information

about

the specific

MOA)

for dose-response

analysis.

Determine

extrapolation

based

on infomiat

inn

about

specific

MOA.

Nonlinear

Line

ar, but

nonmutagenic

Linearitydueto

mutagenicMOA

V

Suppèmental

G.iidancefor

Early-Life

Expures

Were

chemical-specific

data available

Yes

[vebp

chemical-specific

in MOA

analysis

to

evaluate

differences

risk estimates

incorporiting

between

adults

and juveniles

(more,

lifestage

susceptibility.

,orthe

sume

susceptibility)?

No

V

Early- life

suscept

thility

assumed.

Apply

age-

dependent

adist ment

factors

(ADAFs)

as

appropnateto

develop

risk

estimates.

1-22

---

2.

HAZARD

ASSESSMENT

2.1. OVERVIEW

OF HAZARD

ASSESSMENT

AND

CHARACTERIZATION

2.1.1.

Analyses

of Data

The purpose

of

hazard

assessment

is to

review

and

evaluate

data

pertinent

to two

questions:

(1)

whether

an

agent

may

pose

a

carcinogenic

hazard

to human

beings,

and

(2)

under

what

circumstances

an identified

hazard

may be

expressed

(NRC,

1994). Hazard

assessment

involves

analyses

of a variety

of

data

that may

range

from

observations

of

tumor

responses

to

analysis

of

structure-activity

relationships

(SARs).

The

purpose

of

the

assessment

is

not simply

to

assemble

these

separate

evaluations;

its

purpose

is to construct

a

total

analysis

examining

what

the biological

data reveal

as a

whole

about carcinogenic

effects

and mode

of

action

of the

agent,

and

their

implications

for

human

hazard

and dose-response

evaluation.

Conclusions

are

drawn

from weight-of-evidence

evaluations

based on

the combined

strength

and

coherence

of

inferences

appropriately

drawn

from

all

of

the

available

information.

To

the

extent

that data

permit,

hazard

assessment

addresses

the

question

of

mode

of

action

of an agent

as both

an

initial

step

in

identifying

human

hazard

potential

and as a

component

in

considering

appropriate

approaches

to

dose-response

assessment.

The

topics

in this

chapter

include

analysis

of

tumor

data, both

human

and

animal,

and

analysis

of other

key

information

about

properties

and effects

that

relate

to carcinogenic

potential.

The

chapter

addresses

how

information

can be

used

to evaluate

potential

modes

of

action.

It also

provides

guidance

on performing

a

weight

of

evidence

evaluation.

2.1.2.

Presentation

of

Results

Presentation

of the

results

of

hazard

assessment

should

be informed

by Agency

guidance

as discussed

in

Section

2.6. The

results

are presented

in a technical

hazard

characterization

that

serves

as a

support

to later

risk

characterization.

It

includes:

•

a summary

of

the

evaluations

of hazard

data,

•

the rationales

for

its

conclusions,

and

2-1

---

an explanation

of the

significant

strengths

or

limitations

of the

conclusions.

Another

presentation

feature

is

the

use

of

a

weight

of evidence

narrative

that

includes

both

a conclusion

about

the

weight

of

evidence

of

carcinogenic

potential

and

a summary

of

the

data

on which

the conclusion

rests.

This

narrative

is a brief

summary

that

in

toto replaces

the

alphanumerical

classification

system

used

in

EPA’s

1986

cancer

guidelines

(U.S.

EPA,

1986a).

2.2.

ANALYSIS

OF

TUMOR

DATA

Evidence

of

carcinogenicity

comes

from

finding

tumor

increases

in

humans

or

laboratory

animals

exposed

to

a given

agent

or from

finding

tumors

following

exposure

to structural

analogues

to

the

compound

under

review.

The

significance

of observed

or

anticipated

tumor

effects

is evaluated

in reference

to

all the

other

key data

on

the agent.

This

section

contains

guidance

for

analyzing

human

and

animal

studies

to

decide

whether

there

is an

association

between

exposure

to

an

agent

or a structural

analogue

and

occurrence

of

tumors.

Note

that

the

use

of the

term

“tumor”

in

these

cancer

guidelines

is defined

as malignant

neoplasms

or

a

combination of

malignant

and corresponding

benign

neoplasms.

Observation of

only

benign

neoplasia

may

or

may

not have

significance

for

evaluation

under

these

cancer

guidelines.

Benign

tumors

that

are

not

observed

to

progress

to malignancy

are assessed on a case-by-case

basis.

There

is

a range

of

possibilities for

their

overall

significance.

They

may

deserve

attention

because

they

are

serious

health

problems

even

though

they are

not

malignant;

for

instance,

benign

tumors

may

be

a health

risk

because

of their

effect

on

the

function of a target

tissue

such

as

the

brain.

They

may

be

significant

indicators

of

the

need

for

further

testing

of an

agent

if they

are

observed

in

a

short-

term

test protocol,

or

such

an

observation

may

add

to the

overall

weight

of evidence

if the

same

agent

causes

malignancies

in a

long-term

study.

Knowledge of

the mode

of action

associated

with

a

benign

tumor

response

may

aid

in the

interpretation

of

other

tumor

responses

associated

with

the

same

agent.

In other

cases,

observation of

a

benign

tumor

response

alone

may have

no

significant

health

hazard

implications

when

other

sources

of

evidence

show

no

suggestion

of

carcinogenicity.

2-2

---

2.2.1.

Human

Data

Human

data

may

come

from

epidemiologic

studies

or

case

reports.

(Clinical

human

studies,

which

involve

intentional

exposures

to

substances,

may

provide

toxicokinetic

data,

but

generally

not

data

on

carcinogenicity.)

The

most

common

sources

of

human

data

for

cancer

risk

assessment

are

epidemiologic

investigations.

Epidemiology

is

the

study

of the

distribution

of

disease

in

human

populations

and

the

factors

that

may

influence

that

distribution.

The

goals

of

cancer

epidemiology

are

to

identify

distribution

of

cancer

risk

and determine

the

extent

to

which

the

risk

can

be attributed

causally

to

specific

exposures

to

exogenous

or

endogenous

factors

(see

Centers

for

Disease

Control

and Prevention

[CDC,

2004]).

Epidemiologic

data

are

extremely

valuable

in risk

assessment

because

they

provide

direct

evidence

on whether

a substance

is

likely

to

produce

cancer

in

humans,

thereby

avoiding

issues

such

as:

species-to-species

inference,

extrapolation

to

exposures

relevant

to

people,

effects

of concomitant

exposures

due to

lifestyles.